Medicinal Chemistry 7
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in MedicinaI Chemistry 7
G. P. ELLIS, B.SC., PH.D., F.R.I.C. Department of Chemistry,
University of Wales Institute of Science and Technology. King
Edward VII Avenue, Cardiff
G. B. WEST, B.PHARM.,D.SC.,PH.D., F.I.BIOL Barking Regional
College of Technology, North-east London Polytechnic, Longbridge
Road, Dagenham , Essex
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In BDFl mice qd 1-1 1, observed 1-12.
 (as well as all other anticancer agents). However, the
relative effects of these drugs on the two tissues vary. For
example, 6-mercaptopurine, 2-aminoadenine, and 6-chloropurine
produce similar lesions in the intestinal epithelium when given in
doses that cause bone-marrow depression; the effects of thioguanine
are largely limited to the bone marrow, in which most
haematopoietic elements are susceptible. 6-Methylpurine appears to
selectively depress erythro- genesis. The xanthine oxidase
oxidation products of purine and 2-chloroadenine crystallize in the
renal tubules causing kidney damage . Hepatic damage occurs
with many analogues, but is particularly prominent with
Caminopyrazolo [3, 4-dlpyrimidine . These various toxicities,
and skin rashes [362, 3631 are also observed clinically along with
anorexia, nause?, vomiting, and diarrhoea. The limiting clinical
toxicity with 6-(methy1thio)purine ribonucleoside is
gastrointestinal toxicity, particularly of the upper tract  ,
whereas bone- marrow toxicity is usually limiting with
6-mercaptopurine and thioguanine.
Administration of 3 '-amino-3 '-deoxy-N,N-dimethyladenosine (the
amino- nucleoside of puromycin) to rats produces a nephrotic
syndrome that is clinically indistinguishable from the nephrotic
syndrome of unknown origin frequently observed in children  .
Rats, monkeys, and humans are susceptible to this nephrotoxicity
and susceptibility has been related to specie ability to
demethylate the aminonucleoside [ 2 131 . N6-Methyladenosine
prevents develop- ment of this syndrome [365a].
THE BIOCHEMICAL BASIS FOR THE DRUG ACTIONS OF PURINES
Because of their effects on rapidly dividing tissue, the purine
analogues have a marked effect on the developing embryo. The
analogues differ not only in the amounts required to produce
toxicity in the embryo but in their teratogenicity. I t is possible
t o produce teratogenic effects in the chick embryo with a
sublethal amount of 8-azaguanine but not with 6-mercaptopurine
. Compounds such as 6-mercaptopurine and thioguanine affect
both cellular multiplication and differentiation  .
The abilityofpurine analogues to affect rodent embryos in ufero
at doses that are non-toxic to the mother is well documented. When
6-mercaptopurine  , thioguanine , some of their
S-substituted derivatives [370, 3711, and 6-chloropurine  are
given to the rat at the time o f implantation of fertilized ova, a
high percentage of the foetuses are destroyed. To exhibit peak
activity, 2-aminoadenine must be given before implantation  .
6-Mercaptopurine, 6-mercaptopurine ribonucleoside,
h-mercaptopurine-3-oxide, and N-hydroxy- adenine are teratogenic
when administered on the eleventh day of gestation [373a] . The
teratogenicity of 8-azaguanine in mice depends o n the timing and
amount of the dose [ 3731 .
The finding that the administration of 6-mercaptopurine to
rabbits following exposure to bovine serum albumin prevented
antibody formation 13741 formed the basis for a new area of
chemotherapy for purine analogues and other anti- metabolites and
was soon followed by the use of these drugs for the therapy of
autoimmune disease and the suppression o f homograft rejection.
This subject has been reviewed in depth [ 12, 375, 375al , has
occasioned a symposium , and has received much recent
publicity as a result of human heart transplants.
Certain purines are capable of specifically inhibiting the
immune response during the induction period of the response, and
the inhibition is increased by increasing the antigenic stimulus.
There is a close resemblance between drug- inducedand
antigen-excess repression of the response, and although the
mechanism by which these compounds suppress is not clear, the
suggestion has been made that it is probably related to their
cytotoxic nature [ 121.
Fortunately for the potential of immunosuppressive agents in the
treatment of homograft rejection, they have much less effect on a
secondary than on a primary immune response, although they are
useful in the treatment of a number of autoimmune diseases such as
psoriases, and undesirable effects have been reported  .
A number of thiopurines (thioguanine, 6-mercaptopurine,
6xmethylthio) purine, azathioprine (6((
l-methyl-4-nitro-5-imida~olyl)thio] purine) [ 121 ,and other
derivatives o t 6-rnercaptopurine  ) have all been used to
successfully prolong homografts, and azathioprine (Imuran) appears
t o be superior in its action [ 2 6 8 ] .
A. MONTGOMERY 105
Pla tele t aggrega tion
Circulating platelets adhere to the site of damage of blood
vessels aggregating into clumps or white bodies, which stop the
flow of blood causing clots. Adenosine diphosphate causes the
aggregation of platelets in blood plasma both in vitro  andin
vivo , and this effect is antagonized by adenylic acid and
even more by adenosine. Of the thirty odd purine nucleosides that
have been evaluated as platelet aggregation inhibitors [38E382]
only 2-aza-adenosine and the 2-haloadenosines showed significant
activity. 2-Chloroadenosine was more active than adenosine, but
also caused respiratory arrest in rabbits . A correlation has
been noted between the ability of these compounds to inhibit
platelet aggregation and their vasodilator activity  .
The pyrazolo[3, 4-d] pyrimidines are substrates for and
inhibitors of xanthine oxidase [ 266,267].4-Hydroxypyrazolo[3,4-d]
pyrimidine was first investignted for its ability to protect
6-mercaptopurine and other analogues from oxidation by xanthine
oxidase , but it also inhibits the oxidation of the natural
purines, hypoxanthine, and xanthine. Its profound effect on uric
acid metabolism made it an obvious choice for the treatment of gout
and its utility in the control of this disease has been
On invading organisms
Micro-organisms (bacteria and protozoa)
Much information on the mechanism of action and cross-resistance
of purine analogues has been obtained in bacteria, some of which
are quite sensitive to certain of these compounds in vitro. There
is a great deal of variation in response of the various bacteria to
a particular agent and of a particular bacterium to the various
cytotoxic purine analogues. Some, if not most, of these differences
are probably due to differences in the anabolism of the various
compounds. Despite the fact that certain purine analogues have
quite a, spectrum of antibacterial activity in vitro, none has been
useful in the treatment of bacterial infections in vivo because
their toxicity is not selective-the metabolic events whose blockade
is responsible for their antibacterial activity are also blocked in
mammalian cells and thus inhibition of bacterial growth can only be
attained at the cost of prohibitive host toxicity. In contrast, the
sulpha drugs and antibiotics such as penicillin act on metabolic
events peculiar to bacteria.
It is of historical interest that Tetrohyrnenagelii, whose
metabolism has been described in detail , is inhibited by
8-azaguanine  and other purine analogues [389, 3901. Of more
importance to chemotherapy is the fact that pathogenic protozoa
such as the trypanosomes respond in vitro to a number of
THE BIOCHEMCAL BASIS FOR THE DRUG ACTIONS OF PURINES
purines such as 6-mercaptopurine [39 11 , thioguanine 139 11,
and 2-aminoadenine . More active than these compounds, in
vitro and in vivo, however, is the aminonucleoside of puromycin, 3
'-amino-3 '-deox y-N,N-dimethy ladenosine, which is more effective
than puromycin itself [ 39 1,3931 . Primaquine appears to be more
effeGtive than the aminonucleoside on the flagellate forms of T.
cruzi; so the combination was tested in mice and found extremely
effective . Puromycin alone was not effective against T. cruzi
in humans , but was effective against early infection of T.
gambiense . T. equiperdum and T. gumbiense in mice respond to
both puromycin and the aminonucleoside [397-4001. Puromycin was
also effective in suppressing T. equiperdum, T. equinum. T. Evansi,
and T. rhodesiense in mice, but was ineffective against T.
congolense . T. equiperdum infections in mice 14011 and T.
congolense, T. gambiense, and T. equinum in mice and rats are cured
by treatment with nucleocidin [4021.
Although inferior to pyrimethamine plus sulphonamides, both
puromycin and the aminonucleoside are active against Toxoplasma
gondii in vivo . These drugs are also effective against
Endamoeba histolytica in vifro  , and puromycin is active
against the infection in man .
The mechanism of inhibition of these protozoal infections by the
most active drugs, puromycin and the aminonucleoside, is not known.
Puromycin and nucleocidin both intertere with protein synthesis,
but the aminonucleoside does not. It is known to be demethylated to
3'-amino-3'-deoxyadenosine, which is phosphorylated and interferes
with nucleic acid metabolism (see above). Whether puromycin must be
converted to the aminonucleoside before it can inhibit protozoa has
not been established. Some purine analogues known to interfere with
nucleic acid metabolism, however, are less effective as
antiprotozoal agents, even in vifro, perhaps because their effects
are primarily on the de novo pathway which many, if not all,
protozoa do not use .
Viruses and cancer
2-Aminoadenosine, the first purine found to possess antiviral
activity, inhibits vaccinia , spring-summer encephalitis
, psittacosis , and poliomyelitis  viruses in cell
culture. 8-Azaguanine has been reported a$ both active  and
inactive  against vaccinia virus, and active against
psittacosis and encephalomyocarditis. 6-Mercaptopurine interfered
with the replication of both RNA and DNA viruses in Lass cells [41
I ] . 9-P-D-Arabino- furanosyladenine has a remarkable inhibitory
action on the multiplication of the DNA viruses [41 l a ] , herpes,
vaccinia [412, 4131, and cytomegalovirus , which also responds
Puromycin is active against a number of viruses in cell culture.
In chick embryo cells it delayed the replication of western equine
encephalitis [4 151 and inhibits Venezulian equine encephalitis [4
161 . It interferes with the replication
A. MONTGOMERY 107
of poliomyelitis [417-4191 and western equine encephalitis 
in HeLa cells. I t is reported to inhibit  and not inhibit
 encephalomyocarditis and t o inhibit reovirus  and
influenza (4231, but not herpes  in L cells. If added early in
the eclipse stage it inhibits adenovirus in monkey kidney cells
 . I t also inhibits polyoma virus in mouse embryo cells 
Activity of an agent against a virus in cell culture is only an
initial lead. Many false positives are found because there is no
measure of host toxicity at viricidal levels or of the many other
complicating factors. Unfortunately the purine analogues have shown
minimal activity against viral infections in the whole animal.
2-Aminoadenine reduced the mortality of mice infected with spring-
summer encephalitis  , bu t puromycin had no effect on herpes
keratitis in rabbits  . A number of purine analogues failed t
o inhibit Semliki Forest virus infections in mice [ 3721 .
9-p-D-Arabinofuranosyladenine was the only purine of a large number
evaluated for in viuo activity against influenza and vaccinia
viruses that was inhibitory and its effectiveness was confined to
In vivo studies with virus-induced cancers mostly limited t o
virus leukemias in mice and the Rous sarcoma in chicks, have been
concerned primarily with the anticancer aspect of the problem, and
have placed little emphasis on the viral aspects. 6-Mercaptopurine,
its ribonucleoside, thioguanine, and azathioprine all prolong the
life span of mice infected with the Friend virus leukemia [430,43 1
] . In addition t o these compounds, 9cyclopentyl-6-mercaptopurine,
9-butyl-6- mercaptopurine, 6xbenzylthio)purine ribonucleoside, and
thioguanosine are also active  . 6-Mercaptopurine  and
thioguanine were active against both the Friend and Rauscher
viruses in an in vitro assay system . 6-Mercaptopurine showed
only minimal effects against the Moloney virus leukemia [435, 4361,
although other purine analogues such as thioguanine and
6chloropurine ribonucleoside are reported t o increase survival
time of infected mice [ 3 6 6 , 4 3 7 ] .
Although inactive against the Kous sarcoma in the standard
post-infection test, 6-mercaptopurine, 2-aminoadenine, and
8-azaguanine inhibited the develop- ment of the tumour if given
prior t o infection of the chicks [417 ,418] .
Most of the adenine and adenosine analogues discussed in the
precedine sections are converted to adenosine triphosphate
analogues and are highlY cytotoxic. Unfortunately, their
specificity for cancercells is low so that, although they show some
activity in sensitive experimental animal systems such as Ehrlich
ascites carcinoma, they are not useful agents; and those that have
been evaluated clinically (i.e., 2-aminoadenine  and
4-aminopyrazolo[3, 4-d] pyrimidine  ) are not effective, but
are toxic t o man. The ribonucleoside  of N-hydroxyadenine
 , an inactive adenine analogue, may be an exception to
thisstatement, since it is quite active against L1210 leukemia
 , but haemolysis at low dosage occurred in preliminary
clinical trials [439a]. Since other N-substituted adenosines are
phosphorylated to the monophosphate stage only, the active form of
this analogue is probably N-hydroxyadenylic acid, rather
THE BIOCHEMICAL BASIS FOR THE DRUG ACTIONS OF PURINES
than the triphosphate, which may be part of the reason for its
selective action on cancer cells. Trimethylpurin-6-ylammonium
chloride [44 11 and some of its derivatives
[442, 4431 inhibit the growth of adenocarcinoma 755, but not
sarcoma 180 or leukaemia L1210 in mice; little additional
information is available on this series of compounds.
6-Chloropurine, as its ribonucleotide, is active against a
number of animal neoplasms  and human leukaemias , but is
less effective than the purinethiones, which it resembles in its
8-Azaguanine is inhibitory to several experimental animal tumour
systems , but is not highly active. Clinically its toxicity
has been more apparent than its anticancer effects [362,363].
Of the purine analogues investigated thus far, the purinethiones
are by far the most effective anticancer agents. 6-Mercaptopurine
remains the agent of choice clinically [363, 445-4471 , since other
thiopurines, such as thioguanine, 6-(methylthio)purine,
azathiopurine, 9-ethyl-6-mercaptopurine, and 6-mercapto- purine
ribonucleoside, which are also active in man, appear to offer no
real advantage over it. 6-Mercaptopurine is useful in the treatment
of acute granulocytic, acute lymphocytic, and chronic granulocytic
leukaemia and chorio- carcinoma [ 12, 363, 445-4471 . The
combination of 6-mercaptopurine and 6(methylthio)purine
ribonucleoside, however, is more effective in the treatment of
acute adult leukaemia than either drug alone .
6-Mercaptopurine is considerably less effective in the treatment of
solid tumours  .
The reason for the selective toxicity of 6-mercaptopurine
remains to be established, but two factors may be of primary
importance. 6-Mercaptopurine is anabolized primarily, if not
exclusively, to the monophosphate level, and it is readily
catabolized by xanthine oxidase, an enzyme that is low in most
cancer cells compared to normal cells. Another factor that must be
considered is the metabolic state of the target cells. Actively
proliferating leukaemia cells are more sensitive to
6-mercaptopurine, as they are to all antimetabolites, than cells in
the so-called Go or stationary phase. Although this does not
explain the difference between 6-mercaptopurine and other purine
analogues, it may explain the ineffectiveness of 6-mercaptopurine
against solid tumours, most of the cells of which are in the
Certain derivatives of 6-mercaptopurine, such as
6-(methylthio)purine, 6-mercaptopurine-3-oxide [448a] , and
6-mercaptopurine ribonucleoside and its acylated derivatives
apparently owe their activity to their in vivo conversion to
6-mercaptopurine [ 11,131. It would appear, however, that the
9-alkyl derivatives of 6-mercaptopurine, and its arabinosyl and
xylosyl derivatives, are not metabolized-except in the case of the
9-alkyl derivatives, t o a limited extent to their
S-glucuronides-and that their mechanism of action is quite
different from that of 6-mercaptopurine.
Thioguanine is 5-30 times as toxic to rodents (depending on
schedule) as 6-mercaptopurine and somewhat more effective against
A. MONTGOMERY 109
although its therapeutic index is not greater. It would seem
likely that 6-mercaptopurine and thioguanine inhibit cancerous
growths in a similar manner. Changes in the structure of
thioguanine also give rise to active structures. but no significant
improvement in effectiveness [ 1 1,131 .
THE PROBLEM OF RESISTANCE Mechanisms
Both natural and acquired resistance constitute a serious
problem to therapy witH purine analogues, particularly in the case
of cancer. Why one acute leukaemia responds well to methotrexate
but not to 6-mercaptopurine, whereas a morphologically identical
leukaemia responds to 6-mercaptopurine but not to methotrexate, and
a third, seemingly identical leukaemia responds to neither is a
vexing problem that has so far defied solution .
In the case of acquired resistance, a patient may respond well
to a drug initially and appear to be completely cancer-free, only
to succumb later to a cancer that now does not respond to therapy
with the same drug. Such a situation may indicate that the cancer
cell population has, before resumption of treatment, multiplied to
a size where it can no longer be controlled by a drug dose th?t the
patient can tolerate , or it may indicate that a
drug-resistant mutant population has replaced the original
heterogeneous population containing almost entirely drug-sensitive
The necessity for most purine analogues to be converted to their
nucleotides to show their inhibutory effects has been discussed.
Cells deficient in hypo- xanthine-guanine phosphoribosyltransferase
activity cannot convert 6- mercaptopurine, thioguanine, or
8-azaguanine to their ribonucleotides and are resistant to these
analogues [8,98, 101,260,451455] , but are still sensitive to
adenine analogues such as 2-fluoroadenine, 2-aminoadenine, and
4-aminopyrazolo [3, 4:d] pyrimidine . Conversely, cells
deficient in adenine phosphoribo- syltransferase activity are
resistant to the various adenine analogues, such as 2-aminoadenine
[ 1 13, 3041 and 2-fluoroadenine [ 1281, but are still sensitive to
cytotoxic hypoxanthine-guanine analogues [ 128, 1471 . Although
mammalian cells are naturally resistant to xanthine analogues,
because they are deficient in xanthine phosphoribosyltransferase
activity, bacteria possess this enzyme and are sensitive to
8-azaxanthine. Bacteria that have become resistant to 8-azaxanthine
were shown to have lost their xanthine phosphoribo'syltransferase
activity . Resistance to 2-aminoadenine and 8-azaguanine in
Salmonella typhimurium is apparently due, in some cases, to
genetically controlled alterations of the
phosphoribosyltransferases to forms of the enzymes that can still
convert the natural substrates to nucleotides but not the purine
analogues [457,458]. Cells deficient in adenosine kinase fail to
respond to adenosine analogues, unless they are cleaved to adenine
analogues that can be converted to ribonucleotides by adenine
phosphoribosyltransferase. Cells deficient in both these enzymes
fail to respond to adenine and adenosine analogues, but are still
sensitive to hypoxanthine-guanine analogues [ 1471 . Resistance to
the various purine
THE BIOCHEMICAL BASIS FOR THE DRUG ACTIONS OF PURINES
analogues due to these enzyme deletions has been observed in
bacteria, mammalian cells in culture, and neoplasms in experimental
animals indicating that this is a ubiquitous and an important cause
of acquired resistance . Since these enzymes catalyse the
so-called 'salvage' pathways of purine utilization they are not
essential to cellular metabolism, and their loss does not, in
general, affect the ability of cells to proliferate at normal
rates, which may explain why resistance by these deletions occurs
so readily and frequently. However, acquired resistance is thought
to result from chemical selection and overgrowth of specific
drug-resistant mutant cells from a heterogeneous population, and
hence it is not surprising that more than one type of resistance to
a particular agent has been found. Other mechanisms of resistance
to purine analogues that have been advanced are inaccessibility of
the nucleotide-forming enzyme system to the analogue [459, 4601,
increased rate of degradation of the analogue or its metabolities
[461-463], and a decreased affinity of the activating enzyme for
the analogue [ 1001 .
One of the first demonstrations that acquired resistance could
be circumvented was the inhibition of S. faecalis resistant to
8-amguanine by 8-azaxanthine. Thus, cells that possess xanthylic
acid phosphoribosyltransferase activity could form 8-azaxanthylic
acid, which was then converted to 8-azaguanylic acid and
incorporated in nucleic acids as such 1981 .
Early attempts to inhibit H.Ep.-2 cells resistant to
6-mercaptopurine [464J resulted in the finding that a number of
9-alkyl derivatives of 6-mercaptopurine were highly active in this
test system. 9-Alkylhypoxanthines and adenines were less effective
6-Mercaptopurine ribonucleotide is not active against cells
resistant to 6-mercaptopurine, presumably because nucleotides
cannot penetrate cell membranes intact  (its activity in
sensitive cells is no doubt due to its cleavage back to
6-mercaptopurine  ).
This stumbling block led to the synthesis of esters of
6-mercaptopurine ribonucleotide [468, 4691 that might penetrate
cell walls intact and then either inhibit per se or be cleaved back
to the ribonucleotide. Two such derivatives, bis(thioinosine) 5 ',
5 "'-phosphate  and the monophenyl ester of. 6-mercaptopurine
ribonucleotide [ 13, 4681 do inhibit H.Ep.-2 cells resistant to
6-mercaptopurine, but some cross-resistance was noted. Because of
the relatively low therapeutic index of all known purine
antagonists, this cross-resistance did not otter encouragement for
in vivo activity against resistant neoplasms, and, indeed, the
monophenyl ester did not inhibit leukaemia L1210 resistant to 6-
mercaptopurine. More successful in this regard was the use of
6-(methylthio) purine ribonucleoside against MP-resistant cells.
Thus, this nucleoside, which is converted to the nucleotide by
adenosine kinase, is highly active against both resistant H.Ep.-2
cells in culture and resistant L1210 leukaemia in mice .
Furthermore, it is therapeutically synergistic with
6-mercaptopurine in the
A. MONTGOMERY 111
sensitive line of L1210 . Similar observations were made in
the Ehrlich ascites carcinoma system . The clinical utility of
this combination  has been discussed above.
AC KNOW L E DG EM EN TS
The author gratefully acknowledges the helpful criticism of Dr.
Lee L. Bennett, Jr. Thanks are due to Mr. Vladimir Minic and Miss
Linda Scott for checking references to the literature and to Mrs.
Frances K. Hoffman for preparation of the manuscript.
1. E. R. Stadtman, Adv. Enzymol., 1966,28,41 2. J. F. Henderson,
Progr. Exp. TumorRes., 1965,6,84 3. N. 0. Kaplan and M. Friedkin,
Advan. Chemother., 1964, 1,499 4. H. J. Grav, Merhods in Cancer
Research (Ed. H. Busch), Vol. 3, Academic Press, New
York, 1967, p. 243 5. H. G. Mandel, Pharmacol. Rev., 1959,
11,743 6. R. E. Handschumacher and A. D. Welch, The Nucleic Acids
(Eds. E. Chargaff and J. N.
Davidson), Vol. 3, Academic Press, New York, 1960, p. 453 7. R.
W. Brockman and E. P. Anderson, Annu. Rev. Biochem., 1963,32,463 8.
R. W. Brockman, Adv. Cancer Res., 1963.7. 129 9. J. F. Henderson
and H. G. Mandel, Adv. Phormacol., 1963,2; 297
10. G. H. Hitchings and G. B. Elion, Metabolic Inhibitors (Eds.
R. M. Hochster and J. H. Quastel), Vol. 1. Academic Press, New
York, 1963, p. 213
11. J. A. Montgomery, Progr. Drug Res., 1965,8,431 12. G . B.
Elion and G. H. Hitchings, Adv. Chernother., 1965,2,91 13. L. L.
Bennett and J. A. Montgomery, Methods in Cancer Research (Ed. H.
Vol. 3, Academic Press, New York, 1967, p. 549 14. M. Friedkin
and H. Kalckar, The Enzymes (Eds. P. D. Boyer, H. Lardy and K.
Myrback), Vok. 5 , Academic Press, New York, 1961, p. 237 15. H.
L. A.Tan, Can. J. Biochern Physiol., 1958,36,517 16. E. W. Ysmada,
J. Biol. Chem, 1961,236, 3043 17. W. Fiers and J. de Bersaques,
Enzymologia, 1962,24, 197 18. A. M. Gotto, A. W. Meikle and 0.
Touster, Biochim. Biophys. Acta, 1964,80,552 19. B. Pinto and 0.
Touster, J. Bid . Chem., 1966,241,772 20. T. A. Krenitsky,Mol.
Pharmacol., 1967, 3,526 21. H. L. A. Tarr and J. E. Roy, Can J.
Biochem., 1967,45,409 21a. T. A. Krenitsky, G. B. Elion, A.M.
Henderson and G. H. Hitchings, J. Biol. Chem,
1968,243,2876 21b. R. P. Agarwal and R. E. Parks, J. Biol.
Chem., 1969,244,644 22. M. Zimmerman and D. Hatfield, Biochim.
Biophys. Acta, 1964,91,326 23. R. Abrams, M. Edmonds and L.
Libenson, Biochem. Biophys. Res. Comtnun, 1965,
24. A. R. P. Paterson and A. I. Simpson,Can. J. Biochem,
1965,43, 1996 25. T. Sakai,T. Tochikura and K. Ogata, Agr. Biol.
Chern, 1965,29,742 26. M. Zimmerman, J. Biol. Chern, 1966, 241,4914
27. R. Caputto, The Enzymes (Eds. P. D. Boyer, H. Lardy and K.
Myrback), Vol. 6,
Academic press, New York, 1962, p. 133 28. L. A. Heppel, The
Enzymes (Eds. P. D. Boyer, H. Lardy and K. Myrback), Vol. 5,
Academic Press, New York, 1961, p. 49
29. E. R. Stadtman, The Enzymes (Eds. P. D. Boyer, H. Lardy and
K. Myrback), Vol. 5, Academic Press, New York, 1961, p. 55
30. G. Schmidt, The Enzymes (Eds. P. D. Boyer, H. Lardy and K.
Myrback), Vol. 5, Academic Press, New York, 1961, p. 37
31. J. Lisowski, Biochim. Biophys. Acta, 1966, 113, 321 32. M.
Center and F. J . Behal, Arch. Biochem. Biophys., 1966, 114,414 33.
S. J . Levin and 0. Bodansky, J. Biol. Chem., 1966, 241,Sl 34. C.
S. Song and 0. Bodansky, Biochem. J . , 1966, 1 0 1 , S c 35. C.
Arsenis and 0. Touser, J. Biol. C h e m , 1967, 242, 3399 36. P. L.
Ipata, Biochem. Biophys. Res. Commun., 1967, 27, 337 37. H. C. Neu,
J. Biol. Chem., 1967,242, 3896 37a. C. Arsenis and 0. Touser, J.
Biol. C h e m , 1968, 243.5702
THE BIOCHEMICAL BASIS FOR THE DRUG ACTIONS OF PURINES
43. 44. 45. 45a
M. R. Atkinson and R. K. Morton, Comp. Biochem, 1960, 2, 1 L.
Noda, The Enzymes (Eds. P. D. Boyer, H. Lardy and K. Myrback), Vol.
6, Academic Press, New York, 1962, p. 139 J . lmsande and
P.Handler, TheEizzyrnes (Eds. P. D. Boyer, H. Lardy and K.
Myrback), Vol. 5, Academic Press, New York, 1961, p. 281 M. Hori
and J . F. Henderson, J. Biol. C h e m , 1966, 241, 3404 M. Hori,
R. E. A. Gadd and J . F. Henderson, Biochem Biophys. Res. Commun.,
1967, 28, 616 A. W. Murray, Biochem J . , 1967,103, 271 A. W.
Murray and P. C. L. Wong, Biochern. J . , 1967, 104, 669 A. W.
Murray, Biochem J . , 1967, 104,675 T. A. Krenitsky, S. M. Nei1,G.
B. Elion and G. H. Hitchings, J. Biol. Chem., 1929,244, 4779 C. E.
Carter,J. Amer. Chem. SOC., 1951, 73, 1508
46a. M. Terada, M. Tatibana and 0. Hayaishi, J. Biol. Chern.,
1967, 242,5578 47. H. P. Schnebli,D. L. Hill and L. L. Bennett, J.
Biol. Chem., 1967,242, 1997 48, B. Lindberg, H. Klenow and K.
Hanscn, J. Biol. C h e m , 1967, 242,350 49. M. A. Brewster and E.
S. Younathan, Can. J. Biochem, 1 9 6 6 , 4 , 1469 50. R. J . Haslam
and D. C. B. Mills, Biochem J., 1967, 103,773 51. C.Chiu, S. Su and
S. J. Russell, Biochim Biophys Acta, 1967, 132, 361 52. S. Su and
S. J . Russell, Biochirn. Biophys. Acta, 1967, 132, 370 53. A.
Larsson and P. Reichard, Progr. Nucleic Acid Res. Mol. Biol., 1967,
7, 303 54. P. Reichard, Eur. J. Biochem., 1968, 3, 259 55. R. C.
Hartenstein and I . Fridovich, J. Biol. Cliem., 1967, 242, 740 56.
L. G . Howell and I . ridovich. J. Biol. Chem., 1967, 242,4930 57.
A. Coddington, Biochim. Biophys. Acta, 1965,99, 442 5 8 . S.
Minato, T. Tagawa and K . Nakanishi, J. B iochem, 1965,58,519 59.
R. Wolfenden, J. Amer. Chem SOC., 1966,88, 3157 60. S. Minato, T.
Tagawa, M. Miyaki, B. Shimizu and K. Nakanishi, J. B iochem, 1966,
265 61. M. Rockwell and M. H. Maguire,Mol. Pharmacol., 1966, 2,
574 62. R. Wolfcnden, T. K. Sharpless and R. Allan, J. Biol. Chem.,
1967, 242, 977 63. B. M. Chassy and R. J . Suhadolnik, J. Biol.
Chem., 1967, 242, 3655 64. V. D. Hoagland and J . R. Fisher, J.
Biol. C h e m , 1967, 242,4341 64a. P. M. Murphy, M. Noonan, P.
Collins, E. Tully and T. G . Brady, Biochim Biophys
Acta, 1969, 171, 157 65. J. M. Buchanan, The Nucleic Acids
(Lids. E. Chargaff and J . N. Davidson), Vol. 3,
Academic Press, New York, 1960, p. 303 66. A. Hampton, J. Biol.
Chem., 1962, 237, 529 67. M. R. Atkinson, R. K . Morton and A. W.
Murray, Biochem. J., 1964,92, 398 68. R. H. Weaver, The Enzymes
(Eds. P. D. Boyer, H. Lardy and K. Myrback) Vol. 6,
Academic Press, New York, 1962, p. 151 69. N. Mourad and R. E.
Parks, Biochern. Biophys. Res. C o m m u n , 1965, 19, 312
A. MONTGOMERY 1 1 3
N. Mourad and R. E. Parks, J. BioL C h e m , 1966, 241, 271 N.
Mourad and R. E. Parks, J. Biol. C h e m , 1966, 241, 3838 W. W.
Kielley, The Enzymes (Eds. P. D. Boyer, H. Lardy and K. Myrback)
Vol. 5, Academic Press, New York, 1961, p. 159 Y. P. Lee, The
Enzymes (Eds. P. D. Boyer, H. Lardy and K. Myrback) Vol. 4,
Academic Press, New York, 1960, p. 279 B. S. Cunningham and J. M.
Lowenstein, Biochim Biophys. A c f a , 1965, %, 535 A. Razin and J.
Mager, Israel J. Med Sci., 1966, 2, 614 K. L. Smiley and C. H.
Suelter, J. Biol. Chem., 1967,242,1980 K. L. Smiley, A. T. Berry
and C. H. Suelter, J. Biol. C h e m , 1967, 242,2502 A. W. Nichol,
A. Nomura and A. Hampton, Biochemisfty, 1967,6,1008 H. G. Khorana,
The Nucleic Acids, (Eds. E. Chargaff and J. N. Davidson) Vol. 3,
Academic Press, New York, 1960, p. 105 H. M. Keir, Progr. Nucleic
Acid Res. Mol. Biol., 1965, 4, 81 N. B. Furlong, Methods in Cancer
Research (Ed. H. Busch) Vol. 3, Academic Press, New York, 1967, p.
28 H. L. A.Tarr, Can. J. Biochem, 1964,42, 1535 E. S. Zimmerman and
B. Magasanik, J. Biol. C h e m , 1964, 239,293, R. C. Bray, Enzymes
(Eds. P. D. Boyer, H. Lardy and K. Myrback), Vol. 7, Academic
Press, New York, 1963, p. 533
74. 75. 76. 77. 78. 79.
82. 83. 84.
85. A. W. Murray, Biochem-J., 1966, 100,664 85a. T. A.
Krenitsky, R. Papaioannou and G. B. Elion, J. Biol. C h e m , 1969,
244, 1263 85b. T. A. Krenitsky and R. Papaioannou, J. Biol. C h e m
, 1969, 244, 127 1 85c. J. H. Anderson and A. C. Sartorelli. J.
Biol. C h e m . 1968. 243.4762 86.
88. 89. 90. 91.
92. 93. 94.
95. 96. 96a.
J. Mager and R. Magasanik, J. Biol. Chern., 1960,235,1474 H. R.
Mahler, Enzymes (Eds. P. D. Boyer, H. Lardy and K. Myrback), Vol.
8, Academic Press, New York, 1963, p. 285 R. Currie, F. Bergel and
R. C. Bray, Biochem. J., 1967, 104,634 H. Kuramitsu and H. S.
Moyed, J. Biol. C h e m , 1966,241, 1596 T. T. Fukuyama, J. Biol.
Chem., 1966,241,4745 R. P. Miech, R. E. Parks, J. H. Anderson and
A. C. Sartorelli, Biochem. Pharmacol., 1967, 16, 2222 A. Kornberg,
I. Lieberman and E. S. Simms, J. Amer. Chem Suc., 1954, 76,2027 A.
Kornberg, I . Lieberman and E. S. Simms, J. Biol. Chem.,
1955,215,417 E. D. Korn,C. N. Remy, H. C. Wasgejko and J. M.
Buchanan,.I. Biol. Chem., 1955, 217,875 C. N. Remy, W. T. Remy and
J. M. Buchanan, J. Biol. C h e m , 1955,217,885 J . G. Flaks, M. T.
Erwin and J. M. Buchanan, J. Biol. Chcm., 1957,228, 201
, T. A. Krenitsky, Biochim. Biophys. Acfa , 1969, 179,506 96b. J
. F. Henderson, L. W. Brox, W. N. Kelley, F. M. Rosenbloom and J.
96c. J. F. Henderson, Can. J. Biochem, 1969,47,69 97. J . G.
Flaks, Methods in Enzymology (Eds. S . P. Colowick and N. 0.
Kaplan) Vol. 6,
Academic Press, New York, 1963, p. 136 98. R. W. Brockman, C.
Sparks, D. J. Hutchison and H. E. Skipper, CancerRes, 1959,
19, 177 99. C. P. Kalle, J. S. Cots and C. Abramson, Fed. Proc.,
1960, 19, 310
100. R. W. Brockman, C. S. Debavadi, P. Stut t sand D. J.
Hutchison, J. Biol. C h e m , 1961, 236,1471
101. R. W. Brockman, L. L. Bennett, M. S. Simpson, A. R. Wilson,
J. R. Thomson, and H. E. Skipper, Cancer Res., 1959, 19, 856
102. M. R. Atkinson and A. W. Murray, Biochem J . , 1965,94,64
103. A. W. Murray, Biochem J., 1966, 100,671 104. R. Pomales, G. B.
Elion and G. H. Hitchings, Biochim. Biophys. Acfo , 1965.95,505
J. Biol. C h e m , 1968,243,2514 . ,
THE BIOCHEMICAL BASIS FOR T H E DRUG ACTIONS OF PURINES
105. W. N. Kelley, F. M. Rosenbloom, J. F. Henderson, and J. E.
Seegmiller, Biophys. Res. Comtnun., 1967, 28, 340
106. R. D. Berlin and E. R. Stadtman, J. Biol. Chem,
1966,241,2679 107. A. Bendich, J . F. Tinker and G. B. Br0wn.J.
Amer. Chem. Soc., 1948,70, 3109 108. J. A. Montgomery and I(.
Hewson, J. Amer. Chem SOC., 1960, 82, 463 109. R. K. Robins, J.
Amer. Chem. Soc., 1956,78,784 110. E. N. Shaw and D. W. Woolley, J.
Biol. Chem., 1952,194,641 11 1. R. 0. Roblin, J. 0. Lampen, J. P.
English, Q. P. Cole, and J. R. Vaughan, J. Amer.
Chem Soc., 1945,67,290 112. J. L. Way and R. E. Parks, J. Biol.
Chem, 1958,231,467 11 3. J . K. Roy, A. G. Haavik, and R. E. Parks,
Proc. Amer. Assoc. Cancer Res , 1960, 3, 146 114. C. N. Remy and M.
S. Smith, J. Biol. Chem., 1957, 228,325 115. C. N. Remy, Biochem.
Biophys. Acra, 1967, 138,258 116. D. G. R. Blair and A. D. Hall,
Can. J. Biochem., 1965,43,1857; Blair, Can. J. Biochem,
117. G. P. Wheeler and H. E. Skipper, J. Biol. Chem.,
1953,205,749 118. L. L. Bennett, D. Smithers, C. Teague, H. T.
Baker, and P. Stutts, Biochem.
Phartnacol., 1962, 11.81 119. J . F.Henderson and I.G.
Junga,CancerRes., 1961,21, 118 120. G. B. Elion, E. Burgi and G. H.
Hitchings, J. Amer. Chem. Soc., 1952,74,411 121. D. E. Duggan and
E. Titus, Biochim. Biophys. Acra, 1962,55,273 122. C . E. Jamison,
J. W. Huff,and M. P. Gordon,Cancer Res., 1962,22, 1252 123. D. E.
Duggan, M. G. Weigert, W. E. Grieb and E. 0. Titus, Biochim.
1963,68,519 124. C. N . Remy, J. Biol. Chem.. 1961,236,2999 125.
D. E. Duggan, Biochim. Biophys. Acta, 1963,68,319 126. G. B. Brown
and V. S. Weliky, J. Org. Chem., 1958,23, 125 127. J . A.Carbon, J.
Amer. Chem. SOC., 1958,80,6083 128. L. L. Bennett, M. H. Vail, S.
Chumley and J . A. Montgomery, Biochem. Pharmacol.,
129. M. P. Gordon, 0. M. Intrieri and G. B. Brown, J. Biol.
Chem, 1957,22Y, 641 130. A. Hampton and A. R. P. Paterson, Biochim.
Biophys. Acta, 1966,114, 185 131. I. W. F. Davidson and J. Fellig,
Fed. Proc., 1962,21, 160 132. G. B. Elion and G. H. Hitchings,J.
Amer. Chem. Soc., 1955,77.1676 133. R. K. Robins,J. Org. Chem.,
1956,21,489 134. L. N. Lukens and K. A. Herrington, Biochim.
Biophys. Acta, 1957,24,432 135. C. E. Carter, Biochem. Pharmacol.,
1959.2, 105 136. A. R. Paterson, Acta Unio Intern. Contra Cancrum,
1964,20,1033 136a. M. L. Meloni and W. 1. Rogers,
Biochem.Pharmacol., 1969,18,413 137. D. W. Woolley and E. N.
Shaw,J. Biol. Chem., 1951,189,401 138. J. A. Montgomery and H. J.
Th0mas.J. Org. Chem., 1961,26,1926 139. A. Hampton and M. H.
Maguire, J. Amer. Chem. SOC., 1961,83,150 140. (a)
J.K.Roy,D.C.Kvam, J. L. Dahland R. E. Parks,J. Biol. Chem.,
(b) J. L. Way, J. L. Dahl and R. E. Parks,J. Biol. Chem.,
1959,234, 1241 141. D. 1. Magrath and C . B. Brown,J. Amer. Chem.
SOC., 1957.79,3252 142. M. F. Utter, The Enzymes (Eds. P. D. Boyer,
H. Lardy and K. Myrback), Vol. 2,
Academic Press, New York, 1960, p. 75 143. G. A. LePage and I.
G. Junga, Cancer R e s , 1963, 23, 739 144. G. A. LePage and I. G .
Junga, Mol. Pharmacol., 1967,3,31 144a. G . A. LePage, Can. J.
Biochem., 1968,46,655 145. K. J. Pierre, A. P. Kimball and G . A.
LePage, Can. J. Biochem., 1967.45, 1619; K. J.
Pierre and G. A. LePage,Proc. SOC. Exp. Biol. Med. , 1968,
127,432 146. A. Kornberg and W. E. Pricer, J. Biol. Chem.,
A. MONTGOMERY 115
147. L. L. Bennett, H. P. Schnebli, M. H. Vail, P. W. Allan and
J. A. Montgomery, Mol. Pharmacol., 1966, 2, 432
148. W. W. Lee, A. Benitez, L. Goodman and B. R. Baker, J .
Amer. Chem. Soc., 1960,82, 2648
149. C. P. J. Gluademans and H. G. Fletcher, J . Org. Chem,
1964.29, 3286 150. P. Changand B. Lythgoe,J. Chem. SOC., 1950, 1992
151. B. R. Baker and K. Hewson, J. Org. Chem., 1957, 22,966 152. J.
J. Brink and G. A. LePage, Cancer Res., 1964.24.1042 153. D. B.
Ellis and G. A. LePage, Cancer Res., 1966,26A, 893 154. J. J. Brink
and G. A. LePage, Cancer Res., 1964,24,312 155. J. L. York and G.
A. LePage, Can. J. Biochem., 1966.44, 19 156. D. B. EUis and G. A.
LePage, Can. J. Biochem., 1965,43,617 157. D. B. Ellis and G. A.
LePage,Mol. Pharmacol., 1965, 1.23 1 158. J. A. Johnson and H. J.
Thomas, J. Amer. Chem. Soc., 1956,78,3863 159. A. Hampton, J. J.
Biesele, A. E. Moore and G. B. Br0wn.J. Amer. Chem. SOC., 1956
78,5695 160. J . A. Montgomery, T. P. Johnston, A. Gallagher, C.
R. Stringfellow and F. M. Schabe
J. Med.Pharm. Chem., 1961,3,265 161. L. L. Bennett, R. W.
Brockman, H. P. Schnebli, S. Chumley, G. J . Dixon, F. M.
Schabe1,E. A. Dulmadge, H. E. Skipper, J. A. Montgomery and H. J
. Thomas, Nature, 1965,205,1276
162. I. C.Caldwell,J. F. Henderson and A. R. P. Paterson, Can.
J. Biochem., 1966,44,229 162a. D. H. W. Ho, J . K. Luce and E.
Frei, Biochem. Pharmacol., 1968, 17, 1025 163. R. M. Bock, The
Enzymes (Eds. P. D. Boyer, H. Lardy and K. Myrback), Vol. 2,
Academic Press, New York, 1960, p. 3 164. K. G. Cunningham, S.
A. Hutchison, W. Manson and F. S. Spring, J. Chem. SOC.,
195 1,2299 165. E. A. Kaczlta, N. R. Trenner, B. H. Arison, R.
W. Walker and K. Folkers, Biochem.
Biophys. Res. Commun.. 1964,14.456 166. W. W. Lee,A. Benite2.C.
D. Anderson, L. Goodman and B. R. Baker, J. Amer. Chem.
SOC., 1961,83,1906 167. H. Klenow.Biochim. Biophys Acta,
1963,76,347 168. H. Klenow, Biochim. Biophys. Acta, 1963,76, 354
169. H. T. Shigeura and C. N. Gordon, J. Biol. Chem., 1965,240,806
170. B. R. Baker, R. E. Schaub and H. M. Kissman, J. Amer. Chem.
Soc., 1955,77,5911 171. N. N. Gerber and H. A. Lechevalier, J. Org.
Chem., 1962,27, 1731 172. A. J. Guarino and N. M. Kredich, Biochim.
Biophys. Acta, 1963.68, 317 173. H. T. Shigeura, G. E. Boxer, M. L.
Meloni and S. D. Sampson, Biochemistry, 1966,s.
994 174. J. A. Johnson,H. J: Thomasand H. J . Schaeffer, J .
Amer. Chem. Soc., 1958,80,699 175. A. Coddington, Biochim. Biophys.
Acta, 1962,59,472 176. E.Walton, F. W. HoHy,G. E. Boxer,R. F. Nutt
and S. R. Jenkina, J. Med. Chem., 1965,
177. H. T. Shigeura,S. D. Sampson and M. L. Meloni, Arch.
Biochem. Biophys., 1966,115, 462
178. 179. 180. 181. 182.
183. 184. 185.
G. B. Brown and V. S. Weliky, J. Biol. Chem., 1953,204, 1019 M.
P. Gordon and G. B, Brown, J. Biol. Chem., 1956,220,927 G. R.
Barker, J. B. Lloyd, M. D. Montague and N. F. Wood, Biochem. J. ,
1959,72,9P J . F. Paterson, Can. J. Biochem. Physiol., 1959,37,
1011 H. T. Shigeura,G. E. Boxer, S. D. Sampmn and M. L. Meloni,
Arch. Biochem. Biophys 1965,111,713 J. Davoll and B. A. Lowy, J.
Amer. Chem. Soc., 1951,73,1650 T. Naito, K. Ueno and F. Ishikawa,
Chem. Pharm. Bull. (Tokyo), 1964, 12.95 1 M. Tatibana and H.
Yoshikawa, Biochim. Biophys, Acta, 1962,57,613
186. H. J. Schaeffer and H. J. Thomaa, J. Amer. Chem. SOC.,
1958,80,3738 187. K. Anzai, G. Nakamura and S . Suzki, J. Antibiot.
(Tokyo), Ser. A , 1957, 10,201 188. S. Suzuki and S . Marumo, J.
Anribiot. (Tokyo), Ser. A , 1960,13, 360 189. Y. Mizuno, M.
Ikehara, K. A. Watanabe, S. Suzaki and T. Itoh, J. Org. Chem.,
28,3329 190. G. Acs, E. Reich and M. Mori,Proc. Nut. Acad. Sci.
U. S., 1964,52,493 191. H.Nishimura,K. Katagiri,K.Sato,M.Mayamaand
N. Shimaoka, J. Anribiot. (Tokyo),
Ser. A , 1956,9,60; K. Ohkuma, J. Antibiot. (Tokyo), 1961, 14,
343 192. G. Acs and E. Reich, Antibiotics (Eds. D. Gottlieb and P.
D. Shaw), Vol. 1: Springer-
Verlag New York, Inc., New York, 1967, p. 494 193. R. J.
Suhadolnik, T. Uematsu and H. Uematsu, Biochim. Biophys Acfa ,
41 194. H. G. Mandel, P. E. Car10 and P. K. Smith, J. Biol.
Chem, 1954,206,181 195. R. E. F. Matthews and J. D. Smith, Nuture,
1956,177,271 196. H. G. Mandel and R. Markham, Biochem. J. ,
1958,69,297 197. E. C. Moore and G. A. LePage, Cancer Res., 1958,
18,1075 198. G. A. LePage, Cancer Res., 1960,20,403 199. R. H.
Iwamoto, E. M. Acton and L. GoodmanJ. Med. Chem., 1963,6,684 200. S
. Bieber, L. S. Dietrich, G. B. Elion, G. H. Hitchings and D. S .
Martin, Cancer R e s ,
1961,21,228 201. J. P. Scannell and G. H. Hitchings, h o c .
SOC. Exp. Biol. Med., 1966, 122,627 202. A. Bloch. R. J. Leonard
and C. A. Nichol, Biochim. Biophys Acfa , 1967,'138, 10 202a. K. V.
Rao, J. Med. Chem., 1968,11,939 202b. R. J. Suhadolnik, S. I.
Finkeland B. M. Chassy, J. Biol. Chem., 1968,243, 3532 202c. B. M.
Chasay and R. J. Suhadolnik,J. Biol. Chem., 1968,243,3538 203. C.
N. Remy, J. Biol. Chem., 1959,234,1485 204. C. N. Remy. J. Biol.
Chem.. 1963,238,1078 205. E. J. Sarcione and L. Stutzman, Cancer
Res., 1960,20,387 206. P. W. Allan. H. P. Schnebli and L. L.
Bennett, Biochim. Biophys. Acfu, 114,
641 207. P. Mazel, J. F. Henderson and J. Axelrod, J. Pharmacol.
Exp. Ther., 1964, 143,1 208. J. F. Henderson and P. Mazel,
Biochern. Pharmacol., 1964,13,207 209. J.N.Porter,R. L. Hewitt, C.
W. Hesseltine, G. C. Krupka, J. A. Lowery, W. S. Wallace,
N. Bohonor and J. H. Williams, Anfibiot. Chemother., 1952,2,409
210. B. R. Bake1,R.E. Schaub, J. P. Joseph and J. H. Williams,J.
Amer. Chem. Soc., 1955,
77,12 211. B. R. Baker, J. P. Joseph and J. H. Williams,/. Amer.
Chem. SOC., 1955,77,1 212. P. Mazel, A. Kerza-Kwiatecki and J.
Simanis, Biochim. Biophys. Actu, 1966, 114,72 213. H. T. Nagasawa,
K. F. Swingle and C. S . Alexander, Biochem. Pharmacol., 1967,
221 1 214. P. Mazel and J. F. Henderson, Biochem. Pharmacol.,
1965,14,92 215. J. F. Henderson and P. Mazel, Biochem. Phurmacol.,
1964,13,1471 216. H. T. Shigeura and S . D. Sampmn, Biochim.
Biophys Actu, 1967, 138, 26 217. A. E. Farnham and D. T. Dubin,
Biochim. Biophys. Act@, 1967,138,35 218. G . P. Wheeler and B. J.
Bowdon,J. Biol. Chem, 1966,241,1114 219. M. R. Atkinaon, G.
Eckermann and J. Stephenson, Biochim. Biophys. Acra, 1965,
108, 320 220. S. Frederikaen, Biochim. Biophys. Actu, 1963,
76,366 221. G. B. Brown, G. Levin, S. Murphy, A. Sele, H. C.
Reilly, G. S. Tarnowski, F.A. Schmid,
M. N. Teller and C. C. Stock, J. Med. Chem, 1965,8,190 222. J.
F. Paterson, Can. J. Biochem., 1965,43,257 223. T. A. Krenitsky, G.
B. Elion, R. A. Strelitz and G. H. Hitchings, J. Biol. Chem..
242,2675 224. M. Friedkin,Biochim. Biophys. Acta, 1955,
THE BIOCHEMICAL BASIS FOR THE DRUG ACTIONS OF PURINES
A. MONTGOMERY 117
225. A. W. Meikle, A. M. Gotto and G. Touster, Biochim. Biophys.
Acra, 1967, 138,445 226. J. F. P a t e r m and A. Sutherland, Can.
J. Biochem., 1964.42, 1415 226a. T. A. Krenitsky, G. B. Elion, A.
M. Henderson and G . H. Hitchhgs, J . Biol. Chem.,
1968,243,2876 227. 228. 229. 230. 231. 232.
233. 234. 235. 236.
237. 237a. 238. 239. 240. 241. 242. 243.
250. 251. 252. 253. 254.
255. 256. 257. 258. 259. 260. 261. 262.
G. A. LePage and I. G. Junga, Cancer Rex , 1965,25,46 A. Bloch
and C. A. Nichol, Antimicrob. Agents Chemother., 1965,530 F.
Rottman and A. G. Guarino, Biochim. Biophys. Acta, 1964,80,632 J. A
. Montgomery and K. Hewson, J. Med. Chem., 1968,11,48 J. Davoll and
K. A. Kenidge, J. Chem. SOC., 1961,2589 J. A.Montgomery,S. J.
Clayton and W. E. Fitzgibbon, J. Heterocycl. Chem., 1964, 1, 215 J.
A. Montgomery and K. Hewson, unpublished J. A. Montgomery and K.
Hewson, J. Heterocycl. Chem., 1964, 1,213 J. F. Gerster, J. W.
Jones and R. K. Robins, J. Org. Chem., 1963,28,945 B. R. Baker, K.
Hewson, H. J. Thomas and J. A. Johnson, J. Org. Chem., 1957,22, 954
H. P. Baer and G . I. Drummond, Biochem. Biophys. Res. Commun..
1966,24,584 S . Minato, J. Biochem., 1968,64,815 J. G . Cory and R.
J. Suhadolnik, Biochemistry, 1965,4,1733 J. G . Cory and R. J.
Suhadolnik, Biochemistry, 1965,4, 1729 S . FrederikseqArch.
Biochem. Biophys., 1966, 113, 383 H. P. Baer, G. I. Drummond and E.
L. Duncan, Mol. Pharmacol., 1966,2,67 0. P. Chilson and J. R.
Fisher, Arch. Biochem. Biophys., 1963, 102,77 D. A.Clarke, J.
Davoll, F. S . Phillips and G. B. Brown, J. Pharmacol. Exp. Ther.,
1952. 106,291 M. Hori, E. Ito, T. Takita, Y. Koyama, J. Takeuchi
and H. Umezawa, J. Antibiot. (Tokyo), Ser. A 1964. 17,96 G. Koyama,
K. Maeda, H. Umezawa and Y. Iitaka, Tetrahedron Lett . , 1966, SY7
R. K. Robins, L. B. Townsend, F. Cassidy, J. F. Gerster, A. F.
Lewis and R. L. Miller, J. Heterocycl. Chem., 1966. 3. 110 S.
Frederiksen, Biochim. Biophys. Acta, 1964,87,514 Y. Fukagawa, T.
Sawa, T. Takeuchi and H. Umezawa, J. Antibiot. (Tokyo), Ser. A . ,
1965.18.191 T. Sawa, Y. Fukagawa, S. Homma, T. Takeuchi and H.
Umezawa, J. Antibiot. (Tokyo) Ser. A , 1967,20,221 J. L. York and
G. A. LePage, Can. J. Biochem., 1966,44, 331 E. J. Reist, D. E.
Gueffroy and L. Goodman, J. Amer. Chem. SOC., 1964,86,5658 Y. F.
Shealy and J. D. Clayton, J. Amer. Chem. SOC., 1966,88, 3885 L. L.
Bennett, P. W. Allan and D. L. Hill, Mol. Pharmacol., 1968,4,208 N.
Dickie, L. Norton, R. F. Derr, C. S. Alexander and H. T. Nagasawa,
Proc. SOC. Exp. Biol. Med., 1966, 123,421 J. J . Brink and G . A.
LePage, Can. J. Biochem., 1965,43,1 H. J. Schaeffer and R. Vince,
J. Med. Chem., 1967, 10,689 A. H. Roush and E. R. Norris, Arch.
Biochem. Biophys., 1950,29,124 J. Kream and E. Chargaff, J. Amer.
Chem. Soc., 1952,74,4274 P. E. Car10 and H. G. Mandel, Cancer Res.,
1954,14,459 R. W . Brockman, Cancer Rex, 1960.20, 643 B. R. Baker
and D. V. Santi, J. Med. Chem., 1967,10, 62 M. Dixon and R.
Lemberg, Biochem. J., 1934, 28, 2065; F. Bergmann, H. Kwietny, G.
Levin and D. J. Brown,-J. Amer. Chem. SOC., 1960,82,598
263. D. E. Duggan and E. Titus, J. Biol. Chem., 1959,234,2100
264. D. E. Duggan and E. Titus, J. Pharmacol. Exp. Ther., 1960,130,
375 265. H. Lettre, N. K. Kapoor and D. Werner, Biochem.
Pharmacol., 1967, 16, 1747 265a. H. Lettre and D. Werner,Biochem.
Pharmacol., 1968, 17, 1951
THE BIOCHEMICAL BASIS FOR THE DRUG ACTIONS OF PURINES
266. P. Feigelson, J. D. Davidson and R. K. Robins, J. Biol.
Chem., 1957,226,993 267. P. Feigelson and J. D. Davidson, Cancer
Rex, 1958,18,226 267a. T . Spector and D. G. Johns, Biochem.
Biophys. Res. Commun., 1968,32,1039 268. G. B. Elion, Fed. Proc.,
1967,26,898 269. T. L. Loo, C. Lim and D. G. Johns, Biochim.
Biophys. Acta, 1967,134,467 270. G. B. Elion, S. Callahan, S.
Bieber, G. H. Hitchings and R. W. Rundles, Cancer
Chemother. Rept., 1961, 14, 93 271. G. B. Elion, S. Bieber and
G. H. Hitchings, Cancer Chemothcr. Rept., 1960,8, 36 272. T. P.
Johnston, L. B. Holum and J. A. Montgomery, J. Amer. Chem. SOC.,
6265 273. J. A. Montgomery and C. Temple, J. Amer. Chem. Soc.,
1957,79,5238 274. J. A. Montgomery and C. Temple,J. Amer. Chem
SOC., 1958,80,409 275. C. W. Noell and R. K. Robins, J. Med. Pharm.
Chem., 1962, 5 , 5 5 8 276. H. J. Hansen, W. G. Giles and S. B.
Nadler, Cancer Res., 1962,22,761 217. H. J. Hansen,W.G.Gilesand S.
B.Nadler,Proc. SOC. Exp. Biol. Med., 1963,113,163 278. H. G.
Khorana, J . F. Fernandes and A. Kornberg, J. Biol. Chem.,
1958,230,941 279. D. E. Atkinson and L. Fall, J. Biol. Chem.,
1967,242,3241 280. F. Rottman and A. J. Guarino, Biochim Biophys.
Acta, 1964,80,640 281. H. Klenow and K. Overgaard-Hansen, Biochim.
Biophys. Acta, 1964,80,500 282. K. Overgaard-Hansen, Biochim.
Biophys, Acta, 1964,80.504 283. J . F. Henderson, A. R. P.
Paterson, I. C. Caldwell and M. Hori, Cancer Res., 1967,27,
7 15 284. H. Yuntsen, K. Ohkuma, Y. Ishii and H. Yonehara, J.
Antibiot. (Tokyo), Ser. A ,
1956.9. 195 285. 286. 287.
288. 289. 290.
291. 292. 293. 294. 295.
296. 297. 297a. 298. 299. 300. 301. 302. 303. 304. 305.
306. 307. 308. 308a.
H. Hoeksema and G. Slomp, Tetrahedron Lett., 1964, 1787 A. Bloch
and C. A. Nichol, Biochem. Biophys. Res. Commun., 1964, 16, 400 C.
T. Carkey, D. M. Ashton and J. B. Wyngaarden, J. Biol. Chem.,
1964,239,2570; D. P. Nierlich and B. Magasanik, J. Biol. Chem.,
1965,240,358 S . C. Hartman and J. M. Buchanan, J. Biol. Chem.,
1958,233,45 1 D. L. Hill and L. L. Bennett, Biochemistry,
1969.8.122 R. J. McCollister, W. R. Gilbert, D. M. Ashton and I .
B. Wyngaarden, J. Biol. Chem, 1964,239,1560 J. P. Henderson and M.
K. Y. Khoo, J. Biol. Chem., 1965,240,3104 L. L. Bennett, L.
Simpaon, J. Golden and T . L. Barker, Cancer R e s , 1963,23, 1574
M. T. Hakala and C. A. Nichol, Biochim. Biophys. Acta, 1964,80,665
R. W. Brockman and S. Chumley, Biochim. Biophys. Acta, 1965,95,365
E. A. Dulmadge, G, J. Dixon, S. Chumley and R. W. Brockman, Proc.
Amer. Asroc. Cancer Res., 1965,6,16 P. W. Allan and L. L.
Bennett,Proc. Amer. Assoc. Cancer Res., 1968,9, 2 I.. L. Bennett
and D. Smithers,Biochem. Pharmacol., 1964,13,1331 J. Henderson,
Cancer Chemother. Rept., 1968, 1, 375 G. A. LePage and M. Jones,
Cancer Res., 1961,21,642 A. C. Sartorelli and G. A. LePage, Cancer
Res., 1958,18,1329 J . F. Henderson, Biochem. Pharmacol., 1963,
12,551 J. Davoll, J. Chem. SOC., 1958, 1593 F. Rottman and A. J.
Guarino, Biochim. Biophys. Acta, 1964,89,465 I. C.Caldwell,J. F.
Henderson and A. R. P. Paterson, Can. J. Biochem., 1967,45,735 I.
Lieberman and P. Ove, J. Biol. Chem., 1960,235,1765 W. N. Kelley,
F. N. Rosenbldom, J. F. Henderson and J. E. Seegmiller, Proc. Nut.
Acad. Sci. U. S., 1967, $7, 1735 J. E. Seegmiller, F. M. Rosenbloom
and W. N. Kelley, Science, 1967, 155, 1682 M. R. Atkinson and A. W.
Murray, Biochem. J., 1965,94,71 A. J. Tomisek, A. P. V. Hoskins and
M. R. Reid, Cancer Res., 1965,25, 1925 J. F. Henderson and R. E. A.
Gadd, Cancer Chemother. Rept., 1968, 1, 363
310. 311. 312.
313. 314. 315. 316. 317. 317a.
119 JOHN A. MONTGOMERY
J. D. Davidson, Cancer Res., 1960,20,225 J. Salser, D. J.
Hutchison and M. E. Balis,J. Biol. Chem., 1960,235,429 A. Hampton,
Fed. Proc., 1962,21, 370 M. E. Balis, P. Pecora and J. S. Salser,
Exp. Cell. Res., Suppl , 1963,9,472; J. S. Salscr and M. E. Balis,
Cancer Res, 1965,25,539 H. T . Baker and L. L. Bennett, Biochim.
Biophys. Acta. 1964,80,497 H. T. Shigeura and C. N. Gordon,J. Biol.
Chem., 1962,237,1932 H. T . Shigeura and C. N. Gordon,J. Biol.
Chem., 1962,237,1937 A. Hampton, J. Biol Chem, 1963,238,3068 A.
Hampton and A. Nomura, Biochemistry, 1967,6,679 L. W . Brox and A.
Hamuton. Biochemistrv. 1968.7.2589
318. 319. 320. 321. 322.
323. 324. 325. 326. 327. 328 329.
329a. 330. 331.
335. 335a. 336. 337. 338. 339. 340. 341. 342. 342a.
. , L. W. Brox and A. Hampton, Biochemistw: 1968; 7; 398 A. C.
Sartorelli and B. A. Booth, Biochim. Biophys. Acta, 1962,55,214 S .
Udaka and H. S . Moyed, J. Biol. Chem., 1963,238,2797 H. Yunsen, J.
Antibiot. (Tokyo), Ser. A., 1958, 11,244 T. E. Eble, H. Hoeksema,
G, A. Boyack and G. M. Savage, Antibiot. 419 W . Schroeder and H.
Hoeksema,J. Amer. Chem. SOC., 1959,81,1767 L. J. Hanka, J.
Bacteriol., 1960,80,30 L. Slechta, Biochem. Pharmacol., 1960,5,96
L. Slechta, Biochem. Biophys. Res. Commun., 1960,3,596 W . E. Magee
and F. S. Eberts, Cancer Res., 1961,21,611 T. T. Fukuvama and H. S.
Moyed. Biochemistry, 1964,3,1488 A. J. Guanno, Antibiotics (Fds.
Gottlieb and Shaw), Vol. 1: Springer-Verhg, New York, Inc.. New
York. 1967. p. 464 R. P. Miech, R. York and R. E. Parks,Mol.
Phamcol . . 1969,5,30 E. C. Moore and S. S. Cohen, J. Biol. Chem..
1967,242.2116 E. J. Reist,A. Benitez, L. Goodman, B. R. Baker and
W. W . Lee,J. Org. Chem, 1962,2 3274 A.P. Kimball, B. Bowman,P, S.
Bush, J. Herriot and G . A. LePage, Cancer R e s , 1966, 26,1337 A.
P. Kimball, G. A. LePage and P. S . Allinson, Cancer Res.,
1967,27A, 106 A. P. Kimball and G. A. LePage, Cancer Res.,
1962,22,1301; Cancer R e s , 1963,23, 1792 J. J. Furth and S. S .
Cohen. Cnncer Res.. 1967,27, 1528 J. J. Furth and S . S . Cohen,
Cnncer Res., 1968,28,2061 R. E. F. Matthews, Pharmacol. Rev.,
1958,10,359 J. H. Mitchell, H. E. Skipper and L. L. Bennett, Cancer
Res., 1950,10,647 H. G. Mandel, Fed. Roc . , 1967,26,905 G . A.
LePage and M. Jones, Cancer Res., 1961,21, 1590 G. A. LePage,
Cancer Res., 1963,23, 1202 H. G. Mandel, R. G. Latimer and M. Riis,
Biochem. Pha?macol., 1965,14,661 L. L. Bennett, personal
communication S. C. Uretsky, G. Acs, E. Reich, M. Mori and L.
Altwerger, J. Biol Chem., 1968,243,
306 342b. R. J. Suhadolnik, T. Uematsu and H. Uematsu, J. Biol.
Chem, 1968,243,2761 343 344.
H. T. Shigeura and G. E. Boxer, Biochem. Biophys. Res. Commun.,
1964,17,758 J.G.Cory, R. J.Suhadolnik, B. Resnickand M. A.
Rich,Biochim Biophys. Acta, 1965, 103,646 M. Ikehara, K. Murao, F.
Harada and S. Nishimura, Biochim. Biophys Acta, 1968, 155, 82 S. S.
Cohen, Prog. Nucleic Acid Res., 1966, 5 , 1 D. Gruenberger, L.
Meissner, A. Holy and F. Sorm, Bwchim. Biophys. Acta, 1966,
349. 350. 351. 352. 353.
3 5 5 . 356.
357. 358. 359.
7/13. 364. 365.
366. 367. 368. 369. 370. 371. 372. 372a. 373. 374. 375. 375a.
378. 319. 380. 381. 382. 383. 384.
347. D.Gruenberger,C. ONealand A. Nirenberg, Biochim. Biophys.
Acra, 1966, 119,581 347a. D. Grunberger, A. Holy and F. Sorm,
Biochim. Biophys. Acta, 1968, 161,1A7
D. Nathans, Antibiorics (Eds. D. Gottlieb and P. D. Shaw), Vol.
1 : Springer-Verlag New York, Inc., New York, 1967, p. 259
THE BIOCHEMICAL BASIS FOR THE DRUG ACTIONS OF PURINES
N. M. Kredich and A. J . Guarino, J.-Biol. Chem., 1961, 236,
3300 A. J . Guarino, M. L. Ibershof and R . Swain, Biochim.
Biophys, Acta, 1963, 72, 62 A. J. Guarino and N. M. Kredich, Fed.
Proc., 1964, 23, 371 J. J . Fox, K. A. Watanabe and A. Bloch,
Progr. Nucleic Acid Res., 1966,5 , 25 1 G. 0. Morton, J . E.
Lancaster, G. E. Van Lear, W. Fulmor and W. E. Meyer,J. Amer. Chem.
SOC., 1%9,91,1535 J. R. Florini, Antibiotics (Eds. D. Gottlieb and
P. D. Shaw), Vol. 1 : Springer-Verlag New York, Inc., New York,
1967, p. 427 M. R. Atkinson, J . F .Jackmn,and R. K. Morton,Nafure,
1961, 192,946 M. R. Atkinson, J. F. Jackson, R. K. Morton and A. W.
Murray, Nature, 1962, 196, 35 S . Garattini and R. Paoletti, G.
Ital. Chemiother., 1956, 3 ,55 H. E. Skipper and L. L.
Bennett,Annu. Rev. Biochem., 1958.27, 137 F. M. Schabel, J. A.
Montgomery, H. E. Skipper, W. R. Laster and J . R. Thomson, Cancer
Res. , 1961, 21, 690 F. S. Philips, S. S. Sternberg, L. Hamilton
and D. A. Clarke, Ann. N. Y. Acad. Sci., 1954,60 ,283 R. K. Shaw, R
. N. Shulman, J . D. Davidson, D. P. Rall and E. Frei, Cancer,
1960, 13, 482 G. C. Armstead, J. H. Burchenal, D. A. Karnofsky and
C. M. Southam, Cancer, 1949, 2,1087 1 . H. Burchenal, Current
RexCancer Chemother., 1956,4, 3 T. L. LOO, J. K. Luce,M. P.
Sullivan and E.Frei,Clin. Pharmacol. Therap., 1968,9,180 E. B.
Fiegelson, J . W. Drake and L. Recant, J. Lab. Clin. Med., 1957,50
,437; u. c. Dubach,Progr. DrugRes.. 1964.7 . 341 R. F. Derr, D. K.
Loechler, C. S. Alexander and H. T . Nagasawa, J. Lab. Clin. Med.,
1968.72, 363 D. A..Karnofsky, Cancer Res. Suppl., 1955 ,3 ,83 S.
Bieber and G. H. Hitchings, Cancer Res., 1959, 19, 112 J . B.
Thiersch,Ann. N. Y. Acad. Sci., 1954,60, 220 J. B. Thiersch, Proc.
Soc. Exp. Biol. Med., 1957 ,94 ,40 J . B. Thiersch,J. Reprod.
Fert., 1962.4, 291 J . B. Thiersch, J. Reprod. Fert., 1962.4, 297
R. L. Thompson and C. F. Lavender, Proc. SOC. Exp. Biol. Med.,
1953,84 ,483 C. Kury, S. ChaubL: and M. L. Murphy, Arch. Pathol.,
1968,86 , 395 G. L . Woodside,Anat. Rec., 1952, 113,551 R.
Schwartz, J . Stack,and W.Dameshek, Proc. Soc. Exp. Biol. Med.,
1958, 99, 164 G. H. Hitchings and G. B. Elion,Pharmacol. Rev.,
1963, 15, 365 G. H. Hitchings and G. B. Elion, Accounts Chem. Rex,
1969, 2 ,202 Various authors, Fed. Proc., 1967, 26, 877 A. P.
Kimball, S. J . Herriott andG. A. LePage. Proc. Soc. Exp. Biol.
Med., 1966, 121, 929, A. P. Kimball, S. J . Herriott and P. S.
Allinson,Proc. Soc. Exp. Biol. Med., 1967 126, 181 G. V. R . Born
and M. J . Cross, Nuture, 1963, 197,974 D. Regoli and V. Clark,
Nature, 1963, 200,546 S . Clayton, G. V. R. Born and M. J. Cross,
Nature, 1963,200, 138 G. V. R. Born, Nature, 1964,202, 95 G . V. R
. Born, R. J. Haslam, M. Goldman and R. D. Lowe, Nature,
1965,205,678 G. V. R . Born, A. J . Honour and J . R. A. Mitchell,
Nature, 1964, 202,761 R. L. Thampson, M. L. Price, S. A. Minton, G.
B. Elion and G. H. Hitchings.J. Immunol., 1950,65 ,529
A. MONTGOMERY 121 R. W. Rundles, J . B. Wyngaarden, G. H.
Hitchings, G. B. Elion and H. R. Silberman, Trans. Assoc. Amer.
Physicians, 1963,16, 126 J. R. Klinenberg, S. E. Goldfinger and J.
E. Seegmiller,Ann. InternalMed., 1965,62, 639 D. L. Hill and P.
Chambers,J. Cell. Physiol., 1967,69, 321 G. W. Kidder and V. C.
Dewey,J. Biol. Chem., 1949,179, 181 G. W. Kidder and V. C.
Dewey,Arch. Biochem. Biophys., 1957,66,486 V. C. Dewey, G. W.
Kidder and D. G. Markees, Proc. SOC. Exp. Biol. Med., 1959, 102,
306 J . F. Fernandes and 0. Castellani, Exp. Parasitol., 1958,7,
224 M. Nakamura and M. B. James, Exp. Parasitol., 1953, 2, 19 L. H.
Silva, S. Yoneda and J. F. Fernandes, Exp. Parasitol., 1959,8,486
G. E. S. Moraes, J . L. Faria and J. F. Fernandes, Rev. Inst.
Med.Trop. SZoPaulo, 1960, 2,147 J. A . Meira, V. A. Neto, J. T.
Tartari and R. Sonntag, Rev. BrasilMed., 1954, 11,829 F.
Hawking,Experimental Chemotherapy (Ed. R. J. Schnitzer and F.
Hawking), Vol. 1: Academic Press, New York, 1963, p. 129 R. L.
Hewitt. W. S. Wallace, A. R. Gumble, E. R. Gill and J. H. Williams,
387. 388. 389. 390.
391. 392. 393. 394.
397. Med. Hyg., 1953,2,254 E. J. Tobie, Amer. J. Trop. Med.
Hyg., 1954, 3,852 E. J . Tobie and B. Highman, Amer. J. Trop. Med.
Hyg., 1956,5,504 J. J . Jaffe. Biochem. Pharmacol., 1961,8,216 R.
L. Hewitt. A. R. Gumble. L. H. Taylor and W. S. Wallace,
Antibiotics Annual, 1956-1 95 7 (Eds. H. Welch and F. Marti-Ibanez)
Medical Encyclopedia, New York, 1957, p. 722
402. E. J . Tobie, J. Parasitol., 1957, 43, 291 403. D. E. Eyles
and N. Coleman, Antibiot.Chemother., 1954,4,649 404. M. Nakamura
and S. Jonsson, Arch. Biochem. Biophys.1957,66, 183 405. G. H.
Hitchings, Ciba Found. Symp. Chem. Biol. Purines, 1957, 177 406. J
. J . Jaffe, Trans. N. Y. Acad. Sci., 1967,29, 1057 407. C. Friend,
Proc. SOC. Exp. Biol. Med., 1951,78, 150 408. H. R. Morgan, J. Exp.
Med., 1952,95,277 409. G. C. Brown,J. Imrnunol., 1952,69,441 410. J
. Cogniaux-Le Clerc, Brit. J. Exp. Puthol., 1962,43,587 41 1. J. W.
St. Geme,Proc. SOC. Exp. Biol. Med., 1964,116, 228 411a. F. M .
Schabel, Chemotherapy, 1968, 13, 321 412. M. P. de Garilhe and J.
de Rudder, C. R. Acad. Sci., Paris, 1964,259,2725 413. J. de Rudder
and M . P. de Garilhe,Anfimicrob. Agents Chemo., 1965,578 414. R.
W. Sidwell, G. Arnett and G. J . Dixon, Abs. 7th Interscience
Conference on Anti-
microbial Agents and Chemotherapy, Chicago, 1967, p. 28 415. T.
Sreevalsan and R. Z. Lockart, Virology, 1964,24,91 416. V. M.
Zhdanov and F. I . Ershov,Antibiotiki, 1965, 10, 255 417. V.
Groupe, F. J. Rauscher and W. R. Bryan, Science; 1956,1073 418. V.
Groupe, F. J . Rauscher and W. R. Bryan, Proc. SOC. Exp. Biol.
Med., 1956,91, 113 419. E. Wecker. Nature, 1963. 197. 1277 420. G.
A. Galegov and N. V. Kaverin, Experientia, 1967.23,83 421. A.
E..Farnham, Virology, 1965,27,73 422. H. Kudo and A. F. Graham,
Biochem. Biophys. Res. Commun., 1966,24,150 423. K. S. Pilcher and
J. N . Hobbs, J. Pharm. Sci., 1966,55, 119 424. A. A . Newton,
Biochem. J., 1965,94,9P 425. H. D. Mayor,J. Exp. Med., 1964,119,433
426. J . M. Bowen, R. G. Hughes and L. Dmochowski, Texas Rep. Biol.
Med., 1966, 24, 143 427. A. E. Moore and C. Friend, Proc. SOC. Exp.
Biol. Med., 1951, 78, 153 428. H. Neubauer, D. Falke and C.
Simonis,Arch. Ophthalmol., 1965,168,256 429. R. w. Sidwell, G. J .
Dixon, S. M. Sellers and F. M. Schabel, Appl. Microbiol., 1968,
398. 399. 400. 401.
430. 431. 432.
439a. 440. 441. 442. 443.
445. 446. 447. 448.
448a. 449. 450. 451.
THE BIOCHEMICAL BASIS FOR THE DRUG ACTIONS OF PURINES
K. Sugiura, Gann, 1959,50 ,251 K. Sugiura, Cancer Res. Suppl.,
1962,22 ,93 R. W. Sidwell, G . J. Dixon, S. M. Sellers and F. M.
Schabel, Cancer Chemother. Rep., 1966,50,299 E. A. Mirand, N. Back,
T. C. Prentice, J . L. Ambrus and J. T. Grace, Proc. SOC. Exp.
Biol. Med., 1961, 108, 360 M. A. Chirigos. Ann. N. Y. Acad. Sci.,
1965. 130,56 M. A. Chirigos, J. B. Moloney, S. R. Humphreys, N.
Mantel and A. Goldin, Cancer Res. 1961,21,803 J. P. Glynn, A. R.
Bianco and A. Goldin, Cancer Rex, 1964,24, 1303 A. Goldin, J. P.
Glynn, A. R. Bianco, J . M. Venditti and J. B. Moloney, Proc. 3rd
Inter. Congr. Chemotherapy, Stuttgart, 1963, p. 812; A. Goldin, J.
P. Glynn, J. B. Moloney, S. R. Humphreys and M. A. Chirigos, Acta
Unio Inter. Contra Cancrum, 1964,20, 157 C. A. Nichol, Cancer Res.,
1965,25, 1532 A. Giner-Sorolla, L. Medrek and A. Bendich, J. Med.
Chem., 1966, 9, 143; J. H. Burchenal, M. Dollinger, J .
Butterbaugh, D. Stoll and A. Giner-Sorolla, Biochem Pharmacol.,
1967,16 ,423 I. H. Krakoff and M. R. Dollinger,Proc. Amer. Assoc.
Cancer Res., 1969, 10 ,47 A. Giner-Sorolla and A. Bendich, J. Amer.
Chem. SOC., 1958,80, 3932 J. P. Howitz and V. K. Vaitkevicius,
Experientia, 1961, 17 ,552 F. R. White. Cancer Chemothcr. Rept.,
1963.30,57 J. A. Montgomery, C. Temple, T. P. Johnston F. M.
Schabel, unpublished observations J. A. Stock, Experimental
Chemotherapy Eds. R. J. Schnitzer and F. Hawking), Vol. 4: Academic
Press. New York. 1966, p. 80 G. Zubrod, Arch. Int. Med., 1960,
106.663 E. Frei and E. J. Freireich, Adv. Chemother., 1965,2, 269
J. K. Luce, G. P. Bodey and E. Frei, HospitalPractice, 1967,42 G.
P. Bodey, H. S. Brodovsky, A. A. Isassi, L. Samuels and E. J.
Freireich, Cancer Chemother. Rept., 1968.52, 315 K. Sugiura, Cancer
Chemother. Rept., 1968, 1, 383 J. H. Burchenal, Cancer Res.,
1963,23, 1186 H. E. Skipper, F. M. Schabel and W. S. Wilcox, Cancer
Chemother. Rept., 1964, 35.1 R. W. Brockman, M. C. Sparks and M. S.
Simpson, Biochim. Biophys. Acta, 1957; 26, 67 1 R. W. Brockman, M.
C. Sparks, M. S. Simpson and H. E. Skipper, Biochem.
1959,2,77 453. R. W. Brockman,G. G. Kelley, P. Stutts and V.
Copeman, Nature, 1961,191,469 454. P. Stutts and R. W.
Brockman,Biochem. Pharmacob, 1963, 12 ,97 455. R. W. Brockman,
CancerRes., 1963,23, 1191 456. R. W. Brockman,Clin. Pharmacol.
Ther., 1961, 2,237 457. G. P. Kalle and J. S. Gots, Science, 1963,
142,680 458. J. C. Adye and J. S. Gots,Biochim. Biophys. Acta,
1966, 118, 344 459. A. R. Paterson, Can. J. Biochem. Physiol.,
1960,38.1117 460. A. R. Paterson,Can. J. Bwchem. Physiol., 1962.40,
195 461. A. C. Sartorelli, G. A. LePage and E. C. Moore, Cancer
Res., 1958, 18, 1232; D. B.
Ellis and G. A. LePage, Cancer Res., 1963.23.436 462. A. L.
Bieber and A. C. Sartorelli, Cancer Res., 1964,24, 1210 463. L. L.
Bennett, P. W. Allan, D. Smithers and M. H. Vai1,Biochem.
18,725 464. G . G. Kelley, M. H. Vail, D. J. Adamson and E. A.
Palmer, Amer. J. Hyg., 1961, 73,
23 1 465. G. G. Kelley, G. P. Wheeler and J. A.
Montgomery,Cancer Res., 1962,22, 329
A. MONTGOMERY 123
466. P. M . Roll, H. Weinfeld, E . Carroll and G . B. Brown, J.
Biol. Chem.. 1956,220,439 467. J . A . Montgomery, F. M . Schabel
and H. E. Skipper, Cancer Rex, 1962, 22,504 468. J . A .
Montgomery, H . J . Thomas and H . J . Schaeffer,J. Org. Chem.,
1961, 26,1929 469. H . J . Thomas and J . A. Montgomery, J. Med.
Plzarm. Cllem.,1962,5, 24 470. J . A . Montgomery, G . J . Dixon,
E. A. Dulmadge, H . T . Thomas, R . W. Brockman and
H. E. Skipper, Nature, 1963, 199, 769 471. F . M . Schabel. W .
R . Laster and H . E. Skipper, Cancer Chemother. Rep. , 1967,51, 1
1 1 472. M . C. Wang, A . 1. Simpson and A. R. P. Paterson, Cancer
Chemofher. Rep. . 1967,51,
The Chemistryof Guanidines and their Actions at Adrenergic Nerve
Endings G. J. DURANT, B.Sc., Ph.D., A.R.I.C. Smith Kline and French
Research Institute, Welwyn Garden City, Herts.
A . M . ROE, M.A., D. Phil., F.R.I.C. Smith Kline and French
Research Institute, Welwyn Garden City, Herts.
A. L. GREEN, B.Sc., Ph.D. Department of Biochemistry, University
of Strathclyde, Glasgow.
INTRODUCTION THE STRUCTURE AND PHYSICAL PROPERTIES O F
GUANIDINES SYNTHETIC METHODS
Effect on blood pressure Effect on the sympathetic nervous
PHARMACOLOGICAL TEST PROCEDURES
STRUCTURE-ACTIVITY RELATIONSHIPS FOR ADRENERGIC NEURONE
Guanethidine and close analogues Aryloxyalkylguanidines and
related structures Araky lguanidines Miscellaneous guanidines
Structural requirements for adrenergic neurone blockade
OTHER PHARMACOLOGICAL EFFECTS ON SYMPATHETIC NERVES BIOCHEMICAL
Depletion of noradrenaline Antagonism of noradrenaline depletion
Effect of guanidines on enzymes involved in noradrenaline
metabolism Mechanism of guanethidine-induced depletion Relationship
between noradrenaline depletion and adrenergic neurone blockade
125 126 130 130
15 1 160
185 188 193 196 200 203
J . DURANT, A . M . ROE, A. L . GREEN. 125
Guanidines have been studied for many years as a possible source
of medically useful compounds, but the recent vast increase in the
literature on guanidine derivatives (from about 200 references in
Chemical Abstracts in 1958 t o over 1000 in 1965) stems principally
from the discovery [ I ] of the potent hypotensive properties of
guanethidine (oktadin, Azetidin, Dopom, Eutensol, Guanexil,
Guethine, Ipoctal, Ipoguanin, Iporal, Ismelin, Izobarin, Normorif,
Octadinum, Octatensine, Pressidin, Sanotensin, Su-5864, Visutensil,
Around 40 years ago, the short-lived use of synthalin (11) as a
hypoglycaemic drug [ 2 ] led t o numerous studies on guanidines as
potential insulin substitutes  . Synthalin itself was withdrawn
when it was reported that it can cause liver damage , and the
widespread interest in guanidines eventually lapsed until the
introduction of guanethidine nearly 30 years later.
It is chastening t o note how often during these early
investigations on guanidines, marked cardiovascular actions were
reported but not pursued. One such report referred t o
phenethylguanidine (111) in the following terms the latter
compound, in larger doses, exerts a powerful effect on the flow of
Ph(CH2 ) 2 .NH.C=NH I
evidenced by the difficulty of bleeding the animals: [ 5 ] .
Synthalin itself caused a fall in blood pressure, and also had
curare-like effects  which were subse- quently rediscovered in
the related compound decamethonium. However, since the object of
this early work was t o find drugs which lowered blood sugar rather
than blood pressure, these observations were apparently not
followed up. During the 1930s several aralkylguanidines were shown
by Japanese workers to lower blood pressure [7, 81, but the
mechanism of this hypotensive action was not understood a t the
time, and again it was not followed up.
Synthetic guanidine derivatives have been used successfully in
the treatment of a variety of diseases, but the major success has
undoubtedly been their exploitation as antihypertensive drugs.
Guanethidine has still not been displaced,
GUANIDINES A N D ADRENERGIC NERVE ENDINGS
although it now has many competitors such as bethanidine
(benzanidine, Esbatal,' Eusmanid, B.W. 467C60, IV), guanoxan
(Envacar, V), guanoclor (Vatensol, VI) and debrisoquine (Declinax,
VII). The comparative clinical value of some of these compounds has
been reviewed recently [ 9 ] .
All of these drugs appear to lower blood pressure by blockade of
nerves, and the present review is confined to this particular
aspect of the pharmacology of guanidines. The structure, physical
properties and synthesis of guanidines are summarized first, and
then, after an outline of the methods used for testing these drugs,
the relationships between structure and adrenergic neurone blockade
are discussed. The relevant biochemical effects connected with
these pharmacological actions are surveyed, with particular
reference to possible mechanisms of action. The review is written
primarily for the medicinal chemist, and detailed pharmacology is
generally included only where necessary for under- standing the
An excellent review of the pharmacological actions of adrenergic
neurone blocking agents has been given by Boura and Green [ l o ] .
The biochemistry of guanethidine itself has been reviewed by Furst
[ 1 I ] , with particular emphasis on tissuz distribution and
metabolism; consequently these two topics are not discussed i n
THE STRUCTURE AND PHYSICAL PROPERTIES OF GUANIDINES
A prerequisite t o a full understanding of tlie nature of tlie
interactions of guanidines with living tissue is an accurate
expression of the molecular and physico- chemical behaviour of both
interactants. The molecular arrangement, and hence
J . DURANT, A. M. ROE, A. L. GREEN. 127
the physicochemical properties, of the biological surfaces with
which this review is concerned are still unknown; but the position
with respect to the guanidine partner in these interactions is
reasonably well understood.
Guanidine (VIII) and those substituted guanidines with which we
shall be concerned are strong bases [12-191, and form stable salts
with relatively weak acids [ 201 . Table 3.1 lists the published
pK, values of some simple guanidines. The increased stability of
symmetrical guanidinium ions is reflected in the high basic
strength of guanidine and in the still higher basicity of
N,N:N':trimethyl- guanidine. In strong acid, both the guanidinium
ion and the aminoguanidinium ion can accept a second proton. The
second pK, of guanidine has been estimated [ 151
Table 3.1. THE BASlCITY OF SOME SIMPLE GUANIDlNES*
R' I t 2 R3 R4 RS P K ,
H H H H H H Me H H H Me H Me Me H H Me H Me Me Me Me Me H Me Me
Me H H H H H H Me H H H Me H H H H H H H H Ph H H H H
Guanethidine ( I )
H H H H H Me H Me Me H H H H H H H H
13.65 (131 13.6 (141 13.74  13.4 1141 13.4 1141 13.6 
13.6 [ 141 13.9 [ 141 13.6 1141 13.9 [ 141 13.8 [ 141 10.8 (171
11.0 1381 10.6 [ 3 7 ] 10.5 (381 12.6 (371 10.85 [ 371 11.4 1381
* 9.9  9.8 (4181 11.04 (4191 11.97 1211 11.3-11.4 
'The references should be consulted for the temperature and
other conditions under which these measurements were made.
to be -10.9 on the Ho scale. The very large difference between
the first and second pK, values of guanidine is thought to be
associated with the loss of symmetry which arises when the
guanidinium ion accepts another proton [ 151. The second pK, of
(benzy1amino)guanidine is -3.2 on the Ho scale .
GUANIDINES AND ADRENERGIC NERVE ENDINGS
When the pK, of a guanidine is greater than 13, the ratio of
guanidinium ion to guanidine is greater than 1 O6 : 1 under
physiological conditions  ; amino- guanidine will exist as the
protonated ion to the extent of at least lo4 : 1, relative to the
unprotonated species. In view of the foregoing, the ensuing
discussion will concentrate on the structure and properties of the
mono-protonated species, that is, on guanidinium ions.
There is ample crystallographic evidence that the guanidinium
ion is planar and symmetrical [23, 241. Both ions in the crystal of
methylguanidinium nitrate exhibit almost perfect trigonal symmetry
 , and the aminoguanidinium ion has also been shown to be
planar . The formal similarity between the guanidinium ion, the
carbonium ion, and the carbonate anion has long been recognized
, and many papers have been devoted to defining the precise
electronic structure of guanidinium ions [28-361.
Infra-red studies  and molecular orbital calculations
[33,34] have led to the description of the guanidinium ion as a
tri-amino carbonium ion with the nelectron charge distribution
shown (IX) Most of the positive charge is located in the vicinity
of the central carbon atom. The relevance of this description to
the pharmacological properties of guanidinium ions will be
discussed later. For typographical convenience, guanidines will be
formulated in this review in the unprotonated form.
, tO.086 Y
H\ rH H2N.C-H N- C+O .7L 2
/ 1 .318 \ N 4 /
I H N H2 (VIII)
Some aspects of the structure and properties of amidines,
including guanidines, in relation to their biological properties
have been discussed by Fastier [36a] . The formation of relatively
rigid amidinium carboxylate ion-, pairs, formulated as
eight-membered rings stabilized by two hydrogen bonds, is thought
to precede the formation of crystalline salts and is suggested
[36b, 36c] as the basis for their biologcal activity. An
alternative formulation of a guanidinium carboxylate ion-pair has
been proposed [36d]. The affinity of amidinium groups for anionic
sites, such as carboxylate and phosphate, has been stressed
The similarity of the guanidinium ion, in which the distance
between the carbon and the hydrogen atoms is about 2.1A, to the
hydrated sodium ion [Na(OH,),]+, in which the distance between the
sodium and the hydrogen atoms is about 2.3A, has been pointed out
[33, 36a], and the physiological
J . DURANT, A. M. ROE, A. L. GREEN. 129
properties of these ions have been compared [33, 36al. A
comparison, which is more relevant to this review and is pursued
later, may be made with the trimethyl- ammonium group. Finally, it
has been suggested  that the activities of certain
aryloxyalkylguanidines depend on their ability to adopt an
internally hydrogen-bonded conformation such as (LXXVIII) and
(LXXIX) (p. 172 ). The strength of the hydrogen bond in these
systems is related to the basicity of the oxygen atom, which in
turn is markedly affected by the position and nature of the
substituents in the aromatic ring.
Although not strictly relevant to the present discussion, some
other physico-chemical aspects of guanidines are summarized here,
since no review of this subject has been published previously.
The structures of aromatic guanidines and their conjugate acids,
in which the T-electrons of the ring can interact with the
delocalized electrons of the guanidine system, have been studied.
From the ultra-violet absorption spectra and acid dissociation
constants of pchlorophenylguanidine, structure (X) was preferred [
371 over structure (XI); in contrast, the most probable structures
for phenylguanidine and its conjugate acid were considered [ 171 to
be (XI) and (XII). A more extensive study of some para-substituted
phenylguanidines, which includes an estimate of the
Ar N H - G N H
1 ArN=C-NH2 ArNH-C=hH,
Hammett p constant (+ 2.30) for the formation of the conjugate
acid and the Up constant of the guanidinium substituent (+0'317 to
+ 0.443), supported the conclusion [ 3 M ] that the base has the
structure (X). A different view [ 391 was based on the fact that
since p for substituted anilines is + 2-77, dissociationof the
phenylguanidinium ion most likely takes place from the nitrogen
atom which bears the aromatic ring. This argument, however,
neglects the delocalization of charge in the ion. The directing
effect of the guanidinium substituent in electrophilic aromatic
substitution is a measure of the interaction of this substituent
with an aromatic ring. The guanidinium substituent is not such a
powerful meta- directing group as those substituents in which the
positive Charge is localized on the atom which bears the aromatic
ring  .
The ultra-violet spectra of guanidines have often been
determined in connection with the measurements of dissociation
constants [ 17, 38, 411, and other studies have been reported
[42-441. There have been many reports on the infra-red spectra [31,
35, 42, 45-48], the nuclear magnetic resonance spectra [ 38, 49-5 1
) (see also p. 134). the Raman spectra [52-541, force constants [
35, 361, and mass spectra [SS] of substituted guanidines.
Guanidine forms salts with such relatively weak acids as
nitromethane, phthalimide, phenol and carbonic acid  .
lnteractions between carboxylate anions of proteins and added
guanidinium ion are thought [19, 561 to be weaker than the
interactions with ammonium ions; the role of
guanidinium-carboxylate interactions in stabilizing natural protein
conformations has been discussed [36c]. A few reports of metal
complex formation by guanidines 157-601, and aminoguanidines 
CUANIDINES AND ADRENERCIC NERVE ENDINGS
Much attention has been given recently to the chromatographic
behaviour of guanidines [ 62-69), and various techniques for the
detection and determination of guanidines are described there and
elsewhere [ 70-761.
Guanidines have been prepared by a wide variety of methods, of
which two are of much greater importance than the others. These two
methods, (a) the addition of amines to cyanamides and (b) the
displacement of an alkylmercaptan by an amine from an
alkylisothiouronium salt, together with close variants, are
discussed first, and this discussion is followed by a survey of
less frequently used procedures.
Since an excellent summary of some of the methods that have been
used to obtain guanidines is available  , the following
discussion concentrates on those aspects of synthetic chemistry
that are likely to be of interest to medicinal chemists. Patents
are only cited when the experimental methods described supplement
those available elsewhere.
It is worth stressing at this point that although many
statements have been made concerning the relative merits of one
method of synthesis compared with another, there is little
consistency and much contradiction to be found. Except where a
comparative study by the same workers has been carried out, it is
unwise to rely on these generalizations as a guide for preparing
novel guanidines. It is probable that much of the confusion arises
from the use of inappropriate methods of isolation rather than from
Method (a) RzNH + RZN-CN + RZNGNH I
Guanidine itself was obtained by Erlenmeyer  in 1868 from
the action of ammonia on cyanamide, a method that soon led to the
synthesis of phenyl- guanidine from aniline hydrochloride and
cyanamide [79,80]. This method has been used to prepare many
arylguanidines, and the use of substituted cyanamides has given
NJdiary1-  , N-aryl-N-alkyl- (or N-aryl-N:N:dialkyl-) , and
N-aryl-Nbenzoyl-guanidines  . Arylguanidines are sometimes
advantageously prepared by using the benzoylguanidine as an
Reaction between an amine salt and cyanamide has been used
successfully for the synthesis of many mono- and
poly-alkylguanidines [84-95], and also of alkoxyguanidines [96, 971
and aryloxyguanidines . The reaction is usually carried out in
boiling water or ethanol for from 1 to 24 hours. Higher
temperatures have been employedusingsealed tubes [99, 1001 or
J. DURANT, A. M. ROE, A. L. GREEN. 131
Very dilute acetic acid [lo21 and ethyl acetate [lo31 have also
been used as solvents. The fusion of amine salts with cyanamide or
a substituted cyanamide is often more satisfactory than using a
solvent [ 107-109, 2281, particularly for sterically hindered
guanidines such as t-butylguanidine  .
The preparation of alkylguanidines by fusing amine salts with
dicyandiamide at 180" for three hours has been advocated ,
however it has been shown that, depending on the conditions, a
guanidine or a biguanide can result [105, 106).
Odo studied the formation of methylguanidine from cyanamide and
aqueous mixtures of methylaminc and methylamine hydrochloride in
various proportions [ 1101 . He concluded that the reaction
occurred by a reversible nucleophilic attack of the free amine on
cyanamide, and that an acid was required to shift the equilibrium
in the direction of the guanidine.
This method of formation of guanidines is considered especially
suitable for arylguanidines  . The dihydrochloride of
p-aminobenzylamine (XIII) reacted with cyanamide to give a
mono-guanidine which was assumed [ 11 11 to be the arylguanidine
(XlV) on the grounds that benzvlamine hydrochloride did not react
under the same conditions, whereas aniline hydrochloride did. An
isomer was obtained [ 1 1 1 ] when p-aminobenzylamine reacted with
S-methylisothiouronium sulphate, and this isomer was formulated as
(XV). However, these structural
assignments need verification. It is relevant to note that the
free base (XIII) reacted with cyanamide to give the bis-guanidine [
11 I ] . Further, guanidines have been obtained by reaction of
cyanamide with salts of benzylamine  and p-nitrobenzylamine
[87, 1011. The product from the latter was reduced [87, 1011 to
authentic p-aminobenzylguanidine (XV) dihydrochloride, which
decomposed only 3-5" above the reported [ 1 1 1 ] decomposition
point of the dihydrochloride of the isomer assigned structure
Method (b) RZNH + RzN.C=NR R2 N G N R I - I + H X
The most frequently used synthesis of guanidines involves the
displacement by an amine of a suitable group, X, from the
amidine-type compound shown.
The preparation of phenylguanidine from ammonia and
phenylthiourea was claimed [ 1 121 in 1879 but the authenticity of
the product has been questioned
GUANIDINES A N D ADRENERGIC NERVE ENDINGS
 . The generally recognized originator of this synthesis of
guanidines is Rathke who showed that ammonia reacts with
S-ethyl-N,N'-diphenylisothiourea to form N,N-diphenylguanidine [
1131 . That this product can be formulated in two ways:
PhNH.C(:NPh)NH, or PhNH.C(:NH)NHPh, was clearly recognized at that
time. Similarly, guanidine itself was obtained from
S-ethylisothiourea and ammonia [ 1141.
Although 0-ethylisourea was reported not t o react with ammonia
or with aniline [ 7 9 ] , the synthetic potential of this method
became apparent when various polymethylguanidines were prepared
from S-alkylisothiouronium hydr- iodides [ 14, 115, 1161 or, more
conveniently, from S-methylisothiouronium sulphate [ 14, 1171.
Aniline was reported not t o react with the latter salt [ 1171, but
a later paper [ 1181 described its conversion into
Many different alkvl- and awl-guanidines have been obtained by
this procedure [SS, 86, 1 1 1, 119-1321, as have alkoxyguanidines
[97, 1331, and benzoylguanidines [ 134, 1351 .
It is usual t o carry out the reaction in water or ethanol, or
in mixtures of the two, a