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8/18/2019 Journal of Medicinal Chemistry Volume 21 Issue 6 1978 [Doi 10.1021%2Fjm00204a013] Hansch, Corwin; Hathewa…
1/4
574 Jou rna l of Medicinal Chemistry, 1978, Vol. 21, No. 6
(13) (a ) Y. T. Lin, T. L. Loo,
S.
Vadlam udi, and A. Goldin, J .
Med . Chem., 15, 201 (1972); (b) W.
J.
Dunn 111, M. J.
Greenberg, and S.
S.
Callejas, ibid., 19, 1299 (1976).
(14) H. Druckrey, Xenobiotica,
3,
271 (1973).
(15) D. D. Bed, J. L. Ski bba , W. A. Croft, S. M. Cohen, and
G.
(16) D. J. Thompson, J. A. Molello, R. J. Strebing, and I. L. Dyke,
(17)
T.
M. Ong and F. J. De Serres, M ut at . Res., 20, 17 (1973).
18) E. Vogel, R. Fahrig, and G. Obe, Mu ta t. Res., 21,12 3 (1973).
(19) R.
Suss,
U. Kinzel, and
J.
D. Scribner, “Cance r”, Spring-
20)
C. Hansch, S.
H.
Unger, and A. B. Forsythe, J . Med. Chem.,
T. Bryan,
J .
Na tl. Cancer Inst. , 54, 951 (1975).
Toxicol. Appl. Pharmacol. , 33, 281 (1975).
er-Verlag, New Yo rk, N.Y., 197 3, p p 49-52.
H ansch e t a l .
16, 1217 (1973).
(21)
S.
L. Edwards, J.
S.
Sherfinski, and R. E. Marsh,
J .
Am.
Chem. SO C., 6, 2593 (1974).
(22) C. Hansch, R. N. Smith, and R. Engle in “Pharmacological
Basis of Cancer Chemotherapy”, Williams and Wilkins,
Baltimo re, Md., 1975, p 231.
(23) V. A. Levin, D. Crafts, C. B. Wilson, P. Kapra, C. Hansch,
E. Boldrey,
J.
En ot, and M. Neely, Cancer Chemother. Rep.,
59, 327 (1975).
(24) All new compounds prepared in the Pomona Laboratory
were tested in CDF mice by the NCI, qdl-9, using Klucel
as the vehicle. DTI C was used as a positive control; see
R.
I.
Geran, N. H. Greenberg,
M. M.
Macdonald, A. M.
Schumach er, and B. J. Abbott, Cancer Ch emother. Rep.,
3 (no. 2) (1972).
25) C. Hansch and T. Fujita, J . Am. C hem. SOC., 6,1616 (1964).
(26) G.
F.
Kolar and R. Preussmann,
2
Naturforsch. B, 26,950
(1971).
(27)
T.
Fujita,
J.
Iwasa, and C. Hansch,
J .
Am. Chem. SOC.,6,
5175 (1964).
(28) W. Haggerty, Midwest Research Institu te, unpublished
results.
(29) A. Leo, C. Hansch, an d D. Elkins, C hem. Rev., 71,525 (1971).
(30) C. Hansch, A. Leo, S. H. Unger, K. H. Kim, D. Nikaitani,
and E . J. Lien, J . Med. Chem ., 16, 1207 (1973).
(31) C. Hansch,
S.
D. Rockwell, P.
Y.
C. Jow,
A.
Leo, and E . E.
Steller, J . Med. Chem., 20, 304 (1977).
(32) A. Leo, P.
Y.
C. Jow, C. Silipo, and C. Hansch, J . Med.
Chem., 18, 865 (1975).
(33) C. Hansch, G.
J.
Hatheway,
F.
R. Quinn , and N. Greenberg,
J . Med . Chem ., following pape r in this issue.
Antitumor l-(X-Aryl)-3,3-dialkyltriazenes.. On the Role of Correlation Analysis
in Decision Making in Drug Modification. Toxicity Quantitative
Structure-Activity Relationships
of
l-(X-Phenyl)-3,3-dialkyltriazenesn Mice1
C o r w i n H a n s c h , * G e r a r d
J.
H a t h e w a y ,
Dep artm ent of Chem istry, Pomona College, Claremont, California 91 711
Frank R. Q u i n n ,
Laboratory of Medicinal Ch emistry and Biology, Developmental Therapeutics Program, Division of Cancer Trea tme nt,
National Cancer Ins t i tute , National Ins t i tutes of Health, Bethesda, Maryland
20014
and N a t h a n i e l G r e e n b e rg
Drug Evalu ation Branch, Developmental Therapeutics Program, Division of Cancer Treat men t, Nati ona l Cancer Ins titu te,
National Ins t i tutes of Health, Bethesda, Maryland 20014. Received Sep tember 23,
1977
A series of
11
triaze nes (X-C6H,N=NNRCH,) was char acter ized for toxicity in mice
(LD,,).
The quanti ta t ive
structure-activity relationship (QSAR) obtained for toxicity was comp ared with th e QSAR for antitum or activity.
Th e close correspondence of the two QSAR leaves essentially no means for th e synthe sis of more p oten t, less toxic
triazenes.
In the pr evious paper in th i s s e rie s, 2 eq 1
was
f or mula ted
l og 1 / C =
0.10
logP -
0.04
( l o g
P)’
-
0.31
E:*
-
0.18
MR-2 6
0.39
E -R 4.12
1)
=
61; r
=
0.836;s
= 0 . 1 9 1 ;
logPo
= 1.18
f o r t h e a n t i t u m o r a c t i v i t y of X-C6H4N=N-NR1R2 ac t ing
a g a i n s t
L E 1 0
l e u k e m i a i n m i ce .
C
i n e q
1
s t h e c o n -
c e n t r a t i o n ( m o l e s per ki logr am) pr oduc ing a T / C of 140,
MR-2,6
is the sum of
molar
r e f ra c t i v it y o f s u b s t i t u e n t s i n
the
two ortho
pos i t ions , and
E,-R
i s t h e T a f t s t e r ic pa-
r amete r f or the larger of
R1 and
Rz.
The
log Po of 1.18sets
the u p p e r l i m i t o f p o t e n c y w h i c h can be o b t a i n e d i n t h i s
s e r i e s b y m a n i p u l a t i o n o f
the
l i p o p h i l i c / h y d r o p h i l i c
ba lance . Essent ia l ly the same log Po was f o u n d f o r i m -
idazolyl- and pyrazolyl tr iazenes .2
The
o n l y a d v a n t a g e t o
be g a i n e d f r o m the MR-2,6 t e r m i s o b t a i n e d w h e n
both
0022-2623
,I
81 1821-0574$01.00/0
o r t h o p o s i ti o n s
are
u n s u b s t i t u t e d . For pr ac t ica l pur poses ,
t h e E,-R
te rm
l i m i t s o n e t o t h e N ( C H & s i nc e NHCHB
c o m p o u n d s a r e so unstable.
A t f i r s t g l a n c e , o n e
presumes that
m o r e a c t i v it y c o u l d
be o bta ined by in t r oduc ing mor e e lec t ron- re leas ing gr oups
( large negative Zu’); however, the
QSAR
of eq 2 effectively
log k x / k ,
= -4 .42
-
0.16
=
14;
r = 0.995; s = 0.171
l i m i t s t h i s a v e n u e .
E q u a t i o n 2 c o r r e l a t e s t h e r a t e o f
hydr o lys i s o f phenyl t r i azenes .2 Th is i s
so
e n o r m o u s l y
p r o m o t e d b y e l e c t r o n - r e l e a s i n g g r o u p s
that
i t i s not
poss ib le in pr ac t ice to go beyond th e 4- O CH 3 ( hal f -l i fe =
1 2 m i n ) i n the use of e lec t r on- r e leas ing f unc t ions .
At-
t e m p t s to i n c r e a s e p o t e n c y t h r o u g h s t e r i c a n d / o r h y -
dr ogen- bonding e f f ec t s o f o r tho subs t i tuen ts have r eached
978 American Chemical Society
8/18/2019 Journal of Medicinal Chemistry Volume 21 Issue 6 1978 [Doi 10.1021%2Fjm00204a013] Hansch, Corwin; Hathewa…
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Ant i tumor 1
X-Aryl ) -3 ,3 -d ia lkyl t r iazenes .
2
Table I. Constants for LD,, vs. Rats of
X-C,H,N= N-N(CH,),
115
log
og
1 c
X Obsd Calcdb l/Cl LogPC
u
4-NO, 2.06
2 . 15 0 . 09
2 . 7 1 0 . 7 9
H 2.54
2 . 4 9 0.05
2 . 5 9 0.00
4-CH3 2.62
2 . 7 4 0 . 1 2
2 . 9 3 - 0 . 3 1
4-I 2.68
2 . 75 0 . 07
3 . 7 0 0 . 1 4
4-C1 2.71
2 . 65 0 . 06
3 . 3 3 0 . 1 1
4- F 2 . 71
2 . 5 5 0 . 1 6
2 . 67 -0 . 07
4-OCH, 2 . 7 2 2 . 7 8 0 . 0 6 2 . 30 -0 . 78
4-Br 2.73
2 . 68
0 . 0 6
3 . 4 8 0 . 1 5
calculated using eq 7 in ref 2 except for the experimen-
tally determined value for the unsubstituted compound.
a From ref 3. Calculated using eq 4.
Log P values
Table 11.
Constants for LD,, vs. Mice of
H
IA log
og 1 / c
R Obsd Calcdb l /C l L og P
Methyl 2.44
2 . 4 1 0 . 0 3 - 0 . 2 4
Ethy l 2 . 75
2 . 6 3 0 . 1 2
0 . 7 6
Propyl 2.70 2 . 86 0 . 16
1 . 7 6
Butyl 2 .91 3 . 08 0 . 17
2 . 1 6
Pentyl 3.49
3 . 3 1 0 . 1 8 3 . 7 6
a From ref 4.
Calculated using eq 5.
the point where no obvious opportunities present them-
selves for exploitation.
T he single remaining ro ute to more effective triazenes
appeared to be th at of decreasing their toxicity and thereby
obtainin g congeners with better therapeutic ratios. Th e
purpos e of this re port is to consider th is possibility.
Tw o previous studies3v4 f toxicity of triazenes hav e been
reporte d; however, both suffer seriously from a poor se-
lection of derivatives. We have formulate d eq
3-5
from
LD r a t s of X - C 6 H 4 N = N N ( C H 3 ) 2 Tab le I )
log
1/C
-0 .355 k0.36)
U +
+
2.60
k0.15)
= 8; =
0.698 ;
s =
0.175;
Fl x=
5.71
log
1 / C
=
-0 .47 k0 .27)
U*
0.29 k0.24)
l o g P
n = 8; r =
0.906 ;
s
= 0.113; , , x =
9.22
LD mice4 of
[x
( Tab le 11)
l o g
1/C 0.23 k0.19)
l o g P
2.46 k0.42)
n
= 5 ;
r
=
0.912; s
=
0.185;
F , , x =
19.8
the da ta presented in these two s tudies . Th e data upon
which eq
3
an d
4
rest (Table
I)
contain a good spread in
u
of substituents but a poor spread in log P values.
Equat ion
3
indicates that the electronic term is most
impo rtant. Th e confidence limits on the log P term in eq
4
are broad so th at we cannot place much confidence in
this term. Adding a term in (log P 2 oes not improve
things. About all tha t one can conclude from eq 3 and 4
is tha t electron-releasing groups increase toxicity a nd t ha t
u
gives a slightly bette r correlation th an
u,
suggesting a
role for through resonance. T he results with the imida-
zolyltriazenes (Table
11)
are also of little value because of
the confidence limits on the log P te rm and the few data
points.
We have now determined the LD50 values for 11 phe-
3 )
1 .75 k0 .73) 4 )
CONH2
N = N N ( R ) 2
H
5)
Journal
of
Medicinal C hemistr y, 1978, Vol. 21, No. 6
575
Scheme I
/ microsomal
C,H.N=N-N
\
oxidation
C,H,N= NN
-+ C , H , N = N N H CH ,O
\
proximal
W O H ca rcin ogen
H l O
CH: [HO N=N CH ,] C,H,NH, ,H,NHN =NC H,
nyltriazenes. In this set of
11
congeners, we have included
compo unds with a wide range of log P values (0.98-4.70),
as well as a good sprea d in u values
(-0.78 t o 0.66).
Results
Equat ions 6 an d 7 have been derived from the d ata in
log 1/C - 0.0283 k0.02) ( log
P ) 2
n
=
;
r = 0.731 ; s = 0.174; F1,x = 10.31
log
1/C
=
0.0241 k0 .013)
( log
P ) 2
-
7 )
=
11;
r =
0.913;
s = 0 110; , 9 x=
14.3
Table 111 on the LD50 of phenyltriazenes for mice.
Equat ion 7 is a significant improvement over the best
single-variable equation, eq 6
F1,9;u=0.01
10.6;
F1,8;u=0.01
=
11.3). Subs t i tu t ing
u
for
u
gives the same quality
correlation
r = 0.910).
Adding
a
term in log
P
to eq
7
does
not afford a significant reduction in the variance. C n
the se equations is the concentration producing th e LD,.
Log Po represents the ideal Iipophilicity for the most toxic
compound; since its value is 0, making congeners eith er
more or less lipophilic would reduce their toxicity in terms
of th e LD,; however, because of the sma ll coefficient with
this t erm , significant changes are afforded only by large
changes in log P. For example, substitu ting log P of 6 in
eq 7 (with
u =
0) yields log 1/C
=
2.6; substituting log
P of 6 in eq 1 (with
u =
0, MR-2,6
= 0.2,
E,-R
=
-1.24)
yields log 1 / C of 2.7; therefore, the therapeutic ratio is 1.04.
Doing the same with log P of 1 (ideal log P for potency)
yields a thera peu tic ratio of 0.95;hence, there is virtually
nothing to be gained therapeutically by the manipulation
of log P. Furthermore, not only do the
u+
terms of eq 1
and 7 cancel each other as far as th e thera peutic index is
concerned but, in addition, eq 2 tells us that trying to
increase potency by using substituents more electron
releasing than 4-OCH3 will simply produce drugs too
unstab le with which to work. All path s appear to be
blocked to bette r drugs in th is series.
Discussion
In order t o assess more clearly what remains to be done,
it behooves us a t this point in our analysis to take a
broader view of the w ork which has been done with tr i-
azenes. Although th e antitum or activity of the triazenes
was discovered5 in
1955
and a large am oun t of work has
been done with these substances in the pas t
2
years, the
mechanism of their antitumor action is still poorly un-
derstood. Since the triazenes ar e also carcinogenic, a
considerable effort has been m ade to establish how they
react in mammals.
Preus sma nn an d his colleagues6 mad e one of the first
3.483 k0 .18) 6)
0.264 k0.16)
u
3.490 k0.12)
8/18/2019 Journal of Medicinal Chemistry Volume 21 Issue 6 1978 [Doi 10.1021%2Fjm00204a013] Hansch, Corwin; Hathewa…
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576
Journal of Medicinal Chemis try ,
1978,
Vol. 21 No. 6
Hansch e t
al .
Table 111.
Cons tan ts for LD,, of X-C,H,N=NNCH,R vs. CD F, Mice
IA log
og
1/c
X R Obsd Calcd
1/c
Log P
U
NSC no.
4 - N H C ( = O ) N H 2
CH3 3.68 3 .63 0 .05
1 . 2 5
4- O CH 3
CH3 3.5 5 3.57 0.0 2 2.30'
4-CONH,
C,H,
3 .46 3 .25 0.21 2.46
3 .43 3 .33
0.10 2.59
3.32 3.36
0.04 1 . 2 0
3 .26
3.37 0.11 2.93'
3.24 3 .33
0 .09 1 .70
3.20
3 .18 0 .02 2 .39
3.05
3 .00 0 .05 3 .6ga
2.80
2.87
0 .07 4 .70
H CH3
4-CONH2 CH,
4-CH3 CH3
4- CO N H 2 C*H ,
4- SO 2N H , CH , 3 .20 3 .32 0 .12 0 .98
4-CN CH3
4-CF3 CH,
4 - C O N H 2 C P , ,
DTIC 2.68 -0.24
' og P calculated us ing techn iques and eq
7
in ref 2.
Table IV. Activi ty against L1210 Leukemia
Dose, Activity NSC
C o m p d m g / k g V / C ) n o .
1
1 2 7 5 2 3 7 1
O.J,,N=N~(C~H '*
3 2 1 4 5 7 5 9 4 7
c
KCHb
2 5 0 126 4 0 6 8 0 1
N= U
CH3 N = N N m O
20
1 2 4 1 2 3 1 5 1
WCH,
NINN(C2H512
4 5 0 1 4 1 1 3 6 0 7 4
studies of the action of microsomes on the simple phe-
nyltriazene I. They postulated t he following mechanism
I
for the generation of carbonium ions which they con sidered
to be the carcinogenic agent (Scheme I). Th ey also
suggested that the monomethyltr iazene is the actual
proximal carcinogen.
They showed that, under their
experimental conditions, HN (CH 3)2was not dealkylated
by microsomes and the benzene diazonium ion was not
reduced to aniline; this was interp reted to mean th at any
C6H 6N2 + roduced via hydrolysis is not the active carci-
nogen. Th eir belief tha t CH3+ is the active moiety is
supported by the findings that triazenes alkylate DNA and
RNA in vitro and in vivo to produce 7-m ethylguanine and
other methylated nucleic acid bases. ̂ ^ C6H5N=N-NH-
C2H6produces 7-ethylguanine. An impor tant difference
between carcinogenicity and antitumor action of the
triazenes is that C 6H 5N= NN (C2H ,), is carcinogenic but
-0.69
- 0 .78
0 .36
0.00
0.36
- 0 .31
0.36
0.57
0.66
0.61
0.36
2 6 8 4 9 2
5 1 5 4 6 0
8 7 4 2 9
3 0 9 4
8 6 4 4 1
4 8 8 2 1
2 7 6 3 7 5
1 5 7 0 3 0
1 5 7 034
1 5 7 0 3 3
2 7 6 7 4 1
4 5 3 8 8
has been reported as having no antitumor activity
(however, see below). Th is suggests tha t Schem e I may
not be the m echanism responsible for antitumo r activity.
Another confusing finding of Preu ssm ann an d Hengy6
is that dealkylation occurred with liver or lung microsomes
bu t not with brain or kidney microsomes; yet triazenes do
not cause liver or lung cancer but do produce brain and
kidney tumors. They suggested tha t the intermediates
[ C 6 H5 N=NN( C H3 ) C H2 0 H o r C 6 H5 N=NNHC H3 ] a r e
produced in the liver and the n transpo rted to other parts
of the body where they decompose to produce carbonium
ions. The y found tha t the half-life of C6H5N=N NHC H3
a t p H 7.4 and 37 C in the presence of serum is 6 min;
while this m ight explain tum ors in other p arts of the body,
it is indeed strange tha t liver tumors a re not found. Since
triazenes alkylate guanine, it may be tha t guanine, in some
stage of D NA synthesis, is more exposed to alkylation t han
in liver tissue.
Pitt i l lo et ala9 ound th at in bacterial cells, DTIC
[4-
(3,3-dimethyl-l-triazeno imidazole-5-carboxamide]s more
effective in inhibiting dividing cells than resting cells (>56
to 1). In this respect
it
differs from alkylating agen ts such
as nitrogen mustards, which are only three times as ef-
fective against dividing cells, and C1CH2CH2N(NO)CO-
NHCH ,CH,Cl, which is only 13 tim es more effective
against dividing cells. Again, the evidence points ou t that
triazenes do n ot behave as ypical alkylating agents in their
antitum or activity.
Geru lath e t al.1° have stud ied the effect of DT IC with
reference to the phases of the cell cycle in Chinese ham ster
ovary cells in vitro. Th ey conclude tha t DT IC kills cells
most effectively in t he G1 an d early S phase and tha t
it
is only moderately lethal to cells in other p hases of the cell
cycle. Thi s evidence in mammalian cells also supports a
different mode of action of DTIC from typical alkylating
agents.
Hrad ec and Kolar'l have shown th at various triazenes
promote t he formulation of aminoacyl-tRNA in cell-free
systems. Th is was also found for other carcinogens.
A recent report by Connors e t al.12 suggests tha t th e fact
that substituents in the phenyltr iazene series may be
strongly electron releasing or withdrawing has little or no
effect on antitumor activity of phenyltriazenes acting
against TL X 5 lymphoma. Th is, of course, is not in line
with our findings on
L1210
leukemia or Dunn et al.13
findings on Sarcom a
180
tumor. In addition to noting that
the electronic effect of ring substituents had no effect on
antitumor activity, Connors et al. concluded, as others
have, tha t an NC H3 group is essential for activity. Data
in Table IV from th e N ational Cancer Ins ti tute indicate
tha t this point is not yet sett led.
Another conclusion of Connors et al. is that when
a
8/18/2019 Journal of Medicinal Chemistry Volume 21 Issue 6 1978 [Doi 10.1021%2Fjm00204a013] Hansch, Corwin; Hathewa…
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Ant i tum or 1- X-Aryl) -3,3-dialkyl tr iazenes . 2
methyl group and a larger alkyl group are on the 3-nitrogen
atom , the larger alkyl group is more rapidly dealkylated.
Th eir own work shows th at N (E & is dealkylated only half
as f ast a s N(C H3) 2. McMahon’s work,14 which has been
treated in QSAR terms,15 shows t ha t N-dem ethylation
occurs in preference t o dealkylation of larger alkyl groups.
If
the larger group were always dealkylated more rapidly,
the n one might surmise th at t he biologically active species
is the C H3+ fragment; the results in T able IV do n ot
suppor t th is .
In sum mar y, we can say that neither t he mechanism of
ant itum or activity nor the m echanism of carcinogenicity
of the triazenes is well understood; however, there is no
doubt that these compounds are both quite toxic in a
nons pecific model (LD50) an d highly carcinogenic. Since
we have not been able to separ ate the structura l features
for toxicity from those for efficacy, there is little supp ort
to encourage further work on triazenes
as
antitumor agents.
Dunn13 has also concluded t ha t “...the separatio n of toxic
and antitum or activities would be difficult...” on the basis
of two QSAR, one for efficacy and one for LD5o.
One mig ht argue that m ost of our evidence in sup por t
of discontinuing work on triazenes comes from the X-
C6H4N=NN< series and that exploration of aromatic
heterocycles m ight uncover new leads. While there is no
absolute way to refute this argum ent, the
QSAR
for py-
razolyl- and imidazolyltriazenes2does not suggest any leads
in this direction. In addition, Hutchinson16has shown that,
as far as increased survival time in mice is concerned,
DTIC, C6H5N=NN(CH,), , and C6H5N =NNH CH3 all
gave the sam e increase in life span, although ab out three
times as much D TIC was needed. Thi s follows from its
suboptimal log
P
and t he relatively greate r electronega-
tivity of the imidazole ring compared with the phenyl ring.
The important element is the electronic factor s ince
phenyltr iazene has a superop timal log P value.
Since there a re almost an infinite number of conceivable
aryltriazenes, it is impossible to s tate now, or even after
several thousand more congeners have been made and
tested, tha t a better derivative cannot be found. However,
it is our belief tha t there a re many much more interesting
lead compounds for antitum or activity in which it would
be more profitable to invest one’s resources. Unless one
had new biochemical or molecular biological information
suggesting that a new triazene might be more effective in
some specific way, we would not recomm end the synthesis
and testing of new congeners.
Journal of Medicinal Chemistry, 1978,
Vol.
21 No. 577
Method
Th e log P values and u constants used in this study are
the same as those in paper 1 n this series.2
Th e drug adm inistra tion regimen for determination of
LDWvalues consisted of daily injections on days 1-9.17 Th e
LDWvalues were calculated by plotting percent mortality
vs. log dose utilizing th e pr obit method.I8
References and Notes
1) This research was suppo rted by the F. J. Robbins Research
Fun d a nd by C ontract N01-CM-67062 from t he Division of
Cancer Treatment, National Cancer Institute, National
Institutes of Health.
(2) G.
J.
Hatheway, C. Hansch, K. H. Kim,
S.
R. Mils tein, C.
L.
Schmidt, and R. N. Smith, J .
Med. Chem. ,
preceding
paper in this issue.
(3)
0.
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