Research Article Synthesis, Structural Characterization ...downloads.hindawi.com/journals/bca/2014/916361.pdfResearch Article Synthesis, Structural Characterization, and Evaluation

Research ArticleSynthesis Structural Characterization and Evaluation of theBiological Properties of Heteroleptic Palladium(II) Complexes

Hizbullah Khan1 Nek Daraz1 Muhammad Nasim Khan2 Muhammad Said3

Nosheen Akhtar1 Amin Badshah4 Amir Sada Khan15 and Murad Ali2

1 Department of Chemistry University of Science and Technology Bannu 28100 Pakistan2Department of Chemistry Kohat University of Science and Technology Kohat 26000 Pakistan3Department of Chemistry Abdul Wali Khan University Mardan 23200 Pakistan4Department of Chemistry Quaid-i-Azam University Islamabad 45320 Pakistan5 PETRONAS Ionic Liquid Centre Department of Chemical Engineering Universiti Teknologi PetronasSeri Iskandar 31750 Tronoh Perak Malaysia

Correspondence should be addressed to Hizbullah Khan hizbmarwatyahoocom

Received 6 May 2014 Revised 15 July 2014 Accepted 18 July 2014 Published 7 September 2014

Academic Editor Francesco P Fanizzi

Copyright copy 2014 Hizbullah Khan et alThis is an open access article distributed under the Creative CommonsAttribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Five heteroleptic palladium(II) complexes of the general formula Pd(PR3)(tu)Cl

2 where PR

3= triphenylphosphine (1) diphenyl-o-

tolylphosphine (2) diphenyl-p-tolylphosphine (3) diphenyl-t-butylphosphine (4) and diphenyl-o-methoxyphenylphosphine (5)and tu = 13-bis(2-methoxyphenyl) thioureaThey all have been synthesized and characterized by various spectroscopic techniques(elemental analysis FTIR and 1HNMR and the ligand 13-bis(2-methoxyphenyl) thiourea was synthesized by single crystal X-raydiffraction technique) The synthesized compounds were screened for their antibacterial activity against four strains of bacteria(Escherichia coli Shigella flexneri Staphylococcus aureus and Bacillus subtilis) The antitumor potential was evaluated in terms ofactivity against brine shrimp eggs andDNA interactionThemixed ligand complexes have exhibitedmoderate antibacterial activityand promising antitumor potential

1 Introduction

Metals medicinal applications are almost several hundredyears old But due to the lack of experience of pharmacologistsand traditional medicinal chemists in dealing with biologi-cally active metal complexes the field of metal-based drugscould not flourish at the desired rate However it providesan opportunity to transition metal chemists to establish thedevelopment of exciting new drugs [1ndash5] With the improve-ment in the understanding of metalloprotein function someoutstanding models of metal ion active sites and recentadvances in discovering how naturally occurring metal ionsare delivered to these active sites and how metal ions arecomplexed in the reduction of some diseases specify newroles for metal ions in curative strategies [6ndash10] Althoughsome nonmetal species like tamoxifen and taxol also showbiological functions it is clear that a major role is played by

metal ions in biochemical process Metal ions are consideredto exert an inductive effect by coordination to the site ofreaction and they work as reduction-oxidation sites thatfunction either through electron or atom transfer [11ndash14]The present development of successful metal based pharma-ceuticals which include the platinum anticancer drugs andradiodiagnostic agents shows the usefulness of complexes asboth diagnostic and therapeutic agents [15ndash19] Cancer is oneof the diseases that are responsible for the high death rateglobally Consequently there has been a great need for contin-uous research to synthesize new drugs to control this disease

During the mid-1970s initial antitumor studies with cis-diamminedichloroplatinum(II) (cisplatin) indicated signifi-cant activity against some of the cancer cell-lines especiallyleukemia L1210 tumors Cisplatin remains to be the mosteffective drug in clinical treatment for ovarian testicularbladder head and neck cancers In combination with other

Hindawi Publishing CorporationBioinorganic Chemistry and ApplicationsVolume 2014 Article ID 916361 7 pageshttpdxdoiorg1011552014916361

2 Bioinorganic Chemistry and Applications

H3CO

2H2N CS2

OCH3OCH3

H2S

HN NH

S

C

++273K 6-hr stirring

n-hexane

Scheme 1 Synthesis of the substituted thiourea

anticancer drugs such as doxorubicin and 5-fluorouracil itis widely used in treatment of neck cancer However thereis a built-in and acquired resistance that limits the clinicalusefulness of the drug Platination of DNA is considered tobe responsible for the antitumor activity of various platinumcontaining drugs through bonding to guanine [20 21]Palladium(II) analogues are structurally similar to those ofPt(II) complexes which have a very similar coordinationgeometry and coordination process [22ndash24] Generally Pt(II)complexes are less stable than Pd(II) compounds ThereforePd(II) systems are frequently used as model complexes [25]Pd(II) binding to the guanine ring has been proposed fromIR and NMR data in several models The models revealcoordination with C=OndashPdndashN

7bridge between adjacent

guanine rings and chelation through N7and C=O of a

guanine ring [26]We report here the synthesis spectral characterization

and biological activities of the heteroleptic Pd(II) complexesof the general formula Pd(PR

3)(tu)Cl

2 where PR

3= triphen-

ylphosphine (1) diphenyl-o-tolylphosphine (2) diphenyl-p-tolylphosphine (3) diphenyl-t-butylphosphine (4) and di-phenyl-o-methoxyphenylphosphine (5) tu = 13-bis(2-me-thoxyphenyl) thiourea

2 Experimental

21 Materials and Methods Ethanol methanol n-hexanefish sperm DNA dichloromethane chloroform carbon di-sulfide and PdCl

2 sea salt and brine shrimp eggs were ob-

tained fromMerck Germany and Sigma-Aldrich All the sol-vents and chemicals were of analytical grade and were usedas received without further purification

22 Synthesis of the Substituted Thiourea Substituted thiou-rea was synthesized by the reaction of o-methoxyphenyl-amine with carbon disulphide (2 1) respectively at 273Kelvin in n-hexane as shown in Scheme 1 by the reportedliterature method with slight modification [27] The reac-tion mixture was magnetically stirred for six hours andthe reaction progress was continuously monitored by thinlayer chromatography The solvent was evaporated under thereduced pressure and the light brown solid was dissolvedin a mixture of dichloromethane and n-hexane (2 1 vv) forrecrystallization Needle shaped light brown crystals wereobtained by the slow evaporation of the solvents at roomtemperature and a suitable crystal was separated for singlecrystal diffraction analysis

23 Synthesis of the Complexes (1ndash5) Themixed ligand Pd(II)complexes were synthesized in two steps [28] In the firststep Pd-organophosphine complex was formed by reactingorganophosphine ligand dissolved in acetone with palla-dium chloride dissolved in dry methanol and few dropsof concentrated hydrochloric acid in 2 1 molar ratio Thesolid golden yellow product was obtained by evaporating thereaction mixture at reduced pressure In the second step thegolden yellow product was dissolved in dichloromethane andwas reacted with 13-bis(2-methoxyphenyl) thiourea solutionin dichloromethane in 1 1 molar ratio The final heterolepticPd(II) complex was obtained by rotary evaporation of thereaction mixture

231 [Pd(13-bis(2-methoxyphenyl) thiourea)(PPh3)Cl2] (1)

Quantities usedwere 032 g (047mmol) of Pd(PPh3)2Cl2and

015 g (047mmol) of 13-bis(2-methoxyphenyl) thiourea in25mL of dichloromethane Yield 029 g (87) Mp 231-232∘C FTIR (powder cmminus1) 3316 120592(NndashH) 1122 120592(CndashN) 622120592(C=S) 2831 120592(CndashH aliphatic) and 2943 120592(CndashH aromatic)1H NMR (300MHz CDCl

3) 120575-ppm 372 (s 3H ndashOCH

3)

405 (s 2H ndashNH) and 635ndash759 (m 23H ArndashH) Anal Calcfor C33H31Cl2N2O2PPdS C 5445 H 429 N 385 S 440

Found C 5450 H 426 N 387 S 440

232 [Pd(13-bis(2-methoxyphenyl) thiourea)(PPh2-o-tolyl)

Cl2] (2) Quantities used were 035 g (047mmol) of Pd

(PPh2-o-tolyl)

2Cl2and 015 g (047mmol) of 13-bis(2-me-

thoxyphenyl) thiourea in 25mL of dichloromethane Yield030 g (85) Mp 237-238∘C FTIR (powder cmminus1) 3313120592(NndashH) 1022 120592(CndashN) 633 120592(C=S) 2832 120592(CndashH aliphatic)and 2942 120592(CndashH aromatic) 1H NMR (300MHz CDCl

3) 120575-

ppm 233 (s 3H ndashCH3) 375 (s 3H ndashOCH

3) 400 (s 2H

ndashNH) and 633ndash763 (m 22H ArndashH) Anal Calc for C34

H33Cl2N2O2PPdS C 5503 H 448 N 378 S 432 Found

C 5510 H 447 N 378 S 433

233 [Pd(13-bis(2-methoxyphenyl) thiourea)(PPh2-p-tolyl)


(PPh2-p-tolyl)



3)

120575-ppm 234 (s 3H ndashCH3) 370 (s 3H ndashOCH

3) 402 (s

2H ndashNH) and 630ndash765 (m 22H ArndashH) Anal Calc for

Bioinorganic Chemistry and Applications 3

C34H33Cl2N2O2PPdS C 5503 H 448 N 378 S 432

Found C 5509 H 444 N 377 S 429

234 [Pd(13-bis(2-methoxyphenyl) thiourea)(PPh2-t-butyl)


(PPh2- t-butyl)


thoxyphenyl) thiourea in 25mL of dichloromethane Yield027 g (81) Mp 269-270∘C FTIR (powder cmminus1) 3321120592(NndashH) 1023 120592(CndashN) 647 120592(C=S) 2831 (CndashH aliphatic)and 2945 120592(CndashH aromatic) 1H NMR (300MHz CDCl

3)

120575-ppm 242 (s 9H ndashC(CH3)3) 369 (s 3H ndashOCH

3) 401

(s 2H ndashNH) and 637ndash735 (m 18H ArndashH) Anal Calcfor C31H35Cl2N2O2PPdS C 5258 H 498 N 396 S 452

Found C 5249 H 497 N 396 S 451

235 [Pd(13-bis(2-methoxyphenyl) thiourea)(PPh2-o-metho-

xyphenyl)Cl2] (5) Quantities used were 036 g (047mm-

ol) of Pd(PPh2-t-butyl)

2Cl2and 015 g (047mmol) of 13-

bis(2-methoxyphenyl) thiourea in 25mL of dichlorometh-ane Yield 030 g (84) Mp 252-253∘C FTIR (powdercmminus1) 3328 120592(NndashH) 1022 120592(CndashN) 636 120592(C=S) 2835 120592(CndashHaliphatic) and 2946 120592(CndashH aromatic) 1H NMR (300MHzCDCl


3) and 401 (s 2H ndashNH)

Anal Calc for C31H35Cl2N2O2PPdS C 5387 H 439 N

370 S 423 Found C 5375 H 438 N 369 S 420

24 Structural Study of the Ligand 13-Bis(2-methoxyphenyl)Thiourea The crystal structure of the thiourea derivative wasdeveloped by the evaporation method from the solvent ofmethanol Colorless needle shaped crystals were obtainedafter slow evaporation of the solvent from a methanolic solu-tion of the ligand at room temperature The needle shapedcrystal was mounted on a glass fiber using epoxy glue Themeasurements were made at 293K on a Bruker APEX II areadetector diffractometer equipped with graphite monochro-matic Mo-K120572 radiation (071073 A) The programme usedfor retrieving the cell parameters and data collection wasAPEX [29] The data were integrated using the programmeSAINT [30] and were corrected for Lorentz and polarizationeffects The structure was solved and refined using SHELXS-97 and SHELXL-97 [31] All the non-H atoms were refinedanisotropically The hydrogen atoms were placed at theidealized positionsThe crystal data and structure refinementparameters are shown in Table 1

25 Biological Assays

251 Antibacterial Assay All the synthesized metal com-plexes were investigated for their antibacterial activity againstfour strains of bacteria (Escherichia coli Shigella flexneriStaphylococcus aureus and Bacillus subtilis) The agar welldiffusion method [32] was used to determine the inhibitionzone and minimum inhibitory concentration (MIC) Brothculture (070mL) containing ca 106 colony forming units(CFU) per mL of the test strain was added to 70mL of nutri-ent agar medium at 45∘C mixed well and then poured into a14 cm diameter sterile petri plate The media was allowed tosolidify and 8mm wells were dug by a sterile metallic borer

Table 1 Crystal data and details of the structure refinement of theligand 13-bis(2-methoxyphenyl) thiourea

Molecular formula C15H16N2O2SMolecular weight 28836Space group C2c

Cell lengths (A)a 14442b 13032c 16187

Cell angles (∘)120572 9000120573 10389120574 9000

Cell volume (A)3 295744

Z Z1015840 Z 8Z1015840 0

119877-factor () 291Temperature 293(2) KWavelength 071073 A

DMSO test sample (100 120583L) at 1mgmL was added to therespective wells DMSO was acting as a negative controlwhile the standard drug Imipenem (10120583gdisc) was used as apositive control Triplicate plates of each bacterial strain wereprepared and incubated aerobically at 37∘C for 24 hours Theactivity was determined by measuring the diameter of zone(mm) with the aid of a Vernier Caliper (precision plusmn 01mm)The growth inhibition was calculated with reference to thepositive control

252 Cytotoxicity Screenings Stock solutions of the com-pounds were prepared by dissolving 5mg5mL in methanolFrom the stock solution three other solutions of 50 120583gmL100 120583gmL and 500 120583gmL concentrations were prepared byusing the dilution formula As the assay was carried outin duplicate each solution was divided into two parts thuspreparing three other solutions 50120583gmL 100 120583gmL and500120583gmL respectively Two test tubes for control were alsoprepared having only 5mL of media

An amount of 28 g of sea salt was dissolved in 100mL ofdistilled water (28 g100mL) and put on the magnetic stirrerfor two hours A rectangular tray having many pores in itspartition was taken for hatching the shrimps The media andshrimp eggs were put in the tray covered with aluminum foilprovided with an air pump After 24 hours incubation (usingtable lamp) the larvae were shifted from the darkened sideto the open portion of the tray The larvae were collected byposter pipette

A volume of 05mL (500 120583L) of each solution was takenin a separate test tube labeled as 50 120583gmL 100120583gmL and500120583gmL and eight larvae were transferred to each test tubewith the help of a poster pipette dropper The solution wasmade 5mL by the addition of media A separate test tubecontaining only 5mL media was also taken and labelled ascontrol After taking all the necessary measures each testtube was tightly packed with cotton and incubated at 28∘Cfor 24 hours After 24 hours incubation the number of living


H3CO

H3CO

OCH3 OCH3

HN

NH

NH S

S

C

+

Cl

Cl

Cl

ClPd

Pd

R3P

R3P

PR3

NHCH2Cl2

6-hr reux

Scheme 2 Synthesis of heteroleptic Pd(II) complexes

Table 2 Antibacterial activity of the complexes (in vitro) againstfour different bacterial pathogens (diameter of inhibition zone inmm)

Sample codes E coli B subtilis S flexneri S aureus1 18 19 20 232 19 17 15 223 14 14 18 184 18 13 16 245 20 17 19 25Standard DrugImipenem 30 32 35 40

Conc of the standard drug ldquoImipenemrdquo = 10120583gdiscConcentration of sample = 5mgmL (stock solution) and 10 120583gdisc

shrimps was counted and calculations were made by usingAbbotrsquos formula and the results are shown in Table 3

death = (control minus samplecontrol) times 100 (1)

26 Absorption Spectroscopy At room temperature absorp-tion spectra were recorded on Shimadzu UV-1800 KoyotoJapan Standard quartz cells of 1-cm path length were usedThe concentration of the complex solution was kept constantat 2120583M while the concentration of the DNA solution waschanged by 20 120583L after each addition in such a way that thetotal volume of the blank and the complex was constant Thechange in the absorption spectra of the complexes with theincreasing concentration of the DNA is shown in Table 4

3 Results and Discussions

31 Structural Study of the Ligand 13-Bis(2-methoxyphenyl)Thiourea The capped sticks diagram of the substitutedthiourea with selected bond lengths and angles is shown inFigure 1 The carbon atom in NndashC=S moiety of the ligandis sp2 hybridized The compound crystallizes in C

2c space

group The C8ndashS1bond length 1690(2) A is greater than

C=S double bond (160 A) but shorter than CndashS single bond(182 A) distance [33 34] The torsion angle measurementsshow that C

1O1C2C3are almost planar with the torsion angle

of minus23(3)∘ Similarly the other methoxy group is lying inmore planarity with the aromatic ring with the torsion angleof minus11(3)∘ (C

15O2C14C13)

Table 3The number of surviving shrimps after 24 hours incubationin the complexes and control

Compounds 50120583gmL

100120583gmL

500120583gmL Control Mean

death1 6 5 2 8 4583 plusmn 21242 3 1 0 8 8333 plusmn 15603 5 3 2 8 4583 plusmn 25124 4 3 2 8 7083 plusmn 13175 7 4 3 8 4167 plusmn 2124

32 Synthesis of the Complexes and Their CharacterizationMixed ligand Pd(II) complexes were synthesized by reactingsubstituted thiourea ligand with the palladium phosphinecomplexes as shown in Scheme 2

33 Infrared Spectroscopy According to the literature ten-tative assignments were made [35] and the appearance ofthe signal in the range of 3313ndash3328 cmminus1 demonstrates thepresence of NndashH group in the complexes The IR peak in therange of 1021ndash1122 cmminus1 confirms the CndashN bond and the 622ndash647 cmminus1 shift shows the presence of C=S peak and aliphaticand aromatic peaks were observed in the respective regionsAfter the complexation the C=S peak was slightly shifted toa lower frequency value which indicates the bond formationbetween the C=S group and the palladium moiety

34 1H NMR Study The proton NMR spectra of the com-plexes confirm all the protons present in the complexes TheNndashH peak was observed in the range of 400ndash405 ppm and asinglet peak in the range of 369ndash375 shows the OCH

3group

and the aromatic protons were observed as multiplets in therange of 633ndash763 in the synthesized metallopharmaceuticaldrugs The presence of all the protons was confirmed by theproton NMR which ensures the complex formation betweenthe ligand and the metal atom

35 Cytotoxicity The results show that concentration of thecomplexes is directly proportional to death of brineshrimps The maximum death is shown by 500120583gmL the100 120583gmL concentration showed moderate cytotoxicityand the sample 50 120583gmL showed minimum cytotoxic


Table 4 UV data of Pd(II) complexes of the type formula [Pd(PR3)(tu)Cl2]

S number Code of the complex 120582max of the complex 120582max of the complex after DNA addition 120583L of DNA added and absorbance at 120582max

20 120583L 40 120583L 60 120583L 80 120583L1 C1 306 304 1132 1138 1145 11512 C2 332 329 0964 0975 0979 09873 C3 290 285 1441 1459 1463 14704 C4 304 303 1422 1459 1463 14705 C5 308 304 0943 0947 0952 0957

C1 O1

O2

N1 N2

C8 C9

C7

C2

C3

C4

C5

C6

C10

C11

C12

C13C14

C15

S1

Figure 1The capped sticks diagram of 13-bis(2-methoxyphenyl) thiourea Selected bond lengths (A) and angles (deg) S1ndashC8(1690(2)) N

1ndash

C8(1352(2)) N

2ndashC8(1342(3)) N

1ndashC7(1429(2)) N

2ndashC9(1432(3)) O

1ndashC1(1426(3)) O

1ndashC2(1367(3)) O

2ndashC14(1370(3)) O

2ndashC15(1429(3))

C15ndashO2ndashC14(1180(2)) C

1ndashO1ndashC2(1183(2)) S

1ndashC8ndashN1(1202(1)) S

1ndashC8ndashN2(1229(1)) and N

1ndashC8ndashN2(1169(2))

activity The compound C5 (Pd(13-bis(2-methoxyphenyl)thiourea)(PPh

2-o-methoxyphenyl)Cl

2) is the least cyto-

toxic while the complex C2 (Pd(13-bis(2-methoxyphenyl)thiourea)(PPh

2-o-tolyl)Cl

2) has exhibited maximum cyto-

toxicity The least cytotoxicity of the complex C5 may beassigned to the active methoxy group present in the organo-phosphine group which is sufficiently reactive to react withother groups before reaching the target site

36 DNA Interaction Electronic absorption spectroscopy-isone of the versatile techniques to evaluate the interactionmode of complex and DNA molecule In general the hypo-chromism and the red shift reveal the intercalation mode ofinteraction involving a strong stacking interaction betweenthe aromatic chromophore of the complex and the base pairsof DNA [36] The data in Table 3 show that there mightbe some interactions between the drug molecule and DNArevealed by the brine shrimp activity Hyperchromism hasbeen observed which exhibits that theDNA interaction is notthe classical intercalation mode rather it is a groove binding[37]The groove binding is generally shown by the moleculeshaving unfused aromatic rings linked by bonds with torsionalfreedom that molecule may adopt conformations which areclosely matched with the helical turn of DNA groove [38]As far as the mixed-ligand Pd(II) complexes are concernedit is clear that these compounds have unfused rings in the

organophosphine ligands that may provide the VanderWaalrsquosinteraction in the helical DNA grooves

37 Antibacterial Activity The synthesized metallodrugswere screened for their antibacterial activity against twogram negative (E coli and S flexneri) and two gram posi-tive (B subtilis and S aureus) bacterial strains the resultsare presented in Table 2 All the metal complexes are lessactive than the standard drug Imipenem however theyhave shown moderate antimicrobial activity The compound5 (Pd(13-bis(2-methoxyphenyl) thiourea)(PPh

2-o-methoxy-

phenyl)Cl2) has shown maximum activity while compound

3 (Pd(13-bis(2-methoxyphenyl) thiourea)(PPh2-p-tolyl)Cl

2)

is the least active compound of all the five synthesizedcompounds The antibacterial results indicate that variationin the phosphine ligand changes the activity considerablyGenerally the compounds having the tertiary-butyl ortho-tolyl and para-tolyl groups have less activity as compared tothe compounds having triphenylphosphine and diphenyl-o-methoxyphenyl groups

4 Conclusions

Five heteroleptic Pd(II) complexes have been synthesized andcharacterized by elemental analysis FT-IR and 1HNMR andthe ligand thiourea derivative has also been characterized by


single crystal X-ray diffraction The synthesized compoundshave exhibited moderate antibacterial activity against thefour strains of bacteria The cytotoxicity screening and theDNA binding interaction reveal that the compounds havepromising antitumor potential

Additional Data

The crystallographic data for the structural analyses of the li-gand 13-bis(2-methoxyphenyl) thiourea has been depositedwith the Cambridge Crystallographic Data Centre CCDCno CCDC 929755 Copy of this information may be ob-tained free of charge from the Director CCDC 12 UnionRoad Cambridge CBZ 1EZ UK (fax +44 1223 336 033email depositccdccamacuk or httpwwwccdccamacuk)

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Acknowledgment

The authors are highly thankful to the Higher EducationCommission of Pakistan for providing the financial assistancefor the research work

References

[1] J Kasparkova O Vrana N Farrell and V Brabec ldquoEffect ofthe geometry of the central coordination sphere in antitumortrinuclear platinum complexes on DNA bindingrdquo Journal ofInorganic Biochemistry vol 98 no 10 pp 1560ndash1569 2004

[2] V Brabec and J Kasparkova ldquoModifications of DNA by plat-inum complexes relation to resistance of tumors to platinumantitumor drugsrdquoDrug Resistance Updates vol 8 no 3 pp 131ndash146 2005

[3] S Ahmad ldquoPlatinum-DNA interactions and subsequent cel-lular processes controlling sensitivity to anticancer platinumcomplexesrdquo Chemistry and Biodiversity vol 7 no 3 pp 543ndash566 2010

[4] D Jaramillo N J Wheate S F Ralph W A Howard Y Torand J R Aldrich-Wright ldquoPolyamide platinum anticancer com-plexes designed to target specific DNA sequencesrdquo InorganicChemistry vol 45 no 15 pp 6004ndash6013 2006

[5] A Brozovic and M Osmak ldquoActivation of mitogen-activatedprotein kinases by cisplatin and their role in cisplatin-resistancerdquo Cancer Letters vol 251 no 1 pp 1ndash16 2007

[6] S Moradell J Lorenzo A Rovira et al ldquoPlatinum complexesof diaminocarboxylic acids and their ethyl ester derivatives theeffect of the chelate ring size on antitumor activity and interac-tions with GMP and DNArdquo Journal of Inorganic Biochemistryvol 96 no 4 pp 493ndash502 2003

[7] I Kostova ldquoPlatinum complexes as anticancer agentsrdquo RecentPatents on Anti-Cancer Drug Discovery vol 1 no 1 pp 1ndash222006

[8] E Gabano M Ravera and D Osella ldquoThe drug targetingand delivery approach applied to Pt-antitumour complexes A

coordination point of viewrdquo Current Medicinal Chemistry vol16 no 34 pp 4544ndash4580 2009

[9] A Arbuse M Font M A Martınez et al ldquoDNA-cleavage in-duced by new macrocyclic Schiff base dinuclear Cu(I) com-plexes containing pyridyl pendant armsrdquo Inorganic Chemistryvol 48 no 23 pp 11098ndash11107 2009

[10] H Mansouri-Torshizi M I Moghaddam A Divsalar and AA Saboury ldquoDiimine platinum(II) and palladium(II) com-plexes of dithiocarbamate derivative as potential antitumoragents synthesis characterization cytotoxicity and detailDNA-binding studiesrdquo Journal of Biomolecular Structure andDynamics vol 26 no 5 pp 575ndash586 2009

[11] K Lemma T Shi and L I Elding ldquoKinetics and mechanismfor rreduction of the anticancer prodrug transtranstrans-[PtCl

2(OH)

2(c-C6H11NH2)(NH

3)] (JM335) by thiolsrdquo Inorg

Chem vol 39 pp 1728ndash1734 2000[12] M D Hall and TW Hambley ldquoPlatinum(IV) antitumour com-

pounds their bioinorganic chemistryrdquo Coordination ChemistryReviews vol 232 no 1-2 pp 49ndash67 2002

[13] M D Hall H R Mellor R Callaghan and T W HambleyldquoBasis for design and development of platinum(IV) anticancercomplexesrdquo Journal of Medicinal Chemistry vol 50 no 15 pp3403ndash3411 2007

[14] K R Barnes A Kutikov and S J Lippard ldquoSynthesis char-acterization and cytotoxicity of a series of estrogen-tetheredplatinum(IV) complexesrdquo Chemistry and Biology vol 11 no 4pp 557ndash564 2004

[15] K Sakai Y Tomita T Ue et al ldquoSyntheses antitumor activityand molecular mechanics studies of cis-PtCl

2(pzH)

2(pzH=

pyrazole) and related complexes Crystal structure of a novelMagnus-type double-salt [Pt(pzH)

4][PtCl

4][cis-PtCl

2(pzH)

2]2

involving two perpendicularly aligned 1D chainsrdquo InorganicaChimica Acta vol 297 no 1-2 pp 64ndash71 2000

[16] K Sakai andHOzawa ldquoHomogeneous catalysis of platinum(II)complexes in photochemical hydrogen production fromwaterrdquoCoordination Chemistry Reviews vol 251 no 21ndash24 pp 2753ndash2766 2007

[17] K HusainM Abid andA Azam ldquoNovel Pd(II) complexes of 1-N-substituted 3-phenyl-2-pyrazoline derivatives and evaluationof antiamoebic activityrdquo European Journal of Medicinal Chem-istry vol 43 no 2 pp 393ndash403 2008

[18] A Boixassa J Pons X Solans M Font-Bardia and J RosldquoReaction of platinum(II) derivatives with 1-hydroxyalkyl-35-dimethylpyrazole ligands Cleavage of the N(pz) C(sp3)bond X-ray crystal structure of cis-[PtCl

2(HL2)

2] (HL2=1-

(2- hydroxyethyl)-35-dimethylpyrazole) and trans-[PtCl2(dm-

pz)2] (dmpz= 35-dimethylpyrazole)rdquo Inorganica Chimica Acta

vol 355 pp 254ndash263 2003[19] E Budzisz U Krajewska M Rozalski A Szulawska M Czyz

and B Nawrot ldquoBiological evaluation of novel Pt(II) and Pd(II)complexes with pyrazole-containing ligandsrdquo European Journalof Pharmacology vol 502 no 1-2 pp 59ndash65 2004

[20] D S Pilch S U Dunham E R Jamieson S J Lippardand K J Breslauer ldquoDNA sequence context modulates theimpact of a cisplatin 12-d(GpG) intrastrand cross-link onthe conformational and thermodynamic properties of duplexDNArdquo Journal of Molecular Biology vol 296 no 3 pp 803ndash8122000

[21] E R Jamieson and S J Lippard ldquoStructure recognition andprocessing of cisplatin-DNA adductsrdquo Chemical Reviews vol99 no 9 pp 2467ndash2498 1999


[22] Z Nagy and I Sovago ldquoThermodynamic and structural char-acterisation of the complexes formed in the reaction of [Pd(en)(H2O)2]2+ and [Pd(pic)(H

2O)2]2+ with N-alkyl nucleobases

and N-acetyl amino acidsrdquo Journal of the Chemical SocietyDalton Transactions pp 2467ndash2475 2001

[23] A A El-Sherif M M Shoukry and R van Eldik ldquoComplex-formation reactions and stability constants for mixed-ligandcomplexes of diaqua(2-picolylamine)palladium(II) with somebio-relevant ligandsrdquo Dalton Transactions no 7 pp 1425ndash14322003

[24] S Zhu A Matilla J M Tercero V Vijayaragavan and J AWalmsley ldquoBinding of palladium(II) complexes to guanineguanosine or guanosine 51015840 -monophosphate in aqueous solu-tion potentiometric and NMR studiesrdquo Inorganica ChimicaActa vol 357 no 2 pp 411ndash420 2004

[25] J M Tercero-Moreno A Matilla-Hernandez S Gonzalez-Garcıa and J Niclos-Gutierrez ldquoHydrolytic species of the ioncis-diaqua(ethylenediamine)palladium(II) complex and of cis-dichloro(ethylenediamine)palladium(II) fitting its equilibriummodels in aqueous media with or without chloride ionrdquoInorganica Chimica Acta vol 253 no 1 pp 23ndash29 1996

[26] N SummaW Schiessl R Puchta N van EikemaHommes andR van Eldik ldquoThermodynamic and kinetic studies on reactionsof Pt(II) complexes with biologically relevant nucleophilesrdquoInorganic Chemistry vol 45 no 7 pp 2948ndash2959 2006

[27] H Khan M Aziz C Neuhausen G Murtaza and F Shaheenldquo[(Methylcarbamothioyl)disulfanyl]methyl N-methylcarba-modithioaterdquo Acta Crystallographica E Structure ReportsOnline vol 66 no 10 p o2671 2010

[28] H Khan H Badshah Z Rehman et al ldquoNew dimeric and su-pramolecular mixed ligand Palladium(II) dithiocarbamates aspotent DNA bindersrdquo Polyhedrone vol 39 no 1 pp 1ndash8 2012

[29] Bruker APEX 2 Version 202 Bruker AXS Madison Wis USA2005

[30] Bruker SAINT Version 707a Bruker AXS Inc Madison WisUSA 2003

[31] G Murtaza A Badshah M Said et al ldquoUrease inhibition andanti-leishmanial assay of substituted benzoylguanidines andtheir copper(ii) complexesrdquoDalton Transactions vol 40 no 36pp 9202ndash9211 2011

[32] A Rahman M I Choudhary and W J Thomsen BioassayTechniques for Drug Development Harward Academic PressAmsterdam The Netherlands 2001

[33] H Khan A Badshah G Murtaz et al ldquoSynthesis characteri-zation and anticancer studies of mixed ligand dithiocarbamatepalladium(II) complexesrdquoEuropean Journal ofMedicinal Chem-istry vol 46 no 9 pp 4071ndash4077 2011

[34] F H Allen O Kennard D G Watson L Brammer A GOrpen and R Taylor ldquoTables of bond lengths determinedby X-ray and neutron diffraction Part 1 Bond lengths inorganic compoundsrdquo Journal of the Chemical Society PerkinTransactions 2 no 12 pp S1ndashS19 1987

[35] D Fregona L Giovagnini L Ronconi et al ldquoPt(II) andPd(II) derivatives of ter-butylsarcosinedithiocarbamate syn-thesis chemical and biological characterization and in vitronephrotoxicityrdquo Journal of Inorganic Biochemistry vol 93 no3-4 pp 181ndash189 2003

[36] V A Bloomfield D M Carothers and I Tinoco Jr PhysicalChemistry of Nucleic Acids Harper and Row New York NYUSA 1974

[37] R Vijayalakshmi M Kanthimathi V Subramanian and B UNair ldquoInteraction of DNA with [Cr(Schiff base)(H

2O)2]ClO4rdquo

Biochimica et Biophysica Acta General Subjects vol 1475 no 2pp 157ndash162 2000

[38] L Strekowski and B Wilson ldquoNoncovalent interactions withDNA an overviewrdquo Mutation Research Fundamental andMolecular Mechanisms of Mutagenesis vol 623 no 1-2 pp 3ndash13 2007

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Inorganic ChemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

International Journal ofPhotoenergy


Carbohydrate Chemistry

International Journal of


Journal of

Chemistry


Advances in

Physical Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom

Analytical Methods in Chemistry

Journal of

Volume 2014

Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

SpectroscopyInternational Journal of


The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of


Chromatography Research International


Applied ChemistryJournal of



Theoretical ChemistryJournal of


Journal of

Spectroscopy

Analytical ChemistryInternational Journal of


Journal of


Quantum Chemistry


Organic Chemistry International

ElectrochemistryInternational Journal of



CatalystsJournal of


H3CO

2H2N CS2

OCH3OCH3

H2S

HN NH

S

C

++273K 6-hr stirring

n-hexane

Scheme 1 Synthesis of the substituted thiourea

anticancer drugs such as doxorubicin and 5-fluorouracil itis widely used in treatment of neck cancer However thereis a built-in and acquired resistance that limits the clinicalusefulness of the drug Platination of DNA is considered tobe responsible for the antitumor activity of various platinumcontaining drugs through bonding to guanine [20 21]Palladium(II) analogues are structurally similar to those ofPt(II) complexes which have a very similar coordinationgeometry and coordination process [22ndash24] Generally Pt(II)complexes are less stable than Pd(II) compounds ThereforePd(II) systems are frequently used as model complexes [25]Pd(II) binding to the guanine ring has been proposed fromIR and NMR data in several models The models revealcoordination with C=OndashPdndashN

7bridge between adjacent

guanine rings and chelation through N7and C=O of a

guanine ring [26]We report here the synthesis spectral characterization

and biological activities of the heteroleptic Pd(II) complexesof the general formula Pd(PR

3)(tu)Cl

2 where PR

3= triphen-

ylphosphine (1) diphenyl-o-tolylphosphine (2) diphenyl-p-tolylphosphine (3) diphenyl-t-butylphosphine (4) and di-phenyl-o-methoxyphenylphosphine (5) tu = 13-bis(2-me-thoxyphenyl) thiourea

2 Experimental

21 Materials and Methods Ethanol methanol n-hexanefish sperm DNA dichloromethane chloroform carbon di-sulfide and PdCl

2 sea salt and brine shrimp eggs were ob-

tained fromMerck Germany and Sigma-Aldrich All the sol-vents and chemicals were of analytical grade and were usedas received without further purification

22 Synthesis of the Substituted Thiourea Substituted thiou-rea was synthesized by the reaction of o-methoxyphenyl-amine with carbon disulphide (2 1) respectively at 273Kelvin in n-hexane as shown in Scheme 1 by the reportedliterature method with slight modification [27] The reac-tion mixture was magnetically stirred for six hours andthe reaction progress was continuously monitored by thinlayer chromatography The solvent was evaporated under thereduced pressure and the light brown solid was dissolvedin a mixture of dichloromethane and n-hexane (2 1 vv) forrecrystallization Needle shaped light brown crystals wereobtained by the slow evaporation of the solvents at roomtemperature and a suitable crystal was separated for singlecrystal diffraction analysis

23 Synthesis of the Complexes (1ndash5) Themixed ligand Pd(II)complexes were synthesized in two steps [28] In the firststep Pd-organophosphine complex was formed by reactingorganophosphine ligand dissolved in acetone with palla-dium chloride dissolved in dry methanol and few dropsof concentrated hydrochloric acid in 2 1 molar ratio Thesolid golden yellow product was obtained by evaporating thereaction mixture at reduced pressure In the second step thegolden yellow product was dissolved in dichloromethane andwas reacted with 13-bis(2-methoxyphenyl) thiourea solutionin dichloromethane in 1 1 molar ratio The final heterolepticPd(II) complex was obtained by rotary evaporation of thereaction mixture

231 [Pd(13-bis(2-methoxyphenyl) thiourea)(PPh3)Cl2] (1)

Quantities usedwere 032 g (047mmol) of Pd(PPh3)2Cl2and

015 g (047mmol) of 13-bis(2-methoxyphenyl) thiourea in25mL of dichloromethane Yield 029 g (87) Mp 231-232∘C FTIR (powder cmminus1) 3316 120592(NndashH) 1122 120592(CndashN) 622120592(C=S) 2831 120592(CndashH aliphatic) and 2943 120592(CndashH aromatic)1H NMR (300MHz CDCl


3)

405 (s 2H ndashNH) and 635ndash759 (m 23H ArndashH) Anal Calcfor C33H31Cl2N2O2PPdS C 5445 H 429 N 385 S 440

Found C 5450 H 426 N 387 S 440

232 [Pd(13-bis(2-methoxyphenyl) thiourea)(PPh2-o-tolyl)


(PPh2-o-tolyl)



3) 120575-

ppm 233 (s 3H ndashCH3) 375 (s 3H ndashOCH

3) 400 (s 2H

ndashNH) and 633ndash763 (m 22H ArndashH) Anal Calc for C34

H33Cl2N2O2PPdS C 5503 H 448 N 378 S 432 Found

C 5510 H 447 N 378 S 433

233 [Pd(13-bis(2-methoxyphenyl) thiourea)(PPh2-p-tolyl)


(PPh2-p-tolyl)



3)

120575-ppm 234 (s 3H ndashCH3) 370 (s 3H ndashOCH

3) 402 (s

2H ndashNH) and 630ndash765 (m 22H ArndashH) Anal Calc for


C34H33Cl2N2O2PPdS C 5503 H 448 N 378 S 432

Found C 5509 H 444 N 377 S 429



(PPh2- t-butyl)



3)


3) 401


Found C 5249 H 497 N 396 S 451









370 S 423 Found C 5375 H 438 N 369 S 420







Cell angles (∘)120572 9000120573 10389120574 9000


Z Z1015840 Z 8Z1015840 0







H3CO

H3CO

OCH3 OCH3

HN

NH

NH S

S

C

+

Cl

Cl

Cl

ClPd

Pd

R3P

R3P

PR3

NHCH2Cl2

6-hr reux










2c space





15O2C14C13)



100120583gmL






3group






20 120583L 40 120583L 60 120583L 80 120583L1 C1 306 304 1132 1138 1145 11512 C2 332 329 0964 0975 0979 09873 C3 290 285 1441 1459 1463 14704 C4 304 303 1422 1459 1463 14705 C5 308 304 0943 0947 0952 0957

C1 O1

O2

N1 N2

C8 C9

C7

C2

C3

C4

C5

C6

C10

C11

C12

C13C14

C15

S1


1ndash

C8(1352(2)) N

2ndashC8(1342(3)) N

1ndashC7(1429(2)) N

2ndashC9(1432(3)) O

1ndashC1(1426(3)) O

1ndashC2(1367(3)) O

2ndashC14(1370(3)) O

2ndashC15(1429(3))










2-o-tolyl)Cl






2-o-methoxy-



2)


4 Conclusions




Additional Data




Acknowledgment


References













2(OH)

2(c-C6H11NH2)(NH







2(pzH)

2(pzH=


4][PtCl

4][cis-PtCl

2(pzH)

2]2





2(HL2)

2] (HL2=1-


























2O)2]ClO4rdquo












Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


C34H33Cl2N2O2PPdS C 5503 H 448 N 378 S 432

Found C 5509 H 444 N 377 S 429



(PPh2- t-butyl)



3)


3) 401


Found C 5249 H 497 N 396 S 451









370 S 423 Found C 5375 H 438 N 369 S 420







Cell angles (∘)120572 9000120573 10389120574 9000


Z Z1015840 Z 8Z1015840 0







H3CO

H3CO

OCH3 OCH3

HN

NH

NH S

S

C

+

Cl

Cl

Cl

ClPd

Pd

R3P

R3P

PR3

NHCH2Cl2

6-hr reux










2c space





15O2C14C13)



100120583gmL






3group






20 120583L 40 120583L 60 120583L 80 120583L1 C1 306 304 1132 1138 1145 11512 C2 332 329 0964 0975 0979 09873 C3 290 285 1441 1459 1463 14704 C4 304 303 1422 1459 1463 14705 C5 308 304 0943 0947 0952 0957

C1 O1

O2

N1 N2

C8 C9

C7

C2

C3

C4

C5

C6

C10

C11

C12

C13C14

C15

S1


1ndash

C8(1352(2)) N

2ndashC8(1342(3)) N

1ndashC7(1429(2)) N

2ndashC9(1432(3)) O

1ndashC1(1426(3)) O

1ndashC2(1367(3)) O

2ndashC14(1370(3)) O

2ndashC15(1429(3))










2-o-tolyl)Cl






2-o-methoxy-



2)


4 Conclusions




Additional Data




Acknowledgment


References













2(OH)

2(c-C6H11NH2)(NH







2(pzH)

2(pzH=


4][PtCl

4][cis-PtCl

2(pzH)

2]2





2(HL2)

2] (HL2=1-


























2O)2]ClO4rdquo












Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


H3CO

H3CO

OCH3 OCH3

HN

NH

NH S

S

C

+

Cl

Cl

Cl

ClPd

Pd

R3P

R3P

PR3

NHCH2Cl2

6-hr reux










2c space





15O2C14C13)



100120583gmL






3group






20 120583L 40 120583L 60 120583L 80 120583L1 C1 306 304 1132 1138 1145 11512 C2 332 329 0964 0975 0979 09873 C3 290 285 1441 1459 1463 14704 C4 304 303 1422 1459 1463 14705 C5 308 304 0943 0947 0952 0957

C1 O1

O2

N1 N2

C8 C9

C7

C2

C3

C4

C5

C6

C10

C11

C12

C13C14

C15

S1


1ndash

C8(1352(2)) N

2ndashC8(1342(3)) N

1ndashC7(1429(2)) N

2ndashC9(1432(3)) O

1ndashC1(1426(3)) O

1ndashC2(1367(3)) O

2ndashC14(1370(3)) O

2ndashC15(1429(3))










2-o-tolyl)Cl






2-o-methoxy-



2)


4 Conclusions




Additional Data




Acknowledgment


References













2(OH)

2(c-C6H11NH2)(NH







2(pzH)

2(pzH=


4][PtCl

4][cis-PtCl

2(pzH)

2]2





2(HL2)

2] (HL2=1-


























2O)2]ClO4rdquo












Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of




20 120583L 40 120583L 60 120583L 80 120583L1 C1 306 304 1132 1138 1145 11512 C2 332 329 0964 0975 0979 09873 C3 290 285 1441 1459 1463 14704 C4 304 303 1422 1459 1463 14705 C5 308 304 0943 0947 0952 0957

C1 O1

O2

N1 N2

C8 C9

C7

C2

C3

C4

C5

C6

C10

C11

C12

C13C14

C15

S1


1ndash

C8(1352(2)) N

2ndashC8(1342(3)) N

1ndashC7(1429(2)) N

2ndashC9(1432(3)) O

1ndashC1(1426(3)) O

1ndashC2(1367(3)) O

2ndashC14(1370(3)) O

2ndashC15(1429(3))










2-o-tolyl)Cl






2-o-methoxy-



2)


4 Conclusions




Additional Data




Acknowledgment


References













2(OH)

2(c-C6H11NH2)(NH







2(pzH)

2(pzH=


4][PtCl

4][cis-PtCl

2(pzH)

2]2





2(HL2)

2] (HL2=1-


























2O)2]ClO4rdquo












Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of



Additional Data




Acknowledgment


References













2(OH)

2(c-C6H11NH2)(NH







2(pzH)

2(pzH=


4][PtCl

4][cis-PtCl

2(pzH)

2]2





2(HL2)

2] (HL2=1-


























2O)2]ClO4rdquo












Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of




















2O)2]ClO4rdquo












Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of










Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of

Documents

Research Article Synthesis, Structural Characterization ...downloads.hindawi.com/journals/bca/2014/916361.pdfResearch Article Synthesis, Structural Characterization, and Evaluation