Shefali Arora, Shilpi Agarwal, Shailey Singhal


There have been tremendous development in the chemotherapy of cancer and researches are still developing new and more effective drugs to combat this disease. Thiosemicarbazides and thiosemicarbazone possess a wide range of biological applications. This key biological role is often related with their capability to inhibit the enzyme ribonucleotide reductase, similar to what is observed with potent anticancer drugs such as triapine and methisazone. Recent studies have revealed that thiosemicarbazones can inhibit topoisomerase II enzyme. This review discusses current advances of an emerging ‘new wave’ of thiosemicarbazide/thiosemicarbazone and their metal complexes as potent anticancer agents, mode of action and toxicity caused by them.



Anticancer, Antineoplastic, Antitumor, Thiosemicarbazide, Topoisomerase.


West DX, Swearingen JK, Valdes-Martinez J, Hernandez-Ortega S, El-Sawaf AK, van Meurs F, et al.“Spectral and Structural Studies of Iron(III), cobalt(II,III) and Nickel(II) complexes of 2-pyridineformamide N(4)-methylthiosemicarbazone”. Polyhedron 1999;18:2919-29.

Tarasconi P, Capacchi S, Pelosi G, Cornia M, Albertini R, Bonati A, et al.“Synthesis, spectroscopic characterization and biological properties of new natural aldehydes thiosemicarbazones”. Bioorg Med Chem 2000;8:157-62.

Ghazy SE, Kabil MA, El-Asmy AA, Sherief YA.“Sulfur containing reagent for ion flotation and spectrophotometric determination of palladium(II)”. Anal Lett 1996;29:1215–29.

Dilworth JR, Cowley AH, Donnelly PS, Gee AD, Heslop JM.“Acetylacetonatebis(thiosemicarbazone) complexes of copper and nickel: towards new copper radiopharmaceuticals”. J Chem Soc Dalton Trans 2004;2404–12.

Abou-Hussen AA, El-Metwally NM, Saad EM, El-Asmy AA.“Spectral, magnetic, thermal and electrochemical studies on phthaloylbis(thiosemicarbazide) complexes”. J Coord Chem 2005;58:1735-49.

Lobana TS, Sharma R, Bawa G, Khanna S.“Bonding and structure trends of thiosemicarbazone derivatives of metals-An overview”. Coord Chem Rev 2009;253(7-8):977–1055.

Mendes IC, Costa FB, de Lima GM, Ardisson JD, Garcia-Santos I, Castineiras A, et al.“Tin(IV) complexes with 2-pyridineformamide-derived thiosemicarbazones: Antimicrobial and potential antineoplasic activities”. Polyhedron 2009;28(6):1179–85.

Rivadeneira J, Barrio DA, Arrambide G, Gambino D, Bruzzone L, Etcheverry SB.“Biological effects of a complex of vanadium (V) with salicylaldehydesemicarbazone in osteoblasts in culture: mechanism of action”. J Inorg Biochem 2009;103:633–42.

Kovala-Demertzi D, Papageorgiou A, Papathanasis L, Alexandratos A, Dalezis P, Miller JR, et al.“In vitro and In vivo antitumor activity of platinum(II) complexes with thiosemicarbazones derived from 2-formyl and 2-acetyl pyridine and containing ring incorporated at N(4)-position: Synthesis, spectroscopic study and crystal structure of platinum(II) complexes with thiosemicarbazones, potential anticancer agents”. Eur J Med Chem 2009;44:1296–302.

Belicchi-Ferrari M, Bisceglie F, Buschini A, Franzoni S, Pelosi G, Pinelli S, et al.“Synthesis, structural characterization and antiproliferative and toxic bio-activities of copper(II) and nickel(II) citronellal N4-ethylmorpholine thiosemicarbazonates”. J Inorg Biochem 2010;104:199–206.

Vrdoljak V, Ðilović I, Rubčić M, Pavelić SK, Kralj M, Matković–Čalogović D, et al.“Synthesis and characterisation of thiosemicarbazonato molybdenum(VI) complexes and their In vitro antitumor activity”. Eur J Med Chem 2010;45:38–48.

El-Ayaan U, Youssef MM, Al-Shihry S.“Mn(II), Co(II), Zn(II), Fe(III) and U (VI) complexes of 2-acetylpyridine 4N-(2-pyridyl) thiosemicarbazone (HAPT); structural, spectroscopic and biological studies”. J Mol Stru 2009;936:213–9.

El-Asmy AA, Al-Gammal OA, Saad DA,Ghazy SE.“Metal complexes of 1-(3,4-dihydroxybenzylidine)thiosemicarbazide: Synthesis, spectral, magnetic, thermal and Eukaryotic DNA degradation”. J Mol Stru 2009;934:9–22.

Li M, Zhou J, Zhao H, Chen C, Wang J.“Iron(III) complex of 2-acetylpyrazine thiosemicarbazone: synthesis, spectral characterization, structural studies and antitumoral activity”. J Coord Chem 2009;62(9):1423–9.

Marzano C, Pellei M, Tisato F, Santini C. “Copper complexes as anticancer agents”. Anticancer Agents Med Chem 2009;9:185–211.

Scott MP.“Cancer: a twist in the Hedgehog’s tale”. Nat 2003;425:780-2.

Folkman J, Kalluri R.“Cancer without disease”. Nat 2004;427(6977):787.

Dholakia SP, Suhagia BN, Patel AK, Kapupara PP, Sureja DK.“Review: novel target for cancer therapy”. J Chem Pharm Res 2011;3(4):315-32.

Padhye S, Afrasiabi Z, Sinn E, Fok J, Mehta K, Rath N.“Antitumor Metallothio semi carbazonates: structure and antitumor activity of palladium complex of phenanthrene quinine thiosemi carbazone”. Inorg Chem 2005;44:1154-6.

Saha DP, Padhye S, Sinn E, Newton C.“Metal complexes as antitumor agents 4:synthesis, structure, spectroscopy and in vitro antitumor activity of hydroxynaphtho quinonethiosemi carbazone metal complexes against mcf-7 human breast cancer cell lines”. Indian J Chem 2002;41A:279-83.

Quiroga AG, Ranninger CN. “Contribution to the SAR field of metallated and coordination complexes: Studies of the palladium and platinum derivatives with selected thiosemicarbazones as antitumoral drugs”. Coord Chem Rev 2004;248:119-33.

Zhang H, Thomas R, Oupicky D, Peng F.“Synthesis and characterization of new copper thiosemicarbazone complexes with an ONNS quadridentate system: cell growth inhibition, S-phase cell cycle arrest and proapoptotic activities on cisplatin-resistant neuroblastoma cells”. J Biol Inorg Chem 2008;13:47-55.

Mylonas S, Mamalis A. “Synthesis and antitumor activity of new thiosemicarbazones of 2-acetylimidazo[4,5-b]pyridine”. J Heterocyclic Chem 2005;42(7):1273-81.

Elford HL, Freese M, Passamani E, Morris HP. “Ribonucleotide reductase and cell proliferation. I. Variations of ribonucleotide reductase activity with tumor growth rate in a series of rat hepatomas”. J Biol Chem 1970;245(20):5228-33.

Moore EC, Zedeck MS, Agrawal KC, Sartorelli AC. “Inhibition of ribonucleoside diphosphate reductase by 1-formylisoquinoline thiosemicarbazone and related compounds”. Biochem 1970;9:4492–8.

Yousef TA, Badria FA, Ghazy SE, El-Gammal OA, Abu El-Reash GM.“In vitro and In vivo antitumor activity of some synthesized 4-(2-pyridyl)-3-Thiosemicarbazides derivatives”. Int J Med Med Sci 2011;3(2):37-46.

Zhang HJ, Qian Y, Zhu DD, Yang XG, Zhu HL. “Synthesis, molecular modeling and biological evaluation of chalconethiosemicarbazide derivatives as novel anticancer agents”. Eur J Med Chem 2011;46:4702-8.

El-Zahar MI, El-Karim SSA, Haiba ME, Khedr MA.“Synthesis, antitumor activity nd molecular docking study of novel benzofuran-2-yl pyrazole pyrimidine derivatives”. Acta Poloniae Pharm Drug Res 2011;68(3):357-73.

Sari A, Cukurovali A. “MDA effect of the thiosemicarbazone derivative schif base 1-(1-mesityl-1-methylcyclobutane-3-yl)-2-suksinimido etanonthiosemicarbazone in rabbits”. Int Con Biosci Bioche Bioinformatics IPCBEE 2012.

Patel HD, Divatia SM, De Clereq E. “Synthesis of some novel thiosemicarbazonederiatives having anti-cancer, anti-HIV as well as anti-bacterial activity”. Indian J Chem 2013;52B:535-45.

Serda M, Musiol R, Polanski J. “New thiosemicarbazones based on quinoline scaffold as anticancer iron chelators”. 14th International electronic conference on synthetic organic chemistry (ECSOC 14) 2010.

Padhye SB, Kauffmann GB. “Transition metal complexes of semicarbazones and thiosemicarbazones”. Coord Chem Rev 1985;63:127-60.

West DX, Padhye SB, Sonawane PB. “Structural and Physical correlation in the biological properties of transition metal N-hetero-cyclic thiosemicarbazones and S-alkyldithiocarbazate”. Stru Bonding 1991;76:1-50.

West DX, Padhye SB, Sonawane PB, Chikate RC. “Copper (II) complexes of tridentate (O,N,S) thiosemicarbazones”. Asian J Chem 1990;1:125.

Singh NK, Singh SB, Shrivastava A, Singh SM. “Spectral, magnetic and biological studies of 1,4-dibenzoyl-3-thiosemicarbazide complexes with some first row transition metal ions” In: Proceedings of the Indian Academy of Sciences: Chem Sci 2001;113(4):257-73.

Afrasiabi Z, Sinn E, Chen J, Ma Y, Rheingold AL, Zakharov LN, et al. “Appended 1,2-naphtho-quinone as anticancer agents: synthesis, structural, spectral and antitumor activities of ortho-naphthaquinonethiosemicarbazone and its transition metal complexes”. Inorganica Chimica Acta 2004;357(1):271-8.

Baldini M, Belicchi M, Bisceglle F, Agllo PPD, Pelos G, Pinelli S, et al.“Copper (II) complexes with substituted thiosemicarbazones of α-ketoglutaric acid: synthesis, X-ray structures, DNA binding studies and nuclease and biological activity”. J Inorganic Chem 2004;43:7170-9.

Borges RHU, Paniago E, Beraldo H. “Equilibrium and kinetic studies of iron (II) and iron (III) complexes of some α (N)-heterocyclic thiosemicarbazone: reduction of the iron (III) complexes of 2-formylpyridine thiosemicarbazone and 2-acetyl pyridine thiosemicarbazone by cellular thiol-like reducing agents”. J Inorganic Biochem 1997;65:2267-75.

Subrahmanyam Naidu PV, Prakash MMSK. “Structure and biological activities of novel phytochemicals Cu(ii)-quercetinthiosemicarbazone and its derivatives: potential anti-cancer drugs”. Int J Pharm Med Bio Sci 2012;1(2):55-65.

Jalilian AR, Rowshanfarzad P, Akhlaghi M, Sabet M, Kamali-dehghan M, Pouladi M.“Preparation and Biological Evaluation of a [55Co]-2-Acetylpyridine Thiosemicarbazone”. Sci Pharm 2009;77:567–78.

Lovejoy DB, Jansson PJ, Brunk UT, Wong J, Ponka P, Richardson DR. “Antitumor activity of metal-chelating compound Dp44mT is mediated by formation of a redox-active copper complex that accumulates in lysosomes”. Cancer Res 2011;71(17):1-10.

Kellner U, Sehested M, Jensen PB, Gieseler F, Rudolph P.“Culprit and victim-DNA topoisomerase II”. Lancet Oncol 2002;3:235–43.

Kaufmann SH, Gore SD, Miller CB, Jones RJ, Zwelling LA, Schneider E, et al. “Topoisomerase II and the response to antileukemic therapy”. Leuk Lymphoma1998;29:217–37.

Wei L, Easmon J, Nagi RK, Muegge BD, Meyer LA, Lewis JS. “64Cu-Azabicyclo [3.2.2]Nonane Thiosemicarbazone Complexes: Radiopharmaceuticals for PET of Topoisomerase II Expression in Tumors”. J Nucl Med 2006;47:2034–41.

Adharvanachary M, Mskinthada PM. “Synthesis, charecterization and nuclease activity of Au(III)-complexes of alloxanthiosemicarbazone (All. Tsc) and substituted thiosemicarbazones”. Int J Pharm Biol Arch 2011;2(3):1006-10.

ZhengaLP, Chena CL, Zhoua J, Lia MX, Wua YJ. “Synthesis, crystal structure and antitumor study of an Iron (III) complex of 2-acetylpyrazine N (4)-methylthiosemicarbazone”. Z Naturforsch 2008;63b: 1257–61.

Feng CQ, Ma WL, Zheng WL. “Research advances on effect of arsenic trioxide on tumor”. Aizheng 2002;21:1386-9.

Bahlis NJ, McCafferty-Grad J, Jordan-McMurry I, Neil J, Reis I, Kharfan-Dabaja M, et al. “Feasibility and correlates of arsenic trioxide combined with ascorbic acid-mediated depletion of intracellular glutathione for the treatment of relapsed/refractorymultiple myeloma”. Clin Cancer Res 2002;8:3658-68.

Moghaddam-Banaem L, Jalilian AR, Jamre M, Salek N, Mazidi M, Ghannadi-Maragheh M. “Radiosynthesis of 191Os-2-acetylpyridine thiosemicarbazone complex,as an In vivo therapeutic radionuclide generator”. Iran J Nucl Med 2013;21(2):53-9.

Bakalova A, Buyukliev R, Momekov G, Ivanov D. “Synthesis and cytotoxic activity of new platinum and palladium complexes with 3-amino-α-tetralonespiro-5’-hydantoin”. J Chem Technology Metallurgy 2013;48(6):631-6.

Matesanz AI, Pe´rez JM, Navarro P, Moreno JM, Colacio E, Souza P. “Synthesis and characterization of novel palladium(II)complexes of bis(thiosemicarbazone). Structure, cytotoxic activity and DNA binding of Pd(II)-benzyl bis(thiosemicarbazonate)”. J Inorganic Biochem 1999;76:29–37.

Kalyani P, Adharvanachary M, Kinthada PMMS. “Synthesis, characterization and nuclease activity of Ru(III)-complexes of isatinthiosemicarbazone (Is. Tsc) and substituted thiosemicarbazones”. Int J Pharm Biomed Sci 2012;3(2):70-4.

Gangadharan R, Amritha CS, Anto RJ, Cheriyan VT. “Synthesis, thermal and antitumour studies of Th(IV) complexes with furan-2-carboxaldehyde4-phenyl-3-thiosemicarbazone”. J Serb Chem Soc 2010;75(6):749–61.

Sedaghat S, Ghammamy S, Hosseinzadeh R, Amini Z, Mirrahimi MM.“Synthesis, characterization and antitumor activity of new transition metal and uranyl complexes”. Latest Trends Energy Development Environment Biomedicine 2010;83-6.

Baviskar AT, Madaan C, Preet R, Mohapatra P, Jain V, Agarwal A, et al.“N-fused imidazoles as novel anticancer agents that inhibit catalytic activity of topoisomerase IIα and induce apoptosis in G1/S phase”. J Med Chem 2011;54:5013–30.

Schneider N, Hindle S, Lange G, Klein R, Albrecht J, Briem H, et al. “Substantial improvements in large-scale redocking and screening using the novel HYDE scoring function”. J Comput Aided Mol Des 2012;26:701–23.

Reulecke I, Lange G, Albrecht J, Klein R, Rarey M. “Towards an integrated description of hydrogen bonding and dehydration: Decreasing false positives in virtual screening with the HYDE scoring function”. Chem Med Chem 2008;3:885–97.

Siwek A, Stączek P, Wujec M, Bielawski K, Bielawska A, Paneth P. “Cytotoxic effect and molecular docking of 4-ethoxycarbonylmethyl-1-(piperidin-4-ylcarbonyl)-thiosemicarbazide—a novel topoisomerase II inhibitor”. J Mol Model 2013;19(3):1319-24.

Hanahan D, Weinberg RA. “The hallmarks of cancer”. Cell 2000;100(1):57–70.

Hodgson S. “Mechanisms of inherited cancer susceptibility”. J Zhejiang Univ Sci B2008;9(1):1–4.

Perera FP. “Environment and cancer: who are susceptible?”. Sci 1997;278(5340):1068–73.

Corrie PG, Pippa G. “Cytotoxic chemotherapy: clinical aspects”. Medicine 2008;36(1):24–8.

Rang HP, Dale MM, Ritter JM. “Anticancer drugs”, Text book of Pharmacology. 7th edition; Elsevier 2012.

Brenner GM, Stevens CW. “Antineoplastic drugs”, Text book of Pharmacology. 3rd edition; Saunders Elsevier 2010.

Gupta S, Tannous R, Friedman M. “Incidence of anaemia in CHOP-treated intermediate-grade non-Hodgkin’s lymphoma (IGNHL)”. Euro J Cancer 2001;S94:339.

Hoagland HC, Gastineau DA. “Haematological complications of cancer chemotherapy”, The chemotherapy source book. 2nd ed. Michael C Perry; 1992.

Berg SL, Balis FM, Pop lack DG. “Cancer Chemotherapy: Haematology of infancy and childhood”, 5th ed. Nathan and Oski’s; 1998.

Early DS. “Gastrointestinal complication of chemotherapy”, Cancer chemotherapy source book. Michel C Perrie 2001;3:427-31.

Remesh A. “Toxicities of anticancer drugs and its management”. Int J Basic Clil Pharm 2012;1(1):2-12.

Stillwell TJ, Benson RC. “Cyclophosphamide induced haemorrhagic cystitis”. Cancer 1988;61:451-7.

Kreisman H, Wolkove N. “Pulmonary toxicity of antineoplastic therapy”. Semin Oncol 1992;19:508-20.

About this article




Anticancer, Antineoplastic, Antitumor, Thiosemicarbazide, Topoisomerase.



Additional Links

Manuscript Submission


International Journal of Pharmacy and Pharmaceutical Sciences
Vol 6, Issue 9, 2014 Page: 34-41

Online ISSN



2049 Views | 1439 Downloads

Authors & Affiliations

Shefali Arora
Department of Chemistry, University of Petroleum & Energy Studies, Dehradun 248007 (Uttarakhand), India

Shilpi Agarwal
Department of Chemistry, University of Petroleum & Energy Studies, Dehradun 248007 (Uttarakhand), India

Shailey Singhal
University of Petroleum & Energy Studies, Dehradun (Uttarakhand), India


Article Tools



  • There are currently no refbacks.