Thiosemicarbazones as Potent Anticancer Agents and their Modes of Action

Author(s): Bhushan Shakya, Paras Nath Yadav*

Journal Name: Mini-Reviews in Medicinal Chemistry

Volume 20 , Issue 8 , 2020

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Graphical Abstract:


Thiosemicarbazones (TSCs) are a class of Schiff bases usually obtained by the condensation of thiosemicarbazide with a suitable aldehyde or ketone. TSCs have been the focus of chemists and biologists due to their wide range of pharmacological effects. One of the promising areas in which these excellent metal chelators are being developed is their use against cancer. TSCs have a wide clinical antitumor spectrum with efficacy in various tumor types such as leukemia, pancreatic cancer, breast cancer, non-small cell lung cancer, cervical cancer, prostate cancer and bladder cancer. To obtain better activity, different series of TSCs have been developed by modifying the heteroaromatic system in their molecules. These compounds possessed significant antineoplastic activity when the carbonyl attachment of the side chain was located at a position α to the ring nitrogen atom, whereas attachment of the side chain β or γ to the heterocyclic N atom resulted in inactive antitumor agents. In addition, replacement of the heterocyclic ring N with C also resulted in a biologically inactive compound suggesting that a conjugated N,N,S-tridentate donor set is essential for the biological activities of thiosemicarbazones. Several possible mechanisms have been implemented for the anticancer activity of thiosemicarbazones.

Keywords: Cancer, thiosemicarbazone, iron chelation, ribonucleotide reductase, reactive oxygen species, apoptosis.

World health organization. (Accessed Oct 22, 2018).
Fitzmaurice, C. Regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 cancer groups, 1990 to 2015 a systematic analysis for the global burden of disease study. JAMA Oncol., 2017, 3(4), 524-548.
Park, S.; Magar, T.B.T.; Kahayan, T.M.; Lee, H.J.; Bist, G.; Shrestha, A.; Lee, E.S.; Kwon, Y. Rational design, synthesis, and evaluation of novel 2,4-chloro- and hydroxy-substituted topoisomerase I and II dual inhibitor. Eur. J. Med. Chem., 2017, 127, 318-333.
Thurston, D.E. Chemistry and Pharmacology of Anticancer Drugs.1st ed.; CRC, Taylor & Francis, Boca Raton,; , 2006.
Matesanz, A.I.; Souza, P. α-N-heterocyclic thiosemicarbazone derivative as potential antitumor agents: A structure-activity relationships approach. Mini Rev. Med. Chem., 2009, 9(12), 1389-1396.
Hamre, D.; Bernstein, J.; Donovick, R. Activity of p-aminobenzaldehyde 3-thiosemicarbazone on vaccinia virus in the chick embryo and in the mouse. Proc. Soc. Exp. Biol. Med., 1950, 73, 275-278.
Heiner, G.G.; Fatima, N.; Russell, P.K.; Haase, A.T.; Ahmad, N.; Mohammed, N.; Thomas, D.B.; Mack, T.M.; Khan, M.M.; Knatterud, G.L.; Anthony, R.L.; McCrumb, F.R., Jr Field trials of methisazone as a prophylactic agent against smallpox. Am. J. Epidemiol., 1971, 94(5), 435-449.
Shipman, C., Jr; Smith, S.H.; Drach, J.C.; Klayman, D.L. Antiviral activity of 2-acetylpyridine thiosemicarbazones against Herpes Simplex virus. Antimicrob. Agents Chemother., 1981, 19(4), 682-685.
Bal, T.R.; Anand, B.; Yogeeswari, P.; Sriram, D. Synthesis and evaluation of anti-HIV activity of isatin β-thiosemicarbazone derivative. Bioorg. Med. Chem. Lett., 2005, 15, 4451-4455.
Dobek, A.S.; Klayman, D.L.; Dickson, E.T.; Scovill, J.P.; Tramont, E.C. Inhibition of clinically significant bacterial organisms in vitro by 2-acetylpyridine thiosemicarbazones. Antimicrob. Agents Chemother., 1980, 18(1), 27-36.
Kolocouris, A.; Dimas, K.; Pannecouque, C.; Witvrouw, M.; Foscolos, G.B.; Stamatiou, G.; Fytas, G. Zoidis; G.; Kolocouris, N.; Andrei, G.; Snoeck, R.; De Clerq, E. New 2-(1-adamantylcarbonyl)- pyridine and 1-acetyladamantane thiosemicarbazones-thiocarbono-hydrazones: Cell growth inhibitory, antiviral and antimicrobial activity evaluation. Bioorg. Med. Chem. Lett., 2002, 12(5), 723-727.
Zhu, Y.J.; Song, K.K.; Li, Z.C.; Pan, Z.Z.; Guo, Y.J.; Zhou, J.J.; Wang, Q.; Liu, B.; Chen, Q.X. Antityrosinase and antimicrobial activities of trans-cinnamaldehyde thiosemicarbazone. J. Agric. Food Chem., 2009, 57, 5518-5523.
Domagk, G.; Behnisch, R.; Mietzsch, F.; Schimidt, H. Über eine neue ĝeĝen tuberkelbakterien in vitro wirksame verbindungsklasse. Naturwissenchaften, 1946, 33, 315-319.
Pavan, F.R.; Maia, P.I. da S.; Leite, S.R.A.; Deflon, V.M.; Batista, A.A.; Sato, D.N.; Franzblau, S.G.; Leite, C.Q.F. Thiosemicarbazones, semicarbazones, dithiocarbazates and hydrazide/hydrazones: Anti-Mycobacterium tuberculosis activity and cytotoxicity. Eur. J. Med. Chem., 2010, 45(5), 1898-1905.
Wilson, H.R.; Revankar, G.R.; Tolman, R.L. In vitro and in vivo activity of certain thiosemicarbazones against Trypanosoma cruzi. J. Med. Chem., 1974, 17(7), 760-761.
Vieites, M.; Otero, L.; Santos, D.; Olea-Azar, C.; Norambuena, E.; Aguirre, G.; Cerecetto, H.; González, M.; Kemmerling, U.; Morello, A.; Maya, J.D.; Gambino, D. Platinum-based complexes of bioactive 3-(5-nitrofuryl)acrolein thiosemicarbazones showing anti-Trypanosoma cruzi activity. J. Inorg. Biochem., 2009, 103(3), 411-418.
Klayman, D.L.; Bartosevich, J.F.; Griffin, T.S.; Mason, C.J.; Scovill, J.P. 2-Acetylpyridine thiosemicarbazones. 1. A new class of potential antimalarial agents. J. Med. Chem., 1979, 22(7), 855-862.
Khanye, S.D.; Gut, J.; Rosenthal, P.J.; Chibale, K.; Smith, G.S. Synthesis and in vitro antimalarial and antitubercular activity of gold(III) complexes containing thiosemicarbazone ligands. J. Organomet. Chem., 2011, 696, 3296-3396.
Benns, B.G.; Gingras, B.A.; Bayley, C.H. Antifungal activity of some thiosemicarbazones and their copper complexes. Appl. Microbiol., 1960, 8, 353-356.
Opletalova, V.; Kalinowski, D.S.; Vejsova, M.; Kunes, J.; Pour, M.; Jampflek, J.; Buchta, V.; Richardson, D.R. Identification and characterization of thiosemicarbazones with antifungal and antitumor effects: Cellular iron chelation mediating cytotoxic activity. Chem. Res. Toxicol., 2008, 21, 1878-1889.
Turk, S.R.; Shipman, C., Jr; Drach, J.C. Structure-activity relationships among α-(N)-heterocyclic acyl thiosemicarbazones and related compounds as inhibitors of Herpes simplex virus type 1-specified ribonucleoside diphosphate reductase. J. Gen. Virol., 1986, 67, 1625-1632.
Pervez, H.; Chohan, Z.H.; Ramzan, M.; Nasim, F.U.; Khan, K.M. Synthesis and biological evaluation of some new N4-substituted isatin-3-thiosemicarbazones. J. Enzyme Inhib. Med. Chem., 2009, 24, 437-446.
Chen, L.H.; Hu, Y.H.; Song, W.; Song, K.K.; Liu, X.; Jia, Y.L.; Zhuang, J.X.; Chen, Q.X. Synthesis and antityrosinase mechanism of benzaldehyde thiosemicarbazones: Novel tyrosinase inhibitors. J. Agric. Food Chem., 2012, 60, 1542-1547.
Soares, M.A.; Almeida, M.A.; Marins-Goulart, C.; Chaves, O.A.; Echevarria, A.; de Oliveira, M.C.C. Thiosemicarbazones as inhibitors of tyrosine enzyme. Bioorg. Med. Chem. Lett., 2017, 27(15), 3546-3550.
Brockman, R.W.; Thomson, J.R.; Bell, M.J.; Skipper, H.E. Observations on the antileukemic activity of pyridine-2-carboxaldehyde thiosemicarbazone and thiocarbohydrazone. Cancer Res., 1956, 16, 167-170.
Blanz, E.J., Jr; French, F.A. The carcinostatic activity of 5-hydroxy-2-formylpyridine thiosemicarbazone. Cancer Res., 1968, 28(12), 2419-2422.
Hu, W.; Zhou, W.; Xia, C.; Wen, X. Synthesis and anticancer activity of thiosemicarbazones. Bioorg. Med. Chem. Lett., 2006, 16, 2213-2218.
Mackenzie, M.J.; Saltman, D.; Hirte, H.; Low, J.; Johnson, C.; Pond, G.; Moore, M.J. A phase II study of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) and gemcitabine in advanced pancreatic carcinoma - A trial of the princess Margaret hospital phase II consortium. Invest. New Drugs, 2007, 25, 553-558.
Ma, B.; Goh, B.C.; Tan, E.H.; Lam, K.C.; Soo, R.; Leong, S.S.; Wang, L.Z.; Mo, F.; Chan, A.T.C.; Zee, B.; Mok, T. A multicenter phase II trial of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, Triapineβ) and gemcitabine in advanced non-small-cell lung cancer with pharmacokinetic evaluation using peripheral blood mononuclear cells. Invest. New Drugs, 2008, 26, 169-173.
Kolesar, J.M.; Schelman, W.R.; Geiger, P.G.; Holen, K.D.; Traynor, A.M.; Alberti, D.B.; Thomas, J.P.; Chitambar, C.R.; Wilding, G.; Antholine, W.E. Electron paramagnetic resonance study of peripheral blood mononuclear cells from patients with refractory solid tumors treated with Triapineβ. J. Inorg. Biochem., 2008, 102, 693-698.
Dilovic, I.; Rubcic, M.; Vrdoljak, V.; Pavelic, S.K.; Kralj, M.; Piantanida, I.; Cindric, M. Novel thiosemicarbazone derivatives as potential antitumor agents: Synthesis, physicochemical and structural properties, DNA interactions and antiproliferative activity. Bioorg. Med. Chem., 2008, 16, 5189-5198.
Nutting, C.M.; van Herpen, C.M.L.; Miah, A.B.; Bhide, S.A.; Machiels, J.P.; Buter, J.; Kelly, C.; de Raucourt, D.; Harrington, K.J. Phase II study of 3-AP Triapine in patients with recurrent or metastatic head and neck squamous cell carcinoma. Ann. Oncol., 2009, 20, 1275-1279.
Richardson, D.R.; Kalinowski, D.S.; Richardson, V.; Sharpe, P.C.; Lovejoy, D.B.; Islam, M.; Bernhardt, P.V. 2-Acetylpyridine thiosemicarbazones are potent iron chelators and antiproliferative agents: Redox activity, iron complexation and characterization of their antitumor activity. J. Med. Chem., 2009, 52, 1459-1470.
Yu, Y.; Kalinowski, D.S.; Kovacevic, Z.; Siafakas, A.R.; Jansson, P.J.; Stefani, C.; Lovejoy, D.B.; Sharpe, P.C.; Bernhardt, P.V.; Richardson, D.R. Thiosemicarbazones from the old to new: Iron chelators that are more than just ribonucleotide reductase inhibitors. J. Med. Chem., 2009, 52, 5271-5294.
Kalinowski, D.S.; Quach, P.; Richardson, D.R. Thiosemicarbazones: The new wave in cancer treatment. Future Med. Chem., 2009, 1, 1143-1151.
da Silva, A.P.; Martini, M.V.; de Oliveira, C.M.A.; Cunha, S.; de Carvalho, J.E.; Ruiz, A.L.T.G.; da Silva, C.C. Antitumor activity of (-)-α-bisabolol-based thiosemicarbazones against human tumor cell lines. Eur. J. Med. Chem., 2010, 45, 2987-2993.
Lessa, J.A.; Mendes, I.C.; da Silva, P.R.O.; Soares, M.A.; Dos Santos, R.G.; Speziali, N.L.; Romeiro, N.C.; Barreiro, E.J.; Beraldo, H. 2-Acetylpyridine thiosemicarbazones: Cytotoxic activity in nanomolar doses against malignant gliomas. Eur. J. Med. Chem., 2010, 45, 5671-5677.
Traynor, A.M.; Lee, J.W.; Bayer, G.K.; Tate, J.M.; Thomas, S.P.; Mazurczak, M.; Graham, D.L.; Kolesar, J.M.; Schiller, J.H.A. A phase II trial of triapine (NSC# 663249) and gemcitabine as second line treatment of advanced non-small cell lung cancer: Eastern Cooperative Oncology Group Study 1503. Invest. New Drugs, 2010, 28, 91-97.
Merlot, A.M.; Kalinowski, D.S.; Richardson, D.R. Novel chelators for cancer treatment: Where are we now? Antioxid. Redox Signal., 2013, 18, 973-1006.
Stefani, C.; Jansson, P.J.; Gutierrez, E.; Bernhardt, P.V.; Richardson, D.R.; Kalinowski, D.S. Alkyl substituted 2′-benzoylpyridine thiosemicarbazone chelators with potent and selective anti-neoplastic activity: Novel ligands that limit methemoglobin formation. J. Med. Chem., 2013, 56, 357-370.
Zeidner, J.F.; Karp, J.E.; Blackford, A.L.; Smith, B.D.; Gojo, I.; Gore, S.D.; Levis, M.J.; Carraway, H.E.; Greer, J.M.; Ivy, S.P.; Pratz, K.W.; McDevitt, M.A. A phase II trial of sequential ribonucleotide reductase inhibition in aggressive myeloproliferative neoplasms. Haematologica, 2014, 99, 672-678.
Sartorelli, A.C.; Booth, B.A. Inhibition of the growth of sarcoma 180 ascites cells by combinations of inhibitors of nucleic acid biosynthesis and the cupric chelate of kethoxal bis-(thiosemicarbazone). Cancer Res., 1967, 27, 1614-1619.
Sartorelli, A.C.; Agrawal, K.C.; Moore, E.C. Mechanism of inhibition of ribonucleoside diphosphate reductase by α-(N)-heterocyclic aldehyde thiosemicarbazones. Biochem. Pharmacol., 1971, 20, 3119-3123.
Antholine, W.; Knight, J.; Whelan, H.; Petering, D.H. Studies of the reaction of 2-formylpyridine thiosemicarbazone and its iron and copper complexes with biological systems. Mol. Pharmacol., 1977, 13, 89-98.
French, F.A.; Blanz, E.J., Jr The carcinostatic activity of α-(N)-heterocyclic carboxaldehyde thiosemicarbazones. I. Isoquinoline-1-carboxaldehyde thiosemicarbazone. Cancer Res., 1965, 25, 1454-1458.
French, F.A.; Blanz, E.J., Jr The carcinostatic activity of thiosemicarbazones of formyl heteroaromatic compounds. III. Primary correlation. J. Med. Chem., 1966, 9, 585-589.
Klayman, D.L.; Scovill, J.P.; Bartosevich, J.F.; Bruce, J. 2-Acetylpyridine thiosemicarbazones. 5. 1-[l-(2-pyridyl)ethyl]-3-thiosemicarbazides as potential antimalarial agents. J. Med. Chem., 1983, 26, 35-39.
Ferrari, M.B.; Capacchi, S.; Pelosi, G.; Reffo, G.; Tarasconi, P.; Albertini, R.; Pinelli, S.; Lunghi, P. Synthesis, structural characterization and biological activity of helicin thiosemicarbazone monohydrate and a copper(II) complex of salicylaldehyde thiosemicarbazone. Inorg. Chim. Acta, 1999, 286, 134-141.
French, F.A.; Blanz, E.J., Jr; DoAmaral, J.R.; French, D.A. Carcinostatic activity of thiosemicarbazones of formyl heteroaromatic compounds. vii. 2-formylpyridine derivatives bearing additional ring substituents. J. Med. Chem., 1970, 13(6), 1124-1130.
Creasey, W.A.; Agrawal, K.C.; Capizzi, R.L.; Stinson, K.K.; Sartorelli, A.C. Studies on the antineoplastic activity and metabolism of α-(N)-heterocyclic carboxaldehyde thiosemicarbazones in dogs and mice. Cancer Res., 1972, 32, 565-572.
Krakoff, I.H.; Etcubanas, E.; Tan, C.; Mayer, K.; Bethune, V.; Burchenal, J.H. Clinical trial of 5-hydroxypicolinaldehyde thiosemicarbazone (5-HP; NSC-107392), with special reference to its iron chelating properties. Cancer Chemother. Rep., 1974, 58, 207-212.
De Conti, R.C.; Toftness, B.R.; Agrawal, K.C.; Tomchick, R.; Mead, J.A.; Bertino, J.R.; Sartorelli, A.C.; Creasey, W.A. Clinical and pharmacological studies with 5-hydroxy-2-formylpyridine thiosemicarbazone. Cancer Res., 1972, 32, 1455-1462.
Bhatta, M.R.; Adhikari, S.; Lamichhane, J.; Yadav, P.N. Synthesis, characterization and antineoplastic activity of zinc complex of 3-hydroxy-2-formylpyridine N(4)-ethylthiosemicarbazone. J. Nepal Chem. Soc., 2013, 31, 43-49.
Mehta, P.K.; Joshi, B.; Yadav, P.N. Platinum(II) complex of 5-hydroxypyridine-2-carbaldehyde N(4)-ethylthiosemicarbazone: Synthesis, characterization and antineoplastic activity. J. Bangladesh Chem. Soc., 2015, 27, 132-138.
Liu, M.C.; Lin, T.S.; Sartorelli, A.C. Synthesis and antitumor activity of amino derivatives of pyridine-2-carboxaldehyde thiosemicarbazone. J. Med. Chem., 1992, 35(20), 3672-3677.
Finch, R.A.; Liu, M.C.; Cory, A.H.; Cory, J.G.; Sartorelli, A.C. Triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone; 3-AP): An inhibitor of ribonucleotide reductase with antineoplastic activity. Adv. Enzyme Regul., 1999, 39, 3-12.
Finch, R.A.; Liu, M.; Grill, S.P.; Rose, W.C.; Loomis, R.; Vasquez, K.M.; Cheng, Y.; Sartorelli, A.C. Triapine (3-Aminopyridine-2-carboxaldehyde-thiosemicarbazone): A potent inhibitor of ribonucleotide reductase activity with broad spectrum antitumor activity. Biochem. Pharmacol., 2000, 59, 983-991.
Chaston, T.B.; Lovejoy, D.B.; Watts, R.N.; Richardson, D.R. Examination of the antiproliferative activity of iron chelators: Multiple cellular targets and the different mechanism of action of Triapine compared with desferrioxamine and the potent pyridoxal isonicotinoyl hydrazone analogue 311. Clin. Cancer Res., 2003, 9, 402-414.
Shao, J.; Zhou, B.; Chu, B.; Yen, Y. Ribonucleotide reductase inhibitors and future drug design. Curr. Cancer Drug Targets, 2006, 6, 409-431.
Sartorelli, A.C.; Agrawal, K.C. Development of α-(N)-heterocyclic carboxaldehyde thiosemicarbazones with clinical potential as antineoplastic agents, In: Cancer Chemotherapy; ACS Symposium Series; American Chemical Society: Washington, DC. , 1976.
Agrawal, K.C.; Sartorelli, A.C. Potential antitumor agents. II. Effects of modifications in the side chain of 1-formylisoquinoline thiosemicarbazone. J. Med. Chem., 1969, 12(5), 771-774.
Richardson, D.R. Iron chelators as therapeutic agents for the treatment of cancer. Crit. Rev. Oncol. Hematol., 2002, 42, 267-281.
Spingarn, N.E.; Sartorelli, A.C. Synthesis and evaluation of the thiosemicarbazone, dithiocarbazonate, and 2′-pyrazinylhydrazone of pyrazinecarboxaldehyde as agents for the treatment of iron overload. J. Med. Chem., 1979, 22, 1314-1316.
Easmon, J.; Heinish, G.; Holzer, W.; Rosenwirth, B. Novel thiosemicarbazones derived from formyl- and acyldiazines: Synthesis, effects on cell proliferation, and synergism with antiviral agents. J. Med. Chem., 1992, 35, 3288-3296.
Becker, E.; Richardson, D.R. Development of novel aroylhydrazone ligands for iron chelation therapy: 2-pyridylcarboxaldehyde isonicotinoyl hydrazone analogs. J. Lab. Clin. Med., 1999, 134, 510-521.
Richardson, D.R. The controversial role of deferiprone in the treatment of thalassemia. J. Lab. Clin. Med., 2001, 137(5), 324-329.
Lovejoy, D.B.; Richardson, D.R. Novel “hybrid” iron chelators derived from aroylhydrazones and thiosemicarbazones demonstrate high anti-proliferative activity that is selective for tumor cells. Blood, 2002, 100, 666-676.
Ocean, A.J.; Christos, P.; Sparano, J.A.; Matulich, D.; Kaubish, A.; Siegel, A.; Sung, M.; Ward, M.M.; Hamel, N.; Espinoza-Delgado, I.; Yen, Y.; Lane, M.E. Phase II trial of the ribonucleotide reductase inhibitor 3-aminopyridine-2-carboxaldehyde thiosemicarbazone plus gemcitabine in patients with advanced biliary tract cancer. Cancer Chemother. Pharmacol., 2010, 68(2), 379-388.
Wadler, S.; Makower, D.; Clairmont, C.; Lambert, P.; Fehn, K.; Sznol, M. Phase I and pharmacokinetic study of the ribonucleotide reductase inhibitor, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, administered by 96-hour intravenous continuous infusion. J. Clin. Oncol., 2004, 22, 1553-1563.
Kunos, C.A.; Radivoyevitch, T.; Waggoner, S.; Debernardo, R.; Zanotti, K.; Resnick, K.; Fusco, N. Adams, Redline, R.R.; Faulhaber, P.; Dowlati, A. Radiochemotherapy plus 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, NSC #663249) in advanced-stage cervical and vaginal cancers. Gynecol. Oncol., 2013, 130, 75-80.
Kunos, C.A.; Waggoner, S.; von Gruenigen, V.; Eldermire, E.; Pink, J.; Dowlati, A.; Kinsella, T.J. Phase I trial of pelvic radiation, weekly cisplatin, and 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, NSC #663249) for locally advanced cervical cancer. Clin. Cancer Res., 2010, 16, 1298-1306.
Odenike, O.M.; Larson, R.A.; Gajria, D.; Dolan, M.E.; Delaney, S.M.; Karrison, T.G.; Ratain, M.J.; Stock, W. Phase I study of the ribonucleotide reductase inhibitor 3-aminopyridine-2-carboxaldehyde-thiosemicarbazone (3-AP) in combination with high dose cytarabine in patients with advanced myeloid leukemia. Invest. New Drugs, 2008, 26(3), 233-239.
Yen, Y.; Margolin, K.; Doroshow, J.; Fishman, M.; Johnson, B.; Clairmont, C.; Sullivan, D.; Sznol, M. A phase I trial of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone in combination with gemcitabine for patients with advanced cancer. Cancer Chemother. Pharmacol., 2004, 54, 331-342.
Yuan, J.; Lovejoy, D.B.; Richardson, D.R. Novel di-2-pyridyl-derived iron chelators with marked and selective antitumor activity: In vitro and in vivo assessment. Blood, 2004, 104, 1450-1458.
Kalinowski, D.S.; Richardson, D.R. The evolution of iron chelators for the treatment of iron overload disease and cancer. Pharmacol. Rev., 2005, 57, 547-583.
Whitnall, M.; Howard, J.; Ponka, P.; Richardson, D.R. A class of iron chelators with a wide spectrum of potent antitumor activity that overcomes resistance to chemotherapeutics. Proc. Natl. Acad. Sci. USA, 2006, 103, 14901-14906.
Lovejoy, D.B.; Sharp, D.M.; Seebacher, N.; Obeidy, P.; Prichard, T.; Stefani, C.; Basha, M.T.; Sharpe, P.C.; Jansson, P.J.; Kalinowski, D.S.; Bernhardt, P.V.; Richardson, D.R. Novel second-generation di-2-pyridylketone thiosemicarbazones show synergism with standard chemotherapeutics and demonstrate potent activity against lung cancer xenografts after oral and intravenous administration in vivo. J. Med. Chem., 2012, 55, 7230-7244.
Kovacevic, Z.; Chikhani, S.; Lovejoy, D.B.; Richardson, D.R. Novel thiosemicarbazone iron chelators induce up-regulation and phosphorylation of the metastasis suppressor N-myc down-stream regulated gene 1: A new strategy for the treatment of pancreatic cancer. Mol. Pharmacol., 2011, 80, 598-609.
Kalinowski, D.S.; Yu, Y.; Sharpe, P.C.; Islam, M.; Liao, Y.T.; Lovejoy, D.B.; Kumar, N.; Bernhardt, P.V.; Richardson, D.R. Design, synthesis, and characterization of novel iron chelators: Structure-activity relationships of the 2-benzoylpyridine thiosemicarbazone series and their 3-nitrobenzoyl analogues as potent antitumor agents. J. Med. Chem., 2007, 50, 3716-3729.
Kalinowski, D.S.; Sharpe, P.C.; Bernhardt, P.V.; Richardson, D.R. Design, synthesis, and characterization of new iron chelators with anti-proliferative activity: Structure-activity relationships of novel thiohydrazone analogues. J. Med. Chem., 2007, 50, 6212-6225.
Yu, Y.; Rahmanto, Y.S.; Richardson, D.R. Bp44mT: An orally-active iron chelator of the thiosemicarbazone class with potent anti-tumour efficacy. Br. J. Pharmacol., 2012, 165, 148-166.
Stariat, J.; Kovarikova, P.; Klimes, J.; Lovejoy, D.B.; Kalinowski, D.S.; Richardson, D.R. HPLC methods for determination of two novel thiosemicarbazone anti-cancer drugs (N4mT and Dp44mT) in plasma and their application to in vitro plasma stability of these agents. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci., 2009, 877(3), 316-322.
Richardson, D.R.; Sharpe, P.C.; Lovejoy, D.B.; Senaratne, D.; Kalinowski, D.S.; Islam, M.; Bernhardt, P.V. Dipyridyl thiosemicarbazone chelators with potent and selective antitumor activity form iron complexes with redox activity. J. Med. Chem., 2006, 49, 6510-6521.
Iakovidou, Z.; Papageorgiou, A.; Demertzis, M.A.; Mioglou, E.; Mourelatos, D.; Kotsis, A.; Yadav, P.N.; Kovala-Demertzi, D. Platinum(II) and palladium(II) complexes with 2-acetylpyridine thiosemicarbazone: Cytogenetic and antineoplastic effects. Anticancer Drugs, 2001, 12, 65-70.
Demertzi, D.K.; Alexandratos, A.; Papageorgiou, A.; Yadav, P.N.; Dalezis, P.; Demertzis, M.A. Synthesis, characterization, crystal structures, in vitro and in vivo antitumor activity of palladium(II) and zinc(II) complexes with 2-formyl and 2-acetylpyridine N(4)-1-(2-pyridyl)-piperazinyl thiosemicarbazone. Polyhedron, 2008, 27, 2731-2738.
Demertzi, D.K.; Yadav, P.N.; Demertzis, M.A.; Coluccia, M. Synthesis, crystal structure, spectral properties and cytotoxic activity of platinum(II) complexes of 2-acetyl pyridine and pyridine-2-carbaldehyde N(4)-ethyl-thiosemicarbazones. J. Inorg. Biochem., 2000, 78, 347-354.
Demertzi, D.K.; Demertzis, M.A.; Filiou, E.; Pantazaki, A.A.; Yadav, P.N.; Miller, J.R.; Zheng, Y.; Kyriakidis, D.A. Platinum(II) and palladium(II) complexes with 2-acetylpyridine 4N-ethyl thiosemicarbazone able to overcome the cis-platin resistance. Structure, antibacterial activity and DNA strand breakage. Biometals, 2003, 16, 411-418.
Demertzi, D.K.; Yadav, P.N.; Wiecek, J. Skoulika, S.; Varadinova, T.; Demertzis, M.A. Zinc(II) complexes derived from pyridine-2-carbaldehyde thiosemicarbazone and (1E)-1-pyridin-2-ylethan-1-one thiosemicarbazone: Synthesis, crystal structures and antiproliferative activity of zinc(II) complexes. J. Inorg. Biochem., 2006, 100, 1558-1567.
Serda, M.; Kalinowski, D.S.; Mrozek-Wilczkiewicz, A.; Musiol, R.; Szurko, A.; Ratuszna, A.; Pantarat, N.; Kovacevic, Z.; Merlot, A.M.; Richardson, D.R.; Polanski, J. Synthesis and characterization of quinoline-based thiosemicarbazones and correlation of cellular iron-binding efficacy to anti-tumor efficacy. Bioorg. Med. Chem. Lett., 2012, 22, 5527-5531.
Buss, J.L.; Greene, B.T.; Turner, J.; Torti, F.M.; Torti, S.V. Iron chelators in cancer chemotherapy. Curr. Top. Med. Chem., 2004, 4(15), 1623-1635.
Li, Q.Y.; Zu, Y.G.; Shi, R.Z.; Yao, L.P. Review camptothecin: Current perspectives. Curr. Med. Chem., 2006, 13(17), 2021-2039.
West, D.X.; Ives, J.S.; Krejci, J.; Salberg, M.M.; Zumbahlen, T.L.; Bain, G.A.; Liberta, A.E.; Valdes-Martınez, J.; Hernandez-Ortega, S.; Toscano, R.A. Copper(II) complexes of 2-benzoylpyridine 4N-substituted thiosemicarbazones. Polyhedron, 1995, 14(15-16), 2189-2200.
Liberta, A.E.; West, D.X. Antifungal and antitumor activity of heterocyclic thiosemicarbazones and their metal complexes: Current status. Biometals, 1992, 5, 121-126.
West, D.X.; Ooms, C.E.; Saleda, J.S.; Gebremedhin, H.; Liberta, A.E. Copper(II) and nickel(II) complexes of 2-formylpyridine 3-piperidinyl-, 3-hexamethyleneiminyl- and 3-azabicyclo[3.2.2] nonylthiosemicarbazones. Trans. Met. Chem. , 1994, 19(5), 553-558.
Miller, M.C.; Stineman, C.N.; Vance, J.R.; West, D.X.; Hall, I.H. The cytotoxicity of copper(II) complexes of 2-acetylpyridyl-4N-substituted thiosemicarbazones. Anticancer Res., 1998, 18, 4131-4139.
Milunovic, M.N.M.; Enyedy, E.A.; Nagy, N.V.; Kiss, T.; Trondl, R.; Jakupec, M.A.; Keppler, B.K.; Krachler, R.; Novitchi, G.; Arion, V.B. L- and D-proline thiosemicarbazone conjugates: Coordination behavior in solution and the effect of copper(II) coordination on their antiproliferative activity. Inorg. Chem., 2012, 51, 9309-9321.
Matesanz, A.I.; Joie, C.; Souza, P. Chemistry, antiproliferative activity and low nephrotoxicity of 3,5-diacetyl-1,2,4-triazol bis(4Nthiosemicarbazone) ligands and their platinum(II) complexes. Dalton Trans.,, 2010, 30, 7059-7065.
Enyedy, E.A.; Nagy, N.V.; Zsigo, E.; Kowol, C.R.; Arion, V.B.; Keppler, B.K.; Kiss, T. Comparative solution equilibrium study of the interactions of copper(II), iron(II) and zinc(II) with Triapine (3-aminopyridine-2-carbaldehyde thiosemicarbazone) and related ligands. Eur. J. Inorg. Chem., 2010, 11, 1717-1728.
Enyedy, E.A.; Bognar, G.M.; Nagy, N.V.; Jakusch, T.; Kiss, T.; Gambino, D. Solution speciation of potential anticancer metal complexes of salicylaldehyde semicarbazone and its bromo derivative. Polyhedron, 2014, 67, 242-252.
Rudnev, A.V.; Foteeva, L.S.; Kowol, C.; Berger, R.; Jakupec, M.A.; Arion, V.B.; Timerbaev, A.R.; Keppler, B.K. Preclinical characterization of anticancer gallium(III) complexes: Solubility, stability, lipophilicity and binding to serum proteins. J. Inorg. Biochem., 2006, 100, 1819-1826.
Kowol, C.; Trondl, R.; Heffeter, P.; Arion, V.; Jakupec, M.; Roller, A.; Galanski, M.; Berger, W.; Keppler, B.K. Impact of metal coordination on cytotoxicity of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (Triapine) and novel insights into terminal dimethylation. J. Med. Chem., 2009, 52, 5032-5043.
West, D.X.; Swearingen, J.K.; Valdes-Martinez, J.; Hernandez-Ortega, S.; El-Sawaf, A.K.; van Meurs, F.; Castineiras, A.; Garcia, I.; Bermejo, E. Spectral and structural studies of iron(III), cobalt(II,III) and nickel(II) complexes of 2-pyridineformamide N(4)-methylthiosemicarbazone. Polyhedron, 1999, 18, 2919-2929.
Castineiras, A.; Garcia, I.; Bermejo, E.; West, D.X. Structures of 2-pyridineformamide thiosemicarbazone and its complexes with cadmium halides. Polyhedron, 2000, 19, 1873-1880.
Castineiras, A.; Garcia, I.; Bermejo, E.; West, D.X. Structural and spectral studies of 2-pyridineformamide thiosemicarbazone and its complexes prepared with zinc halides. Z. Naturforsch, 2000, 55b, 511-518.
Ketcham, K.A.; Swearingen, J.K.; Castineiras, A.; Garcia, I.; Bermejo, E.; West, D.X. Iron(III), cobalt(II, III), copper(II) and zinc(II) complexes of 2-pyridineformamide 3-piperidylthio-semicarbazone. Polyhedron, 2001, 20, 3265-3273.
Bermejo, E.; Castineiras, A.; Fostiak, I.M.; Garcia-Santos, I.; Swearingen, J.K.; West, D.X. Spectral and structural studies of Zn and Cd complexes of 2-pyridineformamide N(4)-ethylthiose-micarbazone. Polyhedron, 2004, 23, 2303-2313.
Bermejo, E.; Castineiras, A.; Garcia-Santos, I.; West, D.X. Structural and coordinative variability in zinc(II), cadmium(II), and mercury(II) complexes of 2-pyridineformamide 3-hexamethyl-eneiminyl thiosemicarbazone. Z. Anorg. Allg. Chem., 2004, 630, 1096-1009.
Mendes, I.C.; Moreira, J.P.; Ardisson, J.D.; Dos Santos, R.G.; da Silva, P.R.O.; Garcia, I.; Castiñeiras, A.; Beraldo, H. Organotin(IV) complexes of 2-pyridineformamide derived thiosemicarbazones: Antimicrobial and cytotoxic effects. Eur. J. Med. Chem., 2008, 43, 1454-1461.
Shakya, B.; Yadav, P.N.; Ueda, J.Y.; Awale, S. Discovery of 2-pyridineformamide thiosemicarbazones as potent antiausterity agents. Bioorg. Med. Chem. Lett., 2014, 24, 458-461.
Shakya, B.; Shahi, N.; Ahmad, F.; Pokhrel, Y.R.; Yadav, P.N. 2-Pyridineformamide N(4)-ring incorporated thiosemicarbazones inhibit MCF-7 cells by inhibiting JNK pathway. Bioorg. Med. Chem. Lett., 2019, 29, 1677-1681.
Graminha, A.E.; Vilhena, F.S.; Batista, A.A.; Louro, S.R.W.; Ziolli, R.L.; Teixeira, L.R.; Beraldo, H. 2-Pyridinoformamide-derived thiosemicarbazones and their iron(III) complexes: Potential antineoplastic activity. Polyhedron, 2008, 27, 547-551.
Mendes, I.C.; Soares, M.A.; Dos Santos, R.G.; Pinheiro, C.; Beraldo, H. Gallium (III) complexes of 2-pyridineformamide thiosemicarbazones: Cytotoxic activity against malignant glioblastoma. Eur. J. Med. Chem., 2009, 44, 1870-1877.
Shakya, B.; Adhikari, S.; Lamichhane, J.; Yadav, P.N. Synthesis of N'-(4-Methylpiperazine-1-carbonothioyl)picolino-hydrazonamide as an antineoplastic agent. J. Nepal Chem. Soc., 2013, 32, 11-18.
Ali, A.Q.; Teoh, S.G.; Eltayeb, N.E.; Ahamed, M.B.K.; Majid, A.M.S.A. Synthesis of copper(II) complexes of isatin thiosemicarbazone derivatives: In vitro anti-cancer, DNA binding, and cleavage activities. Polyhedron, 2014, 74, 6-15.
Ali, A.Q.; Teoh, S.G.; Salhhin, A.; Eltayeb, N.E.; Ahamed, M.B.K.; Majid, A.M.S.A. Synthesis of platinum(II) complexes of isatin thiosemicarbazones derivatives: In vitro anti-cancer and deoxyribose nucleic acid binding activities. Inorg. Chim. Acta, 2014, 416, 235-244.
Mathiyan, M.; Surendran, S.; Nattamai, S.P.B.; Anandaram, S. Synthesis and crystal structure of new monometallic and bimetallic copper(II) complexes with N-substituted isatin thiosemicarbazone ligands: Effects of the complexes on DNA/protein-binding property, DNA cleavage study and in vitro anticancer activity. Polyhedron, 2016, 118, 103-117.
West, D.X.; Liberta, A.E. Thiosemicarbazone complexes of copper(II): Structural and biological studies. Coord. Chem. Rev., 1993, 123, 49-71.
Beraldo, H.; Gambino, D. The wide pharmacological versatility of semicarbazones, thiosemicarbazones and their metal complexes. Mini Rev. Med. Chem., 2004, 4(1), 31-39.
Tisato, F.; Marzano, C.; Porchia, M.; Pellei, M.; Santini, C. Copper in diseases and treatments, and copper-based anticancer strategies. Med. Res. Rev., 2010, 30(4), 708-749.
Wang, J.; Yin, D.; Xie, C.; Zheng, T.; Liang, Y.; Hong, X.; Lu, Z.; Song, X.; Song, R.; Yang, H.; Sun, B.; Bhatta, N.; Meng, X.; Pan, S.; Jiang, H.; Liu, L. The iron chelator Dp44mT inhibits hepatocellular carcinoma metastasis via N-myc downstream-regulated gene 2 (NDRG2)/gp130/STAT3 pathway. Oncotarget, 2014, 5, 8478-8491.
Le, N.T.; Richardson, D.R. The role of iron in cell cycle progression and the proliferation of neoplastic cells. Biochim. Biophys. Acta, 2002, 1603, 31-46.
Lieu, P.T.; Heiskala, M.; Peterson, P.A.; Yang, Y. The roles of iron in health and disease. Mol. Aspects Med., 2001, 22, 1-87.
Torti, S.V.; Torti, F.M. Iron and cancer: More ore to be mined. Nat. Rev. Cancer, 2013, 13, 342-355.
Kalinowski, D.S.; Richardson, D.R. Future of toxicology-iron chelators and differing modes of action and toxicity: The changing face of iron chelation therapy. Chem. Res. Toxicol., 2007, 20, 715-720.
Richardson, D.R.; Kalinowski, D.S.; Lau, S.; Jansson, P.J.; Lovejoy, D.B. Cancer cell iron metabolism and the development of potent iron chelators as anti-tumour agents. Biochim. Biophys. Acta, 2009, 1790, 702-717.
Richardson, D.R.; Tran, E.H.; Ponka, P. The potential of iron chelators of the pyridoxal isonicotinoyl hydrazone class as effective antiproliferative agents. Blood, 1995, 86, 4295-4306.
Richardson, D.R. The therapeutic potential of iron chelators. Expert Opin. Investig. Drugs, 1999, 8, 2141-2158.
Richardson, D.R.; Baker, E. The uptake of iron and transferrin by the human malignant melanoma cell. Biochim. Biophys. Acta, 1990, 1053, 1-12.
Andrews, N.C. Disorders of iron metabolism. N. Engl. J. Med., 1999, 341, 1986-1995.
Anderson, G.J.; Vulpe, C.D. Mammalian iron transport. Cell. Mol. Life Sci., 2009, 66, 3241-3261.
Dunn, L.L.; Rahmanto, Y.S.; Richardson, D.R. Iron uptake and metabolism in the new millennium. Trends Cell Biol., 2007, 17, 93-100.
Zhang, C. Essential functions of iron-requiring proteins in DNA replication, repair and cell cycle control. Protein Cell, 2014, 5, 750-760.
Lill, R.; Hoffmann, B.; Molik, S.; Pierik, A.J.; Rietzschel, N.; Stehling, O.; Uzarska, M.A.; Webert, H.; Wilbrecht, C.; Muhlenhoff, U. The role of mitochondria in cellular iron-sulfur protein biogenesis and iron metabolism. Biochim. Biophys. Acta, 2012, 1823, 1491-1508.
Zhao, N.; Gao, J.; Enns, C.A.; Knutson, M.D. ZRT/IRT-like protein 14 (ZIP14) promotes the cellular assimilation of iron from transferrin. J. Biol. Chem., 285, 2010, 32141-32150
Zhang, F.; Tao, Y.; Zhang, Z.; Guo, X.; An, P.; Shen, Y.; Wu, Q.; Yu, Y.; Wang, F. Metalloreductase Steap3 coordinates the regulation of iron homeostasis and inflammatory responses. Haematologica, 2012, 97, 1826-1835.
Pantopoulos, K.; Porwal, S.K.; Tartakoff, A.; Devireddy, L. Mechanisms of mammalian iron homeostasis. Biochemistry, 2012, 51, 5705-5724.
Gkouvatsos, K.; Papanikolaou, G.; Pantopoulos, K. Regulation of iron transport and the role of transferrin. Biochim. Biophys. Acta, 2012, 1820, 188-202.
Zhang, C.; Liu, G.; Huang, M. Ribonucleotide reductase metallocofactor: Assembly, maintenance and inhibition. Front. Biol. (Beijing), 2014, 9, 104-113.
Larrick, J.W.; Cresswell, P. Modulation of cell surface iron transferrin receptors by cellular density and state of activation. J. Supramol. Struct., 1979, 11, 579-586.
Sutherland, R.; Delia, D.; Schneider, C.; Newman, R.; Kemshead, J.; Greaves, M. Ubiquitous cell-surface glycoprotein on tumor cells is proliferation-associated receptor for transferrin. Proc. Natl. Acad. Sci. USA, 1981, 78, 4515-4519.
Trinder, D.; Zak, O.; Aisen, P. Transferrin receptor-independent uptake of diferric transferrin by human hepatoma cells with antisense inhibition of receptor expression. Hepatology, 1996, 23, 1512-1520.
Richardson, D.; Baker, E. Two mechanisms of iron uptake from transferrin by melanoma cells. The effect of desferrioxamine and ferric ammonium citrate. J. Biol. Chem., 1992, 267, 13972-13979.
Chaston, T.B.; Richardson, D.R. Iron chelators for the treatment of iron overload disease: Relationship between structure, redox activity, and toxicity. Am. J. Hematol., 2003, 73, 200-210.
Lippert, B., Ed.; Cisplatin: Chemistry and biochemistry of a leading anticancer drug; Weinheim: Wiley-VCH: New York,. , 1999.
Louie, A.Y.; Meade, T.J. Metal complexes as enzyme inhibitors. Chem. Rev., 1999, 99, 2711-2734.
French, F.A.; Blanz, E.J., Jr; Shaddix, S.C.; Brockman, R.W. α-(N)-Formylheteroaromatic thiosemicarbazone - Inhibition of tumor-derived ribonucleoside diphosphate reductase and correlation with in vivo antitumor activity. J. Med. Chem., 1974, 17(2), 172-181.
Brockman, R.W.; Sidwell, R.W.; Arnett, G.; Shaddix, S. Heterocyclic thiosemicarbazones: Correlation between structure, inhibition of ribonucleotide reductase, and inhibition of DNA viruses. Proc. Soc. Exp. Biol. Med., 1970, 133, 609-614.
Sartorelli, A.C.; Agrawal, K.C.; Tsiftsoglou, A.S.; Moore, E.C. Characterization of the biochemical mechanism of action of α-(N)-heterocyclic carboxaldehyde thiosemicarbazones. Adv. Enzyme Regul., 1976, 15, 117-139.
Goan, Y.G.; Zhou, B.; Hu, E.; Mi, S.; Yen, Y. Overexpression of ribonucleotide reductase as a mechanism of resistance to 2,2-difluorodeoxycytidine in the human KB cancer cell line. Cancer Res., 1999, 59(17), 4204-4207.
Potsch, S.; Drechsler, H.; Liermann, B.; Graslund, A.; Lassmann, G. p-Alkoxyphenols, a new class of inhibitors of mammalian R2 ribonucleotide reductase: Possible candidates for antimelanotic drugs. Mol. Pharmacol., 1994, 45, 792-796.
Holland, K.P.; Elford, H.L.; Bracchi, V.; Annis, C.G.; Schuster, S.M.; Chakrabarti, D. Antimalarial activities of polyhydroxyphenyl and hydroxamic acid derivatives. Antimicrob. Agents Chemother., 1998, 42, 2456-2458.
Bianchi, V.; Borella, S.; Calderazzo, F.; Ferraro, P.; Chieco, B.L.; Reichard, P. Inhibition of ribonucleotide reductase by 2′-substituted deoxycytidine analogs: Possible application in AIDS treatment. Proc. Natl. Acad. Sci. USA, 1994, 91, 8403-8407.
Jordan, A.; Torrents, E.; Sala, I.; Hellman, U.; Gibert, I.; Reichard, P. Ribonucleotide reduction in Pseudomonas species: Simultaneous presence of active enzymes from different classes. J. Bacteriol., 1999, 181, 3974-3980.
Weber, G. Biochemical strategy of cancer cells and the design of chemotherapy: G.H.A. Clowes Memorial Lecture1. Cancer Res., 1983, 43, 3466-3492.
Guarino, E.; Salguero, I.; Kearsey, S.E. Cellular regulation of ribonucleotide reductase in eukaryotes. Semin. Cell Dev. Biol., 2014, 30, 97-103.
Aye, Y.; Li, M.; Long, M.J.; Weiss, R.S. Ribonucleotide reductase and cancer: Biological mechanisms and targeted therapies. Oncogene, 2015, 34, 2011-2021.
Eklund, H.; Uhlin, U.; Farnegardh, M.; Logan, D.T.; Nordlund, P. Structure and function of the radical enzyme ribonucleotide reductase. Prog. Biophys. Mol. Biol., 2001, 77(3), 177-268.
Tanaka, H.; Arakawa, H.; Yamaguchi, T.; Shiraishi, K.; Fukuda, S.; Matsui, K.; Takei, Y.; Nakamura, Y. A ribonucleotide reductase gene involved in a p53-dependent cell-cycle checkpoint for DNA damage. Nature, 2000, 404, 42-49.
Shao, J.; Zhou, B.; Zhu, L.; Bilio, A.J.; Su, L.; Yuan, Y.C.; Ren, S.; Lien, E.J.; Shih, J.; Yen, Y. Determination of the potency and subunit-selectivity of ribonucleotide reductase inhibitors with a recombinant-holoenzyme-based in vitro assay. Biochem. Pharmacol., 2005, 69(4), 627-634.
Xue, L.; Zhou, B.; Liu, X.; Qiu, W.; Jin, Z.; Yen, Y. Wild-type p53 regulates human ribonucleotide reductase by protein-protein interaction with p53R2 as well as hRRM2 subunits. Cancer Res., 2003, 63, 980-986.
Pai, C.C.; Kearsey, S.E. A critical balance: dNTPs and the maintenance of genome stability. Genes (Basel), 2017, 8(2)E57
Shao, J.; Zhou, B.; Di Bilio, J.; Zhu, L.; Wang, T.; Qi, C.; Shih, J.; Yen, Y. A Ferrous-Triapine complex mediates formation of reactive oxygen species that inactivate human ribonucleotide reductase. Mol. Cancer Ther., 2006, 5, 586-592.
Thelander, L.; Reichard, P. Reduction of ribonucleotides. Annu. Rev. Biochem., 1979, 48, 133-158.
Nelson, D.L.; Cox, M.M. Lehninger Principles of Biochemsitry, 5th ed; W. H. Freeman and Company, 2008.
Natarajan, S.; Mathews, R. Modeling and proposed mechanism of two radical scavengers through docking to curtail the action of ribonucleotide reductase. J. Biophys. Str. Biol., 2011, 3(2), 38-48.
Antholine, W.E.; Knight, J.M.; Petering, D.H. Inhibition of tumor cell transplantability by iron and copper complexes of 5-substituted 2-formylpyridine thiosemicarbazones. J. Med. Chem., 1976, 19, 339-341.
Yu, Y.; Rahmanto, Y.S.; Hawkins, C.L.; Richardson, D.R. The potent and novel thiosemicarbazone chelators di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone and 2-benzoylpyridine-4,4-dimethyl-3-thiosemicarbazone affect crucial thiol systems required for ribonucleotide reductase activity. Mol. Pharmacol., 2011, 79(6), 921-931.
Stubbe, J. Ribonucleotide reductases: Amazing and confusing. J. Biol. Chem., 1990, 265, 5329-5332.
Mao, S.S.; Holler, T.P.; Yu, G.X.; Bollinger, J.M.; Booker, S.; Johnston, M.I.; Stubbe, J. A model for the role of multiple cysteine residues involved in ribonucleotide reduction: Amazing and still confusing. Biochemistry, 1992, 31(40), 9733-9743.
Stubbe, J.; van der Donk, W.A. Protein radicals in enzyme catalysis. Chem. Rev., 1998, 98(2), 705-762.
Kolberg, M.; Strand, K.R.; Graff, P.; Andersson, K.K. Structure, function, and mechanism of ribonucleotide reductases. Biochim. Biophys. Acta, 2004, 1699, 1-34.
Thelander, L.; Graslund, A. Mechanism of inhibition of mammalian ribonucleotide reductase by the iron chelate of 1-formylisoquinoline thiosemicarbazone. Destruction of the tyrosine free radical of the enzyme in an oxygen-requiring reaction. J. Biol. Chem., 1983, 258, 4063-4066.
Trossini, G.H.G.; Guido, R.V.C.; Oliva, G.; Ferreira, E.I.; Andricopulo, A.D. Quantitative structure-activity relationships for a series of inhibitors of cruzain from Trypanosoma cruzi: Molecular modeling, CoMFA and CoMSIA studies. J. Mol. Graph. Model., 2009, 28, 3-11.
Pelosi, G. Thiosemicarbazone metal complexes: From structure to activity. The Open Crystall. J.,, 2010, 3, 16-28.
Weinberg, E.D. The role of iron in cancer. Eur. J. Cancer Prev., 1996, 5, 19-36.
D’Autreaux, B.; Toledano, M.B. ROS as signalling molecules: Mechanisms that generate specificity in ROS homeostasis. Nat. Rev. Mol. Cell Biol., 2007, 8, 813-824.
Liu, Z.D.; Hider, R.C. Design of iron chelators with therapeutic application. Coord. Chem. Rev., 2002, 232, 151-171.
Barnham, K.J.; Masters, C.L.; Bush, A.I. Neurodegenerative diseases and oxidative stress. Nat. Rev. Drug Discov., 2004, 3, 205-214.
Fenton, H.J.H. On a new reaction of tartaric acid. Chem. News, 1876, 33, 190-190.
Wardman, P.; Candeias, L.P. Fenton chemistry: An introduction. Radiat. Res., 1996, 145, 523-531.
Liochev, S.I. The mechanism of “Fenton-like” reactions and their importance for biological systems. A biologist’s view. Met. Ions Biol. Syst., 1999, 36, 1-39.
Papanikolaou, G.; Pantopoulos, K. Iron metabolism and toxicity. Toxicol. Appl. Pharmacol., 2005, 202, 199-211.
Andrews, N.C. Iron homeostasis: Insights from genetics and animal models. Nat. Rev. Genet., 2000, 1, 208-217.
Pelicano, H.; Carney, D.; Huang, P. ROS stress in cancer cells and therapeutic implications. Drug Resist. Updat., 2004, 7, 97-110.
Ghaffari, S. Oxidative stress in the regulation of normal and neoplastic hematopoiesis. Antioxid. Redox Signal., 2008, 10, 1923-1940.
Torti, S.V.; Torti, F.M. Ironing out cancer. Cancer Res., 2011, 71, 1511-1514.
West, D.X.; Padhye, S.B.; Sonawane, P.B. Structural and physical correlations in the biological properties of transition metal heterocyclic thiosemicarbazone and S-alkyldithiocarbazate complexes. Struct. Bonding, Springer, 1991, 76, 1-50.
Jansson, P.J.; Sharpe, P.C.; Bernhardt, P.V.; Richardson, D.R. Novel thiosemicarbazones of the ApT and DpT series and their copper complexes: Identification of pronounced redox activity and characterization of their antitumor activity. J. Med. Chem., 2010, 53, 5759-5769.
Buss, J.L.; Neuzil, J.; Ponka, P. Oxidative stress mediates toxicity of pyridoxal isonicotinoyl hydrazone analogs. Arch. Biochem. Biophys., 2004, 421, 1-9.
Basu, S.; Majumder, S.; Chatterjee, S.; Ganguly, A.; Efferth, T.; Choudhuri, S.K. Detection and characterization of a glutathione conjugate of a novel copper complex. In Vivo, 2009, 23, 401-408.
Majumder, S.; Dutta, P.; Mookerjee, A.; Choudhuri, S.K. The role of a novel copper complex in overcoming doxorubicin resistance in Ehrlich ascites carcinoma cells in vivo. Chem. Biol. Interact., 2006, 159, 90-103.
Saryan, L.A.; Mailer, K.; Krishnamurti, C.; Antholine, W.; Petering, D.H. Interaction of 2-formylpyridine thiosemicarbazonato copper(II) with Ehrlich ascites tumor cells. Biochem. Pharmacol., 1981, 30, 1595-1604.
Byrnes, R.W.; Antholine, W.E.; Petering, D.H. Oxidation-reduction reactions in Ehrlich cells treated with copper-neocuproine. Free Radic. Biol. Med., 1992, 13, 469-478.
Liu, Y.; Fiskum, G.; Schubert, D. Generation of reactive oxygen species by the mitochondrial electron transport chain. J. Neurochem., 2002, 80, 780-787.
Tsang, S.Y.; Tam, S.C.; Bremner, I.; Burkitt, M.J. Research communication copper-1,10-phenanthroline induces inter-nucleosomal DNA fragmentation in HepG2 cells, resulting from direct oxidation by the hydroxyl radical. Biochem. J., 1996, 317, 13-16.
Byrnes, R.W.; Mohan, M.; Antholine, W.E.; Xu, R.X.; Petering, D.H. Oxidative stress induced by a copper-thiosemicarbazone complex. Biochemistry, 1990, 29, 7046-7053.
Antholine, W.E.; Taketa, F. Effects of 2-formylpyridine monothiosemicarbazonato copper II on red cell components. J. Inorg. Biochem., 1984, 20, 69-78.
Khan, M.F.; Ohno, Y.; Takanaka, A. Effect of tetrakismu-3,5-diisopropylsalicylatodiaquodicopper(II) on the status of reduced glutathione in freshly isolated hepatocytes. Arch. Toxicol., 1992, 66, 587-591.
Majumder, S.; Panda, G.S.; Choudhuri, S.K. Synthesis, characterization and biological properties of a novel copper complex. Eur. J. Med. Chem., 2003, 38, 893-898.
McCann, M.; Geraghty, M.; Devereux, M.; O’Shea, D.; Mason, J.; O’Sullivan, L. Insights into the mode of action of the anti-Candida activity of 1,10-phenanthroline and its metal chelates. Met. Based Drugs, 2000, 7, 185-193.
Narasimhan, J.; Antholine, W.E.; Chitambar, C.R.; Petering, D.H. Inhibition of iron uptake in HL60 cells by 2-formylpyridine monothiosemicarbazonato Cu(II). Arch. Biochem. Biophys., 1991, 289, 393-398.
Kowol, C.R.; Heffeter, P.; Miklos, W.; Gille, L.; Trondl, R.; Cappelacci, L.; Berger, W.; Keppler, B.K. Mechanisms underlying reductant-induced reactive oxygen species formation by anticancer copper(II) compounds. J. Biol. Inorg. Chem., 2012, 17, 409-423.
Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: The next generation. Cell, 2011, 144, 646-674.
Fang, B.A.; Kovacevic, Z.; Park, K.C.; Kalinowski, D.S.; Jansson, P.J.; Lane, D.J.; Sahni, S.; Richardson, D.R. Molecular functions of the iron-regulated metastasis suppressor, Ndrg1, and its potential as a molecular target for cancer therapy. Biochim. Biophys. Acta, 2014, 1845, 1-19.
Sun, J.; Zhang, D.; Bae, D.H.; Sahni, S.; Jansson, P.; Zheng, Y.; Zhao, Q.; Yue, F.; Zheng, M.; Kovacevic, Z.; Richardson, D.R. Metastasis suppressor, NDRG1, mediates its activity through signaling pathways and molecular motors. Carcinogenesis, 2013, 34, 1943-1954.
Kovacevic, Z.; Fu, D.; Richardson, D.R. The iron-regulated metastasis suppressor, Ndrg-1: Identification of novel molecular targets. Biochim. Biophys. Acta, 2008, 1783, 1981-1992.
Chen, Z.; Zhang, D.; Yue, F.; Zheng, M.; Kovacevic, Z.; Richardson, D.R. The iron chelators Dp44mT and DFO inhibit TGF-beta-induced epithelial-mesenchymal transition via up-regulation of N-Myc downstream-regulated gene 1 (Ndrg1). J. Biol. Chem., 2012, 287, 17016-17028.
Bandyopadhyay, S.; Pai, S.K.; Gross, S.C.; Hirota, S.; Hosobe, S.; Miura, K.; Saito, K.; Commes, T.; Hayashi, S.; Watabe, M.; Watabe, K. The Drg-1 gene suppresses tumor metastasis in prostate cancer. Cancer Res., 2003, 63, 1731-1736.
Guan, R.J.; Ford, H.L.; Fu, Y.; Li, Y.; Shaw, L.M.; Pardee, A.B. Drg-1 as a differentiation related, putative metastatic suppressor gene in human colon cancer. Cancer Res., 2000, 60, 749-755.
Bandyopadhyay, S.; Pai, S.K.; Hirota, S.; Hosobe, S.; Tsukada, T.; Miura, K.; Takano, Y.; Saito, K.; Commes, T.; Piquemal, D.; Watabe, M.; Gross, S.; Wang, Y.; Huggenvik, J.; Watabe, K. PTEN up-regulates the tumor metastasis suppressor gene Drg-1 in prostate and breast cancer. Cancer Res., 2004, 64, 7655-7660.
Lachat, P.; Shaw, P.; Gebhard, S.; van Belzen, N.; Chaubert, P.; Bosman, F.T. Expression of Ndrg1, a differentiation-related gene, in human tissues. Histochem. Cell Biol., 2002, 118(5), 399-408.
Angst, E.; Dawson, D.W.; Stroka, D.; Gloor, B.; Park, J.; Candinas, D.; Reber, H.A.; Hines, O.J.; Eibl, G. N-myc downstream regulated gene-1 expression correlates with reduced pancreatic cancer growth and increased apoptosis in vitro and in vivo. Surgery, 2011, 149, 614-624.
Maruyama, Y.; Ono, M.; Kawahara, A.; Yokoyama, T.; Basaki, Y.; Kage, M.; Aoyagi, S.; Kinoshita, H.; Kuwano, M. Tumor growth suppression in pancreatic cancer by a putative metastasis suppressor gene Cap43/Ndrg1/Drg-1 through modulation of angiogenesis. Cancer Res., 2006, 66, 6233-6242.
Bandyopadhyay, S.; Pai, S.K.; Hirota, S.; Hosobe, S.; Takano, Y.; Saito, K.; Piquemal, D.; Commes, T.; Watabe, M.; Gross, S.C.; Wang, Y.; Ran, S.; Watabe, K. Role of the putative tumor metastasis suppressor gene Drg-1 in breast cancer progression. Oncogene, 2004, 23, 5675-5681.
Zhao, G.; Chen, J.; Deng, Y.; Gao, F.; Zhu, J.; Feng, Z.; Lv, X.; Zhao, Z. Identification of Ndrg1-regulated genes associated with invasive potential in cervical and ovarian cancer cells. Biochem. Biophys. Res. Commun., 2011, 408, 154-159.
Le, N.T.; Richardson, D.R. Iron chelators with high antiproliferative activity upregulate the expression of a growth inhibitory and metastasis suppressor gene: A link between iron metabolism and proliferation. Blood, 2004, 104, 2967-2975.
Lane, D.J.; Saletta, F.; Rahmanto, Y.S.; Kovacevic, Z.; Richardson, D.R. N-myc downstream regulated 1 (Ndrg1) is regulated by eukaryotic initiation factor 3a (eIF3a) during cellular stress caused by iron depletion. PLoS One, 2013, 8e57273
Kadayat, T.M.; Park, C.; Jun, K.Y.; Magar, T.B.T.; Bist, G.; Yoo, H.Y.; Kwon, Y.; Lee, E.S. Hydroxylated 2,4-diphenyl indenopyridine derivatives as a selective non-intercalative topoisomerase IIα catalytic inhibitor. Eur. J. Med. Chem., 2015, 90, 302-314.
Kadayat, T.M.; Park, C.; Jun, K.Y.; Magar, T.B.T.; Bist, G.; Yoo, H.Y.; Kwon, Y.; Lee, E.S. Design and synthesis of novel 2,4-diaryl-5H-indeno[1,2-b]pyridine derivatives, and their evaluation of topoisomerase inhibitory activity and cytotoxicity. Bioorg. Med. Chem., 2015, 23, 160-173.
Bisceglie, F.; Musiari, A.; Pinelli, S.; Alinovi, R.; Menozzi, I.; Polverini, E.; Tarasconi, P.; Tavone, M.; Pelosi, G. Quinoline-2-carboxaldehyde thiosemicarbazones and their Cu(II) and Ni(II) complexes as topoisomerase IIα inhibitors. J. Inorg. Biochem., 2015, 152, 10-19.
Tabassum, S.; Asim, A.; Khan, R.A.; Arjmand, F.; Rajakumar, D.; Balaji, P.; Akbarsha, M.A. A multifunctional molecular entity Cu(II)-Sn(IV) heterobimetallic complex as a potential cancer chemotherapeutic agent: DNA binding/cleavage, SOD mimetic, topoisomerase iα inhibitory and in vitro cytotoxic activities. RSC Advances, 2015, 5, 47439-47450.
Shen, Y.; Chen, W.; Zhao, B.; Hao, H.; Li, Z.; Lu, C.; Shen, Y. CS1 is a novel topoisomerase IIα inhibitor with favorable drug resistance profiles. Biochem. Biophys. Res. Commun., 2014, 453, 302-308.
Majumdar, P.; Bathula, C.; Basu, S.M.; Das, S.K.; Agarwal, R.; Hati, S.; Singh, A.; Sen, S.; Das, B.B. Design, synthesis and evaluation of thiohydantoin derivatives as potent topoisomerase I (Top1) inhibitors with anticancer activity. Eur. J. Med. Chem., 2015, 102, 540-551.
Tabassum, S.; Zaki, M.; Afzal, M.; Arjmand, F. Synthesis and characterization of Cu (II)-based anticancer chemotherapeutic agent targeting topoisomerase Iα: In vitro DNA binding, pBR322 cleavage, molecular docking studies and cytotoxicity against human cancer cell lines. Eur. J. Med. Chem., 2014, 74, 509-523.
Zhang, J.P.; Huang, J.; Liu, C.; Lu, X.F.; Wu, B.X.; Zhao, L.; Lu, N.; Guo, Q.L.; Li, Z.Y.; Jiang, C. Discovery of a series of pyridopyrimidine derivatives as potential topoisomerase I inhibitors. Chin. Chem. Lett., 2014, 25, 1025-1028.
Islam, M.S.; Park, S.; Song, C.; Kadi, A.A.; Kwon, Y.; Rahman, A.F.M.M. Fluorescein hydrazones: A series of novel non-intercalative topoisomerase IIα catalytic inhibitors induce G1 arrest and apoptosis in breast and colon cancer cells. Eur. J. Med. Chem., 2017, 125, 49-67.
Yu, L.M.; Zhang, X.R.; Li, X.B.; Yang, Y.; Wei, H.Y.; He, X.X.; Gu, L.Q.; Huang, Z.S.; Pommier, Y.; An, L.K. Synthesis and biological evaluation of 6-substituted indolizinoquinolinediones as catalytic DNA topoisomerase I inhibitors. Eur. J. Med. Chem., 2015, 101, 525-533.
Li, Z.X.; Li, J.; Li, Y.; You, K.; Xu, H.; Wang, J. Novel insights into the apoptosis mechanism of DNA topoisomerase I inhibitor isoliquiritigenin on HCC tumor cell. Biochem. Biophys. Res. Commun., 2015, 464, 548-553.
Chew, S.T.; Lo, K.M.; Lee, S.K.; Heng, M.P.; Teoh, W.Y.; Sim, K.S.; Tan, K.W. Copper complexes with phosphonium containing hydrazone ligand: Topoisomerase inhibition and cytotoxicity study. Eur. J. Med. Chem., 2014, 76, 397-407.
Wambang, N.; Schifano-Faux, N.; Aillerie, A.; Baldeyrou, B.; Jacquet, C.; Bal-Mahieu, C.; Bousquet, T.; Pellegrini, S.; Ndifon, P.T.; Meignan, S.; Goossens, J.F.; Lansiaux, A.; Pélinski, L. Synthesis and biological activity of ferrocenyl indeno[1,2-c] isoquinolines as topoisomerase II inhibitors. Bioorg. Med. Chem., 2016, 24, 651-660.
Karki, R.; Song, C.; Kadayat, T.M.; Magar, T.B.T.; Bist, G.; Shrestha, A.; Na, Y.; Kwon, Y.; Lee, E.S. Topoisomerase I and II inhibitory activity, cytotoxicity, and structure--activity relationship study of dihydroxylated 2,6-diphenyl-4-aryl pyridines. Bioorg. Med. Chem., 2015, 23, 3638-3654.
Nguyen, T.X.; Abdelmalak, M.; Marchand, C.; Agama, K.; Pommier, Y.; Cushman, M. Synthesis and biological evaluation of nitrated 7-, 8-, 9-, and 10-hydroxyindenoisoquinolines as potential dual topoisomerase I (top1)−tyrosyl-DNA phosphodiesterase I (TDP1) inhibitors. J. Med. Chem., 2015, 58(7), 3188-3208.
Khadka, D.B.; Woo, H.; Yang, S.H.; Zhao, C.; Jin, Y.; Le, T.N.; Kwon, Y.; Cho, W.J. Modification of 3-arylisoquinolines into 3,4-diarylisoquinolines and assessment of their cytotoxicity and topoisomerase inhibition. Eur. J. Med. Chem., 2015, 92, 583-607.
Yao, B.L.; Mai, Y.W.; Chen, S.B.; Xie, H.T.; Yao, P.F.; Ou, T.M.; Tan, J.H.; Wang, H.G.; Li, D.; Huang, S.L.; Gu, L.Q.; Huang, Z.S. Design, synthesis and biological evaluation of novel 7-alkylamino substituted benzo[α]phenazin derivatives as dual topoisomerase I/II inhibitors. Eur. J. Med. Chem., 2015, 92, 540-553.
Ucuncuoglu, N.; Andricioaei, I.; Sari, L. Insights from simulations into the mechanism of human topoisomerase I: Explanation for a seeming controversy in experiments. J. Mol. Graph. Model., 2013, 44, 286-296.
Lin, H.F.; Huang, H.L.; Liao, J.F.; Shen, C.C.; Huang, R.L. Dicentrine analogue-induced G2/M arrest and apoptosis through inhibition of topoisomerase II activity in human cancer cells. Planta Med., 2015, 81, 830-837.
Drwal, M.N.; Marinello, J.; Manzo, S.G.; Wakelin, L.P.G.; Capranico, G.; Griffith, R. Novel DNA topoisomerase IIα inhibitors from combined ligand- and structure based virtual screening. PLoS One, 2014, 9(12)e114904
Chan, M.K.; Fadzil, N.A.; Chew, A.L.; Khoo, B.Y. New molecular biologist perspective and insight: DNA topoisomerases production by recombinant DNA technology for medical laboratory application and pharmaceutical industry. Electron. J. Biotechnol., 2013, 16, 1-10.
Nateewattana, J.; Dutta, S.; Reabroi, S.; Saeeng, R.; Kasemsook, S.; Chairoungdua, A.; Weerachayaphorn, J.; Wongkham, S.; Piyachaturawat, P. Induction of apoptosis in cholangiocarcinoma by an andrographolide analogue is mediated through topoisomerase II alpha inhibition. Eur. J. Pharmacol., 2014, 723, 148-155.
Khadka, D.B.; Tran, G.H.; Shin, S.; Nguyen, H.T.M.; Cao, H.T.; Zhao, C.; Jin, Y.; Van, H.T.M.; Chau, M.V.; Kwon, Y.; Le, T.N.; Cho, W.J. Substituted 2-arylquinazolinones: Design, synthesis, and evaluation of cytotoxicity and inhibition of topoisomerases. Eur. J. Med. Chem., 2015, 103, 69-79.
Wang, J.C. DNA topoisomerases. Annu. Rev. Biochem., 1996, 65, 635-692.
Pommier, Y.; Leo, E.; Zhang, H.; Marchand, C. DNA topoisomerases and their poisoning by anticancer and antibacterial drugs. Chem. Biol., 2010, 17, 421-433.
Schoeffler, A.J.; Berger, J.M. DNA topoisomerases: Harnessing and constraining energy to govern chromosome topology. Q. Rev. Biophys., 2008, 41, 41-101.
Beck, W.T.; Danks, M.K.; Wolverton, J.S.; Chen, M.; Granzen, B.; Kim, R.; Suttle, D.P. Resistance of mammalian tumor cells to inhibitors of DNA topoisomerase II. Adv. Pharmacol., 1994, 29B, 145-169.
Hochhauser, D.; Harris, A.L. The Role of topoisomerase IIα and β in drug resistance. Cancer Treat. Rev., 1993, 19(2), 181-194.
Hwang, J.; Hwong, C.L. Cellular regulation of mammalian DNA topoisomerase. Adv. Pharmacol., 1994, 29A, 167-189.
Woessner, R.D.; Mattern, M.R.; Mirabelli, C.K.; Johnson, R.K.; Drake, F.H. Proliferation- and cell cycle-dependent differences in expression of the 170 kilodalton and 180 kilodalton forms of topoisomerase II in NIH-3T3 cells. Cell Growth Differ., 1991, 2(4), 209-214.
Azarova, A.M.; Lyu, Y.L.; Lin, C.P.; Tsai, Y.C.; Lau, J.Y.; Wang, J.C.; Liu, L.F. Roles of DNA topoisomerase II isozymes in chemotherapy and secondary malignancies. Proc. Natl. Acad. Sci. USA, 2007, 104, 11014-11019.
Toyoda, E.; Kagaya, S.; Cowell, I.G.; Kurosawa, A.; Kamoshita, K.; Nishikawa, K.; Iiizumi, S.; Koyama, H.; Austin, C.A.; Adachi, N. NK314, a topoisomerase II inhibitor that specifically targets the α isoform. J. Biol. Chem., 2008, 283(35), 23711-23720.
Chen, W.; Qiu, J.; Shen, Y. Topoisomerase IIα, rather than IIβ, is a promising target in development of anti-cancer drugs. Drug D. Ther., 2012, 6(5), 230-237.
Chaston, T.B.; Richardson, D.R. Interactions of the pyridine-2-carboxaldehyde isonicotinoyl hydrazone class of chelators with iron and DNA: Implications for toxicity in the treatment of iron overload disease. J. Biol. Inorg. Chem., 2003, 8, 427-438.
Burgess, D.J.; Doles, J.; Zender, L.; Xue, W.; Ma, B.; McCombie, W.R.; Hannon, G.J.; Lowe, S.W.; Hemann, M.T. Topoisomerase levels determine chemotherapy response in vitro and in vivo. Proc. Natl. Acad. Sci. USA, 2008, 105, 9053-9058.
Huang, H.; Chen, Q.; Ku, X.; Meng, L.; Lin, L.; Wang, X.; Zhu, C.; Wang, Y.; Chen, Z.; Li, M.; Jiang, H.; Chen, K.; Ding, J.; Liu, H. A series of α-heterocyclic carboxaldehyde thiosemicarbazones inhibit topoisomerase IIα catalytic activity. J. Med. Chem., 2010, 53, 3048-3064.
Rao, V.A.; Klein, S.R.; Agama, K.K.; Toyoda, E.; Adachi, N.; Pommier, Y.; Shacter, E.B. The iron chelator Dp44mT causes DNA damage and selective inhibition of topoisomerase IIα in breast cancer cells. Cancer Res., 2009, 69, 948-957.
Zeglis, B.M.; Divilov, V.; Lewis, J.S. Role of metalation in the topoisomerase IIα inhibition and antiproliferation activity of a series of α-heterocyclic-N4-substituted thiosemicarbazones and their Cu(II) complexes. J. Med. Chem., 2011, 54, 2391-2398.
Shukla, S.; Srivastava, R.S.; Shrivastava, S.K.; Sodhi, A.; Kumar, P. Synthesis, characterization and antiproliferative activity of 1,2-naphthoquinone and its derivatives. Appl. Biochem. Biotechnol., 2012, 167, 1430-1435.
Wei, L.; Easmon, J.; Nagi, R.K.; Muegge, B.D.; Meyer, L.A.; Lewis, J.S. 64Cu azabicyclo[3.2.2]nonane thiosemicarbazone complexes: Radiopharmaceuticals for PET of topoisomerase II expression in tumors. J. Nucl. Med., 2006, 47, 2034-2041.
Hileti, D.; Panayiotidis, P.; Hoffbrand, A.V. Iron chelators induce apoptosis in proliferating cells. Br. J. Haematol., 1995, 89, 181-187.
Greene, B.T.; Thorburn, J.; Willingham, M.C.; Thorburn, A.; Planalp, R.P.; Brechbiel, M.W.; Jennings-Gee, J.; Wilkinson, J.; Torti, F.M.; Torti, S.V. Activation of caspase pathways during iron chelator-mediated apoptosis. J. Biol. Chem.277, 2002, 25568-25575.
Lim, M.L.R.; Lum, M.G.; Hansen, T.M.; Roucou, X.; Nagley, P. On the release of cytochrome c from mitochondria during cell death signaling. J. Biomed. Sci., 2002, 9, 488-506.
Kaufmann, S.H.; Earnshaw, W.C. Induction of apoptosis by cancer chemotherapy. Exp. Cell Res.256, 2000, 42-49.
Ul-Haq, R.U.; Wereley, J.P.; Chitambar, C.R. Induction of apoptosis by iron deprivation in human leukemic CCRF-CEM cells. Exp. Hematol., 1995, 23, 428-432.
Schwartz, P.E. Current diagnosis and treatment modalities for ovarian cancer. Cancer Treat. Res., 2002, 107, 99-118.
Green, D.R.; Kroemer, G. The pathophysiology of mitochondrial cell death. Science, 2004, 305, 626-629.
Haupt, S.; Berger, M.; Goldberg, Z.; Haupt, Y. Apoptosis - the p53 network. J. Cell Sci., 2003, 116, 4077-4085.
Wyllie, A.H.; Kerr, J.F.; Cumie, A.R. Cell death: The significance of apoptosis. Int. Rev. Cytol., 1980, 68, 251-306.
Cain, K.; Bratton, S.B.; Cohen, G.M. The Apaf-1 apoptosome: A large caspase-activating complex. Biochimie, 2002, 84, 203-214.
Alvero, A.B.; Chen, W.; Sartorelli, A.C.; Schwartz, P.; Rutherford, T.; Mor, G. Triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone) induces apoptosis in ovarian cancer cells. J. Soc. Gynecol. Investig., 2006, 13, 145-152.
Cohen, G.M. Caspases: The executioners of apoptosis. Biochem. J., 1997, 326, 1-16.
Bender, C.E.; Fitzgerald, P.; Tait, S.W.G.; Liambi, F.; McStay, G.P.; Tupper, D.O.; Pellettieri, J.; Alvarado, A.S.; Salvesen, G.S.; Green, D.R. Mitochondrial pathway of apoptosis is ancestral in metazoans. PNAS, 2012, 109, 4904-4909.
Kluck, R.M.; Bossy-Wetzel, E.; Green, D.R.; Newmeyer, D.D. The release of cytochrome c from mitochondria: A primary site for Bcl-2 regulation of apoptosis. Science, 1997, 275, 1132-1136.
Jurgensmeier, J.M.; Xie, Z.; Deveraux, Q.; Ellerby, L.; Bredesen, D.; Reed, J.C. Bax directly induces release of cytochrome c from isolated mitochondria. Proc. Natl. Acad. Sci. USA, 1998, 95, 4997-5002.
Jemmerson, R.; LaPlante, B.; Treeful, A. Release of intact, monomeric cytochrome c from apoptotic and necrotic cells. Cell Death Differ., 2002, 9, 538-548.
Noulsri, E.; Richardson, D.R.; Lerdwana, S.; Fucharoen, S.; Yamagishi, T.; Kalinowski, D.S.; Pattanapanyasat, K. Antitumor activity and mechanism of action of the iron chelator, Dp44mT, against leukemic cells. Am. J. Hematol., 2009, 84, 170-176.
Cardone, M.H.; Roy, N.; Stennicke, H.R.; Salvesen, G.S.; Franke, T.F.; Stanbridge, E.; Frisch, S.; Reed, J.C. Regulation of cell death protease caspase-9 by phosphorylation. Science, 1998, 282, 1318-1321.
Gardai, S.J.; Hildeman, D.A.; Frankel, S.K.; Whitlock, B.B.; Frasch, S.C.; Borregaard, N.; Marrack, P.; Bratton, D.L.; Henson, P.M. Phosphorylation of Bax Ser184 by Akt regulates its activity and apoptosis in neutrophils. J. Biol. Chem., 2004, 279(20), 21085-21095.
Dixon, K.M.; Lui, G.Y.; Kovacevic, Z.; Zhang, D.; Yao, M.; Chen, Z.; Dong, Q.; Assinder, S.J.; Richardson, D.R. Dp44mT targets the AKT, TGF-beta and ERK pathways via the metastasis suppressor Ndrg1 in normal prostate epithelial cells and prostate cancer cells. Br. J. Cancer, 2013, 108, 409-419.
Adsule, S.; Barve, V.; Chen, D.; Ahmed, F.; Dou, Q.P.; Padhye, S.; Sarkar, F.H. Novel Schiff base copper complexes of quinoline-2 carboxaldehyde as proteasome inhibitors in human prostate cancer cells. J. Med. Chem., 2006, 49(24), 7242-7246.
Cabrera, M.; Gomez, N.; Lenicov, F.R.; Echeverria, E.; Shayo, C.; Moglioni, A.; Fernández, N.; Davio, C. G2/M cell cycle arrest and tumor selective apoptosis of acute leukemia cells by a promising benzophenone thiosemicarbazone compound. PLoS One,, 2015, 10, e0136878.
[ journal.pone 0136878]
Brodie, C.; Siriwardana, G.; Lucas, J.; Schleicher, R.; Terada, N.; Szepesi, A.; Gelfand, E.; Seligman, P. Neuroblastoma sensitivity to growth inhibition by desferrioxamine: Evidence for a block in G1 phase of the cell cycle. Cancer Res., 1993, 53, 3968-3975.
Yu, Y.; Kovacevic, Z.; Richardson, D.R. Tuning cell cycle regulation with an iron key. Cell Cycle, 2007, 6, 1982-1994.
Yu, Y.; Wong, J.; Lovejoy, D.B.; Kalinowski, D.S.; Richardson, D.R. Chelators at the cancer coalface: Desferrioxamine to Triapine and beyond. Clin. Cancer Res., 2006, 12, 6876-6883.
Simonart, T.; Degraef, C.; Andrei, G.; Mosselmans, R.; Hermans, P.; van Vooren, J.P.; Noel, J.C.; Boehart, J.R.; Snowck, R.; Heenen, M. Iron chelators inhibit the growth and induce the apoptosis of Kaposi’s sarcoma cells and of their putative endothelial precursors. J. Invest. Dermatol., 2000, 115, 893-900.
Steele, V.E.; Wyatt, G.P.; Kellof, G.J.; Elmore, E. Differential growth response to exogenous calcium in normal and carcinogen-exposed primary human keratinocyte cell cultures. Anticancer Res., 1998, 6A, 4067-4070.
Baldini, M.; Belicchi-Ferrari, M.; Bisceglie, F.; Capacchi, S.; Pelosi, G.; Tarasconi, P. Zinc complexes with cyclic derivatives of α-ketoglutaric acid thiosemicarbazone: Synthesis, X-ray structures and DNA interactions. J. Inorg. Biochem., 2005, 99, 1504-1513.
Baldini, M.; Belicchi-Ferrari, M.; Bisceglie, F.; Dall’Aglio, P.P.; Pelosi, G.; Pinelli, S.; Tarasconi, P. Copper(II) complexes with substituted thiosemicarbazones of α-ketoglutaric acid: Synthesis, X-ray structures, DNA binding studies, and nuclease and biological activity. Inorg. Chem., 2004, 43(22), 7170-7179.
Castino, R.; Fiorentino, I.; Cagnin, M.; Giovia, A.; Isidoro, C. Chelation of lysosomal iron protects dopaminergic SHSY5Y neuroblastoma cells from hydrogen peroxide toxicity by precluding autophagy and Akt dephosphorylation. Toxicol. Sci., 2011, 123, 523-541.
Kurz, T.; Brunk, U.T. Autophagy of HSP70 and chelation of lysosomal iron in a non-redox-active form. Autophagy, 2009, 5, 93-95.
Gutierrez, E.; Richardson, D.R.; Jansson, P.J. The anti-cancer agent di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) overcomes pro-survival autophagy by two mechanisms: Persistent induction of autophagosome synthesis and impairment of lysosomal integrity. J. Biol. Chem., 2014, 289(48), 33568-33589.
Lovejoy, D.B.; Jansson, P.J.; Brunk, U.T.; Wong, J.; Ponka, P.; Richardson, D.R. 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, 5871-5880.
Yu, X.; Blanden, A.; Tsang, A.T.; Zaman, S.; Liu, Y.; Gilleran, J.; Bencivenga, A.F.; Kimball, S.D.; Loh, S.N.; Carpizo, D.R. Thiosemicarbazones functioning as zinc metallochaperones to reactive mutant p53. Mol. Pharmacol., 2017, 91(6), 567-575.
Hientz, K.; Mohr, A.; Guha, D.B.; Efferth, T. The role of p53 in cancer drug resistance and targeted chemotherapy. Oncotarget, 2017, 8(5), 8921-8946.
Kogan, S.; Carpizo, D.R. Zinc metallochaperones as mutant p53 reactivators: A new paradigm in cancer therapeutics. Cancers, 2018, 10, 166-178.

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Year: 2020
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