Cytotoxicity of (2,2‘:6‘,2‘ ‘-Terpyridine)platinum(II) Complexes to Leishmania donovani, Trypanosoma cruzi, and Trypanosoma brucei

Lowe, Gordoǹ; Droz, Anne Sophie; Vilaivan, Tirayut; Weaver, George W.; Tweedale, Lindsay; Pratt, J. M.; Rock, Peter; Yardley, Vanessa; Croft, Simon L.

doi:10.1021/jm981074c

Cited by 123 publications

(102 citation statements)

References 17 publications

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“…This strategy has been performed to enhance the potency of ketoconazole, clotrimazole, benznidazole, risedronate, and quinolones (34)(35)(36)(37)(38)(39). Alternatively, metal complexes which are composed of ligands with unique chemical properties (redox and electrochemical behavior based on ligand reductions) exhibit anti-T. cruzi properties, possibly due to parasite membrane accumulation, in addition to effects on DNA and enzymes (40)(41)(42)(43).…”

Section: Discussionmentioning

confidence: 99%

Nitro/Nitrosyl-Ruthenium Complexes Are Potent and Selective Anti-Trypanosoma cruzi Agents Causing Autophagy and Necrotic Parasite Death

Bastos

Barbosa

Silva

et al. 2014

Antimicrob Agents Chemother

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e cis-[RuCl(NO 2 )(dppb)(5,5=-mebipy)] (complex 1), cis-[Ru(NO 2 ) 2 (dppb)(5,5=-mebipy)] (complex 2), ct-[RuCl(NO)(dppb)(5,5=-mebipy)](PF 6 ) 2 (complex 3), and cc-[RuCl(NO)(dppb)(5,5=-mebipy)](PF 6 ) 2 (complex 4), where 5,5=-mebipy is 5,5=-dimethyl-2,2=-bipyridine and dppb is 1,4-bis(diphenylphosphino)butane, were synthesized and characterized. The structure of complex 2 was determined by X-ray crystallography. These complexes exhibited a higher anti-Trypanosoma cruzi activity than benznidazole, the current antiparasitic drug. Complex 3 was the most potent, displaying a 50% effective concentration (EC 50 ) of 2.1 ؎ 0.6 M against trypomastigotes and a 50% inhibitory concentration (IC 50 ) of 1.3 ؎ 0.2 M against amastigotes, while it displayed a 50% cytotoxic concentration (CC 50 ) of 51.4 ؎ 0.2 M in macrophages. It was observed that the nitrosyl complex 3, but not its analog lacking the nitrosyl group, releases nitric oxide into parasite cells. This release has a diminished effect on the trypanosomal protease cruzain but induces substantial parasite autophagy, which is followed by a series of irreversible morphological impairments to the parasites and finally results in cell death by necrosis. In infected mice, orally administered complex 3 (five times at a dose of 75 mol/kg of body weight) reduced blood parasitemia and increased the survival rate of the mice. Combination index analysis of complex 3 indicated that its in vitro activity against trypomastigotes is synergic with benznidazole. In addition, drug combination enhanced efficacy in infected mice, suggesting that ruthenium-nitrosyl complexes are potential constituents for drug combinations.

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Section: Discussionmentioning

confidence: 99%

Nitro/Nitrosyl-Ruthenium Complexes Are Potent and Selective Anti-Trypanosoma cruzi Agents Causing Autophagy and Necrotic Parasite Death

Bastos

Barbosa

Silva

et al. 2014

Antimicrob Agents Chemother

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“…Recent studies have proposed strategies incorporating the use of cisplatin in combination with other drugs such as perillyl alcohol, other platinum(II) compounds, and AG1478 to accelerate cisplatin-induced apoptosis in several glioma cell lines (24)(25)(26)(27)(28). Furthermore, combination of CsA with other anticancer drugs has been shown to enhance chemotherapeutic efficacy in leukemia and gastric carcinoma cells (29,(39)(40)(41).…”

Section: Discussionmentioning

confidence: 99%

“…A major limitation in clinical use of cisplatin is acquisition of resistance by initially responsive tumors (23). Combinational use of cisplatin with other drugs, such as perillyl alcohol, other platinum(II) compounds, or AG1478, accelerates cisplatininduced apoptosis in several glioma cell lines (24)(25)(26)(27)(28). Moreover, recent studies have indicated that CsA enhances docetaxel-induced apoptosis in human gastric carcinoma cells (29).…”

Section: Introductionmentioning

confidence: 99%

Cyclosporin A and sanglifehrin A enhance chemotherapeutic effect of cisplatin in C6 glioma cells

Han

Yoon²,

Ding³

et al. 2010

Oncol Rep

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Abstract. Glioma is the most common type of brain tumors in adults, and treatment of high-grade gliomas is still palliative. Studies to date have revealed only modest effect in attenuating growth of these tumors with single agent therapy, but combination treatment appears to be more effective. Cyclophilin A (CypA), a target of immunosuppressive drugs cyclosporin A (CsA) and sanglifehrin A (SFA), is an intracellular protein that has peptidyl-prolyl cis-trans isomerase (PPIase) enzymatic activity. Previously, we showed that overexpressed CypA induced chemoresistance in cancer cells. Here we provide evidence that combination of cisplatin with either CsA or SFA synergistically enhances apoptotic cell death in C6 glioma cells, compared with single agent treatment. Enhanced apoptotic cell death is a result of an increase in ROS generation and a decrease in intracellular glutathione levels. Consistently, CypA knockdown by siRNA also enhances cisplatin-induced apoptosis. Immunohistochemical analysis showed increased expression of CypA in human glioblastoma multiforme, but not in normal human astrocytes. CypA was also shown to be up-regulated in C6 glioma cells during hypoxia. In conclusion, CsA or SFA in combination with cisplatin synergistically enhances cisplatin-induced apoptosis in C6 glioma cells via inhibition of PPIase activity of CypA, indicating that development of new drugs that selectively inhibit the CypA PPIase activity without immune suppression may facilitate alleviation of chemoresistance in treatment of high-grade glioma. IntroductionGlioma is the most common type of brain tumors in adults, and accounts for 25% of all brain tumors (1,2). Despite significant advances in cancer therapy, treatment of high-grade gliomas is still palliative. To date, the median survival for patients with high-grade gliomas, including glioblastoma multiforme (GBM; World Health Organization grade IV), is less than 1 year (3,4). Therefore, improved systemic treatment strategies are urgently required.Cyclophilin A (CypA), the prototypical member of the cyclophilin family, is a highly conserved protein in mammalian cells (5). CypA possesses enzymatic peptidyl-prolyl cis-trans isomerase (PPIase) activity, which is essential for protein folding in vivo. Although little is known about the function of CypA in cancer cells, it was recently reported that CypA is overexpressed in many cancer cells (6-11). In addition, our studies, as well as others, previously showed that overexpressed CypA protects cancer cells against cellular stresses, including hypoxia and cisplatin treatment, at least in part as a result of its antioxidant function (12)(13)(14)(15). These reports show that CypA might be important for tumorigenesis in solid tumors. CypA is also an immunophilin and a cytosolic receptor for the immunosuppressive drugs cyclosporin A (CsA) (5) and sanglifehrin A (SFA) (16). CsA binds to CypA, and this complex inhibits calcineurin, a calcium-dependent phosphatase, that regulates the expression of various cytokine genes ONCOLOGY REPORTS 2...

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“…Novel approaches at the design of antileishmanial agents include the specific dihydrofolate reductase inhibitor 78 (IC 50 ¼ 6.0 mM) (Fig. 21) [175] and (terpyridine)-platinum(II) complexes such as 79, which are effective against L. donovani (100% inhibition at 1 mM), T. cruzi (65% inhibition at 1 mM), and T. b. brucei (100% inhibition at 30 nM) [176]. The triphenyltin complex 80 also has antileishmanial activity, and depletes amastigotes in cultured hamster macrophages to undetectable levels at a concentration of 10 mg/L [177].…”

Section: Potential New Therapies For Leishmaniasismentioning

confidence: 99%

Antiprotozoal/Antiparasitic Agents

Woster

2010

Burger's Medicinal Chemistry and Drug Discovery

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Collectively, diseases caused by parasitic protozoa, including human African trypanosomiasis ( HAT ), Chagas' disease and leishmaniasis, threaten more than 550 million people worldwide and cause nearly 150,000 deaths annually. The causative organisms for these diseases are unicellular trypanosomatid parasites of the genera Trypanosoma brucei , Trypanosoma cruzi , and Leishmania sp., respectively. Drug therapies available for these diseases have not changed significantly in the past 50 years, and currently used agents are far less than satisfactory due to extreme toxicity, and because resistant parasitic strains are becoming more prevalent. These diseases are confined to impoverished or rural areas of Mexico, Central America, South America, sub‐Saharan Africa, the Middle East, Indonesia, and India. As such, drug discovery efforts against trypanosomatid diseases are limited because patients in underdeveloped areas cannot afford therapy, and because the infected population is too small to justify the required research expenditures. In addition, antiparasitic research in Third World nations is often hampered by economic issues and political turmoil, virtually assuring that the world's most impoverished people will continue to bear the major burden of parasitic disease. Clearly, there is a need for new anti‐infective agents that are potent, nontoxic and inexpensive to manufacture. In this chapter, the etiology of these diseases and their current treatment are described. The chapter also deals with medicinal chemistry aspects of efforts to identify new drug targets for parasitic diseases, and to produce novel inhibitors of trypanosomatid growth for use as antiparasitic agents.

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Cytotoxicity of (2,2‘:6‘,2‘ ‘-Terpyridine)platinum(II) Complexes to Leishmania donovani, Trypanosoma cruzi, and Trypanosoma brucei

Cited by 123 publications

References 17 publications

Nitro/Nitrosyl-Ruthenium Complexes Are Potent and Selective Anti-Trypanosoma cruzi Agents Causing Autophagy and Necrotic Parasite Death

Nitro/Nitrosyl-Ruthenium Complexes Are Potent and Selective Anti-Trypanosoma cruzi Agents Causing Autophagy and Necrotic Parasite Death

Cyclosporin A and sanglifehrin A enhance chemotherapeutic effect of cisplatin in C6 glioma cells

Antiprotozoal/Antiparasitic Agents

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