- Synthesis, crystallographic characterization and electrochemical property of a copper(II) complex of the anticancer agent elesclomol
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Elesclomol is a novel anticancer agent that has been evaluated in a number of late stage clinical trials. A new and convenient synthesis of elesclomol and its copper complex is described. X-ray crystallographic characterization and the electrochemical properties of the elesclomol copper(II) complex are discussed. The copper(II) cation is coordinated in a highly distorted square-planar geometry to each of the sulphur and amide nitrogen atoms of elesclomol. Electrochemical measurements demonstrate that the complex undergoes a reversible one-electron reduction at biologically accessible potentials. In contrast the free elesclomol is found electrochemically inactive. This evidence is in strong support of the mechanism of action we proposed for the anticancer activity of elesclomol.
- Vo, Nha Huu,Xia, Zhiqiang,Hanko, Jason,Yun, Tong,Bloom, Steve,Shen, Jianhua,Koya, Keizo,Sun, Lijun,Chen, Shoujun
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- Facile and convenient synthesis of N ′1, N ′3-dialkyl- N ′1, N ′3-bis(arylcarbonothioyl)malonohydrazides via propylphosphonic anhydride coupling
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A facile and convenient synthetic method for the anticancer agent elesclomol and its analogues, N′1,N′3-dialkyl-N′1,N′3-bis(arylcarbonothioyl)malonohydrazides, by the direct coupling of N-alkyl-N-(substituted)be
- Xia, Zhiqiang,Jiang, Jun,Sun, Lijun,Tatsuta, Noriaki,Koya, Keizo,Zhang, Junyi,Bohnert, Gary,Chen, Shoujun
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p. 3394 - 3398
(2015/01/09)
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- Syntheses and antitumor activities of N′1, N′3-dialkyl-N′1,N′3-di- (alkylcarbonothioyl) malonohydrazide: The discovery of elesclomol
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A series of N′1,N′3-dialkyl- N′1,N′3-di(alkylcarbonothioyl) malonohydrazides have been designed and synthesized as anticancer agents by targeting oxidative stress and Hsp70 induction. Structure-activity relationship (SAR) studies lead to the discovery of STA-4783 (elesclomol), a novel small molecule that has been evaluated in a number of clinical trials as an anticancer agent in combination with Taxol.
- Chen, Shoujun,Sun, Lijun,Koya, Keizo,Tatsuta, Noriaki,Xia, Zhiqiang,Korbut, Timothy,Du, Zhenjian,Wu, Jim,Liang, Guiqing,Jiang, Jun,Ono, Mitsunori,Zhou, Dan,Sonderfan, Andrew
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p. 5070 - 5076
(2013/09/12)
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- Molecular mechanisms of the biological activity of the anticancer drug elesclomol and its complexes with Cu(II), Ni(II) and Pt(II)
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The bis(thiohydrazide) amide elesclomol has extremely potent antiproliferative activity and is currently in clinical trials as an anticancer agent. Elesclomol strongly binds copper and may be exerting its cell growth inhibitory effects by generating copper-mediated oxidative stress. Nickel(II) and platinum(II) complexes of elesclomol were synthesized and characterized in order to investigate if these biologically redox inactive metal complexes could also inhibit cell growth. The nickel(II)-elesclomol and platinum(II) elesclomol complexes were 34- and 1040-fold less potent than the copper(II)-elesclomol complex towards human leukemia K562 cells. These results support the conclusion that a redox active metal is required for elesclomol to exert its cell growth inhibitory activity. Copper(II)-elesclomol was also shownto efficiently oxidize ascorbic acid at physiological ascorbic acid concentrations. Reoxidation of the copper(I) thus produced would lead to production of damaging reactive oxygen species. An X-ray crystallographic structure determination of copper(II)-elesclomol showed that it formed a 1:1 neutral complex with a distorted square planar structure. The kinetics and equilibria of the competition reaction of the strong copper(II) chelator TRIEN with copper(II)-elesclomol were studied spectrophotometrically under physiological conditions. These results showed elesclomol bound copper(II) with a conditional stability constant 24-fold larger than TRIEN. A log stability constant of 24.2 was thus indirectly determined for the copper(II)-elesclomol complex.
- Yadav, Arun A.,Patel, Daywin,Wu, Xing,Hasinoff, Brian B.
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- PROCESS FOR PREPARING BIS(THIOHYDRAZIDE AMIDES)
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Disclosed herein are methods of preparing a bis(thio-hydrazide amides) compounds of the following structural formula (I), wherein R1., R3 and Y are defined herein.
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Page/Page column 35-37
(2009/07/17)
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- Purification of bis (thiohydrazide amides)
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Disclosed herein are methods of purifying a bis(thio-hydrazide amides) compounds of the following structural formula: wherein R1, R2, R3, R4, R7, R8, Z, and Y are defined herein.
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Page/Page column 8-9
(2008/12/06)
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