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Design, synthesis and biological evaluation of a novel platinum(Ⅱ)complex possessing bioreductive groups for cancer therapy

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Chinese Chemical Letters 2019年第1期30卷 243-246页

作者： Chengken Chen Chunmei Gao Zigao Yuan Yuyang Jiang Department of Chemistry Tsinghua University The Ministry-Province Jointly Constructed Base for State Key Lab-Shenzhen Key Laboratory of Chemical Biology The Graduate School at Shenzhen Tsinghua University College of Chemistry and Chemical Engineering Shenzhen University Shenzhen Kivita Innovative Drug Discovery Institute Department of Pharmacology and Pharmaceutical Sciences School of Medicine Tsinghua University

Cisplatin is one of the most successful antitumor agents, yet also restricted by its poor cellular uptake and low selectivity. Since 3-(2-nitrophenyl) propionic acid(NPPA) has been reported as a bioreductive prodrug moiety, herein we combined NPPA with cisplatin(compound 1) to improve its lipophilicity and targetability and then to improve the antitumor outcomes. In addition, compound 2 possessing 3-phenyl propionic acid(PPA) was also synthesized as a comparison to test the influence of the NPPA to the cytotoxicity, since PPA was not a bioreductive moiety. Bioevaluations showed that 1 displayed more potent antitumor potency than cisplatin and 2, suggesting Pt(II) complexes possessing NPPA groups may be a good strategy for future platinum drug discovery.

关键词： Platinum compounds bioreductive Nitrophenylalkanoic group Cellular uptake Antitumor

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Understanding the Relationship between Metabolism and Toxicity for bioreductive Drugs: a Study on the Anti-Tumour Prodrug CB 1954

Understanding the Relationship between Metabolism and Toxici...

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第十五届国际药理学大会

作者： Magdalene HY Tang Nuala Helsby Michael Goldthorpe William Wilson Saad Al -Ali Malcolm Tingle Department of Pharmacology ＆ Clinical Pharmacology Department of Molecular Medicine ＆ Pathology Auckland Cancer Society Research Centre （ACSRC） Department of Pharmacology ＆ Clinical Pharmacology Auckland Cancer Society Research Centre （ACSRC） Department of Anatomy with Radiology University of Auckland New Zealand Department of Pharmacology ＆ Clinical Pharmacology

＜正＞ bioreductive drugs such as CB 1954. nilutamide （anti - tumour） and nimesulide （NSAID） cause hepatotoxicity possibly due to activation by endogenous reductase （s）. The aim of this study was to investigate the relationship between bioactivationand hepatotoxicity using CB 1954 as a model compound. Drug administration in mice caused a dramatic increase in both alanine （ALT） and aspartate aminotransferase（AST） and in rats only a slight increase in AST. Histopathological examination of the livers revealed centrilobular hepatocyte injury in mouse but periportal（biliary） damage in rat. Aerobic incubation of CB 1954 with mouse or rat liver S9 resulted in formation of cytotoxic 2 - and 4 - nitroreduction metabolites, which were also seen in vivo. In conclusion, both mice and rats are susceptible to the hepatotoxicity of CB 1954. perhaps via different mechanisms, which may involve endogenous bioactivation. These models may be used to investigate potential host toxicity of other bioreductive drugs, some of which are under development in ACSRC.

关键词： bioreductive metabolism hepatotoxicity CB 1954

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