Despite the tremendous progress made in cancer chemotherapy, cancers of various kinds still remain among the leading causes of mortality worldwide. Exploiting the unique features of tumor cells and examining the specific molecular pathways or cellular targets that differentiate cancer cells from normal cells are among the key focuses for modern oncology drug discovery.Scientific evidence reveals that elevated levels of reactive oxygen species (ROS) are present in almost all cancer cells. It is known that an extremely high level of ROS, beyond the survival threshold in cancer cells, can trigger apoptosis. In contrast, the relatively low level of ROS in normal cells can be effectively detoxified by the endogenous antioxidants, and normal cells are much more resistant to ROS induction. In parallel, very high levels of HSP70, a 70 kDa heat shock protein, were found in malignant human tumors of various origins, and the expression of HSP70 in cells has been positively correlated with elevated ROS generation. Recent research and observations have suggested that HSP70 can act as a biomarker of oxidative injury. We initiated a program by screening selected compounds from Synta's unique compound library using an HSP70 induction assay together with a cytotoxic assay using the MES-SA/DX5 cell line, a well-established drug resistant cell line useful for compound screening. Herewith we disclose the discovery, syntheses, and SAR studies of a series of N'1,N'3-dialkyl-N'1,N'3-di(alkylcarbonothioyl) malonohydrazides as anticancer agents, which culminated in the discovery of Elesclomol�  (STA-4783) - a novel small molecule that has been evaluated in a number of clinical trials and showed promising results with patients having low level of lactate dehydrogenase (LDH).The hit generation, lead optimization, process chemistry and final candidates' in vitro/in vivo pharmacologic profiling will be discussed.

Syntheses and anticancer activities of N1, N3-dialkyl-N1, N3-di-(alkylcarbonothioyl)malonohydrazides: The discovery of Elesclomol�

246th National Meeting (2013)

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