Design, synthesis, chemical and biological evaluation of 2,5,5-trisubstitu-ted-1,2-thiazepan-6-one 1,1-dioxides

In this article, we designed and synthesized a series of novel 2,5,5-trisubstituted (including spirocyclic) 1,2-thiazepan-6-one 1,1-dioxides (put simply, gamma,gamma-disubstituted beta-keto e-sultams), prepared a number of derivatives and evaluated their cytotoxic activity against MDA-MB-231 breast cancer cell line. In particular, alkylation of Nmonosubstituted methanesulfonamides with alpha,alpha-disubstituted beta-halogenated esters (including cyclic representatives) afforded the corresponding N-mesylated beta-amino acid esters. The latters were involved in CSIC (Carbanion-mediated Sulfonamide Intramolecular Cyclization) reaction to give the target gamma,gamma-disubstituted beta-keto e-sultams (including spirocyclic representatives) in synthetically useful yields. This class of compounds can be considered as valuable building blocks since they possess carbonyl functionality and an EWG-activated methylene group capable of further functionalization. For instance, the condensation with DMFDMA afforded the corresponding alpha-dimethylaminomethylidene derivatives - the direct precursors for the heterocyclization reactions. Their treatment with hydrazine hydrate or guanidine hydrochloride provided the corresponding pyrazolo- and pyrimidofused e-sultams. Despite the prepared beta-keto e-sultams showing weak cytotoxicity against the MDA-MB-231 breast cancer cell line, their pyrazolofused derivatives appeared perspective pharmacological templates with stable cytotoxic effects. Moreover, beta-keto e-sultams and their heterofused derivatives form watersoluble conjugates with branched polymers based on dextran-polyacrylamide (D-PAA) that can be used as the transport module for targeted drug delivery in biological media.