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

Abstract

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, γ,γ-disubstituted β-keto ε-sultams), prepared a number of derivatives and evaluated their cytotoxic activity against MDA-MB-231 breast cancer cell line. In particular, alkylation of N-monosubstituted methanesulfonamides with α,α-disubstituted β-halogenated esters (including cyclic representatives) afforded the corresponding N-mesylated β-amino acid esters. The latters were involved in CSIC (Carbanion-mediated Sulfonamide Intramolecular Cyclization) reaction to give the target γ,γ-disubstituted β-keto ε-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 α-dimethylaminomethylidene derivatives – the direct precursors for the heterocyclization reactions. Their treatment with hydrazine hydrate or guanidine hydrochloride provided the corresponding pyrazolo- and pyrimidofused ε-sultams. Despite the prepared β-keto ε-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, β-keto ε-sultams and their heterofused derivatives form water-soluble 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.