Effect of stereochemistry at position C20 on the antiproliferative activity and selectivity of N-acylated derivatives of salinomycin

Abstract

Salinomycin (SAL), a natural polyether ionophore, exhibits a broad spectrum of pharmacological activities, including potent anticancer activity. Over the past decade, much effort has been put into developing methods for rational chemical modification of SAL to obtain semisynthetic analogs with higher anticancer activity than the native structure. In this paper, we describe an optimized procedure for synthesizing C20-aminosalinomycin 2 with native stereochemistry at position C20, which was confirmed by single-crystal X-ray diffraction analysis. We further transformed amine precursor 2 into a series of 48 C20–N-(thio)acylated products, including N-(sulfon)amides, N-(thio)ureas, and N-carbamates (urethanes), along with their sulfur analogs, i.e., S-substituted thiocarbamates and dithiocarbamates. This previously unreported class of derivatives showed superior cytotoxicity mostly in the nano- and subnanomolar concentration range and improved selectivity toward human cancer cells compared to those of chemically unmodified SAL and a commonly used oncological drug cisplatin. Of note, the obtained products inhibited the proliferation of reference cancer cells more effectively than their C20-epi-N-acylated counterparts, pointing out the pivotal role of stereochemistry at position C20. Our findings support the premise that the modification of SAL is a fruitful strategy for products with promising biological activity profiles. Moreover, the straightforward protocols should be of significant value for more elaborate modifications of SAL in the future.