Synthesis and cancer cell cytotoxicity of 2-heteroaryl-4-(4-heteroaryl-2-oxobut-3-en-1-ylidene)-substituted benzothiazepanes

The natural product curcumin is often presented as a source of inspiration in the field of drug development because of its therapeutic diversity and safety for human consumption. However, although curcumin indeed shows an interesting profile in terms of in vitro biological activity, its low oral bioavailability, poor stability and unclear mechanism of action considerably weakens its case as a marketable drug. In that context, several modifications to the curcumin structure have previously been realized in our lab, culminating in i.a. benzothiazepane-based derivatives with improved drug-like properties and significant cancer cell cytotoxicity. To further explore their structure-activity relationships and to improve their antitumoral activity, we synthesized a library of new 2-heteroaryl-4-(4-heteroaryl-2-oxobut-3-en-1-ylidene)benzothiazepanes, which were evaluated for cytotoxicity against eight different cancer cell lines. From this screening, pyridine-substituted benzothiazepanes emerged as broad-spectrum anticancer agents, whereas 2-thienyl benzothiazepanes and a side product, formed through a double Michael addition reaction, surfaced as promising structures for further elaboration because of their highly selective activity against the NCI–H460 lung cancer cell line.