Synthesis and Cancer Cell Cytotoxicity of 6-, 7-, or 8-Substituted 2-(Hetero)aryl-4-(4-(Hetero)aryl-2-Oxobut-3-en-1-Ylidene)Benzothiazepanes

Cancer chemotherapy is continuously challenged by serious complications like pronounced side effects and multidrug resistance (MDR). Natural products, such as curcumin, offer promising alternatives due to their diverse biological applications and low toxicity. However, curcumin's clinical utility is limited by poor bioavailability, rapid metabolism, and non-specific (PAINS) activity. Building on previous findings, this study explored the structural modification of curcumin-inspired benzothiazepane derivatives in an attempt to enhance their therapeutic potential through modifications of the two peripheral (hetero)aromatic rings and the benzothiazepane scaffold. In this way, eight new 2-(hetero)aryl-4-(4-(hetero)aryl-2-oxobut-3-en-1-ylidene)benzothiazepanes and two 4-thiobutan-2-one "double Michael addition" derivatives were synthesized and tested for cytotoxicity against a panel of eight cancer cell lines. The screening results indicated that bis-(4-hydroxyphenyl) analogs bearing a chlorinated benzothiazepane ring exhibited the highest potency and broad-spectrum activity at the low micromolar range. Bis-substitutions with 3-pyridinyl and 2-furyl groups showed less potent but more specific activity profiles, potentially reducing PAINS effects. 2-Aminothiophenol-derived double Michael addition products demonstrated increased broad-spectrum activity, highlighting the importance of the free aniline amino group for targeted effects. This study underscores the potential of benzothiazepane derivatives as viable cancer cell cytotoxic agents and provides useful insights for future optimization and evaluation.