Synthesis and anticancer evaluation of Thia-Michael addition derivatives of dehydrocostuslactone: In vitro and in silico studies

Dehydrocostuslactone, a naturally occurring sesquiterpene lactone, is known for its diverse pharmacological properties, particularly its potential anticancer activity. In this study, a library of novel thiol-Michael addition derivatives of dehydrocostuslactone was synthesized through a regioselective approach to explore structural diversity and anticancer activity. The compounds were thoroughly characterized using NMR, mass spectrometry, and HPLC. Their anticancer activity was evaluated against human cancer cell lines, including colon (HCT-116), prostate (PC3), and lung (A549) cancer cells. Among all the derivatives, compound 16 demonstrated the most potent activity, with IC₅₀ values of 4.2 μM, 15.2 μM, and 13.2 μM, respectively, and also exhibited significantly improved selectivity indices compared to the parent compound 1, highlighting its potential as a more selective anticancer agent. Molecular docking studies of compound 16 against MDM2, CDK4, PI3Kα, and PARP1 revealed strong binding interactions, with binding affinities ranging from -7.4 to -9.9 kcal/mol. These interactions suggest its potential to reactivate p53, inhibit cell cycle progression, block survival signaling, and disrupt DNA repair in HCT-116 colon cancer cells. The findings highlight compound 16 as a promising multi-targeted therapeutic candidate for additional experimental validation. The drug-likeness and ADMET properties of all compounds were evaluated and showing favorable pharmacokinetic profiles.