Aromatic scaffold-integrated hybrids of estradiol and benzoxazol-2-ones: synthesis and in vitro anticancer activity of N-substituted regioisomeric pairs.

Molecular hybridization often leads to derivatives with better pharmacokinetic properties and different biological effects than their parent compounds. Several N-substituted benzoxazolone - estradiol chimeras sharing a common benzene ring were prepared by N-alkylation or N-arylation via Chan-Lam cross-coupling of their pre-synthesized unsubstituted precursors. Both the 2,3- and 3,4-fused regioisomers were obtained in good yields and a comparison of the in vitro anticancer activity revealed useful structure-activity relationships. N-Substitution led to benzoxazolone derivatives with high cancer-selectivity. Moreover, the oxazolone ring fusion is more favorable at C2-C3 than at C3-C4 position, as well as the N-alkylation is preferable over N-arylation in terms of both drug-likeness and bioactivity. The most potent derivatives of the current set showed IC50 values between 2.0-5.3 μM on one (6b and 6d) or all of the tested malignant cell lines (6c) with excellent selectivity and triggered apoptosis in cancer cells. The strongest apoptosis-activating molecule was 6d.