The
biological activities of
dehydrocostus lactone and its analogues are suggested to be mediated by the
lactone ring and α,β-methylene-γ-
lactone. However, few studies exist on the structure-activity relationship of 13-amino derivatives of dehydrocostus latone. In this study new 13-amino derivatives of
dehydrocostus lactone DHLC (1-4) were synthesized through Michael addition reactions, and were screened against three different
breast cancer cell lines, namely
hormone receptor positive
breast cancer (MCF-7),
triple-negative breast cancer (HCC70), and non-tumorigenic mammary epithelial (MCF-12A) cell lines.
Dehydrocostus lactone (DHLC) exhibited IC50 values of 1.11 (selectivity index (SI) = 0.06), 24.70 (SI = 0.01) and 0.07 μM against HCC70, MCF-7 and MCF-12A cells, respectively. All the amino derivatives, except DHLC-3 displayed low micromolar IC50 values (ranging from 0.07-4.24 μM) against both
breast cancer cell lines, with reduced toxicity towards MCF-12A non-tumorigenic mammary epithelial cells (SI values ranging from 6.00-126.86). DHLC-1 and DHLC-2 demonstrated the greatest selectivity for the MCF-7 cells (with SI of 121 and 126.86 respectively) over the MCF-12A cells. This reveals that, overall, the derivatives display greatly improved selectivity for
breast cancer over non-tumorigenic mammary epithelial cells, with between 100-fold and 12 000-fold higher SI values. The improved docking scores were recorded for all the 13-amino
dehydrocostus lactone derivatives for the
enzymes analyzed. Compounds DHLC-4, and DHLC-3 recorded higher docking scores of -7.33 and -5.97 Kca/mol respectively, compared to the parent structure,
dehydrocostus lactone (-5.34 Kca/mol) for
protein kinase (
PKC) theta (1XJD) and -6.22 and -5.88 Kca/mol, respectively for
protein kinase iota (1RZR). The compounds further showed promising predicted adsorption, distribution, metabolisms and excretion (ADME) properties. Predicting the ADME properties of these derivatives is of importance in evaluating their
drug-likeness, which could in turn be developed into potential
drug candidates.