13-amino derivatives of dehydrocostus lactone display greatly enhanced selective toxicity against breast cancer cells and improved binding energies to protein kinases in silico.
Kemboi, Douglas ; Langat, Moses K. ; Siwe-Noundou, Xavier ; Tshiwawa, Tendamudzimu ; Krause, Rui W. M. ; Davison, Candace ; Smit, Jane ; De la Mare, Jo-Anne ; Tembu1, Vuyelwa Jacqueline
Kemboi, Douglas
Langat, Moses K.
Siwe-Noundou, Xavier
Tshiwawa, Tendamudzimu
Krause, Rui W. M.
Davison, Candace
Smit, Jane
De la Mare, Jo-Anne
Tembu1, Vuyelwa Jacqueline
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Abstract
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 nontumorigenic 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, Mdistribution, 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.
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Date
2022-08-23
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Public Library of Science
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Keywords
Dehydrocostus lactone, 13-amino derivatives, Hormone receptor, Low micromolar, Nontumorigenic mammary