13-amino derivatives of dehydrocostus lactone display greatly enhanced selective toxicity against breast cancer cells and improved binding energies to protein kinases in silico

Douglas Kemboi; Moses K Langat; Xavier Siwe-Noundou; Tendamudzimu Tshiwawa; Rui W M Krause; Candace Davison; Christie Jane Smit; Jo-Anne de la Mare; Vuyelwa Jacqueline Tembu

doi:10.1371/journal.pone.0271389

13-amino derivatives of dehydrocostus lactone display greatly enhanced selective toxicity against breast cancer cells and improved binding energies to protein kinases in silico

PLoS One. 2022 Aug 23;17(8):e0271389. doi: 10.1371/journal.pone.0271389. eCollection 2022.

Authors

Douglas Kemboi^{1

2}, Moses K Langat³, Xavier Siwe-Noundou⁴, Tendamudzimu Tshiwawa², Rui W M Krause², Candace Davison⁵, Christie Jane Smit⁵, Jo-Anne de la Mare⁵, Vuyelwa Jacqueline Tembu¹

Affiliations

¹ Department of Chemistry, Tshwane University of Technology, Pretoria, South Africa.
² Department of Chemistry, Rhodes University, Makhanda (Grahamstown), South Africa.
³ Royal Botanic Gardens Kew, Kew Green, Richmond, Surrey, United Kingdom.
⁴ Pharmaceutical Sciences Department, Sefako Makgatho Health Sciences University, Pretoria, South Africa.
⁵ Department of Biochemistry and Microbiology, Rhodes University, Makhanda (Grahamstown), South Africa.

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 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.

MeSH terms

Antineoplastic Agents* / pharmacology
Cell Proliferation
Computer Simulation
Drug Screening Assays, Antitumor
Epithelial Cells
Humans
Lactones / chemistry
Lactones / pharmacology
MCF-7 Cells
Molecular Structure
Protein Kinases
Structure-Activity Relationship
Triple Negative Breast Neoplasms* / drug therapy

Substances

Antineoplastic Agents
Lactones
Protein Kinases

Grants and funding

The author(s) received no specific funding for this work.