Diterpenoids from Euphorbia glomerulans with potential reversal activities against P-glycoprotein-mediated multidrug resistance

Aobulikasimu Hasan; Dan Tang; Dilaram Nijat; Hequn Yang; H A Aisa

doi:10.1016/j.bioorg.2021.105442

Diterpenoids from Euphorbia glomerulans with potential reversal activities against P-glycoprotein-mediated multidrug resistance

Bioorg Chem. 2021 Dec:117:105442. doi: 10.1016/j.bioorg.2021.105442. Epub 2021 Oct 21.

Authors

Aobulikasimu Hasan¹, Dan Tang², Dilaram Nijat¹, Hequn Yang¹, H A Aisa³

Affiliations

¹ State Key Laboratory Basis of Xinjiang Indigenous Medicinal Plants Resource Utilization, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi 830011, PR China; University of Chinese Academy of Sciences, Beijing 100039, PR China.
² State Key Laboratory Basis of Xinjiang Indigenous Medicinal Plants Resource Utilization, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi 830011, PR China.
³ State Key Laboratory Basis of Xinjiang Indigenous Medicinal Plants Resource Utilization, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi 830011, PR China. Electronic address: haji@ms.xjb.ac.cn.

PMID: 34742027
DOI: 10.1016/j.bioorg.2021.105442

Abstract

The development of collateral sensitivity agents that are able to modulate P-glycoprotein (P-gp) is the most promising approaches to overcome multidrug resistance (MDR) in cancer. In this study, eight new diterpenoids of jatrophane and ingenane type, 1-8, and three known ones (9-11) were isolated from Euphorbia glomerulans. Their structures were elucidated by spectroscopic analysis and electronic circular dichroism (ECD) calculations. The MDR reversal activity evaluation of these isolates on breast cancer MCF-7/ADR cells demonstrated the four potent MDR modulators (3, 4, 5, and 9) with great chemoreversal ability and low cytotoxicity. The structure-activity relationship (SAR) analysis indicated that the presence of isobutanoyloxy group at C-8 significantly enhance reversal efficiency. Compound 5 exhibited high efficacy (EC₅₀ = 159.5 nM) in reversing MDR resistance, being stronger than verapamil (EC₅₀ = 302.9 nM). The MDR reversal mechanism assays revealed that 5 could promote the accumulation of Rh123 and DOX in drug-resistant cells in a certain dose-dependent manner, and inhibit P-gp transport function. In addition, the possible recognition mechanism of compound 5 and verapamil (VRP) with P-gp was predicted by molecular docking.

Keywords: Euphorbia glomerulans; Macrocyclic diterpenoids; Multidrug resistance reversal activity; P-glycoprotein drug efflux; Structure-activity relationship.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
Antineoplastic Agents, Phytogenic / chemistry
Antineoplastic Agents, Phytogenic / isolation & purification
Antineoplastic Agents, Phytogenic / pharmacology*
Cell Proliferation / drug effects
Diterpenes / chemistry
Diterpenes / isolation & purification
Diterpenes / pharmacology*
Dose-Response Relationship, Drug
Drug Resistance, Multiple / drug effects
Drug Screening Assays, Antitumor
Euphorbia / chemistry*
Humans
Molecular Docking Simulation
Molecular Structure
Structure-Activity Relationship
Tumor Cells, Cultured

Substances

ATP Binding Cassette Transporter, Subfamily B, Member 1
Antineoplastic Agents, Phytogenic
Diterpenes