Design, synthesis, and anticancer evaluation of novel andrographolide derivatives bearing an α,β-unsaturated ketone moiety

Wei Cai; Jieyi Li; Cheng Chen; Jiajia Wu; Jiabin Li; Xiaowen Xue

doi:10.1016/j.bioorg.2021.104941

Design, synthesis, and anticancer evaluation of novel andrographolide derivatives bearing an α,β-unsaturated ketone moiety

Bioorg Chem. 2021 Jul:112:104941. doi: 10.1016/j.bioorg.2021.104941. Epub 2021 Apr 24.

Authors

Wei Cai¹, Jieyi Li¹, Cheng Chen², Jiajia Wu¹, Jiabin Li³, Xiaowen Xue⁴

Affiliations

¹ Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China.
² School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
³ School of Science, China Pharmaceutical University, Nanjing 211198, China.
⁴ Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China. Electronic address: [email protected].

PMID: 33940445
DOI: 10.1016/j.bioorg.2021.104941

Abstract

A series of 1,2-didehydro-3-ox-andrographolide derivatives based on two Michael acceptors were designed, synthesized and evaluated for their anticancer activity against two human cancer cell lines (HCT116 and MCF-7). All tested compounds exhibited significant growth inhibitory effect on HCT116 and moderate to good inhibitory effect on MCF-7 cell proliferation. Compound 10b displayed the best inhibitory activities against both HCT116 and MCF-7 cell lines, with IC₅₀ values of 2.49 and 7.80 μM respectively. Preliminary anticancer mechanistic investigation was performed in terms of the cell cycle arrest and cell apoptosis assays of compound 10b against HCT116 using flow cytometry, and the results indicated that 10b blocked the proliferation of HCT116 cells by inducing cell apoptosis in a concentration-dependent manner and arresting cell cycle in G₂/M phase.

Keywords: Andrographolide; Anticancer; Apoptosis; Cell cycle arrest; Michael acceptor.

Publication types

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

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Cell Cycle / drug effects
Cell Proliferation / drug effects
Diterpenes / chemical synthesis
Diterpenes / chemistry
Diterpenes / pharmacology*
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Humans
Ketones / chemistry
Ketones / pharmacology*
Molecular Structure
Structure-Activity Relationship
Tumor Cells, Cultured

Substances

Antineoplastic Agents
Diterpenes
Ketones
andrographolide