Design, syntheses and biological evaluation of natural product aiphanol derivatives and analogues: Discovery of potent anticancer agents

Licheng Yao; Wenqing Cai; Shanmei Chen; Aidan Wang; Xin Wang; Chuanke Zhao; Chengchao Shou; Yanxing Jia

doi:10.1016/j.bmcl.2023.129326

Design, syntheses and biological evaluation of natural product aiphanol derivatives and analogues: Discovery of potent anticancer agents

Bioorg Med Chem Lett. 2023 Jun 15:90:129326. doi: 10.1016/j.bmcl.2023.129326. Epub 2023 May 12.

Authors

Licheng Yao¹, Wenqing Cai¹, Shanmei Chen², Aidan Wang¹, Xin Wang¹, Chuanke Zhao², Chengchao Shou³, Yanxing Jia⁴

Affiliations

¹ State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, and Chemical Biology Center, Peking University, Beijing 100191, China.
² Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Biochemistry and Molecular Biology, Peking University Cancer Hospital & Institute, Beijing 100142, China.
³ Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Biochemistry and Molecular Biology, Peking University Cancer Hospital & Institute, Beijing 100142, China. Electronic address: cshou@vip.sina.com.
⁴ State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, and Chemical Biology Center, Peking University, Beijing 100191, China. Electronic address: yxjia@bjmu.edu.cn.

PMID: 37182611
DOI: 10.1016/j.bmcl.2023.129326

Abstract

The natural product aiphanol (1) is one of the substances with anticancer biological activity isolated from traditional Chinese medicines (TCM) Smilax glabra Roxb. (Tufuling). Our recent research found that aiphanol could suppress angiogenesis and tumor growth by dual-blocking VEGF/VEGFRs and COX2 signal pathway. In this study, four series of 40 aiphanol derivatives and analogues were designed, synthesized and evaluated for their anticancer activity. Among them, the analogues 10j and 14c exhibited the most potent inhibition and broad-spectrum antiproliferative activity toward nine tumor cell lines. The IC₅₀ values of the analogues 10j and 14c range from 0.81 to 10 μmol/L which up to 80-fold vs. parent compound aiphanol. The structure-activity relationship (SAR) studies indicated that the substrate at 7-position of benzo 1,4-dioxane is very crucial for anticancer activity. Molecular docking indicated that the compound 14c (ent-14c) tightly binds to VEGFR2 and COX2, respectively. Therefore, compounds 10j and 14c could be promising candidates for the development of anticancer agents in the future.

Keywords: Aiphanol; Anticancer; COX2; Structure-activity relationship; VEGFR.

Publication types

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

MeSH terms

Antineoplastic Agents* / chemistry
Antineoplastic Agents* / pharmacology
Biological Products* / pharmacology
Cell Proliferation
Cyclooxygenase 2 / metabolism
Drug Design
Drug Screening Assays, Antitumor
Molecular Docking Simulation
Molecular Structure
Protein Kinase Inhibitors / pharmacology
Structure-Activity Relationship
Vascular Endothelial Growth Factor Receptor-2

Substances

aiphanol
Antineoplastic Agents
Biological Products
Carbon-14
Cyclooxygenase 2
Protein Kinase Inhibitors
Vascular Endothelial Growth Factor Receptor-2
tufuling