Design and Synthesis of Cytotoxic Water-Soluble Rocaglaol Derivatives against HEL Cells by Inhibiting Fli‑1

• Published in: Journal of natural products (Washington, D.C.) D.C.), 2024-02, Vol.87 (2), p.276-285
• Main Authors: Ge, Wei, Ming, Weikang, Li, Zhenkun, Tang, Yunyan, Li, Ya-Nan, Yang, Jue, Hao, Xiaojiang, Yuan, Chunmao
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - pharmacology; Apoptosis; Benzofurans; Cell Line, Tumor; Cell Proliferation; Doxorubicin; Drug Screening Assays, Antitumor; Molecular Structure; Structure-Activity Relationship
• ISSN: 0163-3864; 1520-6025
• DOI: 10.1021/acs.jnatprod.3c00948

Rocaglaol, embedding a cyclopenta­[b]­benzofuran scaffold, was isolated mainly from the plants of Aglaia and exhibited nanomolar level antitumor activity. However, the drug-like properties of these compounds are poor. To improve the physicochemical properties of rocaglaol, 36 nitrogen-containing phenyl-substituted rocaglaol derivatives were designed and synthesized. These derivatives were tested for the inhibitory effects on three tumor cell lines, HEL, MDA-231, and SW480, using the MTT assay. Among them, 22 derivatives exhibited good cytotoxic activities with IC50 values between 0.11 ± 0.07 and 0.88 ± 0.02 μM. Fourteen derivatives exhibited stronger cytotoxicity than the positive control, adriamycin. In particular, a water-soluble derivative revealed selective cytotoxic effects on HEL cells (IC50 = 0.19 ± 0.01 μM). This compound could induce G1 cell cycle arrest and apoptosis in HEL cells. Western blot assays suggested that the water-soluble derivative could downregulate the expression of the marker proteins of apoptosis, PARP, caspase-3, and caspase-9, thus inducing apoptosis. Further CETSA and Western blot studies implied that this water-soluble derivative might be an inhibitor of friend leukemia integration 1 (Fli-1). This water-soluble derivative may serve as a potential antileukemia agent by suppressing the expression of Fli-1.