Synthesis of 2‐phenylnaphthalenoid amide derivatives and their topoisomerase IIα inhibitory and antiproliferative activities

• Published in: Archiv der Pharmazie (Weinheim) 2024-10, Vol.357 (10), p.e2400175-n/a
• Main Authors: Wu, Xiaoxia, Xu, Guangsen, Lu, Chunhua, Shen, Yuemao
• Format: Article
• Language: English
• Subjects: 2‐phenylnaphthalenoids; Amides - chemical synthesis; Amides - chemistry; Amides - pharmacology; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; antiproliferative activity; Apoptosis - drug effects; Cell Line, Tumor; Cell Movement - drug effects; Cell Proliferation - drug effects; DNA Topoisomerases, Type II - metabolism; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Hep G2 Cells; Humans; Molecular Structure; Naphthalenes - chemical synthesis; Naphthalenes - chemistry; Naphthalenes - pharmacology; structure optimization; Structure-Activity Relationship; Topoisomerase II Inhibitors - chemical synthesis; Topoisomerase II Inhibitors - chemistry; Topoisomerase II Inhibitors - pharmacology; topoisomerase IIα
• ISSN: 0365-6233; 1521-4184; 1521-4184
• DOI: 10.1002/ardp.202400175

Topoisomerases are highly associated with cell proliferation, becoming an important target for the development of antitumor drugs. 2‐Phenylnaphthalenoids (2PNs) have been identified as human DNA topoisomerase IIα (TopoIIα) inhibitors. In this study, based on the 2PN scaffold, 20 amide derivatives (J1–J10, K1–K10) were synthesized. Among them, K10 showed high TopoIIα inhibitory activity and stronger antiproliferation activity against HepG‐2 and MDA‐MB‐231 cells (IC50 0.33 and 0.63 μM, respectively) than the positive control VP‐16 (IC50 9.19 and 10.86 μM) and the lead F2 (IC50 0.64 and 1.51 μM). Meanwhile, K10 could also inhibit migration and promote apoptosis of HepG‐2 and MDA‐MB‐231 cells. Therefore, K10 can be developed into a potent TopoIIα inhibitor as an antitumor agent. The structure–activity relationship was also discussed. Twenty N‐[4‐(6‐hydroxy‐2‐naphthyl)phenyl]‐amide derivatives were designed and synthesized, and their antitumor activities and effects on topoisomerase IIα (TopoIIα) were evaluated in vitro. K10 had the strongest inhibition on TopoIIα as well as the strongest inhibitory effect on HepG‐2 and MDA‐MB‐231 cells. K10 can also inhibit cell migration and promote early apoptosis and is more closely bound to topoisomerase.