Synthesis and ABCG2 inhibitory evaluation of 5-N-acetylardeemin derivatives

• Published in: Bioorganic & medicinal chemistry 2015-05, Vol.23 (9), p.2010-2023
• Main Authors: Hayashi, Daigo, Tsukioka, Naoki, Inoue, Yutaka, Matsubayashi, Yoshiki, Iizuka, Toshimasa, Higuchi, Kazuhiro, Ikegami, Yoji, Kawasaki, Tomomi
• Format: Article
• Language: English
• Subjects: ABCG2 modulator; Ardeemin; ATP Binding Cassette Transporter, Sub-Family G, Member 2; ATP-Binding Cassette Transporters - antagonists & inhibitors; Dose-Response Relationship, Drug; Humans; Molecular Structure; Multicomponent reaction; Multidrug resistance; Neoplasm Proteins - antagonists & inhibitors; Pyrimidinones - chemical synthesis; Pyrimidinones - chemistry; Pyrimidinones - pharmacology; Structure-Activity Relationship; Suzuki–Miyaura coupling
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2015.03.017

[Display omitted] An efficient and versatile synthesis of 5-N-acetylardeemin (1a) and sixteen 2-, 3- and 13-substituted derivatives 1b–q was achieved through Ugi three-component reaction of 3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole and cyclization/epimerization. Their inhibitory activity on the drug efflux of breast cancer resistance protein (ABCG2) was evaluated by flow cytometric analysis of accumulation of Hoechst 33342 stain in Flp-In-293/ABCG2 cells. Most of the derivatives exhibited a stronger ABCG2 inhibitory effect compared with natural product 1a. The derivative 1m with a 4-tolyl substituent at the C-13 position exhibited the most potent ABCG2 inhibition. This preliminary structure–activity relationship study indicates that an electron-rich aryl moiety as the 13-substituent is key to increasing the inhibitory activity.