Trimethoxybenzanilide-Based P-Glycoprotein Modulators: An Interesting Case of Lipophilicity Tuning by Intramolecular Hydrogen Bonding

详细信息    查看全文

• 作者：Piero Tardia ; Angela Stefanachi ; Mauro Niso ; Diana Antonella Stolfa ; Giuseppe Felice Mangiatordi ; Domenico Alberga ; Orazio Nicolotti ; Gianluca Lattanzi ; Angelo Carotti ; Francesco Leonetti ; Roberto Perrone ; Francesco Berardi ; Amalia Azzariti ; Nicola Antonio Colabufo ; Saverio Cellamare
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：August 14, 2014
• 年：2014
• 卷：57
• 期：15
• 页码：6403-6418
• 全文大小：797K
• ISSN：1520-4804

文摘

One of the principal reasons for the chemotherapy failure is the overexpression of drug efflux pumps, ABCB1 (also known as MDR1 or P-gp) and ABCC1 (also known as MRP1), whose inhibition remains a priority to circumvent drug resistance. We have recently shown a clear trend between lipophilicity and P-glycoprotein inhibitory activity for a class of galloyl-based modulators targeting P-glycoprotein and MRP1. Herein we report a new series of polymethoxy benzamides, whose lipophilicity was modulated through the establishment of an intramolecular hydrogen bond (IMHB) which allows reaching of P-gp inhibitory activity at the submicromolar IC₅₀ level. The present study provides a strong rationale for candidates in the presence of IMHB as a key element for a high P-gp inhibitory activity.