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

被引：21

作者：

Tardia, Piero ^{[1
]}

Stefanachi, Angela ^{[1
]}

Niso, Mauro ^{[1
]}

Stolfa, Diana Antonella ^{[1
]}

Mangiatordi, Giuseppe Felice ^{[1
]}

Alberga, Domenico ^{[2
,3
]}

Nicolotti, Orazio ^{[1
]}

Lattanzi, Gianluca ^{[2
,3
]}

Carotti, Angelo ^{[1
]}

Leonetti, Francesco ^{[1
]}

Perrone, Roberto ^{[1
]}

Berardi, Francesco ^{[1
]}

Azzariti, Amalia ^{[4
]}

Colabufo, Nicola Antonio ^{[1
]}

Cellamare, Saverio ^{[1
]}

机构：

[1] Univ Bari Aldo Moro, Dipartimento Farm Sci Farmaco, I-70125 Bari, Italy

[2] Univ Bari Aldo Moro, Dipartimento Fis, INFN, I-70126 Bari, Italy

[3] TIRES, I-70126 Bari, Italy

[4] Natl Canc Res Ctr, Ist Tumori Giovanni Paolo II, Clin & Preclin Pharmacol Lab, I-70124 Bari, Italy

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2014年 / 57卷 / 15期

关键词：

TARGETING MULTIDRUG-RESISTANCE; POTENTIAL FUNCTIONS; MOLECULAR-DYNAMICS; BINDING; PERMEABILITY; INHIBITORS; PROTEINS; DESIGN; ENERGY; ASSAYS;

D O I：

10.1021/jm500697c

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 MRPI), 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.

引用

页码：6403 / 6418

页数：16

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