New amide derivatives of Probenecid as selective inhibitors of carbonic anhydrase IX and XII: Biological evaluation and molecular modelling studies

被引：34

作者：

Carradori, Simone ^{[1
]}

Mollica, Adriano ^{[1
]}

Ceruso, Mariangela ^{[2
]}

D'Ascenzio, Melissa ^{[3
]}

De Monte, Celeste ^{[3
]}

Chimenti, Paola ^{[3
]}

Sabia, Rocchina ^{[3
]}

Akdemir, Atilla ^{[4
]}

Supuran, Claudiu T. ^{[2
,5
]}

机构：

[1] G DAnnunzio Univ Chieti Pescara, Dept Pharm, I-66100 Chieti, Italy

[2] Univ Florence, Lab Chim Bioinorgan, Polo Sci, I-50019 Florence, Italy

[3] Univ Roma La Sapienza, Dipartimento Chim & Tecnol Farmaco, I-00185 Rome, Italy

[4] Bezmialem Vakif Univ, Dept Pharmacol, Fac Pharm, TR-34093 Istanbul, Turkey

[5] Univ Florence, Neurofarba Dept, Sect Pharmaceut & Nutraceut Sci, I-50019 Florence, Italy

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2015年 / 23卷 / 13期

关键词：

Probenecid; Selective carbonic anhydrase IX inhibitors; Selective carbonic anhydrase XII inhibitors; Tertiary sulfonamides; Molecular modelling; ISOZYMES IX; TRANSMEMBRANE; CANCER; SULFONAMIDES; ACTIVATORS; INSIGHTS; SCAFFOLD; DESIGN; SALEN; TAIL;

D O I：

10.1016/j.bmc.2015.05.013

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

Novel amide derivatives of Probenecid were synthesized and discovered to act as potent and selective inhibitors of the human carbonic anhydrase (hCA, EC 4.2.1.1) transmembrane isoforms hCA IX and XII. The proposed chemical transformation of the carboxylic acid into an amide group led to a complete loss of hCA I and II inhibition (K(i)s > 10,000 nM) and enhanced the inhibitory activity against hCA IX and XII, with respect to the parent compound (incorporating a COOH function). These promising biological results have been corroborated by molecular modelling studies within the active sites of the four studied human carbonic anhydrases, which enabled us to rationalize both the isoform selectivity and high activity against the tumor-associated isoforms hCA IX/XII. (C) 2015 Elsevier Ltd. All rights reserved.

引用

页码：2975 / 2981

页数：7

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