Selective inhibition of human carbonic anhydrases by novel amide derivatives of probenecid: Synthesis, biological evaluation and molecular modelling studies

被引：36

作者：

D'Ascenzio, Melissa ^{[1
]}

Carradori, Simone ^{[1
]}

Secci, Daniela ^{[1
]}

Vullo, Daniela ^{[2
]}

Ceruso, Mariangela ^{[2
]}

Akdemir, Atilla ^{[4
]}

Supuran, Claudiu T. ^{[2
,3
]}

机构：

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

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

[3] Univ Florence, Neurofarba Dept, Sect Pharmaceut & Nutriceut Sci, I-50019 Florence, Italy

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

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2014年 / 22卷 / 15期

关键词：

Probenecid; Selective carbonic anhydrase IX inhibitors; Selective carbonic anhydrase XII inhibitors; Tertiary sulfonamides; HCA IX INHIBITORS; BREAST-CANCER; THERAPEUTIC APPLICATIONS; TERTIARY BENZENESULFONAMIDES; SULFONAMIDES; HYPOXIA; XII; METABOLISM; ADAPTATIONS; METASTASIS;

D O I：

10.1016/j.bmc.2014.06.003

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Novel amide derivatives of probenecid, a well-known uricosuric agent, were synthesized and evaluated as inhibitors of human carbonic anhydrases (hCAs, EC 4.2.1.1). The transmembrane isoforms (hCA IX and XII) were potently and selectively inhibited by some of them. The proposed chemical modification led to a complete loss of hCA II inhibition (K(i)s > 10,000 nM) and enhanced the inhibitory activity against the tumour-associated hCA XII (compound 4 showed a K-i value of 15.3 nM). The enzyme inhibitory data have also been validated by docking studies of the compounds within the active site of hCA XII. (C) 2014 Elsevier Ltd. All rights reserved.

引用

页码：3982 / 3988

页数：7

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