Novel 2-benzylthio-5-(1,3,4-oxadiazol-2-yl)benzenesulfonamides with anticancer activity: Synthesis, QSAR study, and metabolic stability

被引：49

作者：

Slawinski, Jaroslaw ^{[1
]}

Szafranski, Krzysztof ^{[1
]}

Pogorzelska, Aneta ^{[1
]}

Zolnowska, Beata ^{[1
]}

Kawiak, Anna ^{[2
,3
,4
]}

Macur, Katarzyna ^{[3
,5
]}

Belka, Mariusz ^{[6
]}

Baczek, Tomasz ^{[6
]}

机构：

[1] Med Univ Gdansk, Dept Organ Chem, Al Gen J Hallera 107, PL-80416 Gdansk, Poland

[2] Univ Gdansk, Intercollegiate Fac Biotechnol, Dept Biotechnol, Ul Abrahama 58, PL-80307 Gdansk, Poland

[3] Med Univ Gdansk, Ul Abrahama 58, PL-80307 Gdansk, Poland

[4] Med Univ Gdansk, Lab Human Physiol, Ul Tuwima 15, PL-80210 Gdansk, Poland

[5] Univ Gdansk, Intercollegiate Fac Biotechnol, Lab Mass Spectrometry, Core Facil Labs, Ul Abrahama 58, PL-80307 Gdansk, Poland

[6] Med Univ Gdansk, Dept Pharmaceut Chem, Al Gen J Hallera 107, PL-80416 Gdansk, Poland

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2017年 / 132卷

关键词：

2-Mercaptobenzenesulfonamide; Synthesis; 1,3,4-Oxadiazole; Anticancer activity; QSAR; Metabolic stability; CYTOSOLIC ISOZYMES I; BIOLOGICAL EVALUATION; INHIBITORS; POTENT; AGENTS; SULFONAMIDES; DERIVATIVES; EXPRESSION; DISCOVERY; DOCKING;

D O I：

10.1016/j.ejmech.2017.03.039

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of novel 2-benzylthio-4-chloro-5-(5-substituted 1,3,4-oxadiazol-2-yl)benzenesulfonamides (4 27) have been synthesized as potential anticancer agents. MIT assay was carried out to determine the cytotoxic activity against three human cancer cell lines: colon cancer HCT-116, breast cancer MCF-7 and cervical cancer HeLa as well as to determine the influence on human keratinocyte cell line HaCaT. Relatively high (IC50: 7-17 mu M) cytostatic activity and selectivity against HeLa cell line was found for compounds 6, 7, 9-11 and 16. While compounds 23-27 bearing styryl moieties attached to a 1,3,4-oxadiazole ring at position 5, exhibited significant activity against two and/or three cancer cell lines with IC50: 11-29 mu M. Further quantitative structure-activity relationships based on molecular descriptors calculated by DRAGON software, were investigated by Orthogonal Projections to Latent Structures (OPLS) technique and Variable Influence on Projection (VIP) analysis. Considering molecular descriptors with the highest influence on projection (highest VIP values) lipophilicity of tested compounds was pointed as main factor affecting activity towards HCT-116 cell line, while structural parameters associated with presence of styryl substituent in position 5 of 1,3,4-oxadiazole ring were identified as essential for activity towards MCF-7 breast cancer. In vitro tests for metabolic stability in the presences of pooled human liver microsomes and NADPH showed that some of the most active compounds 26 and 27 presented favorable metabolic stability with t(1/2) in the range of 28.1-36.0 min. (C) 2017 Elsevier Masson SAS. All rights reserved.

引用

页码：236 / 248

页数：13

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