title: Novel 2-benzylthio-5-(1,3,4-oxadiazol-2-yl)benzenesulfonamides with anticancer activity: Synthesis, QSAR study, and metabolic stability.
abstract: 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. MTT 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 μM) 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 μM. 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 t1/2in the range of 28.1-36.0 min.
authors.affiliation: Department of Organic Chemistry, Medical University of Gdańsk, Al. Gen. J. Hallera 107, 80-416 Gdańsk, Poland. Electronic address: jaroslaw@gumed.edu.pl.
authors.forename: Jarosław
authors.initials: J
authors.lastname: Sławiński
authors.affiliation: Department of Organic Chemistry, Medical University of Gdańsk, Al. Gen. J. Hallera 107, 80-416 Gdańsk, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Szafrański
authors.affiliation: Department of Organic Chemistry, Medical University of Gdańsk, Al. Gen. J. Hallera 107, 80-416 Gdańsk, Poland.
authors.forename: Aneta
authors.initials: A
authors.lastname: Pogorzelska
authors.affiliation: Department of Organic Chemistry, Medical University of Gdańsk, Al. Gen. J. Hallera 107, 80-416 Gdańsk, Poland.
authors.forename: Beata
authors.initials: B
authors.lastname: Żołnowska
authors.affiliation: Department of Biotechnology, Intercollegiate Faculty of Biotechnology, University of Gdańsk and Medical University of Gdańsk, ul. Abrahama 58, 80-307 Gdańsk, Poland; Laboratory of Human Physiology, Medical University of Gdańsk, ul. Tuwima 15, 80-210 Gdańsk, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Kawiak
authors.affiliation: Laboratory of Mass Spectrometry, Core Facility Laboratories, Intercollegiate Faculty of Biotechnology, University of Gdańsk and Medical University of Gdańsk, ul. Abrahama 58, 80-307 Gdańsk, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Macur
authors.affiliation: Department of Pharmaceutical Chemistry, Medical University of Gdańsk, Al. Gen. J. Hallera 107, 80-416 Gdańsk, Poland.
authors.forename: Mariusz
authors.initials: M
authors.lastname: Belka
authors.affiliation: Department of Pharmaceutical Chemistry, Medical University of Gdańsk, Al. Gen. J. Hallera 107, 80-416 Gdańsk, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Bączek
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004355:Drug Stability; D006207:Half-Life; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D020128:Inhibitory Concentration 50; D010069:Oxadiazoles; D021281:Quantitative Structure-Activity Relationship; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000096926:Benzenesulfonamides
chemical_list: D000970:Antineoplastic Agents; D010069:Oxadiazoles; D013449:Sulfonamides; D000096926:Benzenesulfonamides; C583463:1,3,4-oxadiazole
keywords: 1,3,4-Oxadiazole; 2-Mercaptobenzenesulfonamide; Anticancer activity; Metabolic stability; QSAR; Synthesis