title: Novel 5-Substituted 2-(Aylmethylthio)-4-chloro-N-(5-aryl-1,2,4-triazin-3-yl)benzenesulfonamides: Synthesis, Molecular Structure, Anticancer Activity, Apoptosis-Inducing Activity and Metabolic Stability.
abstract: A series of novel 5-substituted 2-(arylmethylthio)-4-chloro-N-(5-aryl-1,2,4-triazin-3-yl) benzenesulfonamide derivatives 27-60 have been synthesized by the reaction of aminoguanidines with an appropriate phenylglyoxal hydrate in glacial acetic acid. A majority of the compounds showed cytotoxic activity toward the human cancer cell lines HCT-116, HeLa and MCF-7, with IC50 values below 100 μM. It was found that for the analogues 36-38 the naphthyl moiety contributed significantly to the anticancer activity. Cytometric analysis of translocation of phosphatidylserine as well as mitochondrial membrane potential and cell cycle revealed that the most active compounds 37 (HCT-116 and HeLa) and 46 (MCF-7) inhibited the proliferation of cells by increasing the number of apoptotic cells. Apoptotic-like, dose dependent changes in morphology of cell lines were also noticed after treatment with 37 and 46. Moreover, triazines 37 and 46 induced caspase activity in the HCT-116, HeLa and MCF-7 cell lines. Selected compounds were tested for metabolic stability in the presence of pooled human liver microsomes and NADPH, both R² and Ar = 4-CF₃-C₆H₄ moiety in 2-(R²-methylthio)-N-(5-aryl-1,2,4-triazin-3-yl)benzenesulfonamides simultaneously increased metabolic stability. The results pointed to 37 as a hit compound with a good cytotoxicity against HCT-116 (IC50 = 36 μM), HeLa (IC50 = 34 μM) cell lines, apoptosis-inducing activity and moderate metabolic stability.
authors.affiliation: Department of Organic Chemistry, Medical University of Gda&#324;sk, Al. Gen. J. Hallera 107, Gda&#324;sk 80-416, Poland. zolnowska@gumed.edu.pl.
authors.forename: Beata
authors.initials: B
authors.lastname: Żołnowska
authors.affiliation: Department of Organic Chemistry, Medical University of Gda&#324;sk, Al. Gen. J. Hallera 107, Gda&#324;sk 80-416, Poland. jaroslaw@gumed.edu.pl.
authors.forename: Jarosław
authors.initials: J
authors.lastname: Sławiński
authors.affiliation: Department of Organic Chemistry, Medical University of Gda&#324;sk, Al. Gen. J. Hallera 107, Gda&#324;sk 80-416, Poland. anetapogorzelska@gumed.edu.pl.
authors.forename: Aneta
authors.initials: A
authors.lastname: Pogorzelska
authors.affiliation: Department of Organic Chemistry, Medical University of Gda&#324;sk, Al. Gen. J. Hallera 107, Gda&#324;sk 80-416, Poland. k.szafranski@gumed.edu.pl.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Szafrański
authors.affiliation: Department of Biotechnology, Intercollegiate Faculty of Biotechnology, University of Gda&#324;sk and Medical University of Gda&#324;sk, ul. Abrahama 58, Gda&#324;sk 80-307, Poland. kawiak@biotech.ug.edu.pl.|Laboratory of Human Physiology, Medical University of Gda&#324;sk, ul. Tuwima 15, Gda&#324;sk 80-210, Poland. kawiak@biotech.ug.edu.pl.
authors.forename: Anna
authors.initials: A
authors.lastname: Kawiak
authors.affiliation: Laboratory of Cell Biology, Department of Medical Biotechnology, Intercollegiate Faculty of Biotechnology UG-MUG, Medical University of Gda&#324;sk, ul. Dębinki 1, Gda&#324;sk 80-211, Poland. gstasilojc@gumed.edu.pl.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Stasiłojć
authors.affiliation: Department of Pharmaceutical Chemistry, Medical University of Gda&#324;sk, Al. Gen. J. Hallera 107, Gda&#324;sk 80-416, Poland. mariusz.belka@gumed.edu.pl.
authors.forename: Mariusz
authors.initials: M
authors.lastname: Belka
authors.affiliation: Department of Pharmaceutical Chemistry, Medical University of Gda&#324;sk, Al. Gen. J. Hallera 107, Gda&#324;sk 80-416, Poland. szymon.ulenberg@gumed.edu.pl.
authors.forename: Szymon
authors.initials: S
authors.lastname: Ulenberg
authors.affiliation: Department of Pharmaceutical Chemistry, Medical University of Gda&#324;sk, Al. Gen. J. Hallera 107, Gda&#324;sk 80-416, Poland. tbaczek@gumed.edu.pl.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Bączek
authors.affiliation: Department of Inorganic Chemistry, Gda&#324;sk University of Technology, Narutowicza 11/12, Gda&#324;sk 80-233, Poland. jarekch@pg.gda.pl.
authors.forename: Jarosław
authors.initials: J
authors.lastname: Chojnacki
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry; D000096926:Benzenesulfonamides
chemical_list: D000970:Antineoplastic Agents; D013449:Sulfonamides; D000096926:Benzenesulfonamides
keywords: anticancer; apoptosis; metabolic stability; mitochondrial membrane potential; sulfonamide; synthesis