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Molecules 2016, 21(6), 808; doi:10.3390/molecules21060808

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

1
Department of Organic Chemistry, Medical University of Gdańsk, Al. Gen. J. Hallera 107, Gdańsk 80-416, Poland
2
Department of Biotechnology, Intercollegiate Faculty of Biotechnology, University of Gdańsk and Medical University of Gdańsk, ul. Abrahama 58, Gdańsk 80-307, Poland
3
Laboratory of Human Physiology, Medical University of Gdańsk, ul. Tuwima 15, Gdańsk 80-210, Poland
4
Laboratory of Cell Biology, Department of Medical Biotechnology, Intercollegiate Faculty of Biotechnology UG-MUG, Medical University of Gdańsk, ul. Dębinki 1, Gdańsk 80-211, Poland
5
Department of Pharmaceutical Chemistry, Medical University of Gdańsk, Al. Gen. J. Hallera 107, Gdańsk 80-416, Poland
6
Department of Inorganic Chemistry, Gdańsk University of Technology, Narutowicza 11/12, Gdańsk 80-233, Poland
*
Authors to whom correspondence should be addressed.
Academic Editors: Jean Jacques Vanden Eynde and Annie Mayence
Received: 13 May 2016 / Revised: 8 June 2016 / Accepted: 17 June 2016 / Published: 22 June 2016
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Abstract

A series of novel 5-substituted 2-(arylmethylthio)-4-chloro-N-(5-aryl-1,2,4-triazin-3-yl) benzenesulfonamide derivatives 2760 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 3638 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. View Full-Text
Keywords: sulfonamide; synthesis; metabolic stability; anticancer; apoptosis; mitochondrial membrane potential sulfonamide; synthesis; metabolic stability; anticancer; apoptosis; mitochondrial membrane potential
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Żołnowska, B.; Sławiński, J.; Pogorzelska, A.; Szafrański, K.; Kawiak, A.; Stasiłojć, G.; Belka, M.; Ulenberg, S.; Bączek, T.; Chojnacki, J. 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. Molecules 2016, 21, 808.

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