title: Synthesis, QSAR studies, and metabolic stability of novel 2-alkylthio-4-chloro-N-(5-oxo-4,5-dihydro-1,2,4-triazin-3-yl)benzenesulfonamide derivatives as potential anticancer and apoptosis-inducing agents.
abstract: A series of novel 2-alkylthio-4-chloro-N-(5-oxo-4,5-dihydro-1,2,4-triazin-3-yl)benzenesulfonamide derivatives 12-46 have been synthesized by the reaction of aminoguanidines with an appropriate alpha-oxo-acids hydrates in glacial acetic acid. All the synthesized compounds were evaluated for their anticancer activity against HeLa, HCT-116, and MCF-7 human tumor cell lines. Two compounds 33 and 34 displayed outstanding cytotoxic effect selectively toward HeLa cancer cells (IC50= 19 μm) and did not exhibit toxicity to the non-cancerous HaCaT cells. QSAR analysis determined the most important parameters controlling cytotoxic activity of 5-oxo-1,2,4-triazines against HeLa cells. QSAR model showed five significant descriptors: HATS6s (GETAWAY descriptor), RDF125 m (radial distribution function), SpMax7_Bh(p) (Burden descriptor), SM3_G (3D matrix descriptor), and Hy (hydrophilic factor). The apoptotic potential of the most active compounds was thoroughly analyzed through various assays: cells' morphology, DNA fragmentation, mitochondrial potential disruption, and phosphatidylserine translocation. Selected compounds were tested for metabolic stability in the presence of pooled human liver microsomes and NADPH. Compound 34 was the most resistant for human metabolism (t1/2= 38.5 min) and can be pointed as a hit compound for further investigations.
authors.affiliation: Department of Organic Chemistry, Medical University of Gdańsk, Gdańsk, Poland.
authors.forename: Beata
authors.initials: B
authors.lastname: Żołnowska
authors.affiliation: Department of Organic Chemistry, Medical University of Gdańsk, Gdańsk, Poland.
authors.forename: Jarosław
authors.identifier: http://orcid.org/0000-0003-2794-5031
authors.initials: J
authors.lastname: Sławiński
authors.affiliation: Department of Organic Chemistry, Medical University of Gdańsk, Gdańsk, Poland.
authors.forename: Aneta
authors.initials: A
authors.lastname: Pogorzelska
authors.affiliation: Department of Organic Chemistry, Medical University of Gdańsk, Gdańsk, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Szafrański
authors.affiliation: Department of Biotechnology, Intercollegiate Faculty of Biotechnology, University of Gdańsk and Medical University of Gdańsk, Gdańsk, Poland.|Laboratory of Human Physiology, Medical University of Gdańsk, Gdańsk, Poland.
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 Gdańsk, Gdańsk, Poland.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Stasiłojć
authors.affiliation: Department of Pharmaceutical Chemistry, Medical University of Gdańsk, Gdańsk, Poland.
authors.forename: Mariusz
authors.initials: M
authors.lastname: Belka
authors.affiliation: Department of Pharmaceutical Chemistry, Medical University of Gdańsk, Gdańsk, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Zielińska
authors.affiliation: Department of Pharmaceutical Chemistry, Medical University of Gdańsk, Gdańsk, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Bączek
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D021281:Quantitative Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D014227:Triazines / Q000737:chemistry; D000096926:Benzenesulfonamides
chemical_list: D000970:Antineoplastic Agents; D013449:Sulfonamides; D014227:Triazines; D000096926:Benzenesulfonamides
keywords: QSAR; anticancer; apoptosis; benzenesulfonamide; metabolic stability; mitochondrial membrane potential; synthesis