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

Beata Żołnowska , Jarosław Sławiński , Aneta Pogorzelska , Krzysztof Szafrański , Anna Kawiak , Grzegorz Stasiłojć , Mariusz Belka , Joanna Zielińska , Tomasz Bączek


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.
Author Beata Żołnowska
Beata Żołnowska,,
, Jarosław Sławiński
Jarosław Sławiński,,
, Aneta Pogorzelska
Aneta Pogorzelska,,
, Krzysztof Szafrański
Krzysztof Szafrański,,
, Anna Kawiak (IFB / IB / DBiotech)
Anna Kawiak,,
- Department of Biotechnology
, Grzegorz Stasiłojć (IFB / DMedB)
Grzegorz Stasiłojć,,
- Department of Medical Biotechnology
, Mariusz Belka
Mariusz Belka,,
, Joanna Zielińska
Joanna Zielińska,,
, Tomasz Bączek
Tomasz Bączek,,
Journal seriesChemical Biology & Drug Design, ISSN 1747-0277, (A 25 pkt)
Issue year2017
Publication size in sheets0.8
Keywords in Englishanticancer, apoptosis, benzenesulfonamide, metabolic stability, mitochondrial membrane potential, QSAR, synthesis
ASJC Classification1313 Molecular Medicine; 1303 Biochemistry
Languageen angielski
Score (nominal)25
ScoreMinisterial score = 25.0, 24-07-2019, ArticleFromJournal
Publication indicators Scopus SNIP (Source Normalised Impact per Paper): 2016 = 0.801; WoS Impact Factor: 2017 = 2.328 (2) - 2017=2.404 (5)
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