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

• Published in: Chemical biology & drug design 2017-09, Vol.90 (3), p.380-396
• Main Authors: Żołnowska, Beata, Sławiński, Jarosław, Pogorzelska, Aneta, Szafrański, Krzysztof, Kawiak, Anna, Stasiłojć, Grzegorz, Belka, Mariusz, Zielińska, Joanna, Bączek, Tomasz
• Format: Article
• Language: English
• Subjects: anticancer; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; apoptosis; Apoptosis - drug effects; benzenesulfonamide; Benzenesulfonamides; Cell Cycle Checkpoints - drug effects; DNA Fragmentation - drug effects; Drug Design; Drug Screening Assays, Antitumor; HCT116 Cells; HeLa Cells; Humans; MCF-7 Cells; Membrane Potential, Mitochondrial - drug effects; metabolic stability; mitochondrial membrane potential; QSAR; Quantitative Structure-Activity Relationship; Sulfonamides - chemical synthesis; Sulfonamides - chemistry; Sulfonamides - pharmacology; synthesis; Triazines - chemistry
• ISSN: 1747-0277; 1747-0285
• DOI: 10.1111/cbdd.12955

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. New N‐(5‐oxo‐4,5‐dihydro‐1,2,4‐triazin‐3‐yl)benzenesulfonamides was synthesized The cytotoxic activity toward MCF‐7, HeLa, HCT‐116 was investigated The 5‐oxo‐1,2,4‐trizines exhibited apoptosis‐inducing activity in the HeLa cells The quantitative structure‐activity relationship of cytotoxic activity was found Metabolic stability was studied using pooled human liver microsomes and NADPH