Discovery of the Biginelli hybrids as novel caspase-9 activators in apoptotic machines: Lipophilicity, molecular docking study, influence on angiogenesis gene and miR-21 expression levels

• Published in: Bioorganic chemistry 2019-05, Vol.86, p.569-582
• Main Authors: Janković, Nenad, Trifunović Ristovski, Jovana, Vraneš, Milan, Tot, Aleksandar, Petronijević, Jelena, Joksimović, Nenad, Stanojković, Tatjana, Đorđić Crnogorac, Marija, Petrović, Nina, Boljević, Ivana, Matić, Ivana Z., Bogdanović, Goran A., Mikov, Momir, Bugarčić, Zorica
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; A549 Cells; Aldehydes - chemical synthesis; Aldehydes - chemistry; Aldehydes - pharmacology; ANGIOGENESIS; Antineoplastic Agents, Phytogenic - chemical synthesis; Antineoplastic Agents, Phytogenic - chemistry; Antineoplastic Agents, Phytogenic - pharmacology; APOPTOSIS; Apoptosis - drug effects; Biginelli scaffold; Caspase 9 - metabolism; Caspase-9; CELL CYCLE; Cell Proliferation - drug effects; Cells, Cultured; Cisplatin - chemistry; Cisplatin - pharmacology; Dose-Response Relationship, Drug; Drug Discovery; Drug Screening Assays, Antitumor; GENES; HeLa Cells; HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY; Humans; Hydrophobic and Hydrophilic Interactions; Lipophilicity; MicroRNAs - antagonists & inhibitors; MicroRNAs - genetics; Molecular Docking Simulation; Molecular Structure; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - pathology; Oxazocines - chemical synthesis; Oxazocines - chemistry; Oxazocines - pharmacology; Pyrimidinones - chemical synthesis; Pyrimidinones - chemistry; Pyrimidinones - pharmacology; Selectivity index; Structure-Activity Relationship
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2019.02.026

[Display omitted] •Cytotoxic properties of novel 1,2,3,4-tetrahydropyrimidines and 1,3,5-oxadiazocines.•4c, 4d, 4f, 4k and 4l showed a good-to-excellent cytotoxic activity.•Selected compounds promoted caspase-9 activation.•4f have up to three times higher selectivity towards cancer cells than cisplatin. In order to investigate potential therapeutically agents, novel products of Biginelli reaction (4a-l) were synthesized and exposed to cytotoxic and caspase activities, angiogenesis, cell cycle distribution, gene and microRNA expression levels, lipophilicity assessment and docking study. Among the twelve novel compounds (4a-l) evaluated for the cytotoxic activity, five of them (4c, 4d, 4f, 4k and 4l) that showed excellent activity on the tested cell lines (HeLa, LS174 and A549) were selected for further evaluation. Interestingly, compound 4f has up to three times higher selectivity index (SI) towards cancer cells than cisplatin (on HeLa, LS174 and A549 SI = 18.2, 13.5 and 11.2, respectively). The obtained results from cell cycle distribution and caspase activity indicate that tested compounds (4c, 4d, 4f, 4k and 4l) promoted caspase-9 activation, implicated in the intrinsic pathway of apoptosis. Lipophilicity of 4a-l was determinate by using reversed-phase high-performance liquid chromatography.