Design, synthesis and anticancer activity of new monastrol analogues bearing 1,3,4-oxadiazole moiety

• Published in: European journal of medicinal chemistry 2017-09, Vol.138, p.140-151
• Main Authors: Ragab, Fatma A.F., Abou-Seri, Sahar M., Abdel-Aziz, Salah A., Alfayomy, Abdallah M., Aboelmagd, Mohamed
• Format: Article
• Language: English
• Subjects: 1,3,4-Oxadiazole; Anticancer activity; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Cell cycle arrest; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Dihydropyrimidine; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Humans; Molecular Docking Simulation; Molecular Structure; Oxadiazoles - chemistry; Oxadiazoles - pharmacology; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Structure-Activity Relationship; Thiones - chemical synthesis; Thiones - chemistry; Thiones - pharmacology
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2017.06.026

A series of dihydropyrimidine (DHPM) derivatives bearing 1,3,4-oxadiazole moiety was designed and synthesized as monastrol analogues. The new compounds were screened for their cytotoxic activity toward 60 cancer cell lines according to NCI (USA) protocol. Seven compounds were further examined against the most sensitive cell lines, leukemia HL-60(TB) and MOLT-4. The most active compounds were 9m against HL-60(TB) (IC50 = 56 nM) and 9n against MOLT-4 (IC50 = 80 nM), more potent than monastrol (IC50 = 147 and 215 nM, respectively). Cell cycle analysis of HL-60(TB) cells treated with 9m and MOLT-4 cells treated with 9n showed cell cycle arrest at G2/M phase and pro-apoptotic activity as indicated by annexin V-FITC staining. A series of dihydropyrimidines (DHPMs) bearing 1,3,4-oxadiazole moiety were designed and synthesized as monastrol analogues. Compound 9i, 9k, 9m and 9n possessed significant activity against HL-60(TB) and MOLT-4 compared to monastrol. [Display omitted] •A series of DHPM derivatives bearing 1,3,4-oxadiazole moiety was designed and synthesized as monastrol analogues.•Thirteen compounds were subjected to in vitro NCI antitumor screening at a single dose of 10 μM concentration.•IC50 of the most potent compounds were evaluated against leukemia HL-60(TB) and MOLT-4 cancer cell lines.•Four compounds showed potent activity against HL-60(TB) and MOLT-4 compared to monastrol.