Design, synthesis, and cytotoxicity screening of 5-aryl-3-(2-(pyrrolyl) thiophenyl)-1, 2, 4-oxadiazoles as potential antitumor molecules on breast cancer MCF-7 cells

• Published in: Bioorganic chemistry 2019-05, Vol.86, p.609-623
• Main Authors: Abd el hameid, Mohammed K., Mohammed, Manal R.
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Cycle - drug effects; Cell Proliferation - drug effects; DNA intercalators; DNA Topoisomerases, Type II - metabolism; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Female; HCT116 Cells; Humans; MCF-7 Cells; Molecular Structure; Oxadiazole; Oxadiazoles - chemical synthesis; Oxadiazoles - chemistry; Oxadiazoles - pharmacology; Structure-Activity Relationship; Thiophene; Topoisomerase; Topoisomerase II Inhibitors - chemical synthesis; Topoisomerase II Inhibitors - chemistry; Topoisomerase II Inhibitors - pharmacology; Tumor Cells, Cultured
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2019.01.067

[Display omitted] •The synthetic molecule are designed as antitumor agents based on DNA synthesis inhibition.•Compounds 4c and 14 exhibit potent cytotoxic activity on MCF-7 breast cancer cells by 2.3- and 10-fold higher than prodigiosin (PG).•In vitro topoisomerase assay correlated cytotoxicity of molecules 4c and 14 to DNA synthesis inhibition.•Molecules 4c and 14 exhibit antiproliferative activities on MCf-7 cells by cell cycle arrest at G1 phase and apoptosis inducing activity by increasing cell percentages at pre G1 and G2 /M phases.•Measurement of cell death mediators p53, puma, Bax/Cl2 ratio levels and green immunofluorescence assay for caspases 3/7 assay confirm apoptotic activity of the tested molecules 4c and 14. The work representing the design and the cytotoxic screening of synthetic small molecules (SSMs) such as carbonitriles 3a-c, carboximidamides 4a-c, and oxadiazoles 5–19 as antitumor molecules. Molecules 4c, 9, 12, and 14 show promising cytotoxicity profiles against two cell lines higher than prodigiosin (PG). The results of topoisomerase enzyme inhibition assay show that compounds 4c and 14 display potent inhibitory activity in nano-molar concentration. In addition, DNA-flow cytometry and annexin V analysis also display that compounds 4c, 9, 12, and 14 exhibit antiproliferative activities over MCF-7 cells by cell cycle arrest at G1 phase and apoptosis-inducing activity by increasing cell percentages at pre G1 phase. Moreover, Elisa measurement of p53 and apoptosis mediators, show that carboximidamide 4c and oxadiazoles 9, 12, and 14 significantly up-regulate p53 and cell death mediators as puma and Bax/Bcl-2 ratio levels. Subsequently, pro-apoptotic activities are confirmed by active caspase 3/7 percentages green fluorescence assay.