Design, Synthesis and Screening of 4,6-Diaryl Pyridine and Pyrimidine Derivatives as Potential Cytotoxic Molecules

• Published in: Chemical & pharmaceutical bulletin Vol. 66; no. 10; pp. 939 - 952
• Main Authors: elhameid, Mohammed K. Abd, Ryad, Noha, MY, Al-Shorbagy, mohammed, Manal R., Ismail, Mohammed M., Meligie, Salwa El
• Format: Journal Article
• Language: English
• Published: TOKYO The Pharmaceutical Society of Japan 01.10.2018; Pharmaceutical Society of Japan; Pharmaceutical Soc Japan
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Cell Cycle Checkpoints - drug effects; Cell Proliferation - drug effects; Chemistry; Chemistry, Medicinal; Chemistry, Multidisciplinary; combretastatin A4; Dose-Response Relationship, Drug; Drug Design; Drug Evaluation, Preclinical; Drug Screening Assays, Antitumor; Enzyme-Linked Immunosorbent Assay; HCT116 Cells; HL-60 Cells; Humans; leukemia; Life Sciences & Biomedicine; MCF-7 Cells; Molecular Structure; Oxidative Stress - drug effects; Pharmacology & Pharmacy; Physical Sciences; Polymerization - drug effects; pyridine; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - pharmacology; pyrimidine; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Science & Technology; Structure-Activity Relationship; survivin; tubulin; Tubulin - biosynthesis; leukemia; survivin; APOPTOSIS; CELLS; ANTICANCER AGENTS; pyridine; tubulin; DRUG-RESISTANCE; combretastatin A4; BREAST-CANCER; COLCHICINE SITE; BIOLOGICAL EVALUATION; MYELOID-LEUKEMIA; pyrimidine
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.c18-00269

A new series of pyridine and pyrimidine derivatives is designed and synthesized as potential antitumor molecules. The tested compounds show promising in vitro cytotoxic activity against HL-60 cell line as eight compounds: 4, 6, 11, 13, 14, 15, 18 and 21 exhibit potent cytotoxic activity in sub-micromolar concentration higher than the combretastatin A4 (CA-4). Compound 21 shows a cytotoxic activity 5-fold more potent than CA-4 on HL-60 cells. DNA-Flow cytometry cell cycle analysis and annexin-V assay on HL-60 cells show that compounds 4, 18 and 21 exhibit potent cell growth inhibition, cell cycle arrest at G2/M phase and pro-apoptotic inducing activities. The percentage inhibition assay of β-tubulin polymerization on HL-60 cells shows that the antitumor activity of the tested compounds appears to correlate well with its ability to inhibit β-tubulin polymerization. In addition, enzyme-linked immunosorbene assay (ELlSA) measurement for compound 21 shows apoptotic inducing activities through significant up regulation of p53, Bax/Bcl-2 ratio and caspase-3 proteins parallel to down regulation of the level of survivin proteins.