Design and discovery of novel monastrol-1,3,5-triazines as potent anti-breast cancer agent via attenuating Epidermal Growth Factor Receptor tyrosine kinase

• Published in: Scientific reports 2017-07, Vol.7 (1), p.5851-18, Article 5851
• Main Authors: Srivastava, Jitendra Kumar, Pillai, Girinath G., Bhat, Hans Raj, Verma, Amita, Singh, Udaya Pratap
• Format: Article
• Language: English
• Subjects: 631/92/436/2387; 692/700/155; Antineoplastic Agents - therapeutic use; Antioxidants; Antioxidants - pharmacology; Antitumor activity; Biological activity; Body weight; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - pathology; Catalysis; Cell Line, Tumor; Cervical cancer; Cervix; Drug Design; Drug Discovery; Epidermal growth factor; Epidermal growth factor receptors; ErbB Receptors - metabolism; Female; Hepatocellular carcinoma; Humanities and Social Sciences; Humans; Leukemia; Ligands; Lipid peroxidation; Mammary gland; Molecular Docking Simulation; multidisciplinary; Peroxidation; Phosphorylation - drug effects; Promyeloid leukemia; Protein-tyrosine kinase receptors; Pyrimidines - pharmacology; Pyrimidines - therapeutic use; Rodents; Science; Science (multidisciplinary); Solvents; Thiones - pharmacology; Thiones - therapeutic use; Triazine; Triazines - pharmacology; Triazines - therapeutic use; Tumor Burden; Tumors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-05934-5

A novel series of hybrid analogues of monastrol-1,3,5-triazine were designed and developed via one-pot synthesis using Bi(NO 3 ) 3 as a catalyst. Entire compounds were evaluated for their anticancer activity against HeLa (cervical cancer), MCF-7 (breast cancer), HL-60 (Human promyelocytic leukemia), HepG2 (Hepatocellular carcinoma) and MCF 12A (normal epithelial breast cell line) using MTT assay, where they showed highest inhibitory activity against MCF-7. The molecules were also found to be non-toxic to MCF 12A cells. These molecules showed considerable inhibitory percentage against Epidermal Growth Factor Receptor tyrosine kinase (EGFR-TK), in in-vitro assay. Molecular docking study was carried out on the analogs and reference compound (Erlotinib) into the ATP binding site of EGFR-TK domain (PDB ID:1M17) to elucidate vital structural residues necessary for bioactivity. The effect of most active compound 7l was also estimated in-vivo in DMBA induced mammary tumor in female Sprague-Dawley rats. The effect of anti-breast cancer effect of 7l was quantified on the basis of tumour incidence, body weight and tumor volume in DMBA-induced rats. Its effect on biochemical parameters, such as antioxidant status (SOD, CAT, GPX and GSH) and lipid peroxidation was also studied. The compound 7l showed inhibition of EGFR downstream signalling in the western blot analysis.