Acridone-pyrimidine hybrids- design, synthesis, cytotoxicity studies in resistant and sensitive cancer cells and molecular docking studies

Hybrid systems of acridones with substituted pyrimidines were designed with an objective of discovering next generation anticancer agents targeting multiple mechanisms in the cancer cell. Hybrid compounds were synthesized by simple and convenient methods in the lab, characterized by NMR and Mass spectral methods and screened for cytotoxicity against A549 (lung), Hela (cervical), MCF7 (breast) and MDA-MB-231 (breast) cancer cell lines respectively. Evaluation of compounds for cell proliferation identified active compounds 11b, 11d and 11h against MCF7, MDA-MB-231 and A549 cell lines. Further absorption titrations with CT-DNA and gel electrophoresis identified that hybrid molecules displayed anticancer activity partly by DNA intercalation. Also further results of western blotting assay with Akt kinase identified that hybrid compounds have the ability to inhibit the Akt kinase activity and induce apoptosis, with ABCC1 suggests that active compounds too have the ability to modulate multidrug resistance (MDR) associated with ABCC1/MRP1. Selective Akt1 kinase assay have identified 11a, 11b, 11d and 11h as potential inhibitors. Molecular docking studies identified the orientation and binding interactions at the active site of Akt1 and DNA. Compounds 12e and 12f have shown good cytotoxicity profile against lung cancer cell lines of sensitive and resistant type. Acute toxicity study of compound 12f at the dose of 5000 mg/kg has identified no signs of clinical toxicity. Prediction of ADMET properties and oral toxicity of the drug likeness features of new hybrid systems were carried out using software's. This experimental data suggests that hybrid systems of acridone with substituted pyrimidines can be taken as a lead for the design of efficient inhibitors and active compounds which can be taken up for further studies.