4-Flourophenyl-substituted 5H-indeno[1,2-b]pyridinols with enhanced topoisomerase IIα inhibitory activity: Synthesis, biological evaluation, and structure-activity relationships

A series of fluorinated and hydroxylated 2,4-diphenyl indenopyridinols were designed and synthesized using L-proline-catalyzed and microwave-assisted synthetic methods for the development of new anticancer agents. Adriamycin and etoposide were used as reference compounds for the evaluation of topo II alpha inhibitory and anti proliferative activity of the synthesized compounds. Exploring the structure-activity relationships of 36 prepared compounds and biological results, most of the compounds with ortho- and para-fluorophenyl at 4-position of indenopyridinol ring displayed strong topo II alpha inhibition. In addition, the majority of the ortho-and meta-fluo-rophenyl substituted compounds 1-24 displayed strong anti-proliferative activity against DU145 prostate cancer cell line compared to the positive controls. Interestingly, compound 4 possessing ortho-phenolic and ortho-flu-orophenyl group at 2-and 4-position, respectively of the central pyridine ring showed high anti-proliferative activity (IC50 = 0.82 mu M) against T47D human breast cancer cell line, while para-phenolic and para-fluo-rophenyl substituted compound 36 exhibited potent topo II alpha inhibitory activity with 94.7% and 88.6% inhibition at 100 mu M and 20 mu M concentration, respectively. A systematic comparison between the results of this study and the previous study indicated that minor changes in the position of functional groups in the structure affect the topo II alpha inhibitory activity and anti-proliferative activity of the compounds. The findings from this study will provide valuable information to the researchers working on the medicinal chemistry of topoisomerase II alpha-targeted anticancer agents.