Elucidation of Structure-activity Relationship of 2-Quinolone Derivatives and Exploration of Their Antitumor Potential Through Bax-induced Apoptotic Pathway

3-Aryl-2-quinolone derivates were extensively investigated for their inhibition of farnesyl transferase. Taking this as a cue, we studied the other possible mechanism of antitumor activity of 2-quinolone derivates. A series of new 2-quinolone derivatives have been synthesized and screened for their cytotoxicity by trypan blue assay on Ehrlich ascites carcinoma cells and MTT assay on MCF-7 cells. Compound 1a (nJST) was found to be more effective in both studies with the lowest CTC ₅₀ value among all nine synthesized compounds. This compound was further screened on four different cell lines, viz. human breast adenocarcinoma (MCF-7, MDA-MB-231), colon cancer (HCT-15), murine melanoma (B16F10) cell lines for 24 and 48h. The CTC ₅₀ value of the compound was found to be <10μm. Compound 1a induced DNA damage which was revealed by DNA fragmentation studies and further confirmed by nuclear staining. The compound also showed significant elevation in Bax and reduction Bcl-2 gene expression levels. Acute toxicity study in mice indicated that the compound is safe till 2000mg/kg. Two different doses 50 and 100mg/kg were selected and studied in Ehrlich ascites carcinoma model of cancer and have shown significant improvement in survival time and hematological parameters.