TY - JOUR
T1 - Elucidation of Structure-activity Relationship of 2-Quinolone Derivatives and Exploration of Their Antitumor Potential Through Bax-induced Apoptotic Pathway
AU - Kumar, Nitesh
AU - Raj, Vasanth P.
AU - Jayshree, B. S.
AU - Kar, Sidhartha S.
AU - Anandam, Arvind
AU - Thomas, Seeja
AU - Jain, Prateek
AU - Rai, Amita
AU - Rao, C. M.
PY - 2012/8
Y1 - 2012/8
N2 - 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.
AB - 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.
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U2 - 10.1111/j.1747-0285.2012.01402.x
DO - 10.1111/j.1747-0285.2012.01402.x
M3 - Article
C2 - 22553933
AN - SCOPUS:84864023497
SN - 1747-0277
VL - 80
SP - 291
EP - 299
JO - Chemical Biology and Drug Design
JF - Chemical Biology and Drug Design
IS - 2
ER -
