Synthesis and anti-colon cancer activity of 10-hydroxycamptothecin carbonates
Objective To find novel 10-hydroxycamptothecin derivatives with high efficiency and low toxicity.Methods The 4-aminobutanol was used as the starting material,the hydroxyl group was protected by Z-Gly-Pro-OH through esterification reaction,and the N-terminal was further reacted with p-nitrophenylchloroformate,and then reacted with 10-hydroxycamptothecin or 7-ethyl-10-hydroxycamptothecin to obtain two carbonic acid derivatives,whose structures were confirmed by HR-MS,1H-NMR and 13C-NMR.CCK8 assay was used to test the inhibition of irinotecan on human colon cancer cells(HCT-116 and Caco2),human colon cancer drug resistant cells(HCT-15/Taxol,HCT-8/V,and HCT-116/5-FU)and human normal colon epithelial cells(NCM-460)with irinotecan as positive control.The stability at different pH values was analyzed by HPLC.Results Both carbonic acid derivatives had significant inhibition on 5 colon cancer cells.The derivative derived from 7-ethyl-10-hydroxycamptothecin showed better inhibition on HCT-15/Taxol,HCT-8/V and HCT-116/5-FU cells(with IC50 values being 2.56,2.70 and 1.42 μmol·L-1,respectively)than that on HCT-116 and Caco2 cells.The selection index of HCT-8/V and HCT-116/5-FU was better than that of irinotecan.At pH 1.0,the original drug stabilized at about 70％for 3 h,and then drop sharply to less than 10％after 4 h.At pH 7.4,the original drug stabilized at about 80％～90％within 12 h.Conclusion Carbonic acid derivatives from 7-ethyl-10-hydroxycamptothecin can be further studied as anti-colon cancer drugs.
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