Synthesis and Biological Evaluation of Novel Indomethacin Derivatives as Potential Anti-Colon Cancer Agents.

Abstract

The molecular structure of indomethacin was used as a starting scaffold for the synthesis of 20 novel analogs and to study their effects on the proliferation of three human colon cancer cell lines, HCT-116, HT-29, and Caco-2, by MTT assay. The synthesized indomethacin analogs were characterized on the basis of IR, 1 H NMR, 13 C NMR, mass spectral data, and elemental analysis results. Cytotoxicity assay results showed that the indomethacin amide analog 2 was the most potent anticancer agent (IC50 = 0.78, 0.09, and 0.0127 μg/mL) against the three colon cancer cell lines, respectively, being more potent than the standard 5-fluorouracil (IC50 = 1.8, 0.75, and 5.45 μg/mL). Interestingly, the indomethacin oxazin analog 3 and the indomethacin amide analog 8 displayed very potent anticancer activity against the HCT-116 cell line with IC50 = 0.421 and 0.27 μg/mL, respectively, much better than the reference (IC50 = 1.8 μg/mL). Additionally, analogs 3, 4b, 11, 12c, and 13a exhibited excellent antitumor activity against Caco-2 cells, with IC50 ranging from 1.5 to 4.5 μg/mL. Furthermore, analogs 2 and 8 were additionally examined for their effect on the cell cycle of HCT-116 and HT-29 cells, respectively, using flow cytometric analysis. Analog 2 arrested the cell cycle of HT-29 cells at the S phase, while 8 was found to arrest the cell cycle of HCT-116 cells at the G0/G1 phase.