Developments of Small Molecules to Inhibit COX-2 by Perturbing Mitochondria in Cancer Cells

Abstract

Over a long exposure of drugs through chemotherapy cancer cells develops drug resistance due to which drug is no more effective on cancer cells. To overcome this problem scientists are trying to target a specific organelle in cells such as nucleus, endoplasmic reticulum (ER), mitochondria etc. In this context, we have hypothesised an approach to target a specific organelle of cancer cells, to inhibit a particular enzyme that reduces the chance of cancer cells proliferation. We are mainly interested here to target mitochondria, as mitochondria are being found to be a key factors in biomedical science, and so inhibit the inducible COX-2 enzyme by using selective COX-2 inhibitors like Indomethacin and Ibuprofen, present inside the mitochondria as reported in many literatures. To target mitochondria specifically we have synthesised small molecules attached with a positively charged moiety that helps the molecules to drag and internalise towards mitochondrial negatively charged membrane. For the positive charge different derivatives of Triphenylphosphine (TPP) have been used, simultaneously it is also demonstrated that which of the derivatives is more effective in cellular internalizing the small molecules inside mitochondria, cell viability has been reported by MTT assay using MCF-7 cells which has reported good amount of killing in comparison to free drug. In order to further check the cellular internalization fluorescence compound has been synthesized of the same COX-2 inhibitors. The results suggest that these small molecules can be used to inhibit COX-2 by specifically targeting the mitochondria. Hence, by doing so we can demonstrate which among a particular inhibitor attached to one of the TPP derivatives is more efficient as cancer treatment approach.