Cancer will kill roughly half a million people by the end of 2014. Malignant cells usually undergo abnormally rapid division, which requires increased amounts of nucleotides for continuous DNA production. Many chemotherapeutic approaches to cancer treatment use modified nucleosides and nucleobases that stop DNA replication, thereby causing cancer cells go into apoptosis. Due to their structural similarity to natural analogs, the most potent FDA-approved nucleoside-based anti-cancer drugs elicit severe side effects that are sometimes lethal. Therefore, there is a critical need to explore alternative anti-cancer agents with wider therapeutic window. One of the venues to fill this gap is to develop new antimetabolites with the mechanism of action exclusively focused on targeting replicating DNA directly, with the minimal effect on other intracellular targets. The focus of this project is the synthesis of novel base-modified T-nucleoside analogs and investigating their toxicity in cancer cells. Our initial discovery of the lead compound with better selectivity toward cancer cells compared to 5-fluorouracil has warranted the search for further lead improvement though the structure-activity relationship studies. We used click chemistry to synthesize a diverse library of nucleoside derivatives analogous to current lead compound. Their cytotoxicity has been determined by performing MTT assay on MCF7 breast cancer cells.

Click chemistry approach to diversification of novel base-modified thymidine analogs that exhibit anticancer activity

249th National Meeting (2015)

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