Interfering with DNA synthesis represents a plausible approach to cancer chemotherapy.  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 the therapeutic potential of alternative agents that have wider therapeutic window.  One of the venues to fill this gap is to develop novel antimetabolites with the mechanism of action exclusively focused on targeting replicating DNA directly.  Recently, we discovered base-modified 2'-deoxynucleotides that undergo template-driven incorporation into DNA molecule by natural polymerases more efficiently than their natural counterparts.  Once the incorporation occurs, further addition of nucleotides is obstructed due to the presence of a terminating moiety attached to the nucleobase.  Since nucleosides readily undergo cellular uptake followed by intracellular metabolism into 5'-triphosphates, it was hypothesized that treatment of cancer cells with appropriate base-modified nucleosides will lead to obstruction of their DNA replication process, so the cell division will not pass the restriction checkpoint, thus triggering apoptosis.  A library of novel base-modified thymidines was synthesized followed by cytotoxicity study (MTT assay).  The SAR has revealed a lead compound.

Base-modified nucleotide terminators of DNA synthesis as novel anticancer agents

247th National Meeting (2014)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.