Title : Overcoming therapeutic resistance in oncology: A regioselective borylation platform for resurrecting and evolving nucleoside therapeutics
Abstract:
The emergence of treatment resistance remains a central challenge in oncology, often stemming from the limited chemical diversity and predictable mechanisms of existing drugs. We present a transformative chemical strategy to combat this by creating novel nucleoside-boron hybrids capable of bypassing common resistance pathways. Our method enables the direct, regioselective installation of a versatile boron handle specifically at the C2-position of unprotected adenosine and its therapeutic derivatives—including drugs like Tenofovir and GS-441524—via a mild Minisci-type reaction.
This C2-boryl group serves a dual purpose: as a synthetic linchpin for diversification and as a direct modulator of bioactivity. Computational studies reveal that magnesium chloride guides this exquisite selectivity by pre-organizing the substrate. The boron handle allows for rapid conversion into diverse functionalities, creating a library of next-generation analogues. Crucially, this single modification can "resurrect" inactive nucleoside scaffolds, converting them into potent agents against resistant cancers. For instance, a boron-modified derivative (3u) of an inert precursor exhibited potent, low-micromolar IC₅₀ values across several cancer cell lines.
This platform provides a powerful tool for drug sequencing and combination strategies. It allows for the systematic remodeling of approved nucleoside drugs to overcome resistance and for the creation of hybrid molecules with novel mechanisms. By integrating synthetic innovation with direct biological impact, our work offers a new paradigm for developing adaptive therapeutics designed to address the evolving challenge of treatment resistance.
