Targeted Covalent Inhibition of Telomerase  And Development of New Methods Involving Photoredox Catalysis

Betori, Richard C

doi:https://doi.org/10.21985/n2-wkgv-5y15

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Targeted Covalent Inhibition of Telomerase And Development of New Methods Involving Photoredox Catalysis

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Chapter 1: Telomerase is a ribonucleoprotein enzyme that counteracts the shortening of telomeres by catalyzing the addition of nucleotides to the 3’ ends of chromosomes, resulting in telomerase inhibition attracting interest as a strategy for cancer. Telomerase has also been implicated in other tumorigenic pathways such as DNA damage repair, apoptosis, and response to oxidative stress. Using the natural product chrolactomycin as inspiration, I designed a series of synthetically tractable analogues that inhibit telomerase via a covalent mechanism. In addition, I have demonstrated that our molecular probes impact a variety of extra-telomeric activities of telomerase implicated in cancer. Future work in this area will focus on using these chemical probes to further interrogate the mechanistic role that hTERT has on these pathways. Chapter 2: In this chapter, I will discuss our laboratories’ strategies towards the utilization of arylidene malonates and -umpolung single electron species. Specifically, I have utilized these unique operators in intramolecular reductive annulations and in intermolecular radical-radical arylations, both while avoid conjugate addition-dimerization reactivity that is commonly encountered in enone based photoredox chemistry. This reactivity relies on coordinating species that serve in LUMO lowering catalysis to activate the arylidene malonate for single electron transfer. These photoredox catalysis pathway demonstrates the versatility of stabilized radicals for unique bond forming reactions Chapter 3: Chemical transformations that install heteroatoms into C–H bonds are of significant interest because they streamline the construction of value-added small molecules. Direct C−H oxyfunctionalization, or the one step conversion of a C–H bond to a C–O bond, could be a highly enabling transformation due to the prevalence of the resulting enantioenriched alcohols in pharmaceuticals and natural products. In this chapter, I report on the development of a single-flask photoredox/enzymatic process for direct C–H hydroxylation that proceeds with broad reactivity, chemoselectivity and enantioselectivity. This unified strategy advances general photoredox and enzymatic catalysis synergy and enables chemoenzymatic processes for powerful and selective oxidative transformations.

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