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Research Overview

Professor Driver's research interests are centered on the development of synthetic methodology, mechanism study, and drug discovery and development. The Driver group is focused on the discovery of distinct and unique reactivity patterns of N-aryl- and N-alkenyl divalent nitrogen reactive intermediates and non-carbonyl stabilized metal carbenes to both advance the understanding of these reactive species and leverage their reactivity to create new bonds in privileged N-heterocyclic and carbocyclic scaffolds. These new bond forming reactions can be used to create novel modulators of NAMPT, an important enzyme in the NAD salvage pathway, for the treatment of pulmonary arterial hypertension, stroke and Alzheimer’s disease.

The reactivity N-aryl nitrenoids, nitrosoarenes, and nitroarene radical anions are poorly understood because of the challenges involved in their generation and the dearth of catalysts for tuning and controlling their reactivity towards π-systems and C–H bonds. The Driver group's efforts have been focused on addressing this gap by developing transition metal-catalyzed redox-neutral reactions of aryl azides, oxidative reactions of non-activated aryl amines, and reductive reactions of nitroarenes to generate electrophilic metal N-aryl nitrenes and nitrosoarenes and spur C–N bond formation. The Driver group discovered that radical reactivity can be accessed from nitroarenes using chemical- or cathodic reductants to produce nitroarene radical anions that exhibit unprecedented reactivity patterns. The Driver group is also interested in exploring the reactivity of non-carbonyl stabilized metal carbenes, and they have shown that these metal carbenes exhibit unique reactivity patterns in comparison to metal carbenes generated from α-diazo carboxylates.Together these methods simplify the synthesis of privileged N-heterocyclic- and carbocyclic scaffolds.

Nicotinamide phosphoribosyltransferase (NAMPT) is a multifunctional protein that regulates nicotinamide adenine dinucleotide (NAD) levels and inhibits apoptosis. Its role in apoptosis is particularly important in the context of pulmonary arterial hypertension (PAH), a disease characterized by remodeling of the arterial blood vessels of the lungs with hyperproliferative and apoptosis‐resistant vascular endothelial and smooth muscle cells. This cellular remodeling contributes an increase in pulmonary artery pressure, which leads to heart failure and death. The Driver group synthesized a library of novel nanomolar NAMPT inhibitors—including benzazasiloles from ortho-silyl-substituted aryl azides through a Rh₂(II)-catalyzed C–H bond amination reaction—that also inhibit cell proliferation of pulmonary arterial endothelial cells (PAECs) and pulmonary arterial smooth muscle cells (PASMCS). Animal studies were performed by the Machado group (Indiana University), and they found that the vascular remodeling in pre-clinical PAH animal models (MCT- and hypoxia-SUGEN rats) was reversed using the Driver group's NAMPT inhibitors.

The goal of the Driver group's research program is to develop new mechanism-guided synthetic tools that enable translational research in drug discovery.

Research Interests

• Organic chemistry
• Organometallic chemistry
• Electrochemistry
• Drug discovery and development