SCAFFOLD HOPPING WITH SULFENYLCARBENES AND SULFENYLNITRENES

Abstract

Over the past decade, the cost of drug development, including failures and opportunity costs, has more than doubled. The United States now spends 17.7% of its annual income on healthcare, the highest among developed nations. Although several factors contribute to rising drug prices, a major driver is the high failure rate of new drug candidates during clinical trials and the substantial costs associated with these failures. Developing innovative medicines is inherently risky and demands significant investment in capital, skilled personnel, and advanced technology. While these challenges are widely recognized, it is less appreciated how inefficiencies in chemical research and development directly contribute to the high cost of medications available in local pharmacies. This work demonstrates a “drugs-from-drugs” approach, leveraging the effective and cost-efficient use of sulfur, often sourced from volcanic byproducts, to stabilize reactive intermediates for late-stage functionalization. This strategy enables the efficient generation of chemical libraries for rapid drug discovery.In Chapter 2, a series of versatile sulfur-based carbene precursors (sulfenylcarbenes) were developed to enable late-stage single-carbon atom insertion into existing drug scaffolds, providing access to libraries of new, potentially bioactive molecules. In chapter 3, a series of sulfur-based nitrene precursors (sulfenylnitrenes) was developed for the chemoselective single-nitrogen-atom insertion into existing drugs at the late stage to generate a library of potential new drugs. These precursors are readily synthesized from commercially available reagents derived from volcanic waste (sulfur). These precursors can be produced on a large scale (commercialized by Lookchem), offering strong potential for industrial applications in drug discovery and contributing to efforts to reduce overall healthcare costs. Together, these studies establish a strategy for late-stage scaffold hopping via nitrogen- and carbon-atom insertion into readily accessible drug molecules. This approach enables the generation of structurally complex libraries under metal- and additive-free conditions using sulfur-based reagents. In Chapter 4, more than two dozen sulfur-based carbene and nitrene precursors were developed to enable scaffold hopping of biowaste-derived furans into privileged N-heterocyclic scaffolds commonly found in pharmaceuticals. Furans have long been considered structural alerts in medicinal chemistry due to their susceptibility to metabolic instability and reactivity with cellular components. This work addresses this longstanding challenge by enabling the late-stage transformation of furans, a rare scaffold in approved drugs, into N-heterocycles, which are present in approximately 80% of pharmaceuticals. This approach opens new avenues for drug discovery while offering potential to reduce overall drug development expense. Overall, this dissertation establishes sulfur-based nitrene- and carbene-mediated strategies for late-stage remodeling of existing drugs to generate new therapeutics, enabling rapid and cost-effective drug discovery for affordable healthcare costs.