The Golden research group uses synthetic medicinal chemistry to address issues in chemical biology. We develop synthetic methodology to generate new chemical architecture and explore its associated pharmacology. Currently, projects in my laboratory focus on chemical methodology development and the optimization of anti-infective and anticancer agents in cell and animal models. We work closely with expert collaborators who assess our compounds against various biological targets, and through structural manipulation of our chemical scaffolds, we refine properties to achieve a desired activity profile. Several projects are underway, and a few are represented below.

image showing the span of Golden Lab research from infective projects to synthetic & medicinal chemistry to anti-cancer projects

Project 1: Exploration of a novel quinazolinone rearrangement

We discovered that alpha-chloromethylquinazolinones, when treated with acyclic diamines, rearrange to form amidines. We explored the scope of this reaction as it relates to the electronics governing the susceptibility of the quinazolinone core to rearrange under multiple conditions. We further adapted the transformation to include the conversion of extended BOC-protected amino acids to the desired amidines through an efficient, telescoped sequence that integrates at least 5 chemical transformations in one pot!

figure showing how the extended BOC-protected amino acids become converted into the desired amidines

This methodology has been used to prepare a diverse collection of amidines useful as antiviral agents (Project 2, below). Exchange of the reaction partners is being explored, and we are currently investigating a new methodology that employs this transformation.

Project 2: Development of anti-alphaviral agents with in vivo efficacy

Alphaviruses, RNA viruses spread most commonly by infected mosquitoes, can cause significant disease in animals and humans ranging from fever, rash, persistent arthritis, encephalitis and death. Though several of these agents are classified as bioterrorism threats, there are no FDA approved vaccines or drugs available for any alphavirus infection. Our laboratory has developed several compound classes that show efficacy against select alphaviruses in cells and in mice.

Project 3: Development of broad spectrum antiparasitic compounds

Our group has discovered three distinct structural classes that show broad spectrum inhibition of parasites related to malaria, African sleeping sickness and leishmaniasis. We have defined preliminary structure-activity relationships around each class and are now prepared to derive improved inhibitors for more advanced in vivo studies.

Projects 4-6: Synthetic methodologies that deliver drug-like, unrepresented scaffolds

We are currently exploring three novel synthetic methods that afford distinct, drug-like architecture. The focus of these projects is, first and foremost, to derive useful synthetic transformations; however, compounds will also be assessed broadly for potential biological activity.