Project Summary
Our long-term goal is to develop new chemical reactions for the synthesis of compounds that could be used
as medicines. We will build upon our expertise in the synthesis of cyclic peroxides, a family of natural products
that exhibit a broad range of biological activities, suggesting their application to the treatment of malaria, cancer,
and viral and bacterial infections. During the proposed funding period, we will investigate our hypothesis that
initiation of ferroptosis is a general property of cyclic peroxides, and we will optimize the potency and metabolic
stability of FINO2, a cyclic peroxide we developed that initiates cell death by a new mechanism. The target of
FINO2 is unknown so we will study the mechanism by which cyclic peroxides like FINO2 initiate programmed cell
death, in collaboration with Professor Brent Stockwell (Columbia University). We will also develop new methods
for the synthesis of the cyclic peroxide structural motif found in many naturally occurring peroxides. We will also
investigate the synthesis of aromatic peroxides, a structural class whose synthesis and reactivity have not been
addressed. In the proposed funding period, we will also extend our investigations of mechanisms of acetal
substitution reactions, which are important methods in natural product synthesis and carbohydrate chemistry.
Using systematic studies of model systems, we can identify the factors that contribute to the stability and
reactivity of oxocarbenium ions, which are intermediates involved in many of the reactions of carbohydrates,
including enzymatic reactions. We will determine how the carboxyl group in sugars such as sialic acids influence
the stereoselectivity of reactions involving these sugars. We will demonstrate remote neighboring-group
participation as a means of controlling stereoselectivity in cyclic and acyclic compounds. The proposed research
is innovative because it addresses structural types and reactive intermediates that have received little attention
in the literature. The proposed research is significant because it will lead to new pathways for making biologically
active compounds and will provide deeper mechanistic understanding of chemical and biological processes.
These studies are relevant to human health because they could result in drugs that kill cells by unique pathways,
leading to new treatments for various diseases. Furthermore, the mechanistic understanding of intermediates
involved in reactions of carbohydrates could lead to new ways of designing enzyme inhibitors.