Thursday, April 3, 2025
4/3/2025
Synthetic and translational studies of antitumor and antimicrobial natural products. - PROJECT SUMMARY/ABSTRACT. Our research seeks to elucidate the mechanism of action and structure–function relationships of bioactive sec- ondary metabolites, toward treatments for drug-resistant bacterial infections and cancer. The development of syntheses that enable precise manipulation of each class of molecules, with correlated insights into molecular and biomolecular mechanism, is a unifying goal of each project. We seek to complete the synthesis of the dimeric isolate lomaiviticin A, a glycosylated bacterial metabolite that inhibits cancer cell growth at pM concen- trations by inducing double-strand breaks in DNA. We recently showed that the structure assignment of lo- maiviticin was incorrect and have made significant progress toward the synthesis of the revised structure. In parallel we are pursuing the synthesis of the related nenestatins as these provide an opportunity to probe the biosynthesis of both classes of isolates. We will advance our studies of gukulenin A, a pseudodimeric α-tropo- lone natural product that has demonstrated efficacy and tolerability in murine models of ovarian cancer. We have come very close to completing the synthesis of gukulenin itself and are now in position to begin to evaluate its structure–function relationships and determine its biological target. A novel linchpin reagent and a method for the synthesis of highly-substituted α-tropolones were developed and will be further explored during the fund- ing period. We developed a novel method for the stereocontrolled synthesis of deoxyglycosides involving the addition of a configurationally-defined anomeric anion to a dialkyl peroxide. We will expand the scope of this chemistry to incorporate the synthesis of C-aryl glycosides (by cross-coupling) and 2-hydroxy glycosides (by prior removal of the hydroxyl proton) with the goal of applying these findings to the synthesis of altromycins, antitumor isolates with demonstrated efficacy and tolerability in vivo. An additional effort involves discovering new pleuromutilin antibiotics to treat drug-resistant infections. We developed a synthesis of pleuromutilins that provided access to 17 structurally-distinct derivatives that are impossible to access by semisynthesis. We will use recent structural data of pleuromutilins bound to cfr mutant ribosomes to guide the synthesis of derivatives that overcome this widespread resistance mechanism. We have collaborations in place to evaluate our com- pounds against modern cfr mutants and to obtain crystallographic data of lead compounds bound to mutant and wild-type ribosomes. Finally we will pursue the synthesis of platinum-directed alkylation agents that selectively alkylate O6-guanine. O6-Alkylguanine residues are reversed by MGMT, a DNA repair protein that is expressed in all healthy tissue but which is not expressed in many tumor types. Current clinical agents provide <0.1% yield of O6-guanine alkylation products; identifying agents with increased selectivity for O6-guanine will allow full ex- ploitation of MGMT silencing in chemotherapy. We have a network of collaborators to advance the translational aspects of each project. These studies advance basic chemistry through strategy and reaction development, and will continue to deliver new preclinical candidates to treat cancers and drug-resistant infections.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).