Guthikonda Lectureship: Professor Seth Herzon, Yale University
About the Seminar
"Synthesis of complex alkaloids and development of new anticancer agents to exploit tumor-associated DNA repair defects"
Research in our laboratory is currently focused on two areas: complex molecule synthesis and the development of new anticancer agents that exploit tumor-associated DNA repair defects (TADDs). In the first part of this lecture, I will describe our synthesis of securines, securamines, hexacyclic securamines, and chartellines, complex densely-functionalized alkaloids that contain a cis-enamide, neopentylic alkyl chloride, bromoimidazole, and a pyrroloindoline ring. The synthesis features the modular assembly of a macrolactam followed by a hydrochlorination cascade that introduces several critical substructures in a single step. The pyrroloindoline and hexacyclic skeletons were assembled by sequential oxidative photocyclizations, which may have bearing on the biosynthesis of the isolates. The development of a unified synthetic route that provides access to each class of these isolates will be described.
The second half of the lecture will focus on new anticancer agents that exploit TADDs to obtain selective tumor cell kill. Enzymes that repair DNA display reduced activity in many cancers. We developed DNA alkylation agents that are selectively toxic to cells lacking the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT), a common TADD. More recently, we identified agents targeted to homologous recombination deficient (HRD) tumors, which constitute ~15% of all cancers. The selectivity of these agents vastly exceed all clinically-approved HRD therapies, and they are highly CNS penetrant, suggesting they could be used to treat brain metastases. Both series’ of compounds are efficacious and well-tolerated in vivo. Mechanistic and translational studies of these compounds will be presented.
About the Speaker
Seth Herzon completed his undergraduate studies at Temple University, obtained a Ph.D. in 2006 from Harvard University under the guidance of Professor Andrew G. Myers, and was an NIH postdoctoral fellow with Professor John F. Hartwig at the University of Illinois, Urbana–Champaign. He began at Yale in 2008 and is currently the Milton Harris ’29 Ph.D. Professor of Chemistry. He holds joint appointments in the Departments of Pharmacology and Therapeutic Radiology at the Yale School of Medicine and is a Member of the Yale Cancer Center. Herzon's research is centered on organic synthesis with an emphasis on the molecular mechanism of action and structure–function studies of anticancer and microbiome-derived secondary metabolites. In 2021, he co-founded the oncology company Modifi Biosciences, which was acquired by Merck and Company in the Fall of 2024. From 2018–2023, he served as an Associate Editor for The Journal of Organic Chemistry.
He has been recognized for his accomplishments by a number of awards, including an NSF CAREER Award, a Searle Scholar Award, a Fellowship from the David and Lucile Packard Foundation, a Fellowship from the Alfred P. Sloan Foundation, a Cottrell Scholar Award of the Research Corporation for Scientific Advancement, a Research Scholar Award from the American Cancer Society, the Arthur C. Cope Scholar Award of the American Chemical Society, the Novartis Chemistry Lectureship, the Synthesis/Synlett Award in Organic Chemistry, the Elias J. Corey Award for Outstanding Original Contribution in Organic Synthesis by a Young Investigator, the Thieme–IUPAC Award, the Tetrahedron Young Investigator Award in Organic Synthesis, the Wilson Prize of Harvard University, a Yale Faculty Innovation Award, a Creativity Extension Award from the National Science Foundation, the A.V. Rama Rao Award in Organic and Bioorganic Chemistry, and the ACS Award for Creative Work in Synthetic Organic Chemistry. From 2018–2019, he was a member of the United States Defense Science Study Group, sponsored by the Institute for Defense Analyses.