This proposal describes the synthesis and study of the kinamycins and lomaiviticin A, bacterial metabolites with unprecedented structures and powerful biological activities. These isolates are nanomolar inhibitors of human cancers and microbial infections, which are among the public health issues that are central to the mission of the NIH. Lomaiviticin A is active against ovarian cell lines at single-digit picomolar concentrations, and is approximately 2-5 orders of magnitude more potent than any of the kinamycins. Overall, lomaiviticin may be regarded as a dimeric form of the kinamycins, although other structural dissimilarities exist, most notably four 2, 6-dideoxycarbohydrate residues that are found only in lomaiviticin. Common to all of these metabolites is a unique diazofluorene functional group, which has not been seen before in natural products. This functional group has been established as reactive under reducing conditions, but a clear understanding of the role of this reactivity in the observed biological activity of lomaiviticin A has not been developed. The objective of the proposed research is to complete the synthesis of lomaiviticin A and to elucidate the mechanism of action of this natural product. We hypothesize that the diazofluorene functional group is essential to biological activity, and that peripheral substituents can be used to modulate its reactivity. In order to probe this hypothesis, we will complete the synthesis of lomaiviticin A by developing a method for the dimerization of two """"""""monomeric"""""""" precursors. A robust dimerization method will facilitate the preparation of simple dimeric diazofluorenes for chemical biological investigations. In parallel with these synthetic studies, we have initiated, and will continue, chemical biological investigations to elucidate the mechanism of action of lomaiviticin A. Evidence to date suggests lomaiviticin A targets DNA by a unique mode of interaction. Therefore we will focus our efforts on understanding the interaction of lomaiviticin and related analogs with DNA. Additionally, we will seek to understand the influence of substituent effects on the reactivity of the diazofluorene, with the goal of identifying easily-prepared, diazofluorene-based anticancer agents. To achieve this, we will conduct structure-function studies and probe the interaction of our synthetic constructs, and the natural product, with DNA. We expect that our research will enable efficient access to this entire family of natural products and related diazofluorenes, thereby overcoming the synthetic obstacles that have hindered the study of these natural products. These synthetic studies are complemented by our chemical biological investigations, which are aimed at developing a lucid understanding of the mechanism of action of lomaiviticin. These are important contributions that will provide the foundation for detailed evaluation of these natural products as new treatments for cancers and bacterial infections.

Public Health Relevance

The development of new options for treatment of human cancers is of paramount importance. Naturally- occurring molecules have been the most fertile area for the discovery of such treatments, and the preparation and study of such molecules is the subject of this proposal.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Synthetic and Biological Chemistry A Study Section (SBCA)
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Lees, Robert G
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Yale University
Schools of Arts and Sciences
New Haven
United States
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Herzon, Seth B (2017) The Mechanism of Action of (-)-Lomaiviticin A. Acc Chem Res 50:2577-2588
Surovtseva, Yulia V; Jairam, Vikram; Salem, Ahmed F et al. (2016) Characterization of Cardiac Glycoside Natural Products as Potent Inhibitors of DNA Double-Strand Break Repair by a Whole-Cell Double Immunofluorescence Assay. J Am Chem Soc 138:3844-55
Xue, Mengzhao; Herzon, Seth B (2016) Mechanism of Nucleophilic Activation of (-)-Lomaiviticin A. J Am Chem Soc 138:15559-15562
Woo, Christina M; Li, Zhenwu; Paulson, Eric K et al. (2016) Structural basis for DNA cleavage by the potent antiproliferative agent (-)-lomaiviticin A. Proc Natl Acad Sci U S A 113:2851-6
Murphy, Stephen K; Zeng, Mingshuo; Herzon, Seth B (2016) Stereoselective Multicomponent Reactions Using Zincate Nucleophiles: ?-Dicarbonyl Synthesis and Functionalization. Org Lett 18:4880-4883
Colis, Laureen C; Herzon, Seth B (2016) Synergistic potentiation of (-)-lomaiviticin A cytotoxicity by the ATR inhibitor VE-821. Bioorg Med Chem Lett 26:3122-3126
Colis, Laureen C; Hegan, Denise C; Kaneko, Miho et al. (2015) Mechanism of action studies of lomaiviticin A and the monomeric lomaiviticin aglycon. Selective and potent activity toward DNA double-strand break repair-deficient cell lines. J Am Chem Soc 137:5741-7
Burk, Matthew; Wilson, Nolan; Herzon, Seth B (2015) Multigram Synthesis of 1-O-Acetyl-3-O-(4-methoxybenzyl)-4-N-(9-fluorenylmethoxycarbonyl)-4-N-methyl-L-pyrrolosamine. Tetrahedron Lett 56:3231-3234
Woo, Christina M; Ranjan, Nihar; Arya, Dev P et al. (2014) Analysis of diazofluorene DNA binding and damaging activity: DNA cleavage by a synthetic monomeric diazofluorene. Angew Chem Int Ed Engl 53:9325-8
Kaneko, Miho; Herzon, Seth B (2014) Scope and limitations of 2-deoxy- and 2,6-dideoxyglycosyl bromides as donors for the synthesis of ?-2-deoxy- and ?-2,6-dideoxyglycosides. Org Lett 16:2776-9

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