Work

Synthesis of Myrocin G, the Putative Active Form of the Myrocin Antitumor Antibiotics

Year: 2018

Type: article

Abstract: The antiproliferative antimicrobial fungal metabolites known as the myrocins have been proposed to cross-link DNA by double nucleotide addition. However, the nature of the DNA-reactive species is ambiguous, as myrocins have been isolated as functionally distinct 5-hydroxy-γ-lactone and diosphenol isomers. Based on literature precedent, we hypothesized that the diosphenol 7 (assigned here the trivial name myrocin G) is the biologically active form of the representative isolate (+)-myrocin C (1). To probe this, we developed a short enantioselective route to 7. A powerful fragment-coupling reaction that forms the central ring of the target in 38% yield and in a single step was developed. In support of our hypothesis, 7 was efficiently transformed to the bis(sulfide) 6, a product previously isolated from reactions of 1 with excess benzenethiol. This work provides the first direct access to the diosphenol 7, sets the stage for elucidating the mode of interaction of the myrocins with DNA, and provides a foundation for the synthesis of other pimarane diterpenes.

Source: Journal of the American Chemical Society

DOI: 10.1021/jacs.8b10891

Authors: Christos Economou, Martin Tomanik, Seth B. Herzon

Institution: Yale University

Language: English

Topic: Biological Activity of Diterpenoids and Biflavonoids

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

Open Access status: green

Funders: Yale University, National Institutes of Health, National Cancer Institute, National Institute of General Medical Sciences

Awards: Predoctoral Training at the Interface Chemistry and Biology, Synthetic and Mechanistic Studies of Myrocin Antitumor Agents, Synthetic and translational studies of antitumor and antimicrobial natural products.