Mitomycinoid alkaloids: mechanism of action, biosynthesis, total syntheses, and synthetic approaches.

Abstract

The mitomycins (Figure 1) are a unique family of natural products with a rich history. Hata and coworkers at Kwoya Hakko Kogyo Company in Japan first isolated mitomycins A and B from Streptomyces caespitosus found in soil samples in 1956.[1-3] Although the mitomycins were isolated by researchers at Kwoya Hakko Kogyo, the absolute structure of the mitomycins was determined by Webb and Coworkers at American Cyanamid Company.[4,5] X-ray crystal structures of the mitomycins by Tulinsky also proved critical in determination of the structures of the mitomycins.[6,7] Since that time a number of other members of this family of natural products have been isolated, including FR-900482 and FR-66979 from Streptomyces sandaensis in 1988 (Figure 1).[8, 9] Figure 1 Members of the mitomycin family of natural products. The biological activity attributed to this family of natural products is a manifestation of their ability to form both inter- and intra-strand DNA cross-links in the minor groove with a specificity favoring 5′-CG-3′ steps.[10,11] At the time of this discovery, no previous examples of natural products acting as DNA cross-linking agents were known. It was after this initial finding that several other natural products were found to also form cross-links with DNA.[12-14] Recent studies have shown that in addition to the formation of DNA cross-links, this family of compounds is also capable of forming cross-links with minor groove-binding nuclear proteins, such as high mobility group I/Y (HMG I/Y now named HMG A1) proteins.[15,16] Additionally, it was shown that monoalkylation and not cross-linking was the major adduct found when an FR-900482 derivative was incubated with nucleosomes. This result could suggest alternate modes of action of this family of natural products in the context of cellular chromatin.