Enediyne natural product structure

Timothy J. Montavon was born in Wheelersburg, OH, in 1982. He attended Xavier s University in Cincinnati, OH, where he earned a B.S. in chemistry in 2004. While at Xavier s, he worked in the laboratory of Professor Aaron Baba developing novel fluoroiono-phores. In 2004, he began attending graduate school at Boston College working in the laboratory of Professor Steven Bruner. His current research is focused on the structure and mechanism of aminomutase enzymes used in the biosynthesis of enediyne natural products. 

Figure 3.1 Structures of exemplary enediyne natural products. The star notes the location of their reactive enediyne functionality.

The three types of PKSs described here, the enediyne PKS, the C-0 bondforming PKS, and the AT-less PKS, are only representive examples that reside outside the archetypical PKS paradigms. Continued exploration on the mechanism of polyketide biosynthesis will undoubtly uncover more unusual PKSs. These novel PKSs, in combination with the archetypical ones, will ultimately enhance the toolbox available to facilitate combinatorial biosynthesis and production of iinnatural natural products. The full realisition of the potential embodied by combinatorial biosynthesis of PKSs for natural product structural diversity, however, depends critically on the fundamental characterization of PKS structure, mechanism, and catalysis. 

The cycloaromatization of enediynes, having a structure like 1, proceeds via formation of a benzenoid 1,4-diradical 2, and is commonly called the Bergman cyclization. It is a relatively recent reaction that has gained importance especially during the last decade. The unusual structural element of enediynes as 1 has been found in natural products (such as calicheamicine and esperamicine) which show a remarkable biological activity... 

Golik J, Dubay G, Groenewold G, Kawaguchi H, Konishi M, Krishnan B, Ohkuma H, Saitoh K, Doyle TW. Esperamicins, a novel class of potent antitumor antibiotics. 3. Structures of esperamicins Al, A2, and Alb. J. Am. Chem. Soc. 1987 109 3462-3464. Hamann PR, Upeslacis J, Borders DB. Enediynes. In Anticancer Agents from Natural Products. Cragg GM, Kingston DGI, Newman DJ, eds. 2005. Taylor and Francis, Boca Raton, FL. pp. 451-474. 

The special fascination of strained cyclic enediynes lies in their intrinsic tendency to undergo thermal cyclisation. This aspect has been stimulating the research activities on enediynes since their beginnings more than 20 years ago, [1] and it is this reactivity of the enediyne structure that brings about the pharmacological effectiveness of natural products, like Dynemicin A. [2]... 

Once the structures of the first natural enediyne antibiotics had been elucidated, the scientific community was quick to respond. The mechanisms by which these molecules exert their effects continue to be probed ever deeper, with surprising new details still emerging. The hitherto unprecedented and structurally complex molecular architecture of the natural products has required the development of new synthetic methodology in order to synthesize functional models which would shed new light upon the natural enediyne antibiotics. Researchers in the field have pushed the art of organic synthesis to its present limits with total syntheses of calicheamicin yj (2), the most prominent member of the natural enediyne antibiotics, and a derivative of dynemicin A (4) having been achieved. Furthermore, the factors affecting the... 

Enediynes are natural products with potent antitumor properties because they are able to cleave DNA (page 299). Their cytotoxic properties are due to the enediyne undergoing a cyclization to form a highly reactive diradical intermediate. The intermediate abstracts hydrogen atoms from the backbone of DNA, which triggers its damage. Draw the structure of the diradical intermediate. 

The discovery of the remarkable biological activity of natural enediynes and enyne allenes has further fueled interest in understanding the fundamentals that govern these transformations. Indeed, cycloaromatization reactions have served as a productive playground for testing numerous concepts related to structure and reactivity of organic and organometaUic compounds [2]. Furthermore, the... 

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