Enediyne natural product production

Shen, B., Liu, W. and Nonaka, K. (2003) Enediyne natural products biosynthesis and prospect towards engineering novel antitumor agents. Current Medicinal Chemistry, 10, 2317. 

While enediyne natural products are efficient DNA cleaving agents, synthetic enediynes have been utilized widely to study the mechanistic details and obtain more efficient DNA cleavage activity. Simple enediynes (Fig. 8), with no binding units, show DNA cleavage albeit at very high concentra-... 

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. 

Shen B, Liu W, Nonaka K (2003) Enediyne Natural Products Biosynthesis and Prospect Towards Engineering Novel Antitumor Agents. Curr Med Chem 10 2317... 

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

Liang, Z.-X. (2010) Complexity and simplicity in the biosynthesis of enediyne natural products. Natural Product Reports, 27(4), 499-528. 

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... 

The anticancer activity of complex natural products having a cyclodecenediyne system [for a review see <96MI93>] has prompted the synthesis of 54 (X = CH2 and OCH2) <96CC749> and 55 (R = a-OH and p-OH) <95AG(E)2393> on the basis that such compounds are expected to develop anticancer activity as the P-lactam ring opens. This is because cycloaromatization can only occur in the monocyclic enediyne and the diradical intermediate in the cyclization is thought to be the cytotoxic species. 

The interest in the Bergman Cyclization was somewhat low, due to its limited substrate scope and the availability of alternative methods for the construction of substituted arenes. However, natural products that contain the enediyne moiety have been discovered recently, and these compounds have cytotoxic activity. 

With the discovery of calicheamicin and similar natural products, interest in the Bergman Cyclization has increased. Many enediynes can now be viewed as potential anticancer drugs. Thus, the development of Bergman Cyclization precursors that can undergo cyclization at room temperature has attracted much attention. Now, most publications on this topic deal with the parameters that control the kinetics of the Bergman Cyclization. 

Z)-vinylic tellurides are the source of enynes 212 and enediynes 213 by transformation into vinylcopper species (Section 9.13.8.2.4), followed by reaction with haloalkynes (Scheme 113).278,279 The transformation occurs with retention of the double-bond stereochemistry. This is an efficient and straightforward route to important unsaturated units present in natural products, specially in enediyne antibiotics.280... 

Esperamicin Ai was, however, not the only natural product identified with an enediyne core (Figure 3.1). Studies dating back to 1965s identified a chromoprotein containing a neocarzinostatin core that was able to induce comparable... 

The area of the chemistry of enediyne antibiotics is still very young. This field was only four years old when the first comprehensive review was published in 1991. As is stated in this review, rarely before has a newly discovered class of natural products created such stimulation and excitement in chemistry, biology, and medicine as the enediynes. Equally rare is the beauty and fascination associated with the molecular architecture and mode of action of these naturally occurring substances. The opportunities they offer for challenging and creative scientific endeavors may be overshadowed only by their potential therapeutic... 

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. 

---