A SYNTHETIC AND MECHANISTIC REVIEW OF
ENEDIYNE CHEMISTRY

1.1 Introduction

Man’s fascination with natural products goes back to ancient times. With the discovery of Salicin from willow tree extracts and the development of aspirin in 1899, the art of exploiting natural products became a molecular science. The discovery of a class of compounds called the enediynes in the mid 1980’s and its subsequent drug development represented another milestone in the history of natural products, and marked the beginning of a new chapter in drug discovery, in which bacteria were added to the plant kingdom as a source of biologically active compounds. Indeed, a large portion of today’s major drugs have their origin in nature. Interest in enediynes has grown because of their anticancer activity;1 this class of naturally occurring compounds can selectively cleave DNA. However, enediynes are toxic, and some of them are unstable for biological application. Researchers are currently trying to synthesize and develop analogues, and to investigate mode of action in order to better control their activity. The goal of many researchers is to prepare enediynes, using a synthetically simple strategy, that contain an active site that could be activated in a controlled manner.
In this reviews of anticancer agents and the bicyclic heteroaromatic fused ring systems will be presented, followed by reviews of synthetic methodology most commonly used in enediyne synthesis and reactions under which they can cyclize.





1.2 Classes Of Naturally Occurring Enediynes
Five classes of naturally occurring enediynes are known. The enediyne family of antibiotics (Fig. 1) is characterized structurally by an enediyne core unit consisting of two acetylenic groups conjugated to a double bond or incipient double bond within a 9- or 10-membered ring.2-4 To date, five unique 9-membered enediynes (1–5) (Fig. 1), often designated as the chromoprotein enediynes, and five additional distinct naturally occurring 10-membered enediynes (6–10) (Fig. 1) have been elucidated structurally.5-7 In general, these enediynes contain three distinct structural elements: a DNA-recognition unit, which serves to deliver the metabolite to its target DNA; an activation component, which sets the stage for cycloaromatization; and the enediyne "warhead," which cycloaromatizes to a highly reactive diradical species and, in the presence of DNA, results in oxidative strand scission of the targeted sequence.8-10 In vitro and in vivo studies are consistent with the role of enediynes as DNA-damaging agents and suggest that they may even favour cleavage at certain chromosomal sites and/or tertiary structures.11,12 Although this extraordinary reactivity invokes incredible potency (some enediynes are >8,000-fold), the enediynes are similar to most cytotoxins in their general lack of tissue specificity. However, targeting via polymer-assisted delivery devices 1-poly(styrene-maleic acid)-conjugated neocarzinostatin or conjugation to tumor-specific monoclonal antibodies (as in the 6-based Mylotarg) has led to clinical success.13


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