Cyclic enediynes and enyne-allenes containing additional functionalities
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Natural enediyne antibiotics are perhaps the most potent natural anticancer agents. Their extreme cytotoxicity is attributed to the ability of either (Z)-3-ene-1,5-diyne or (Z)-1,2,4-heptatrien-6-yne fragment to undergo cyclization producing a reactive 1,4-biradical. Enediynes undergo Bergman cyclization, while enyne-allenes undergo Myers-Saito cycloaromatization. These reactions cause simultaneous cleavage of both strands of duplex DNA. Unfortunately, low selectivity, poor thermal stability, and high general toxicity of naturally occurring enediynes, as well as designed compounds, prevent their wide use in clinical practice thus far. The goal of this work was to investigate the mechanism, the kinetics, and the triggering mode of the Bergman and Myers-Saito cyclizations in order to achieve control over the enediyne and enyne-allene activity. We have developed and synthesized 10- (3.1a, 4.1–4.6) and 11- (3.1b) membered cyclic enediynes with conjugated exo-double bond at the acetylenic termini of the (Z)-3-ene-1,5-diyne fragment. Kinetic studies and deuterium-labeling experiments confirmed our hypothesis that keto-endiynes (3.1a and b) undergo Bergman cycloaromatization via rate determining enolization, followed by cyclization of enol into 1,4-biradical. It was also found that electron-donating substituents at the β-position, with respect to the one of acetylenic termini of enediynes, increase the rate of cyclization, while electron-withdrawing groups have an opposite effect. The cyclization step is the rate determining step in these reactions. In order to achieve spatial and temporal control over the action of enediynes, we also developed compounds that are thermally stable, but their action can be triggered photochemically. The reactive allenes (5.3 and 6.4) and enyne-allene (6.10) compounds were proposed. The allene 5.3 was generated by UV irradiation of a thermally stable precursor (5.1) in which an aldehyde group was protected with a photoremovable protecting group as an acetal moiety. Reactive allene 6.4 and cyclic enyne-allene 6.10 were generated from acyclic 2-diazo-1,3- dicarbonyl compounds by the photochemical Wolff reaction. Allene 6.4 and enyne-allene 6.10 readily add nucleophiles to the electron-poor double bond; 6.10 presumably undergoes fast Myers-Saito cyclization in non-nucleophilic solutions.