1.3 Mode Of Action

The enediyne group is often called a warhead because it is ready to cyclize, forming benzene via a highly reactive 1,4-benzeniod diradical intermediate. This diradical intermediate is responsible for the oxidative DNA cleavage. This cyclization process is named the Bergman cycloaromatization reaction.14 The enediyne group readily cyclizes via a diradical intermediate that cleaves the DNA, giving rise to enediynes’ powerful antitumor activity. The antitumor activity of enediyne natural products stems from their ability to cleave double stranded DNA (ds DNA), which induces cell apoptosis.15 The biological mode of action occurs along one of two general pathways, depending the type of enediyne structure (Scheme 1). The majority of enediynes undergo Bergman cyclization.14 The sequence that leads to this cyclization begins when a cellular thiol, such as glutathione attacks the trisulfide bond, liberating a thiolate which then reacts with the unsaturated enone via 1,4- addition. The resulting rehybridization of the bridgehead carbon (sp2 to sp3) induces a conformational change that decreases the distance between diyne termini in 12.




The Bergman cyclization now proceeds readily to afford the p-benzyne diradical 13 that abstracts two hydrogen atoms, one each from the opposite strands of a complementary base pair producing the arene 14.15 The chemical consequences of these hydrogen atom abstractions lead to double-stranded DNA cleavage, which induces apoptosis.15
There are four principle effects of the enediynes on the cell: 1. Mutagenicity; 2. Antimitotic activity associated with cell-cycle arrest;
3. Apoptosis induction; and 4. Differential induction. Mutagenicity, the capacity to induce mutations, of enediynes has been shown to be sulf-hydryl dependent and varies with concentration, which is proportional to the cytotoxicity. That is, as the surviving fraction of cells diminishes, there is an increase of the percentage of remaining cells with a mutant phenotype. Enediynes act as antimitotic agents by inducing a temporary delay in division. Mitosis is a process that takes place in the nucleus of a dividing cell, involves typically a series of steps consisting of prophase, metaphase, anaphase, and telophase, and results in the formation of two new nuclei each having the same number of chromosomes as the parent nucleus. Cell growth remains blocked for some period of time, usually one hour, demonstrating a decrease in the mitotic index. The antimitotic effect is irreversible. Stable, designed enediynes appear to block apoptosis induction (genetically determined destruction of the cell by internal stimulation). Competitive inhibitors, such as receptor-ligand-like interactions, are not universally seen in natural enediynes. The determination of whether a particular cell undergoes apoptosis or differentiation is a function of the endogenous properties of that cell rather than the concentration or nature of the enediyne. All of the enediyne antibiotics were originally derived by fermentation of microorganisms. The various species organisms produced different enediyne complexes.


References

(14) Jones, R. R.; Bergman, R. G. J. Am. Chem. Soc. 1972, 94, 660.
(15) Nicolaou, K. C.; Dai, W. Angew. Chem. Int. Ed. Engl. 1991, 30, 1387 and references therein.