Enediyne Antibiotics

This family of antitumor antibiotics contains as a common structural feature a macrocyclic ring with a conjugated system containing at least one double and two triple bonds. Some members of the group are neocarzinostatin (zinostatin), the oldest of them, isolated from various microorganisms, the esperamicins/calichea-micins, from a Micromonospora echinospora spp. Calichensis, and dynemicin A, from Micromonospora chersina, which combines the structural features of the anthracyclines and the enediynes. In their natural environments, these compounds are stabilized by embedding in a protein, which protects the producing microorganism from their cytotoxic action.

Calicheamicin y1

Generally speaking, the enediynes are too toxic for clinical use, and only neocarzinostatin and calicheamicin have found limited application in some countries. For instance, a chemical conjugate of a synthetic copolymer of styrene maleic acid (SMA) and neocarzinostatin (NCS), known as SMANCS, has been proposed for the treatment of hepatocellular carcinoma.80 More recently, a conjugate of a calicheamicin derivative with an antibody for the CD33 antigen, known as gemtuzumab ozogamicin, has been approved for the treatment of acute myeloid leukemia, which is the most common type of leukemia in adults81 (see also Section 5.2 of Chapter 10 and Section 4.5 of Chapter 11).

These compounds bind to DNA by interaction of parts of the molecule with the minor groove82 and activation to DNA-cleaving biradical species, either by reaction with thiols or by reduction.

The chemical basis for enediyne activation is the Bergmann reaction,83 through which enediyne systems 4.40 undergo cycloaromatization to benzene derivatives, with the intermediacy of the highly reactive 1,4-benzenoid biradical species 4.41 (Fig. 4.30A). In the related Myers reaction, one of the triple bonds can be replaced by an allene unit (4.42), leading to biradical 4.43 (Fig. 4.30B). These processes do not take place in the natural products because their spatial arrangement prevents coplanarity of the three bonds involved in Bergmann-type chemistry, and therefore an activation reaction or cascade of reactions that alters the compound geometry is necessary.

In the case of neocarzinostatin, conjugate nucleophilic addition of a thiol results in epoxide opening and formation of a highly strained cumulene 4.45, which has the correct geometry to undergo a Myers cycloaromatization to biradi-cal 4.46 (Fig. 4.31A).84 In the absence of thiols, a base-catalyzed intramolecular addition reaction takes place, leading to cumulene 4.47 and subsequently to biradical 4.48 (Fig. 4.31B).85

The calicheamicins and esperamicins are also activated by attack of a thiol, in this case to the trisulfide portion, giving the thiolate 4.49, which undergoes a Michael addition to the bridgehead a,p-unsaturated ketone to give the dihy-drothiophene derivative 4.50. The accompanying change in hybridization of the bridgehead atom triggers a Bergmann cyclization to biradical 4.51 (Fig. 4.32).

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