FIGURE 10.20 Binding of trichostatin A to HDAC.

3.2.3. Cyclic tetrapeptides

Some cyclic tetrapeptides are potent inhibitors of HDACs. The best known compound of this group is romidepsin (FK-228, FR901228), a depsipeptide that is currently under clinical studies for the treatment of chronic lymphocytic leukemia and acute myeloid leukemia81 and T-cell lymphoma. It is a natural product, isolated from Chromobacterium violaceum, and it can be considered as a prodrug that is uptaken into the cells and then activated by glutathione. The reduced form (RedFK) has a four-carbon chain between the free sulfhydryl and the cyclic depsipeptide core, and forms a covalent disulfide bond with the only cysteine residue present in the HDAC pocket82 (Fig. 10.21).

Trapoxins A and B, isolated from the fungus Helicoma ambiens, are hydrophobic cyclotetrapeptides that contain, respectively, pipecolinic acid and proline residues, and also two phenylalanines and an unusual amino acid bearing a side chain that contains an epoxide group. These compounds are potent enzyme inactivators that irreversibly inhibit the enzyme, probably by binding covalently through its epoxy group,83 but are too toxic for clinical use. The a-epoxyketone moiety is not essential for activity, as can be deduced from the structure of apicidin, a fungal metabolite with antiprotozoal activity that also inhibits HDACs through induction of the p21WAF1/CIP1 gene84 and is under preclinical assay. CHAP-31 is a

FIGURE 10.21 Inhibition of HDAC by romidepsin.

trapoxin A analog, also under preclinical assay, in which the epoxy group has been replaced with a hydroxamate function,85 and hence it can be considered as a hydroxamic acid-tetrapeptide hybrid.

n = 2 Trapoxin A 0CH3


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