Depsipeptide HDAC inhibitors synthesis

Total Synthesis of Depsipeptide HDAC Inhibitors - Routes to the fi-Hydroxy Acid Fragment... 

Another patent by Fujisawa disclosed [31] the structure of FR-901375 from an extract of Pseudomonas chloroaphis No. 2522. While it is a likely H DAC inhibitor, no data have been reported in this regard and the decision seems to have been made to promote FK228 instead as the clinical candidate. In 2001, additional depsipeptide natural products, the spiruchostatins, were reported [32] by Shin-ya s group at the University of Tokyo and Yamanouchi Pharmaceuticals. These compounds were isolated from an extract of Pseudomonas sp. Q71576, on the basis of the ability to increase expression of luciferase driven by the plasminogen activator inhibitor (PAI-1) promoter. Given the structural similarity to FK228, the spiruchostatins were likely to be HDAC inhibitors and this was confirmed in a later patent [33] and in our biochemical studies (see below) with the natural product prepared by total synthesis. 

Compared to other classes of HDAC inhibitors, the depsipeptides exhibit two impressive features. Firstly, they are highly potent with IC50S in the low nanomolar range. Secondly, they are significantly more active against class I HDACs compared to class II HDACs. Fortuitously, it is the former that are more heavily implicated in cancer and cardiac hypertrophy. On the other hand, the depsipeptides are structurally the most complicated class of HDAC inhibitors. Their elaborate framework has apparently deterred the pharmaceutical industry from the preparation of unnatural analogs and the iterative improvement of their properties. The Fujisawa and Yamanouchi patents only cover the natural products and so far only academic groups have described the total synthesis of depsipeptides. 

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