First generation of histone deacetylase inhibitors. a Evolution of the HDAC inhibitor vorinostat, with IC50 values indicated for the differentiation of murine erythroleukaemia cells. From the initial observation on DMSO (compound 6), the more potent simple amide (compound 7) was generated, although still at a millimolar level. By employing a classic strategy in medicinal chemistry (so-called ‘multivalency’), compound 8 emerged as a better candidate that entered Phase I/II clinical trials in which partial responses were observed in MDS and AML patients. Attempts to increase the valency through tri- or tetra-amides were unsuccessful, so the strategy moved to considered hydroxamic acids as an amide isostere. The resulting compound 9 was indeed more potent than 8. The original idea behind multivalency was reconsidered and one hydroxamic acid was replaced by an amide to pick up hydrophobic interactions. This process led to the new candidate SAHA (compound 10) which was selected for having the right balance between potency and toxicity. b Natural product inhibitors of histone deacetylases (trichostatin A and trapoxin A). c Romidepsin and its conversion to the active metabolite. The natural product itself (compound 11) acts as a cell-permeable prodrug that undergoes disulphide bridge reduction within the cellular environment. In the resulting dithiol (compound 12), one of the thiol groups reversibly coordinates to the active site zinc cation in the same way as vorinostat through the latter’s hydroxamic acid.