Background: In the expanding field of anticancer drugs, HDAC inhibitors
are playing an increasingly important role. To date, four/five HDAC inhibitors have
been approved by FDA. All these compounds fit the widely accepted HDAC inhibitors
pharmacophore model characterized by a cap group, a linker chain and a zinc
binding group (ZBG), able to bind the Zn2+ ion in a pocket of the HDAC active site.
Romidepsin, a natural compound, is the only thiol derivative. We have selected a new
class of synthetic HDAC inhibitors, the thio-(lactam-carboxamide) derivatives, with
ST7612AA1 as drug candidate, pan-inhibitor active in the range of single- to twodigit
nanomolar concentrations. Preliminary results of a synthetic optimization attempt
towards a fast scale-up process are here proposed.
Methods: in the four steps of synthesis, from unsaturated amino acid intermediate to the final product, we
explored different synthetic conditions in order to have a transferable process for a scale-up synthetic
Results: In the first step, isobutyl chloroformate was used and, after a simple work up with 1M HCl, 2
(96% yield) was obtained as a white solid, which was used directly in the next step. For thioacetic acid
addition to the double bond of intermediate 2, two different routes were possible, with addition reaction in
the first (D’) or last step (D). Reactions of 2 to give 5 or of 4 to give ST7612AA1 were both performed in
dioxane. Reactions were fast and did not need the usually advised radical quenching with cyclohexene.
The corresponding products were obtained in good yields (step D’, 89%; step D, 81%) after a flash
Conclusion: ST7612AA1, a thiol derivative prodrug of ST7464AA1, is the first of a new generation of
HDAC inhibitors, very potent, orally administered, and well tolerated. Here, we have identified a synthetic
route, competitive, versatile and easily transferable to industrial processes.