title: Synthesis of ST7612AA1, a Novel Oral HDAC Inhibitor, via Radical  Thioacetic Acid Addition.
abstract: 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-ω(lactam-carboxamide) derivatives, withST7612AA1as drug candidate, pan-inhibitor active in the range of single- to two-digit 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 laboratory.
  
  
  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 intermediate2, two different routes were possible, with addition reaction in the first (D') or last step (D). Reactions of2to give5or of4to giveST7612AA1were 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 chromatography.
  , a thiol derivative prodrug ofST7464AA1, 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.
authors.affiliation: R&D Sigma-Tau IFR S.p.A., Via Pontina Km 30,400, I-00071 Pomezia, Rome, Italy.
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Battistuzzi
authors.affiliation: R&D Sigma-Tau IFR S.p.A., Via Pontina Km 30,400, I-00071 Pomezia, Rome, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Giannini
keywords: ST7612AA1; Thio-ω(lactam-carboxamide) derivatives; Thiol-based HDAC inhibitors; Thiol-ene reaction