Synthesis of ST7612AA1, a Novel Oral HDAC Inhibitor, via Radical Thioacetic Acid Addition

Abstract

BackgroundIn 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, with ST7612AA1 as 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.MethodsIn 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.ResultsIn 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 chromatography.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.

The cyclohexene derivative MC-3129 exhibits antileukemic activity via RhoA/ROCK1/PTEN/PI3K/Akt pathway-mediated mitochondrial translocation of cofilin

“…Compound ZJ-101, containing a cyclohexenyl ring, also exhibited anticancer activity 6 . ST7612AA1, a new generation of HDAC inhibitors, exhibited potential activity against a broad panel of cancer cell lines and in vivo tumor models 7 . These reports indicated that synthetic cyclohexene derivatives might show potential as chemotherapeutic agents for the treatment of human cancer.…”

Tunable Aminooxy‐Functionalized Monolayer‐Protected Gold Clusters for Nonpolar and Aqueous Oximation Reactions

“…Subsequent transformation of the primary alcohol moieties to phthalimido groups was performed using standard Mitsunobu conditions according to the method reported by Grochowski and Jurczak . Installation of the terminal thiol moiety to form 4 was next attempted, also using established conditions . Azobisisobutyronitrile (AIBN)‐initiated radical addition of thioacetic acid to the terminal alkene of 3 proved troublesome; however, on protonation of the amine group using camphorsulfonic acid (CSA) prior to addition of AIBN, the reaction produced thioacetate 4 in good yield.…”

ErbB2 Targeted Epigenetic Modulation: Anti-tumor Efficacy of the ADC Trastuzumab-HDACi ST8176AA1

“…Such ADCs, coded ST8154AA1 and ST8155AA1, are the first example of products targeting epigenetic modulation to tumors. ST7612AA1 is a pan-HDACi previously shown to exhibit anti-tumor activity against a variety of tumor models (12)(13)(14). Despite efficacy, translation of ST7612AA1 into human therapeutic protocols is hampered by the risk of systemic side effects that are also observed with the previously approved HDACi vorinostat (15).…”