Vorinostat-like molecules as structural, stereochemical, and pharmacological tools

Stephen Hanessian; Luciana Auzzas; Andreas Larsson; Jianbin Zhang; Giuseppe Giannini; Grazia Gallo; Andrea Ciacci; Walter Cabri

doi:10.1021/ml100028g

Vorinostat-like molecules as structural, stereochemical, and pharmacological tools

ACS Med Chem Lett. 2010 Mar 11;1(2):70-4. doi: 10.1021/ml100028g. eCollection 2010 May 13.

Authors

Stephen Hanessian¹, Luciana Auzzas², Andreas Larsson³, Jianbin Zhang¹, Giuseppe Giannini⁴, Grazia Gallo⁴, Andrea Ciacci⁴, Walter Cabri⁴

Affiliations

¹ Department of Chemistry, Université de Montréal, P.O. Box 6128, Station Centre-ville, Montréal, QC, H3C 3J7, Canada.
² Department of Chemistry, Université de Montréal, P.O. Box 6128, Station Centre-ville, Montréal, QC, H3C 3J7, Canada ; Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Traversa La Crucca 3, I-07040 Sassari, Italy.
³ Department of Chemistry, Université de Montréal, P.O. Box 6128, Station Centre-ville, Montréal, QC, H3C 3J7, Canada ; Department of Chemistry, Umeå University, 901 87, Umeå, Sweden.
⁴ Sigma-Tau Research & Development, Via Pontina Km 30.400, I-00040 Pomezia, Roma, Italy.

Abstract

The inhibitory activity of an ω-alkoxy analogue of the HDAC inhibitor, Vorinostat (SAHA), against the 11 isoforms of HDAC is described and evaluated with regard to structural biology information retrieved through computational methods. Preliminary absorption and metabolism studies were performed, which positioned this compound as a potential candidate for further preclinical studies and delineated measures for improving its pharmacokinetic profile.

Keywords: HDAC promiscuous inhibitors; HDAC1−11 profile; SAHA analogues; absorption and metabolism; class IIa-specific profile.