ABSTRACT
Several oxime containing molecules, characterized by a SAHA-like structure, were explored to select a potentially new biasing binding element for the zinc in HDAC catalytic site. All compounds were evaluated for their in vitro inhibitory activity against the 11 human HDACs isoforms. After identification of a "hit" molecule, a programmed variation at the cap group and at the linker was carried out in order to increase HDAC inhibition and/or paralogue selectivity. Some of the new derivatives showed increased activity against a number of HDAC isoforms, even if their overall activity range is still far from the inhibition values reported for SAHA. Moreover, different from what was reported for their hydroxamic acid analogues the new α-oxime amide derivatives do not select between class I and class II HDACs; rather they target specific isoforms in each class. These somehow contradictory results were finally rationalized by a computational assisted SAR, which gave us the chance to understand how the oxime derivatives interact with the catalytic site and justify the observed activity profile.
Subject(s)
Amides/chemistry , Amides/pharmacology , Histone Deacetylases/chemistry , Histone Deacetylases/metabolism , Oximes/chemistry , Zinc/metabolism , Amides/chemical synthesis , Amides/metabolism , Catalytic Domain , Histone Deacetylase Inhibitors/chemical synthesis , Histone Deacetylase Inhibitors/chemistry , Histone Deacetylase Inhibitors/metabolism , Histone Deacetylase Inhibitors/pharmacology , Humans , Inhibitory Concentration 50 , Isoenzymes/chemistry , Isoenzymes/metabolism , Molecular Dynamics Simulation , Quantum Theory , Structure-Activity RelationshipABSTRACT
The microwave-assisted aminocarbonylation of ynamides at low pressures of CO is reported. A new class of (E)-acrylamides that are potentially suitable for several applications has been regioselectively synthesized after microwave irradiation for only 20 min by using eco-friendly [Fe(3)(CO)(12)] as the catalyst precursor and triethylamine as the ligand. This transformation is atom economic as all reactants are used in stoichiometric quantities. Furthermore, the transformation is efficiently applied to the alkoxycarbonylation of alkynes as well. Moreover, running these reactions under microwave irradiation allows the simplification of the reaction conditions with remarkable reductions in time, temperature and gas pressure.
Subject(s)
Acrylamide/chemical synthesis , Carbon Monoxide/chemistry , Iron/chemistry , Microwaves , Acrylamide/chemistry , Catalysis , Combinatorial Chemistry Techniques , Molecular Structure , StereoisomerismABSTRACT
Azumamide E, a cyclotetrapeptide isolated from the sponge Mycale izuensis, is the most powerful carboxylic acid containing natural histone deacetylase (HDAC) inhibitor known to date. In this paper, we describe design and synthesis of two stereochemical variants of the natural product. These compounds have allowed us to clarify the influence of side chain topology on the HDAC-inhibitory activity. The present contribution also reveals the identity of the recognition pattern between azumamides and the histone deacetylase-like protein (HDLP) model receptor and reports the azumamide E unprecedented isoform selectivity on histone deacetylases class subtypes. From the present studies, a plausible model for the interaction of azumamides with the receptor binding pocket is derived, providing a framework for the rational design of new cyclotetrapeptide-based HDAC inhibitors as antitumor agents.
