ABSTRACT
In this account, we report the development of a series of substituted cinnamic anilides that represents a novel class of mitochondrial permeability transition pore (mPTP) inhibitors. Initial class expansion led to the establishment of the basic structural requirements for activity and to the identification of derivatives with inhibitory potency higher than that of the standard inhibitor cyclosporine-A (CsA). These compounds can inhibit mPTP opening in response to several stimuli including calcium overload, oxidative stress, and thiol cross-linkers. The activity of the cinnamic anilide mPTP inhibitors turned out to be additive with that of CsA, suggesting for these inhibitors a molecular target different from cyclophylin-D. In vitro and in vivo data are presented for (E)-3-(4-fluoro-3-hydroxy-phenyl)-N-naphthalen-1-yl-acrylamide 22, one of the most interesting compounds in this series, able to attenuate opening of the mPTP and limit reperfusion injury in a rabbit model of acute myocardial infarction.
Subject(s)
1-Naphthylamine/analogs & derivatives , Acrylamides/chemistry , Anilides/chemistry , Cinnamates/chemistry , Mitochondrial Membrane Transport Proteins/antagonists & inhibitors , Myocardial Reperfusion Injury/drug therapy , 1-Naphthylamine/chemical synthesis , 1-Naphthylamine/chemistry , 1-Naphthylamine/pharmacology , Acrylamides/chemical synthesis , Acrylamides/pharmacology , Anilides/chemical synthesis , Anilides/pharmacology , Animals , Calcium/metabolism , Cinnamates/chemical synthesis , Cinnamates/pharmacology , Female , Male , Mice, Inbred C57BL , Mitochondria, Heart/metabolism , Mitochondria, Liver/metabolism , Mitochondrial Membrane Transport Proteins/metabolism , Mitochondrial Permeability Transition Pore , Mitochondrial Swelling/drug effects , Myocardial Infarction/drug therapy , Myocardial Infarction/metabolism , Myocardial Reperfusion Injury/metabolism , Rabbits , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The histone deacetylases (HDACs) are able to regulate gene expression, and histone deacetylase inhibitors (HDACi) emerged as a new class of agents in the treatment of cancer as well as other human disorders such as neurodegenerative diseases. In the present investigation, we report on the synthesis and biological evaluation of compounds derived from the expansion of a HDAC inhibitor scaffold having N-hydroxy-3-phenyl-2-propenamide and N-hydroxy-3-(pyridin-2-yl)-2-propenamide as core structures and containing a phenyloxopropenyl moiety, either unsubstituted or substituted by a 4-methylpiperazin-1-yl or 4-methylpiperazin-1-ylmethyl group. The compounds were evaluated for their ability to inhibit nuclear HDACs, as well as for their in vitro antiproliferative activity. Moreover, their metabolic stability in microsomes and aqueous solubility were studied and selected compounds were further characterized by in vivo pharmacokinetic experiments. These compounds showed a remarkable stability in vivo, compared to hydroxamic acid HDAC inhibitors that have already entered clinical trials. The representative compound 30b showed in vivo antitumor activity in a human colon carcinoma xenograft model.
Subject(s)
Acrylamides/chemical synthesis , Antineoplastic Agents/chemical synthesis , Histone Deacetylase Inhibitors/chemical synthesis , Acrylamides/pharmacology , Antineoplastic Agents/pharmacokinetics , Benzene Derivatives , Cell Proliferation/drug effects , Colonic Neoplasms/drug therapy , Drug Stability , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/therapeutic use , HeLa Cells , Histone Deacetylase Inhibitors/pharmacokinetics , Histone Deacetylase Inhibitors/therapeutic use , Humans , Pyridines , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
The enantioselective synthesis of a simplified eleutherobin analogue by ring closing metathesis (RCM) of the 2,9-divinyl-substituted tetrahydro-oxonin is described; the analogue and an advanced intermediate revealed microtubule stabilising properties in the micromolar range.
Subject(s)
Diterpenes/chemistry , Crystallography, X-Ray , Diterpenes/chemical synthesis , Epoxy Compounds/chemistry , Models, Molecular , Molecular StructureABSTRACT
A series of analogues of the peptide deformylase (PDF) inhibitor BB-3497 where the P3' amide bond was replaced with a ketone functionality is described. The in vitro antibacterial profiling of these compounds revealed that they demonstrate activity against pathogens associated with respiratory tract infections.
