ABSTRACT
Histone deacetylase (HDAC) inhibitors induce the hyperacetylation of nucleosomal histones in carcinoma cells resulting in the expression of repressed genes that cause growth arrest, terminal differentiation, and/or apoptosis. In vitro selectivity of several novel hydroxamate HDAC inhibitors including succinimide macrocyclic hydroxamates and the non-hydroxamate alpha-ketoamide inhibitors was investigated using isolated enzyme preparations and cellular assays. In vitro selectivity for the HDAC isozymes (HDAC1/2, 3, 4/3, and 6) was not observed for these HDAC inhibitors or the reference HDAC inhibitors, MS-275 and SAHA. In T24 and HCT116 cells these compounds caused the accumulation of acetylated histones H3 and H4; however, the succinimide macrocyclic hydroxamates and the alpha-ketoamides did not cause the accumulation of acetylated alpha-tubulin. These data suggest "selectivity" can be observed at the cellular level with HDAC inhibitors and that the nature of the zinc-chelating moiety is an important determinant of activity against tubulin deacetylase.
Subject(s)
Amides/pharmacology , Breast Neoplasms/enzymology , Fibrosarcoma/enzymology , Histone Deacetylase Inhibitors , Histone Deacetylases/metabolism , Hydroxamic Acids/pharmacology , Amides/chemistry , Breast Neoplasms/pathology , Cell Line, Tumor , Cell Proliferation/drug effects , Enzyme Activation/drug effects , Enzyme Inhibitors , Fibrosarcoma/pathology , Histone Deacetylases/chemistry , Humans , Hydroxamic Acids/chemistryABSTRACT
The carboxyl group of the NSAID indomethacin was replaced with a variety of substituted thiazoles to obtain a series of potent, selective inhibitors of COX-2. Additional substitutions were made at the 1-position and 5-position of the indole of indomethacin.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Cyclooxygenase Inhibitors/chemical synthesis , Indomethacin/analogs & derivatives , Isoenzymes/metabolism , Prostaglandin-Endoperoxide Synthases/metabolism , Thiazoles/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Cyclooxygenase 2 , Cyclooxygenase 2 Inhibitors , Cyclooxygenase Inhibitors/pharmacology , Humans , Indomethacin/chemical synthesis , Indomethacin/pharmacology , Inhibitory Concentration 50 , Isoenzymes/drug effects , Membrane Proteins , Prostaglandin-Endoperoxide Synthases/drug effects , Structure-Activity Relationship , Thiazoles/chemical synthesisABSTRACT
A novel series of biaryl ether reverse hydroxamate MMP inhibitors has been developed. These compounds are potent MMP-2 inhibitors with limited activity against MMP-1. Select members of this series exhibit excellent pharmacokinetic properties with long elimination half-lives (7 h) and high oral bioavailability (100%).
Subject(s)
Hydroxamic Acids/chemical synthesis , Matrix Metalloproteinase Inhibitors , Administration, Oral , Animals , Antineoplastic Agents/blood , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacokinetics , Biological Availability , Enzyme Inhibitors/blood , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Half-Life , Hydroxamic Acids/chemistry , Inhibitory Concentration 50 , Injections, Intravenous , Macaca fascicularisABSTRACT
Modification of the biphenyl portion of MMP inhibitor 2a gave analogue 2i which is greater than 1000-fold selective against MMP-2 versus MMP-1. The stereospecific synthesis of both enantiomers of 2i was achieved beginning with (S)- or (R)-benzyl glycidyl ether. The (S)-enantiomer, 11 (ABT-770), is orally bioavailable and efficacious in an in vivo model of tumor growth.
Subject(s)
Biphenyl Compounds/pharmacokinetics , Hydroxamic Acids/pharmacokinetics , Matrix Metalloproteinase Inhibitors , Administration, Oral , Animals , Antineoplastic Agents/blood , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacokinetics , Area Under Curve , Biological Availability , Biphenyl Compounds/blood , Biphenyl Compounds/chemical synthesis , Cell Division/drug effects , Dogs , Enzyme Inhibitors/blood , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Half-Life , Haplorhini , Hydroxamic Acids/blood , Hydroxamic Acids/chemical synthesis , Inhibitory Concentration 50 , Injections, Intravenous , Metabolic Clearance Rate , Neoplasms, Experimental/drug therapy , Rats , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
Two series of compounds synthesized as specific matrix metalloproteinase (MMP) inhibitors have been evaluated for their inhibition of non-MMPs. In a series of substituted succinyl hydroxamic acids, some were found to be significant (IC50 < 1 microM) inhibitors of leucine (microsomal) aminopeptidase, neprilysin (3.4.24.11), and thermolysin. Macrocyclic compounds in which the alpha carbon of the succinyl hydroxamate is linked to the side chain of the P2' amino acid were found to be good inhibitors of aminopeptidase, but not of neprilysin or thermolysin. Compounds of neither series were found to be significant inhibitors of angiotensin converting enzyme or carboxypeptidase A.
Subject(s)
Matrix Metalloproteinase Inhibitors , Metalloendopeptidases/antagonists & inhibitors , Angiotensin-Converting Enzyme Inhibitors , Animals , Bacterial Proteins , Carboxypeptidases/antagonists & inhibitors , Carboxypeptidases A , Cattle , Hydroxamic Acids/chemical synthesis , Hydroxamic Acids/metabolism , Inhibitory Concentration 50 , Leucyl Aminopeptidase/antagonists & inhibitors , Neprilysin/antagonists & inhibitors , Protease Inhibitors/chemical synthesis , Protease Inhibitors/chemistry , Protease Inhibitors/metabolism , Rabbits , Rats , Swine , Thermolysin/antagonists & inhibitors , Zinc/metabolismABSTRACT
Os autores relatam um caso de leiomiossarcoma gastrico diagnosticado inicialmente como neoplasia hepatica. Discutem o aspecto ultra-sonografico correlacionando com a radiologia convencional
