ABSTRACT
Pursuing our efforts in designing 5-pyrimidylhydroxamic acid anti-cancer agents, we have identified a new series of potent histone deacetylase (HDAC) inhibitors. These compounds exhibit enzymatic HDAC inhibiting properties with IC(50) values in the nanomolar range and inhibit tumor cell proliferation at similar levels. Good solubility, moderate bioavailability, and promising in vivo activity in xenograft model made this series of compounds interesting starting points to design new potent HDAC inhibitors.
Subject(s)
Antineoplastic Agents/chemistry , Histone Deacetylase Inhibitors/chemistry , Histone Deacetylases/chemistry , Hydroxamic Acids/chemistry , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Proliferation , Drug Design , Histone Deacetylase Inhibitors/chemical synthesis , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylases/metabolism , Hydroxamic Acids/chemical synthesis , Hydroxamic Acids/pharmacology , Mice , Mice, Nude , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
Based on the structure of R115777 (tipifarnib, Zarnestra), a series of farnesyltransferase inhibitors have been synthesized by modification of the 2-quinolinone motif and transposition of the 4-chlorophenyl ring to the imidazole or its replacement by 5-membered rings. This has yielded a novel series of potent farnesyltransferase inhibitors.
Subject(s)
Antineoplastic Agents/pharmacology , Enzyme Inhibitors/pharmacology , Farnesyltranstransferase/antagonists & inhibitors , Quinolones/pharmacology , Antineoplastic Agents/chemistry , Enzyme Inhibitors/chemistry , Magnetic Resonance Spectroscopy , Models, Molecular , Molecular Structure , Quinolones/chemistryABSTRACT
Real-time analysis of gene expression in experimental tumor models represents a major tool to document disease biology and evaluate disease treatment. However, monitoring gene regulation in vivo still is an emerging field, and thus far it has not been linked to long-term tumor growth and disease outcome. In this report, we describe the development and validation of a fluorescence-based gene expression model driven by the promoter of the cyclin-dependent kinase inhibitor p21waf1,cip1. The latter is a key regulator of tumor cell proliferation and a major determinant in the response to many anticancer agents such as histone deacetylase inhibitors. In response to histone deacetylase inhibitors, induction of fluorescence in A2780 ovarian tumors could be monitored in living mice in a noninvasive real-time manner using whole-body imaging. Single p.o. administration of the histone deacetylase inhibitor MS-275 significantly induces tumor fluorescence in a time- and dose-dependent manner, which accurately predicted long-term antitumoral efficacy in individual mice following extended treatment. These findings illustrate that this technology allows monitoring of the biological response induced by treatment with histone deacetylase inhibitors. In addition to providing experimental pharmacokinetic/pharmacodynamic markers for investigational drugs, this model provides insight into the kinetics of in vivo regulation of transcription, which plays a key role in causing and maintaining the uncontrolled proliferation of tumor tissue.
Subject(s)
Enzyme Inhibitors/pharmacology , Histone Deacetylase Inhibitors , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/genetics , Xenograft Model Antitumor Assays/methods , Animals , Cyclin-Dependent Kinase Inhibitor p21/genetics , Female , Gene Expression , Genes, Reporter , Green Fluorescent Proteins/genetics , Histone Deacetylases/metabolism , Humans , Male , Mice , Mice, Nude , Ovarian Neoplasms/enzymology , Ovarian Neoplasms/pathology , Promoter Regions, GeneticABSTRACT
In this paper we present and discuss a novel, simple and easy to implement parametric modeling approach to assess synergy. An extended three parameter log-logistic model is used to analyse the data and calculate confidence intervals of the interaction indices. In addition the model corrects for the bias due to plate-location effects. The analysis is performed with PROC NLMIXED and SAS-code is provided. The approach is illustrated using data coming from an oncology study in which the inhibition effect of a combination of two compounds is studied using 96-well plates and a fixed-ratio design.
Subject(s)
Biometry/methods , Clinical Trials as Topic/methods , Data Interpretation, Statistical , Drug Combinations , Drug Evaluation, Preclinical/methods , Models, Biological , Algorithms , Animals , Computer Simulation , Dose-Response Relationship, Drug , Models, Statistical , Rats , Treatment OutcomeABSTRACT
A series of pyrimidyl-5-hydroxamic acids was prepared for evaluation as inhibitors of histone deacetylase (HDAC). Amino-2-pyrimidinyl can be used as a linker to provide HDAC inhibitors of good enzymatic potency.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Histone Deacetylase Inhibitors , Hydroxamic Acids/chemical synthesis , Hydroxamic Acids/pharmacology , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Cell Proliferation/drug effects , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Female , HeLa Cells , Humans , Hydroxamic Acids/chemistry , Inhibitory Concentration 50 , Magnetic Resonance Spectroscopy , Molecular Structure , Pyrimidines/chemistry , Spectrometry, Mass, Electrospray IonizationABSTRACT
Replacement of the 1-methylimidazol-5-yl moiety in the farnesyltransferase inhibitor ZARNESTRA series by a 4-methyl-1,2,4-triazol-3-yl group gave us compounds with similar structure-activity relationship profiles showing that this triazole is potentially a good surrogate to imidazole for farnesyltransferase inhibition.
Subject(s)
Alkyl and Aryl Transferases/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Heterocyclic Compounds/chemical synthesis , Quinolones/chemical synthesis , Quinolones/pharmacology , Triazoles/chemical synthesis , Administration, Oral , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Cell Division/drug effects , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Farnesyltranstransferase , Heterocyclic Compounds/administration & dosage , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Humans , Kinetics , Mice , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Models, Molecular , Molecular Conformation , Quinolones/administration & dosage , Structure-Activity Relationship , Triazoles/chemistry , Triazoles/pharmacologyABSTRACT
A series of (4-chlorophenyl)-alpha-(1-methyl-1H-imidazol-5-yl)azoloquinolines and -quinazolines was prepared. These compounds displayed potent Farnesyl Protein Transferase inhibitory activity and tetrazolo[1,5-a]quinazolines are promising agents for oral in vivo inhibition.
Subject(s)
Alkyl and Aryl Transferases/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Quinazolines/chemical synthesis , Quinazolines/pharmacology , Quinolines/chemical synthesis , Quinolines/pharmacology , Animals , Cell Division/drug effects , Drug Design , Enzyme Inhibitors/chemical synthesis , Farnesyltranstransferase , Kinetics , Molecular Conformation , Molecular Structure , Quinolones/chemical synthesis , Quinolones/pharmacology , Structure-Activity RelationshipABSTRACT
The evaluation of structure-activity relationships associated with the modification of the R115777 quinolinone ring moiety displaying potent in vitro inhibiting activity is described.
Subject(s)
Alkyl and Aryl Transferases/antagonists & inhibitors , Antineoplastic Agents/chemical synthesis , Azepines/chemical synthesis , Quinazolines/chemistry , Quinolones/chemistry , Animals , Antineoplastic Agents/pharmacology , Azepines/chemistry , Azepines/pharmacology , Farnesyltranstransferase , Humans , In Vitro Techniques , Indicators and Reagents , Mice , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Quinazolines/chemical synthesis , Quinazolines/pharmacology , Quinolones/chemical synthesis , Quinolones/pharmacology , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
During the course of a screening program intended to identify new antiproliferative agents, a new bafilolide metabolite was discovered. R176502 (1) was isolated from the liquid fermentation cultures of a novel Micromonospora species found in African river bottom sediment. It was purified from ethyl acetate extracts using a series of countercurrent chromatographic steps. The structure was determined using 1- and 2-D NMR experiments. Three previously described bafilomycins (bafilomycins A1 (2), B1 (3), and B2 (4)) were also isolated (from other microbial strains). R176502 exhibited potency for inhibition of tumor cell proliferation in the nM range of concentrations.
Subject(s)
Antineoplastic Agents/isolation & purification , Macrolides/isolation & purification , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor/drug effects , Fermentation , Humans , Macrolides/chemistry , Macrolides/pharmacology , Micromonospora , Structure-Activity RelationshipABSTRACT
Biological assay guided fractionation of a dichloromethane extract of Synaptolepis kirkii led to the isolation of four new and five known daphnane-type diterpene orthoesters, whose structure was established by spectroscopic data. Full spectroscopic data of the new and known natural products are reported here for the first time. Pronounced neurotrophic and substantial antileukaemia activities of these compounds were found in in vitro assays.
