ABSTRACT
The synthesis and biological evaluation of a variety of 4-(heteroarylaminomethyl)-N-(2-aminophenyl)-benzamides and their analogs is described. Some of these compounds were shown to inhibit HDAC1 with IC(50) values below the micromolar range, induce hyperacetylation of histones, upregulate expression of the tumor suppressor p21(WAF1/Cip1), and inhibit proliferation of human cancer cells. In addition, certain compounds of this class were active in several human tumor xenograft models in vivo.
Subject(s)
Aniline Compounds/chemical synthesis , Aniline Compounds/pharmacology , Benzamides/chemical synthesis , Benzamides/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Histone Deacetylase Inhibitors , Aniline Compounds/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Benzamides/chemistry , Breast/cytology , Breast/drug effects , Cell Line , Cyclin-Dependent Kinase Inhibitor p21/biosynthesis , Enzyme Inhibitors/chemistry , Epithelial Cells/cytology , Epithelial Cells/drug effects , HCT116 Cells , Histone Deacetylase 1 , Humans , Imidazoles/chemical synthesis , Imidazoles/chemistry , Imidazoles/pharmacology , Structure-Activity RelationshipABSTRACT
For the first time, the influence of a fused Delta3-arylproline on peptide conformation has been studied by the synthesis and comparison of the conformations of peptides containing proline and pyrrolo-proline, 3 (PyPro). Pyrrolo-proline was demonstrated to be a conservative replacement for Pro in model beta-turns, 4 and 5, as shown by their similar DMSO titration curves, cis/trans-isomer populations, and NOESY spectral data. Pyrrolo-proline may thus be used for studying the structure activity relationships of Pro-containing peptides with minimal modification of secondary structures.
Subject(s)
Oligopeptides/chemistry , Proline/analogs & derivatives , Nuclear Magnetic Resonance, Biomolecular , Proline/chemistry , Protein Conformation , Protein Structure, SecondaryABSTRACT
Fused heteroarylprolines were prepared starting from 4-oxo-N-(PhF)proline benzyl ester (6, PhF = 9-(9-phenylfluorenyl)) following two approaches. First, allylation of oxoproline 6 followed by Wacker oxidation gave 1,4-dione 8 that was selectively converted to pyrroloproline 10b, pyrrolopyrrole 12, and pyridazinoproline 9. Second, aldol condensation of oxoproline 6 with a series of N-(Boc)-alpha-amino aldehydes 15a-e and acid-catalyzed cyclization gave pyrroloprolines 17a-e possessing a variety of pyrrole 5-position substituents. Conditions for the selective deprotection and alkylation of the pyrrole nitrogen of pyrroloprolines 17 were developed to expand the diversity of the heteoaryl systems. Finally, hydrogenolytic cleavage of the PhF and benzyl groups followed by subsequent protection with Boc, Fmoc, and Moz groups was performed to obtain analogues suitable for peptide synthesis. The enantiomeric purity of N-(Boc)pyrrolo-proline 21a was ascertained by coupling to l- and d-phenylalanine methyl ester and examination of the diastereotopic pyrrole protons, which demonstrated the dipeptides to be of >99% diastereomeric purity. These approaches have thus delivered the first series of enantiopure fused arylprolines for application as arylglycine-proline chimeras in structure-activity studies of biologically active compounds.
