RESUMEN
Trans (1R,2R)-diaminocyclohexane was used as a semirigid vicinal diamine to anchor two N-protected tripeptides consisting of L-D-L amino acids as carboxy terminal amides. The bis-tripeptide consisting of L-Ser (OBn)-D-Ser (OBn)-L-Ser (O-p-bromobenzyl) Boc afforded X-ray quality crystals containing benzene and chloroform solvent molecules. Analysis of the solid-state structure revealed a highly H-bonded helical open-ended tubular superstructure. The tripeptide strands intertwine like a pair of self-embracing arms, held together by a gamma-turn and a 14-membered antiparallel H-bonded macroring spanning the first and third amino acid residues within each strand. Whereas the tripeptide from the R,R anchor gave beautiful crystals from benzene and chloroform, the analogous construct from the S,S-anchored diamine gave a gel. Related bis-tripeptides with different amino acids showed extensive intramolecular H-bonding based on NMR titration and dilution experiments.
Asunto(s)
Oligopéptidos/química , Cristalografía por Rayos X , Modelos Moleculares , Resonancia Magnética Nuclear Biomolecular , Oligopéptidos/síntesis química , Conformación Proteica , Espectrometría de Masa Bombardeada por Átomos Veloces , Espectroscopía Infrarroja por Transformada de FourierRESUMEN
Analogues of suberoylanilide hydroxamic acid (SAHA) were prepared by replacing the Zn-binding group with squaric acid, N-hydroxyurea, and 4-hydroxymethyl oxazoline units, also varying the length of the aliphatic chain. No inhibitory activity on HDAC was observed below 1.0 microM and no cytotoxic activity on different tumor cell lines was seen below 20.0 microM.
Asunto(s)
Alquinos/química , Ciclobutanos/química , Inhibidores Enzimáticos/síntesis química , Inhibidores de Histona Desacetilasas , Ácidos Hidroxámicos/química , Hidroxiurea/química , Oxazoles/química , Zinc/química , Diseño de Fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Histona Desacetilasas/metabolismo , Ácidos Hidroxámicos/síntesis química , Ácidos Hidroxámicos/farmacología , Estructura Molecular , VorinostatRESUMEN
Bradykinin (BK) is involved in a wide variety of pathophysiological processes. Potent BK peptide antagonists can be developed introducing constrained unnatural amino acids, necessary to force the secondary structure of the molecule. In this paper, we report a structure-activity relationship study of two peptide analogues of the potent B2 antagonist HOE 140 by replacing the D-Tic-Oic dipeptide with conformationally constrained dipeptide mimetic beta-turn inducers.