RESUMEN
[figure: see text] Under the agency of N-bromosuccinimide, n-pentenyl glycosides, acetonitrile, and carboxylic acids participate in three-component-reactions that afford N-acylated glycosylamines. The procedure tolerate diverse donors, and C2-tetrachlorophthalimido and C2-azido groups effectively control anomeric stereoselectivity. Success of the procedure does not appear to depend on the acid's strength, but for an aromatic acid, substitution pattern affects the rate, while the presence of a lone pair on the para substituent inhibits the process.
Asunto(s)
Glucosamina/análogos & derivados , Glucosamina/síntesis química , Glicoproteínas/síntesis química , Glicosilación , EstereoisomerismoRESUMEN
Thiol-containing diketopiperazines have been recently identified as novel heterocyclic inhibitors of matrix metalloproteinase (MMPs). The compounds described had similar activities against the MMPs collagenase-1 and gelatinase-B. An inhibitor that showed greater than 10-fold selectivity for collagenase-1 over gelatinase-B was desired. Previously published work with peptidyl hydroxamates and thiols indicated that while preparing gelatinase selective inhibitors was straightforward, there was not an obvious route to selective inhibitors of collagenase-1. Combinatorial libraries were prepared and evaluated for their ability to inhibit collagenase-1 and gelatinase-B substrate hydrolysis. A method for estimating the IC50 values of compounds generated by high-throughput parallel synthesis aided in the identification of compounds with the desired properties. We have found that thiol diketopiperazines derived from nitrophenylalanine are both potent and selective inhibitors of collagenase-1. In addition, we have demonstrated that combinatorial chemistry can be utilized to identify molecules with a desired selectivity profile without access to the traditional tools of rational drug design.
Asunto(s)
Inhibidores de la Metaloproteinasa de la Matriz , Piperazinas/síntesis química , Inhibidores de Proteasas/síntesis química , Diseño de Fármacos , Metaloproteinasa 1 de la Matriz , Metaloproteinasa 9 de la Matriz , Piperazinas/química , Piperazinas/farmacología , Inhibidores de Proteasas/química , Relación Estructura-ActividadRESUMEN
The discovery of a novel series of heterocyclic matrix metalloproteinase (MMPs) inhibitors is described. Published crystal structures of peptidyl hydroxamates bound to MMPs were the basis for the rational design of diketopiperazine (DKP) inhibitors. Combinatorial libraries were prepared and evaluated for their ability to inhibit collagenase-1, stromelysin-1, and gelatinase-B substrate hydrolysis. Deconvolution of active pools resulted in the identification of potent inhibitors (IC50's < 100 nM) of collagenase-1 and gelatinase-B, with the most potent inhibitor exhibiting an IC50 of 30 nM against collagenase-1. A description of the combinatorial evaluation process, as well as initial SAR interpretation for this novel series, is provided.
Asunto(s)
Diseño de Fármacos , Inhibidores Enzimáticos , Metaloendopeptidasas/antagonistas & inhibidores , Piperazinas , Dicetopiperazinas , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Enlace de Hidrógeno , Metaloproteinasa 1 de la Matriz , Metaloproteinasa 9 de la Matriz , Inhibidores de la Metaloproteinasa de la Matriz , Piperazinas/síntesis química , Piperazinas/química , Piperazinas/farmacología , Relación Estructura-ActividadRESUMEN
7-Deoxy-7-iodohept-1-enitols react intramolecularly to give 5-carba analogues of pyranoses (pseudo sugars) by the action of tributyltin hydride, which generates a radical at C-7. The configuration at the new chiral centre depends on the relative orientation of the oxygen functions in the starting material and the pattern of substitution.