RESUMO
A series of Val-Leu based peptidic aldehydes containing either a furan or thiophene at the N-terminus was prepared and assayed against ovine m-calpain. In general, potency is favoured by a 2-substituted (rather than 3-substituted) heterocycle, a thiophene rather than a furan, and a shorter chain length at the N-terminus. Molecular docking experiments provide some rationale for these observations.
Assuntos
Calpaína/antagonistas & inibidores , Dipeptídeos/farmacologia , Glicoproteínas/farmacologia , Peptídeos Cíclicos/farmacologia , Aldeídos/química , Animais , Dipeptídeos/química , Furanos/química , Glicoproteínas/química , Modelos Moleculares , Peptídeos Cíclicos/química , Conformação Proteica , Ovinos , Tiofenos/químicaRESUMO
We report the synthesis of macrocycles 1-6 via ring closing metathesis of dienes 7-12. Addition of chlorodicyclohexylborane to thermal and microwave assisted RCM of dienes 8 and 9 markedly improves the yield. The geometric isomers of macrocycles 1-3 and 5 have been assigned using X-ray crystallography and NMR.
RESUMO
The design and elaboration of a series of macrocyclic templates that exhibit a propensity to adopt a beta-strand-like peptide-backbone conformation led to potent and selective inhibitors of calpain 2. Macrocycle 1 retarded calcium-induced opacification in an ovine-lens culture assay and is a lead compound for the development of a drug for cataract treatment. Cbz=carbobenzyloxy.
Assuntos
Calpaína/antagonistas & inibidores , Inibidores de Cisteína Proteinase/química , Modelos Moleculares , Animais , Calpaína/metabolismo , Catarata/induzido quimicamente , Catarata/tratamento farmacológico , Inibidores de Cisteína Proteinase/síntese química , Inibidores de Cisteína Proteinase/farmacologia , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Concentração Inibidora 50 , Cristalino/metabolismo , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/química , Compostos Macrocíclicos/farmacologia , Ovinos , Relação Estrutura-AtividadeRESUMO
A series of N-heterocyclic dipeptide aldehydes 4-13 have been synthesised and evaluated as inhibitors of ovine calpain 1 (o-CAPN1) and ovine calpain 2 (o-CAPN2). 5-Formyl-pyrrole 9 (IC(50) values of 290 and 25nM against o-CAPN1 and o-CAPN2, respectively) was the most potent and selective o-CAPN2 inhibitor, displaying >11-fold selectivity. The amino acid sequences of o-CAPN1 and o-CAPN2 have been determined. Because of the lack of available structural information on the ovine calpains, in silico homology models of the active site cleft of o-CAPN1 and o-CAPN2 were developed based on human calpain 1 (h-CAPN1) X-ray crystal structure (PDB code 1ZCM). These models were used to rationalise the observed SAR for compounds 4-13 and the selectivity observed for 9. The o-CAPN2 selective inhibitor 9 (CAT0059) was assayed in an in vitro ovine lens culture system and shown to successfully protect the lens from calcium-induced opacification.
Assuntos
Aldeídos/farmacologia , Dipeptídeos/farmacologia , Glicoproteínas/química , Aldeídos/química , Animais , Sítios de Ligação , Dipeptídeos/química , Glicoproteínas/síntese química , Glicoproteínas/farmacologia , Humanos , Modelos Moleculares , Ovinos , Relação Estrutura-AtividadeRESUMO
The photoswitchable N-terminal diazo and triazene-dipeptide aldehydes 8a-d, 10a,b, and 17a,b present predominantly as the (E)-isomer, which purportedly binds deep in the S3 pocket of calpain. All compounds are potent inhibitors of m-calpain, with 8b being the most active (IC50 of 35 nM). The diazo-containing inhibitors 8a, 8c, and 10a were irradiated at 340 nm to give a photostationary state enriched in the (Z)-isomer, and in all cases, these were less active. The most water soluble triazene 17a (IC50 of 90 nM) retards calpain-induced cataract formation in lens culture.
Assuntos
Aldeídos/síntese química , Compostos Azo/síntese química , Calpaína/antagonistas & inibidores , Catarata/tratamento farmacológico , Dipeptídeos/síntese química , Sulfonamidas/síntese química , Triazenos/síntese química , Raios Ultravioleta , Aldeídos/química , Aldeídos/farmacologia , Animais , Compostos Azo/química , Compostos Azo/farmacologia , Calpaína/metabolismo , Catarata/enzimologia , Técnicas de Cultura , Dipeptídeos/química , Dipeptídeos/farmacologia , Humanos , Cristalino/efeitos dos fármacos , Modelos Moleculares , Ligação Proteica , Estrutura Terciária de Proteína , Ovinos , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologia , Triazenos/química , Triazenos/farmacologiaRESUMO
[reaction: see text] Stabilized primary radicals can be formed from alkyl halides in an atom transfer process with Et(3)B. This process depends on the strength of the carbon-halogen bond and the stability of the resulting primary radical. Radicals formed from benzyl iodide and ethyl iodoacetate add to glyoxylic oxime ethers; however, more electrophilic radicals do not. Glyoxylic oxime ethers are also good radical acceptors for heterocyclic carbon-centered secondary radicals, giving novel alpha-amino acid derivatives.
Assuntos
Éteres/síntese química , Glioxilatos/síntese química , Compostos Heterocíclicos/química , Oximas/síntese química , Aminoácidos/síntese química , Carbono/química , Éteres/química , Radicais Livres/química , Glioxilatos/química , Conformação Molecular , Oximas/química , EstereoisomerismoRESUMO
A range of dehydro amino acid derivatives has been prepared and subjected to halogenation using either molecular bromine or chlorine, or NBS. Allylic halogenation of the unsaturated amino acid side chains occurs through radical bromination with NBS. The procedure is complementary to treatment with chlorine, which also affords allyl halides. This latter and unusual reaction is shown through a deuterium labelling study to proceed via an ionic mechanism. The choice of NBS or chlorine for allyl halide synthesis is shown to depend on the potential to avoid competing reactions, such as halolactonization of leucine derivatives with chlorine, and hydrogen abstraction and bromine incorporation at multiple sites on treatment of isoleucine derivatives with NBS. The synthetic utility of the allyl halides prepared in this study is indicated through the synthesis of a cyclopropyl amino acid derivative and the extension of the carbon skeleton of an amino acid side chain.