Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Hemólise/efeitos dos fármacos , Peptídeos/farmacologia , Tensoativos/farmacologia , Antibacterianos/química , Antifúngicos/química , Eritrócitos/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Testes de Sensibilidade Microbiana , Peptídeos/química , Estrutura Terciária de Proteína , Sensibilidade e Especificidade , Tensoativos/químicaRESUMO
A series of 36 linear and cyclic beta- and gamma-peptides consisting of as few as two, and as many as 15 residues, was offered as substrates to 15 commercially available proteases of bacterial, fungal, and eukaryotic origin, including a beta-lactamase and amidases, as well as most vigorous, nonspecific proteases, such as the 20S proteasome from human erythrocytes. For comparison, an alpha-eicosapeptide and standard substrates of the proteolytic enzymes were included in the investigation. Under conditions of complete cleavage of the alpha-peptide within 15 min the beta- and gamma-peptides were stable for at least 48 h. Inhibition studies with seven beta- and gamma-peptides and alpha-chymotrypsin show that the residual enzyme activity toward succinyl-Ala-Ala-Pro-Phe-p-nitroanilide is unchanged within experimental error after incubation for 15 min with the peptide analogues. Thus, beta- and gamma-peptides with proteinogenic side chains, that is, consisting of the singly or doubly homologated natural alpha-amino acids (one or two CH(2) groups inserted in the backbone of each residue), are completely stable to common proteases, without inhibiting their normal activity (as demonstrated for alpha-chymotrypsin). This proteolytic stability of peptides built of homologated amino acids is a prerequisite for their potential use as drugs.
Assuntos
Peptídeo Hidrolases/metabolismo , Peptídeos/química , Peptídeos/metabolismo , Estrutura Terciária de Proteína , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Domínio Catalítico , Cromatografia Líquida de Alta Pressão , Inibidores Enzimáticos/metabolismo , Proteínas Fúngicas/química , Proteínas Fúngicas/metabolismo , Humanos , Estrutura Molecular , Peptídeos Cíclicos/química , Peptídeos Cíclicos/metabolismo , Ligação ProteicaRESUMO
[reaction: see text] A new class of doubly functionalized and enantiomerically pure 1-azabicyclo[3.2.2]nonanes derived from quincorine and quincoridine is described. 2,5-Disubstituted quinuclidines with a C9-mesyloxy group were easily transformed into the corresponding halides upon treatment with lithium salts. Subsequent silver salt-mediated ring expansion stereoselectively furnished the title azabicyclics. Chiral carbocations which are configurationally stable and nonplanar are postulated to account for the striking stereoselectivity of the capture of external nucleophile. 5-Ethynyl-2-iodomethylquinuclidines afford the alpha-benzoyloxy amines rather than alpha-methoxy amines, even in MeOH.
Assuntos
Aminas/química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Aminas/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Antagonistas Colinérgicos/química , Espectroscopia de Ressonância Magnética , Conformação Molecular , Quinuclidinas/química , Estereoisomerismo , Difração de Raios XRESUMO
The pseudoenantiomeric title compounds have been prepared from quincorine (QCI) and quincoridine (QCD), respectively, in enantiopure form following an efficient six-step pathway. Nucleophilic attack at the carbonyl group proceeds preferentially from the supposedly more hindered endo pi-face, giving quinuclidinols with natural configuration at C5 (up to 97%). pi-Face selectivity is highest in the QCD series with bulky O-protecting groups, involving an unprecedented 1,7-stereoinduction.
