RESUMO
The azo coupling of the antibiotic olivomycin I (1) with aryl diazonium tetrafluoroborates produced 5-aryldiazenyl-6-O-deglycosyl derivatives of 1. The structures of new compounds were confirmed by (1)H NMR and mass spectrometry analysis. A quantum-chemical study was performed to analyze the possible directions of electrophilic substitution of 1 and the easiness of 6-O-disaccharide hydrolysis in the course of azo coupling. The antiproliferative and anti-retroviral activities of novel derivatives were studied.
Assuntos
Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacologia , Ácidos Bóricos/química , Compostos de Diazônio/química , Olivomicina/química , Olivomicina/farmacologia , Animais , Antibióticos Antineoplásicos/síntese química , Antibióticos Antineoplásicos/toxicidade , Boratos , Ácidos Bóricos/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Compostos de Diazônio/síntese química , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Olivomicina/síntese química , Olivomicina/toxicidade , Vírus/efeitos dos fármacosRESUMO
We describe here the first use of 2,3-anhydrosugars as glycosylating agents for the preparation of 2-deoxypyranosides. In particular, the methodology was used to assemble 2,6-dideoxysugar glycosides. Glycosylation of a panel of alcohols with one of two 6-deoxy-2,3-anhydrosugar thioglycosides (8 and 9) in the presence of a Lewis acid afforded 2,6-dideoxy-2-thiotolyl glycoside products in generally excellent yields with an exclusively syn relationship between the aglycon and the C-3 hydroxyl group. Removal of the 2-thiotolyl group can be achieved upon reaction with tri-n-butyltin hydride and AIBN to give the corresponding 2,6-dideoxy pyranosides. Once developed, the method was applied to the synthesis of oligosaccharide moieties in the natural products apoptolidin and olivomycin A.
Assuntos
Monossacarídeos/síntese química , Produtos Biológicos/síntese química , Glicosídeos , Glicosilação , Macrolídeos/síntese química , Oligossacarídeos/síntese química , Olivomicina/síntese químicaRESUMO
A novel way of chemical modification of the antibiotic olivomycin I at the 2'-keto group of the side chain of the aglycone moiety was developed. Reaction of olivomycin I with the carboxymethoxylamine hemihydrochloride gave the key intermediate, 2'-carboxymethoxime-olivomycin I, which was further reacted with different amines in the presence of benzotriazol-1-yl-oxy-trispyrrolidinophosphonium hexafluorophosphate to give the corresponding amides. The antiproliferative and topoisomerase I (Topo-I)-poisoning activities of the novel derivatives were examined. One of the novel derivatives showed a marked inhibitory activity against Topo-I, a pronounced antitumor activity in in vivo experiments on mice bearing leukemia P-388 and lower toxic side effects compared with the parent olivomycin I.
Assuntos
Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Olivomicina/química , Olivomicina/farmacologia , Inibidores da Topoisomerase I , Animais , Antibióticos Antineoplásicos/síntese química , Sequência de Carboidratos , Linhagem Celular Tumoral , Cromatografia Líquida de Alta Pressão , Cromatografia em Camada Fina , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Humanos , Cetonas/química , Leucemia P388 , Masculino , Espectrometria de Massas , Camundongos , Dados de Sequência Molecular , Olivomicina/síntese químicaRESUMO
Novel analogues of olivomycin A were prepared by selective reactions involving the carbonyl and hydroxyl groups of the aglycon moiety. Electrophilic substitution of the aglycon also was successful. Of 11 analogues, all but two were active in the P-388 murine leukemia assay. One compound, the 2'-methoxime, showed superior activity to olivomycin A based on its wider dose range and greater potency. The methyl imine and the 8-O-methyl ether were equal to olivomycin A in potency and efficacy. Most of the other analogues were slightly less potent or effective.
