RESUMO
Efficient synthesis of the deoxysugar part of versipelostatin (VST) was achieved by direct and stereoselective glycosylation of the reduced VST aglycon. Activation of 2-deoxyglycosyl imidate with IBr under basic conditions enables alpha-selective glycosylation of beta-2-deoxylglycosides without anomerization. Comparison of the synthetic and natural VST products using NMR indicates that versipelostatin has a beta-D-digitoxose-(1,4)-alpha-L-oleandrose-(1,4)-beta-D-digitoxose trisaccharide. In addition, results of a biological assay indicate that the deoxyoligosaccharide unit of the synthetic glycoside was important for biological activity of the compound.
Assuntos
Desoxiaçúcares/síntese química , Macrolídeos/química , Oligossacarídeos/química , Trissacarídeos/química , Linhagem Celular Tumoral , Desoxiaçúcares/química , Glicosilação , Células HeLa , Humanos , Macrolídeos/síntese química , Macrolídeos/toxicidade , Conformação Molecular , Oligossacarídeos/síntese química , Oligossacarídeos/toxicidade , Estereoisomerismo , Trissacarídeos/síntese químicaRESUMO
Four novel glycosylated derivatives of versipelostatin (1), versipelostatins B-E (2-5), were isolated from the culture broth of Streptomyces versipellis 4083-SVS6. The inhibitory activities of the isolated compounds against the expression of molecular chaperone GRP78 induced by 2-deoxyglucose were evaluated. Of the five versipelostatin family members, 1 and 4 were the more potent with IC(50) values of 3.5 and 4.3 microM. These results suggest that the alpha-L-oleandropyranosyl (1-->4)-beta-D-digitoxopyranosyl residue in the sugar moiety may play an important role in down-regulating GRP78 expression induced by 2-deoxyglucose.
Assuntos
Regulação para Baixo/efeitos dos fármacos , Proteínas de Choque Térmico/antagonistas & inibidores , Macrolídeos/farmacologia , Chaperonas Moleculares/antagonistas & inibidores , Oligossacarídeos/farmacologia , Streptomyces/química , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Chaperona BiP do Retículo Endoplasmático , Glicosilação , Proteínas de Choque Térmico/biossíntese , Humanos , Macrolídeos/isolamento & purificação , Chaperonas Moleculares/biossíntese , Conformação Molecular , Oligossacarídeos/isolamento & purificação , EstereoisomerismoRESUMO
A novel compound of antimycin family, JBIR-06 (1), was isolated from Streptomyces sp. ML55. The structure of 1 was established as a twelve-membered macrocyclic skeleton with a 3-(formylamino)-2-hydroxybenzamide based on the spectroscopic data. Compound 1 inhibited the expression of GRP78 induced by 2-deoxyglucose at the IC50 value of 250 nM.
Assuntos
Benzamidas/isolamento & purificação , Proteínas de Choque Térmico/antagonistas & inibidores , Macrolídeos/isolamento & purificação , Chaperonas Moleculares/antagonistas & inibidores , Streptomyces/metabolismo , Antimicina A/análogos & derivados , Antimicina A/isolamento & purificação , Benzamidas/química , Benzamidas/farmacologia , Linhagem Celular Tumoral , Desoxiglucose/farmacologia , Chaperona BiP do Retículo Endoplasmático , Humanos , Macrolídeos/química , Macrolídeos/farmacologia , Conformação Molecular , Relação Estrutura-AtividadeRESUMO
A novel versipelostatin (1) analogue, versipelostatin F (2) was isolated from Streptomyces versipellis 4083-SVS6. The structure of 2 was determined by the analyses of the spectroscopic data. Compound 2 inhibited the expression of GRP78 induced by 2-deoxyglucose with an IC(50) value of 0.3 muM, which is 10-times more potent compared with that of 1.
Assuntos
Antineoplásicos/isolamento & purificação , Inibidores Enzimáticos/isolamento & purificação , Macrolídeos/isolamento & purificação , Oligossacarídeos/isolamento & purificação , Streptomyces/química , Antineoplásicos/química , Linhagem Celular Tumoral , Chaperona BiP do Retículo Endoplasmático , Inibidores Enzimáticos/química , Proteínas de Choque Térmico/antagonistas & inibidores , Humanos , Concentração Inibidora 50 , Macrolídeos/química , Chaperonas Moleculares/antagonistas & inibidores , Oligossacarídeos/química , Análise EspectralRESUMO
In the course of our screening program for regulators of the expression of GRP78 molecular chaperone, JBIR-04 (1) and -05 (2) were isolated from Streptomyces violaceoniger 4541-SVS3 as congeners of prunustatin A (3). The structures of 1 and 2 were determined by the analyses of the spectroscopic data. These compounds mainly consist of an amino acid and amino acid derived alpha-hydroxy acid residues. 1 and 2 inhibited the expression of GRP78 induced by 2-deoxyglucose in human fibrosarcoma HT1080 cells, but their activities were highly reduced compared with those of 3 and SW-163A.
Assuntos
Proteínas de Choque Térmico/biossíntese , Chaperonas Moleculares/biossíntese , Peptídeos Cíclicos/farmacologia , Streptomyces/química , Linhagem Celular Tumoral , Fenômenos Químicos , Físico-Química , Regulação para Baixo/efeitos dos fármacos , Chaperona BiP do Retículo Endoplasmático , Humanos , Indicadores e Reagentes , Macrolídeos/química , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Conformação Molecular , Peptídeos Cíclicos/isolamento & purificação , Espectrometria de Massas por Ionização por Electrospray , Espectrofotometria Infravermelho , Espectrofotometria UltravioletaRESUMO
[structure: see text] Versipelostatin is the first compound which specifically inhibits the expression of GRP78 and the resultant robust cell death under stress conditions, in contrast to the weak cytotoxicity under normal conditions. Versipelostatin consists of a macrocyclic aglycone with an alpha-acyltetronic acid and three sugar moieties. The relative and absolute configuration of the aglycone moiety was established to be 4S, 5S, 6R, 9S, 10S, 13S, 16R, 18R, 19R, 20R, 24R, 27R, and 29S utilizing NMR techniques.
Assuntos
Regulação para Baixo/efeitos dos fármacos , Proteínas de Choque Térmico/biossíntese , Macrolídeos/química , Macrolídeos/farmacologia , Chaperonas Moleculares/biossíntese , Oligossacarídeos/química , Oligossacarídeos/farmacologia , Cicloexanos/química , Chaperona BiP do Retículo Endoplasmático , Proteínas de Choque Térmico/genética , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Chaperonas Moleculares/genética , Estrutura MolecularRESUMO
In the course of our screening program for regulators of a molecular chaperone GRP78 expression, we isolated a novel inhibitor of GRP78 expression, designated as prunustatin A, from Streptomyces violaceoniger 4521-SVS3. The structure of prunustatin A was determined by a series of NMR analyses to be an oxidized type of the neoantimycin family. Prunustatin A inhibited the expression of GRP78 induced by 2-deoxyglucose in human fibrosarcoma HT1080 cells accompanied by global cell death without showing cytotoxicity under normal nutrient condition.
