RESUMO
The jalap roots, Operculina hamiltonii D.F. Austin & Staples (Convolvulaceae), are extensively commercialized as a depurative and laxative remedy in traditional medicine of the north and northeast regions of Brazil. The purification by recycling HPLC and structure elucidation of three new acyl sugars or resin glycosides are described here from a commercial product made of powdered roots. Three macrocyclic structures of a tetrasaccharide of (11S)-hydroxyhexadecanoic acid, operculinic acid C (1), the undescribed hamiltonins II and III (3 and 4), in addition to the known batatinoside III (5), presented a diastereoisomeric relationship as one residue of n-dodecanoic acid esterified the oligosaccharide core on a different position in each compound. Furthermore, hamiltonin IV (6) was characterized as an ester-type homodimer of acylated operculinic acid C with the same substitution pattern identified in hamiltonins II (3) and III (4) for each of the dimer subunits. All the isolated resin glycosides did not display any intrinsic cytotoxicity (IC50 > 25 µM). However, a combination of the individual isolated compounds 3-6 (1-50 µM) demonstrated an enhancement of cytotoxic effects with sublethal doses of vinblastine and podophyllotoxin (0.003 µM) in multidrug-resistant breast carcinoma epithelial cells (MCF-7/Vin).
Assuntos
Convolvulaceae , Neoplasias , Humanos , Células MCF-7 , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Convolvulaceae/química , Glicosídeos/farmacologia , Glicosídeos/química , Resinas Vegetais/química , Oligossacarídeos/química , Oligossacarídeos/farmacologiaRESUMO
ABSTRACT High performance liquid chromatography profiling with mass spectrometry detection was applicable to identify known and novel multidrug-resistance glycolipid inhibitors from the complex resin glycosides mixture of Ipomoea alba L., Convolvulaceae, seeds. Albinosides X and XI were purified by recycling liquid chromatography and their structural elucidation was accomplished by nuclear magnetic resonance. Albinoside XI exerted a strong potentiation of vinblastine susceptibility in multidrug-resistant human breast carcinoma cells.
RESUMO
Multidrug resistance is the expression of one or more efflux pumps, such as P-glycoprotein, and is a major obstacle in cancer therapy. The use of new potent and noncytotoxic efflux pump modulators, coadministered with antineoplastic agents, is an alternative approach for increasing the success rate of therapy regimes with different drug combinations. This report describes the isolation and structure elucidation of six new resin glycosides from moon vine seeds (Ipomoea alba) as potential mammalian multidrug-resistance-modifying agents. Albinosides IV-IX (1-6), along with the known albinosides I-III (7-9), were purified from the CHCl3-soluble extract. Degradative chemical reactions in combination with NMR spectroscopy and mass spectrometry were used for their structural elucidation. Four new glycosidic acids, albinosinic acids D-G (10-13), were released by saponification of natural products 3-6. They were characterized as tetrasaccharides of either convolvulinolic (11S-hydroxytetradecanoic) or jalapinolic (11S-hydroxyhexadecanoic) acids. The potentiation of vinblastine susceptibility in multidrug-resistant human breast carcinoma cells of albinosides 1-6 was evaluated by modulation assays. The noncytotoxic albinosides VII (4) and VIII (5), at a concentration of 25 µg/mL, exerted the strongest potentiation of vinblastine susceptibility, with a reversal factor (RFMCF-7/Vin+) of 201- and >2517-fold, respectively.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Glicosídeos/isolamento & purificação , Glicosídeos/farmacocinética , Ipomoea/química , Resinas Vegetais/química , Sementes/química , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Feminino , Glicosídeos/química , Humanos , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Oligossacarídeos/química , Vimblastina/farmacologiaRESUMO
Recycling liquid chromatography was used for the isolation and purification of resin glycosides from the CHCl3-soluble extracts prepared using flowers of Ipomoea wolcottiana Rose var. wolcottiana. Bioassay-guided fractionation, using modulation of both antibiotic activity against multidrug-resistant strains of Gram-negative bacteria and vinblastine susceptibility in breast carcinoma cells, was used to isolate the active glycolipids as modulators of the multidrug resistance phenotype. An ester-type dimer, wolcottine I, one tetra- and three pentasaccharides, wolcottinosides I-IV, in addition to the known intrapilosin VII, were characterized by NMR spectroscopy and mass spectrometry. In vitro assays established that none of these metabolites displayed antibacterial activity (MIC>512 µg/mL) against multidrug-resistant strains of Escherichia coli, and two nosocomial pathogens: Salmonella enterica serovar Typhi and Shigella flexneri; however, when tested (25 µg/mL) in combination with tetracycline, kanamycin or chloramphenicol, they exerted a potentiation effect of the antibiotic susceptibility up to eightfold (64 µg/mL from 512 µg/mL). It was also determined that these non-cytotoxic (CI50>8.68 µM) agents modulated vinblastine susceptibility at 25 µg/mL in MFC-7/Vin(+) cells with a reversal factor (RFMCF-7/Vin(+)) of 2-130 fold.
Assuntos
Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Glicosídeos/isolamento & purificação , Glicosídeos/farmacologia , Ipomoea/química , Resinas Vegetais/isolamento & purificação , Resinas Vegetais/farmacologia , Antibacterianos/química , Escherichia coli/efeitos dos fármacos , Feminino , Flores/química , Glicosídeos/química , Humanos , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Resinas Vegetais/química , Salmonella/efeitos dos fármacos , Vimblastina/farmacologiaRESUMO
Reinvestigation of the CHCl(3)-soluble extract from aerial parts of Ipomoea purga was carried out to identify mammalian multidrug-resistance inhibitors. Preparative-scale recycling HPLC was used to purify four new resin glycosides, purgins II (1) and III (2) in addition to purginosides III (3) and IV (4), as well as the known purginosides I (5) and II (6) and purgin I (7). The structures of 1-4 were established through NMR spectroscopy and mass spectrometry. Purgins II (1) and III (2) are the first examples of ester-type dimers of operculinic acid B with three different acylating residues in both monomeric units: (2S)-methylbutyric acid, n-hexanoic, n-decanoic, and trans-cinnamic acids. The macrolactonization site was located at C-2 of the second saccharide unit. The position of the ester linkage for monomeric unit B on the macrocyclic unit A was established as C-4 of the terminal glucose. Purginosides III (3) and IV (4) were found to be pentasaccharides of operculinic acid A with a structure related to that previously described for compounds 5 and 6. Reversal of multidrug resistance by compounds 1-7 was evaluated in vinblastine-resistant human breast carcinoma cells (MCF-7/Vin). Purgin II (1) enhanced vinblastine activity >2140-fold when incorporated at 25 µg/mL. For compounds 2-7, a moderate vinblastine-enhancing activity from 1.4-fold to 6.5-fold was observed.
Assuntos
Glicosídeos/isolamento & purificação , Ipomoea/química , Cromatografia Líquida de Alta Pressão , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Feminino , Glicosídeos/química , Glicosídeos/farmacologia , Humanos , México , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Resinas Vegetais/químicaRESUMO
As part of an ongoing project to identify inhibitors of multidrug efflux pumps, three new resin glycosides, albinosides I-III (1-3), were isolated from a CHCl(3)-soluble extract from the seeds of moon vine (Ipomoea alba). Their structures were established through NMR spectroscopy and mass spectrometry as partially acylated branched pentasaccharides derived from three new glycosidic acids, named albinosinic acids A-C (4-6). The same oligosaccharide core formed by two D-quinovose, one D-glucose, and two L-rhamnose units was linked to either convolvulinolic or jalapinolic acid for 1 and 3, respectively. They were partially esterified with (2R,3R)-3-hydroxy-2-methylbutanoic, acetic, or 2-methyl-2-butenoic acid. Compound 2 has two D-quinovose and three L-rhamnose units, linked to convolvulinolic acid, and its esterifying residues were characterized as two units of 2-methyl-2-butenoic acid. The aglycone lactonization site was located at C-2 of the terminal rhamnose unit (Rha) for 1, at C-3 of the terminal rhamnose unit (Rha') for 2, and at C-3 of the second saccharide unit (Glc) for 3. Reversal of multidrug resistance by this class of plant metabolites was also evaluated in vinblastine-resistant human breast carcinoma cells (MCF-7/Vin). The noncytotoxic compound 3 exerted the strongest potentiation effect of vinblastine susceptibility to over 2140-fold, while a moderate activity was observed for 1 (3.1-fold) and 2 (2.6-fold) at a concentration of 25 µg/mL.