RESUMO
The great structural and functional diversity supports polysaccharides as favorable candidates for new drug development. Previously we reported that a drug candidate pectin-like natural polysaccharide, RN1 might target galectin-3 (Gal-3) to impede pancreatic cancer cell growth in vivo. However, the quality control of polysaccharide-based drug research faces great challenges due to the heterogeneity. A potential solution is to synthesize structurally identified subfragments of this polysaccharide as alternatives. In this work, we took RN1 as an example, and synthesized five subfragments derived from the putative repeating units of RN1. Among them, pentasaccharide 4 showed an approximative binding affinity to Gal-3 in vitro, as well as an antiproliferative activity against pancreatic BxPC-3 cells comparable to that of RN1. Further, we scaled up pentasaccharide 4 to gram-scale in an efficient synthetic route with a 6.9 % yield from D-galactose. Importantly, pentasaccharide 4 significantly suppressed the growth of pancreatic tumor in vivo. Based on the mechanism complementarity of galactin-3 inhibitor and docetaxel, the combination administration of pentasaccharide 4 and docetaxel afforded better result. The result suggested pentasaccharide 4 was one of the functional structural domains of polysaccharide RN1 and might be a leading compound for anti-pancreatic cancer new drug development.
Assuntos
Carcinoma , Neoplasias Pancreáticas , Humanos , Pectinas/química , Docetaxel , Polissacarídeos/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Oligossacarídeos , Galectina 3/metabolismoRESUMO
Bioactive polysaccharides from natural resources target various biological processes and are increasingly used as potential target molecules for drug development. However, the accessibility of branched and long complex polysaccharide active domains with well-defined structures remains a major challenge. Herein we describe an efficient first total synthesis of a highly branched heptadecasaccharide moiety of the native bioactive galectin-3-targeting polysaccharide from Carthamus tinctorius L. as well as shorter fragments of the heptadecasaccharide. The key feature of the approach is that a photo-assisted convergent [6+4+7] one-pot coupling strategy enables rapid assembly of the heptadecasaccharide, whereby a photoremovable o-nitrobenzyl protecting group is used to generate the corresponding acceptor for glycosylation in situ upon ultraviolet radiation. Biological activity tests suggest that the heptadecasaccharide can target galectin-3 and inhibit pancreatic cancer cell growth.
Assuntos
Carthamus tinctorius , Neoplasias , Carthamus tinctorius/química , Galectina 3 , Glicosilação , Polissacarídeos/farmacologia , Raios UltravioletaRESUMO
α-Xylosylated glycans and xylosyl derivatives are biomedically important molecules which show numerous bioactivities against infection, cancer, inflammation, and so on. Lacking an efficient α-xylosylation method, the synthesis of α-xyloside-containing molecules was full of challenges. Herein, a robust method is presented for selective α-xylosylation via combination of a rare conformation-controlled strategy and the hydrogen-bond-mediated aglycone delivery method. Various native branched α-xyloside structures necessitate an orthogonally protected xyloside, and a three-pot preparation method of the xylosyl donor was developed for this novel α-xylosylation method, which was further applied in the first synthesis of the side chain N of xyloglucan. This work provides an efficient α-xylosylation method which would make various α-xyloside structures achievable. The conformation-controlled strategy also has important reference to the chemistry of five-carbon pyranose.
Assuntos
Carbono , Monossacarídeos , Hidrogênio , Ligação de Hidrogênio , Conformação MolecularRESUMO
Glyco-PAMAM dendrimers and glyco-agarose beads bearing a core-fucosylated N-glycan trisaccharide GlcNAcß1,4(Fucα1,6)GlcNAc or a non-fucose disaccharide GlcNAcß1,4GlcNAc were successfully synthesized and characterized by monosaccharide analysis with HPAEC-PAD technique. These glycoconjugates as fucose lectin probes were applied in fucose-specific lectin detection and purification. The model fucose lectin AAL indicated binding activity with the FITC-labeled PAMAM carrying core-fucose trisaccharide. An affinity chromatography column stuffed with the agarose beads carrying core-fucosylated trisaccharide exhibited a good specificity in purification of AAL than non-fucose disaccharide agarose beads. These novel glycoconjugates bearing the precise and simplified core-fucose N-glycan structure provided a potential application for core-fucose-specific lectin discovery.
Assuntos
Fucose/química , Glicoconjugados/química , Lectinas/química , Lectinas/isolamento & purificação , Polissacarídeos/química , Trissacarídeos/química , Técnicas Biossensoriais , Glicosilação , Microesferas , Nitrogênio/químicaRESUMO
RN1, a polysaccharide from flowers of Panax pseudo-ginsieng Wall. Var. notoginseng (Burkill) Hoo & Tseng, is a potential multi-targeting drug candidate for pancreatic cancer treatment. However, the active targeting domain of RN1 is still unknown. Herein, three RN1 derived branches were synthesized via [3+2] or [2+2] strategies, efficiently. Two pentasaccharides, 18 and 27, showed similar inhibition effect on pancreatic cancer BxPC-3 cells to that of RN1 at same concentration. Interestingly, tetrasaccharide 21 potently inhibited gemcitabineresistant cell line Panc-1 at high concentration. These suggest that the branches of RN1 might be the active targeting domain and tetrasaccharide 21 might be a potential leading compound for pancreatic cancer with gemcitabine resistance.