Facile synthesis of the naturally cytotoxic triterpenoid saponin Patrinia-glycoside B-II and its conformer.
ABSTRACT: The first chemical synthesis of the natural triterpenoid saponin Patrinia-glycoside B-II, namely oleanolic acid 3-O-?-L-rhamnopyranosyl-(1?2)-[?-D-gluco-pyranosyl-(1?3)]-?-L-arabinopyranoside, has been accomplished in a linear 11-step sequence 11 with 9.4% overall yield. The abnormal 1C4 conformation of the arabinose residue was found to occur via conformational fluctuation during preparation of the intermediates. Molecular mechanism and quantum chemistry calculations showed that Patrinia-glycoside B-II and its conformer 1 cannot interconvert under normal conditions. Preliminary structure-activity relationships studies indicated that the 4C1 chair conformation of the arabinose residue in the unique ?-L-rhamnopyranosyl-(1?2)-?-L-arabinopyranosyl disaccharide moiety is one of the chief positive factors responsible for its cytotoxic activity against tumors.
Project description:Natural product studies explore potential and interesting new compounds to discover innovative drugs. Nigella sativa (N. sativa) (Ranunculaceae) is traditionally used to treat diabetes. Flavonoids and triterpenoid mostly show anti-diabetic activity. The current study aim to identify new compounds by a systematic study of the anti-oxidant and anti-diabetic activity of aerial parts of N. sativa concerning. Phytochemicals were isolated from the methanolic extract of aerial parts of the plant by column chromatography and identified by nuclear magnetic resonance spectroscopy and mass spectroscopy. A new triterpenoid saponin glycoside was isolated along with flavonoids. The anti-diabetic study was carried out by DPPH, ABTS, ? -glucosidase, and protein tyrosine phosphatase 1B assays at doses of 12.5 to 250 µM. The isolated phytochemicals were identified as 3-O-(?-d-xylopyranosyl-(1-3)-?-l-rhamnopyrnaosyl-(1-2)-?-l-arabinopyranosyl]-28-O-(?-l-rhamno-pyranosyl-(1-4)-?-d-glucopyranosyl-(1-6)-?-d-glucopyranosyl] hederagenin (1), flaccidoside III (2), catechol (3), quercetin-3-gentiobiosides (4), magnoflorine (5), nigelflavonoside B (6), nigelloside (7), quercetin sphorotrioside (8), kaempferol-3, 7-diglucoside (9), kaempferol 3-O-rutinoside (10), rutin (11), 3-O-[?-l-rhamnopyranosyl-(1?2)-?-l-arabinopyranpsylhederagenin (12), 3?,23,28-trihydroxyolean-12-ene-3-O-?-l-arabinopyranoside(1?4)-a-rhamnopyranosyl,(1?4)-?-d-gluco-pyranoside (13), 3-O-?-l-rhamnopyranosyl-(1?2)-?-l-arabinopyranpsyl]-28-O-?-d-gluco-pyranosyl hederagenin (14), and ?-hederin (15). These were isolated and are reported for the first time in this study. Compared 13 was identified as a new compound. Compound 2 was isolated for first time from the genus Nigella. Compound 6 was found to be the most active in the DPPH, and ABTS assays and compound 10 was found to be the most active in the ?-glucosidase assay, with IC50 32.7 ± 0.1, 95.18 ± 0.9, 214.5 ± 0.0 µ?, respectively. Compound 12, at a dose of 125 µ?, showed anti-diabetic activity in a PTP1B assay with IC50 91.30 ± 2.5 µ?. In conclusion, the anti-diabetic activity of N. sativa is due to its flavonoids and TTSGs. Therefore, our studies suggest that the aerial parts of N. sativa are also a valuable and alternate source of valuable phytochemicals that could be used to develop anti-oxidant and anti-diabetic medicines.
Project description:The conformation of the L-iduronate residue in non-sulphated di-, tetra- and hexa-saccharides and their alditol derivatives derived from rooster comb dermatan sulphate was investigated by 400 MHz 1H-n.m.r. spectroscopy. The ratio of conformational isomers is obtained by the average spin-spin coupling constants of a mixture of nearly isoenergetic conformers (1C4, 4C1 and 2S0). The non-reducing terminal L-iduronate residue in the tetrasaccharides (I-H-I-H and I-H-G-H) and their alditols (I-H-I-H-ol and I-H-G-H-ol) is in equilibrium with three conformers (1C4, 30%; 4C1, 40%; 2S0, 30%) of nearly equal population. Whereas the internal L-iduronate residue in the tetrasaccharides (I-H-I-H and G-H-I-H) exists as an equilibrium mixture of 1C4 (54%) and 2S0 (42-44%) conformers, that of their alditols (I-H-I-H-ol and G-H-I-H-ol) is in equilibrium between 2S0 conformer (66%) and 1C4 conformer (28%). The conformational population for the internal L-iduronate residue 2I in the hexasaccharide (3I-H-2I-H-1I-H) is also calculated and compared with that for the L-iduronate residue in native dermatan sulphate, which was calculated on the basis of the spin-spin coupling constants reported by Gatti, Casu, Torri & Vercellotti [(1979) Carbohydr. Res. 68, c3-c7].
Project description:Four novel acylglycosides flavones (AGFs) including two quercetin acylglycosides and two kaempferol acylglycosides were isolated from Fuzhuan brick tea (FBT) as follows: quercetin 3-O-[?-l-rhamnopyranosyl (1?3)] [2-O''-(E)-p-coumaroyl] [?-d-glucopyranosyl (1?3)-?-l-rhamnopyranosyl (1?6)]-?-d-galactoside was named as camelliquercetiside E (1), quercetin 3-O-[?-l-rhamnopyranosyl (1?3)] [2-O''-(E)-p-coumaroyl] [?-l-rhamnopyranosyl (1?6)]-?-d-galactoside was named as camelliquercetiside F (2), kaempferol 3-O-[?-l-arabinopyranosyl (1?3)] [2-O''-(E)-p-coumaroyl] [?-d-glucopyranosyl (1?3)-?-l-rhamnopyranosyl (1?6)]-?-d-glucoside was named as camellikaempferoside D (3), kaempferol 3-O-[?-l-arabinopyranosyl (1?3)] [2-O''-(E)-p-coumaroyl] [?-l-rhamnopyranosyl (1?6)]-?-d-glucoside was named as camellikaempferoside E (4). Chemical structures of AGFs were identified by time-of-flight mass (TOF-MS) and NMR spectrometers (¹H NMR, 13C NMR, ¹H-¹H COSY, HMBC and HSQC), and the MS² fragmentation pathway of AGFs was further investigated. The inhibitory abilities of AGFs and their proposed metabolites on ?-glucosidase and HMG-CoA reductase were analyzed by molecular docking simulation, and the results suggested that inhibitory activities of AGFs were significantly affected by acyl structure, number of glycosyl and conformation, and part of them had strong inhibitory activities on ?-glucosidase and HMG-CoA reductase, suggesting that AGFs and their metabolites might be important ingredients that participate in the regulation of hypoglycemic and hypolipidemic effects. The results provided new AGFs and research directions for the practical study of FBT health functions in future.
Project description:Cholera is caused by Vibrio cholerae and is an example of a blood-group-dependent disease. Recent studies suggest that the receptor-binding B subunit of the cholera toxin (CT) binds histo-blood group antigens at a secondary binding site. Herein, we studied the conformational dynamics of Lewis Y (LeY) oligosaccharides, H-tetrasaccharides and A-pentasaccharides, in aqueous solution by conducting accelerated molecular dynamics (aMD) simulations. The flexible nature of both oligosaccharides was displayed in aMD simulations. Furthermore, aMD simulations revealed that for both oligosaccharides in the free form, 4C1 and 1C4 puckers were sampled for all but GalNAc monosaccharides, while either the 4C1 (GlcNAc, Gal, GalNAc) or 1C4 (Fuc2, Fuc3) pucker was sampled in the CT-bound forms. In aMD, the complete transition from the 4C1 to 1C4 pucker was sampled for GlcNAc and Gal in both oligosaccharides. Further, we have observed a transition from the open to closed conformer in the case of A-pentasaccharide, while H-tetrasaccharide remains in the open conformation throughout the simulation. Both oligosaccharides adopted an open conformation in the CT binding site. Moreover, we have investigated the molecular basis of recognition of LeY oligosaccharides by the B subunit of the cholera toxin of classical and El Tor biotypes using the molecular mechanics generalized Born surface area (MM/GBSA) scheme. The O blood group determinant, H-tetrasaccharide, exhibits a stronger affinity to both biotypes compared to the A blood group determinant, A-pentasaccharide, which agrees with the experimental data. The difference in binding free energy between O and A blood group determinants mainly arises due to the increased entropic cost and desolvation energy in the case of A-pentasaccharide compared to that of H-tetrasaccharide. Our study also reveals that the terminal Fuc3 contributes most to the binding free energy compared to other carbohydrate residues as it forms multiple hydrogen bonds with CT. Overall, our study might help in designing glycomimetic drugs targeting the cholera toxin.
Project description:As part of the International Cooperative Biodiversity Group (ICBG) program, in a search for antiproliferative compounds, an ethanol extract of Polyscias duplicata was investigated due to its antiproliferative activity against the A2780 human ovarian cell cancer line (IC50 6 µg/mL). Seven known oleanane glycosides, 3?-[(?-L-arabinopyranosyl)oxy]-16?-hydroxyolean-12-en-28-oic acid (1, IC50 8 µM), 3?-[(?-L-arabinopyranosyl)oxy]-16?,23-dihydroxyolean-12-en-18-oic acid (2, IC50 13 µM), 3?-[(O-?-D-glucopyranosyl-(t-->3)-?-L-arabinopyranosyl)oxy]-16?-hydroxyolean-12-en-28-oic acid (3, IC50 7 µM), 3?-[(O-?-L-rhamnopyranosyl-(1-2)-?-L-arabinopyranosyl)oxy]-16?-hydroxyolean-12-en-28-oic acid (4, IC50 2.8 µM), 3?-[(O-?-D-glucopyranosyl-(l-->3)-?-L- arabinopyranosyl)oxy]-23-hydroxyolean-12-en-28-oic acid (5, IC50 10 µM), ?-[(O-?-L-rhamnopyranosyl-(-1.2)-?-L-arabinopyranosyl)oxy]-23-hydroxyolean-12-en-28-oic acid (6, IC50 3.4 µM), and 3?-[(?-L-arabinopyranosyl)oxy]-23-hydroxyolean-12-en-28-oic acid (7, IC50 3.4 µM) were isolated, and their structures determined using spectroscopic methods.
Project description:Two new bidesmoside triterpenoid saponins which were identifed as 28-O-?-D-xylopyranosyl(1?3)-?-D-xylopyranosyl(1?4)-?-L-rhamnopyranosyl(1?2)-[?-L-rhamno-pyranosyl(1?3)]-?-D-fucopyranosyl gypsogenin 3-O-?-D-glucopyranosyl (1?2)-?-D-glucopyranosiduronic acid (C1) and 28-O-?-D-xylopyranosyl(1?4)-?-L-rhamnopyranosyl (1?2)-[?-L-rhamnopyranosyl(1?3)]-?-D-fucopyranosyl gypsogenin 3-O-?-D-gluco-pyranosyl(1?2)-?-D-glucopyranosiduronic acid (C2) were isolated together with two known compounds from the seeds of Momordica charantia L. Their structures were elucidated by the combination of mass spectrometry (MS), one and two-dimensional NMR experiments and chemical reactions.
Project description:The partition coefficients (logP) between n-octanol and water of 47 purified and characterized hydrolysable tannins were measured with the shake flask method utilizing UPLC and HPLC with UV detection. Results show that galloyl glucoses and gallotannins are clearly more hydrophobic than ellagitannins but the differences in hydrophobicity within ellagitannins are more varied than within galloyl glucoses or gallotannins. Most notable structural features that were found to influence the hydrophobicity of ellagitannins were the number of free galloyl groups, acyclic versus cyclic polyol, substitution of the anomeric position of glucose and 4C1 versus 1C4 conformation of the glucopyranose core.
Project description:The disaccharides IdoA(2SO3)-anManOH(6SO3) and IdoA-anManOH (where IdoA represents alpha-L-iduronate, anManOH represents 2,5-anhydro-D-mannitol and SO3 represents sulphate ester) were prepared from bovine lung heparin using HNO2 depolymerization, borohydride reduction and desulphation, and were examined by 400 MHz 1H-n.m.r. spectroscopy. Three-bond proton-proton coupling constants around the IdoA ring were determined under a range of experimental conditions. For unsulphated IdoA all four proton-proton coupling constants varied markedly as a function of temperature, pH and solvent, providing clear evidence for a rapid conformational equilibrium. These data were analysed in terms of the three most energetically stable IdoA conformers: 1C4, 4C1, and 2S0. Predicted coupling constants for these conformers were determined using a modified Karplus-type relationship. For unsulphated IdoA in dimethyl sulphoxide the equilibrium was provoked strongly in favour of a slightly distorted 4C1 'chair' IdoA conformer for which coupling constants have not previously been reported. For sulphated IdoA in aqueous conditions and at low pH the equilibrium is strongly in favour of the alternative 1C4 chair conformer. Under many conditions, however, significant contributions from all three conformers occur for the non-reducing terminal IdoA in these disaccharides.
Project description:Four new constituents, as cis-6-oxogeran-4-enyl-10-oxy-O-?-arabinopyranosyl-4'-O-?-arabinopyranosyl-2''-octadec-9''',12''',15'''-trienoate (1), geran-3(10)-enyl-1-oxy-O-?-arabinopyranosyl-4'-O-?-arabinopyranosyl-2''-octadec-9''',12''',15'''-trienoate (2), geranilan-8-oxy-O-?-d-xylopyranosyl-2'-n-octadec-9'',12'',15''-trienoate (3), 1-cyclohex-2', 5'-dienyl 1-cyclohexylethanol-O-?-d-xylopyranoside (4), along with six known constituents, guaiacol-O-?-d-arabinopyaranoside (5), n-tetradecanyl oleate (6), oleyl-O-?-d-xyloside (7), n-octadec-9,12-dienoyl-O-?-d-arabinopyranoside (8), linolenyl-O-?-d-arabinofuranoside (9) andglyceryl-1,3-dipalmito-2-olein (10), were isolated and identified from the Dendropanax morbifera bark. The new structures were established by one-and two-dimensional NMR (and in combination with IR, FAB-MSand HR-ESI-FTMS. The comparative evaluation of antioxidant potential by phosphomolybdenum, DPPH, FRAP and the NO assay of four different compounds (1-4), we have found that the compounds 1 and 2 have power as a natural antioxidant, whereas the compound 3 and 4 exhibited mild activity in comparison to compounds 1 and 2.
Project description:Knowledge of multi-dimensional carbohydrate structure is essential when delineating structure-function relationships in the development of analytical techniques such as ion mobility-mass spectrometry and of carbohydrate-based therapeutics, as well as in rationally modifying the chemical and physical properties of drugs and materials based on sugars. Although monosaccharides are conventionally presumed to adopt the canonical 4C1 chair conformation, it is not well known how altering the substituent identity around the pyranose ring affects the favored conformational state. This work provides a comprehensive and systematic computational comparison of all eight aldohexose isomers in the gas phase with reduction and oxidation at the C-6 position using density functional theory (M05-2X/cc-pVTZ(-f)//B3LYP/6-31G**) to determine the conformational and anomeric preference for each sugar in the gas phase. All 6-deoxyhexose and aldohexose isomers favored the 4C1 chair conformation, while oxidation at C-6 showed a shift in equilibrium to favor the 1C4 chair for ?-alluronic acid, ?-guluronic acid, and ?-iduronic acid. The anomeric preference was found to be significantly affected by a remote change in oxidation state, with the alternate anomer favored for several isomers. These findings provide a fundamental platform to empirically test steric and electronic effects of pyranose substituents, with the goal of formulating straightforward rules that govern carbohydrate reactivity and drive quicker, more efficient syntheses. Graphical abstract A systematic comparative conformational analysis of all eight aldohexose isomers using DFT methods (M05-2X/cc-pVTZ(-f)) reveals changes in anomeric and ring conformational preference upon reduction or oxidation at the C-6 position for several sugars.