A novel DNA polymerase inhibitor and a potent apoptosis inducer: 2-mono-O-acyl-3-O-(α-D-sulfoquinovosyl)-glyceride with stearic acid
Synthetic Organic Chemistry Laboratory, RIKEN, Вако, Saitama, Japan Biochimica et Biophysica Acta
(Impact Factor: 4.66).
02/2003; 1645(1):72-80. DOI: 10.1016/S1570-9639(02)00521-6
Sulfo-glycolipids in the class of sulfoquinovosyl diacylglycerol (SQDG) including the stereoisomers are potent inhibitors of DNA polymerase alpha and beta. However, since the alpha-configuration of SQDG with two stearic acids (alpha-SQDG-C(18)) can hardly penetrate cells, it has no cytotoxic effect. We tried and succeeded in making a permeable form, sulfoquinovosyl monoacylglycerol with a stearic acid (alpha-SQMG-C(18)) from alpha-SQDG-C(18) by hydrolysis with a pancreatic lipase. alpha-SQMG-C(18) inhibited DNA polymerase activity and was found to be a potent inhibitor of the growth of NUGC-3 cancer cells. alpha-SQMG-C(18) arrested the cell cycle at the G1 phase, and subsequently induced severe apoptosis. The arrest was correlated with an increased expression of p53 and cyclin E, indicating that alpha-SQMG-C(18) induced cell death through a p53-dependent apoptotic pathway.
Available from: David A Mannock
- "Also, 3 -SO 3 -␤-d-GalAAG may be responsible for the binding of the HIV glycoprotein 120 to spermatozoa and subsequent transmission of HIV to the sexual partner (Brogi et al., 1998 and references therein). Studies of the plant glycolipids have shown that both the nonionic galactolipids and the sulfonoquinovosyldiacylglycerol are potent inhibitors of both eukaryotic DNA polymerases and the HIV reverse transcriptase (Lau et al., 1993; Loya et al., 1998; Mizushina et al., 2003; Murakami et al., 2003; Mannock and McElhaney, 2004, and references therein). In addition, both ionic and nonionic glycolipids have been shown to be potent inhibitors of tumour growth in a variety of cancers (Lu et al., 1994; Colombo et al., 2002; Sahara et al., 2002; Ohta et al., 2001; Mannock and McElhaney, 2004, and references therein). "
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ABSTRACT: The thermotropic phase behaviour of aqueous dispersions of some synthetic 1,2-di-O-alkyl-3-O-(beta-D-galactosyl)-rac-glycerols (rac-beta-D-GalDAGs) with both odd and even hydrocarbon chain lengths was studied by differential scanning calorimetry (DSC), small-angle (SAXS) and wide-angle (WAXS) X-ray diffraction. DSC heating curves show a complex pattern of lamellar (L) and nonlamellar (NL) phase polymorphism dependent on the sample's thermal history. On cooling from 95 degrees C and immediate reheating, rac-beta-D-GalDAGs typically show a single, strongly energetic phase transition, corresponding to either a lamellar gel/liquid-crystalline (L(beta)/L(alpha)) phase transition (N< or =15 carbon atoms) or a lamellar gel/inverted hexagonal (L(beta)/H(II)) phase transition (N> or =16). At higher temperatures, some shorter chain compounds (N=10-13) exhibit additional endothermic phase transitions, identified as L/NL phase transitions using SAXS/WAXS. The NL morphology and the number of associated intermediate transitions vary with hydrocarbon chain length. Typically, at temperatures just above the L(alpha) phase boundary, a region of phase coexistence consisting of two inverted cubic (Q(II)) phases are observed. The space group of the cubic phase seen on initial heating has not been determined; however, on further heating, this Q(II) phase disappears, enabling the identification of the second Q(II) phase as Pn3 m (space group Q(224)). Only the Pn3 m phase is seen on cooling. Under suitable annealing conditions, rac-beta-D-GalDAGs rapidly form highly ordered lamellar-crystalline (L(c)) phases at temperatures above (N< or =15) or below (N=16-18) the L(beta)/L(alpha) phase transition temperature (T(m)). In the N< or =15 chain length lipids, DSC heating curves show two overlapping, highly energetic, endothermic peaks on heating above T(m); corresponding changes in the first-order spacings are observed by SAXS, accompanied by two different, complex patterns of reflections in the WAXS region. The WAXS data show that there is a difference in hydrocarbon chain packing, but no difference in bilayer dimensions or hydrocarbon chain tilt for these two L(c) phases (termed L(c1) and L(c2), respectively). Continued heating of suitably annealed, shorter chain rac-beta-D-GalDAGs from the L(c2) phase results in a phase transition to an L(alpha) phase and, on further heating, to the same Q(II) or H(II) phases observed on first heating. On reheating annealed samples with longer chain lengths, a subgel phase is formed. This is characterized by a single, poorly energetic endotherm visible below the T(m). SAXS/WAXS identifies this event as an L(c)/L(beta) phase transition. However, the WAXS reflections in the di-16:0 lipid do not entirely correspond to the reflections seen for either the L(c1) or L(c2) phases present in the shorter chain rac-beta-D-GalDAGs; rather these consist of a combination of L(c1), L(c2) and L(beta) reflections, consistent with DSC data where all three phase transitions occur within a span of 5 degrees C. At very long chain lengths (N> or =19), the L(beta)/L(c) conversion process is so slow that no L(c) phases are formed over the time scale of our experiments. The L(beta)/L(c) phase conversion process is significantly faster than that seen in the corresponding rac-beta-D-GlcDAGs, but is slower than in the 1,2-sn-beta-D-GalDAGs already studied. The L(alpha)/NL phase transition temperatures are also higher in the rac-beta-D-GalDAGs than in the corresponding rac-beta-D-GlcDAGs, suggesting that the orientation of the hydroxyl at position 4 and the chirality of the glycerol molecule in the lipid/water interface influence both the L(c) and NL phase properties of these lipids, probably by controlling the relative positions of hydrogen bond donors and acceptors in the polar region of the membrane.
Chemistry and Physics of Lipids 08/2007; 148(1):26-50. DOI:10.1016/j.chemphyslip.2007.04.004 · 2.42 Impact Factor
Available from: M. J. Dianez
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ABSTRACT: Methyl 2-benzamido-3,6-di-O-benzoyl-2,4-dideoxy-α-d-glucopyranoside-4-C-sulfonate sodium salt 9 and its galacto epimer 10 were prepared by oxidation with hydrogen peroxide in acetic acid of methyl 4-S-acetyl-2-benzamido-3,6-di-O-benzoyl-2-deoxy-4-thio-α-d-glucopyranoside 7 and its galacto epimer 8, respectively. The 4-thioglucoside 7 was prepared from methyl 2-benzamido-3,6-di-O-benzoyl-2-deoxy-α-d-glucopyranoside by double inversion through triflation, inversion at C-4 with NaNO2, triflation of the resulting methyl 2-benzamido-3,6-di-O-benzoyl-2-deoxy-α-d-galactopyranoside, followed by displacement with potassium thioacetate. Deacylation of 9 with refluxing aqueous sodium hydroxide followed by deionisation yielded methyl 2-amino-2,4-dideoxy-α-d-glucopyranoside-4-C-sulfonic acid 11. Deacylation of the galactopyranoside 10 under the same conditions also gave 11, due to base catalysed isomerisation of galacto to the more stable gluco configuration. The structure of 11, crystallized as the monohydrate, was confirmed by X-ray crystallographic analysis. The asymmetric unit contains two sugar molecules in two unique but similar conformations and two water molecules. The sulfo and the amino groups form a zwitterion, with each ammonium group hydrogen bonded to the sulfonate groups of two other molecules related by symmetry.
Tetrahedron Asymmetry 11/2003; 14(23):3761-3768. DOI:10.1016/j.tetasy.2003.10.004 · 2.16 Impact Factor
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ABSTRACT: Recent advances in the area of glycobiology have been paralleled by progress in our understanding of the physical properties of glycoglycerolipids (GGLs). These advances have been accelerated by interest in the new found roles of these simple glycolipids in nature, by advances in synthetic procedures, and by an interest in the technological application of a group of amphiphiles with unique physical and chemical properties. Here, we consider the phase properties of some GGL/water systems containing either a single hexopyranoside or pentopyranoside headgroup. Recent calorimetric and X-ray diffraction measurements of some GGL diastereomers suggest that both headgroup and interfacial hydration play a major role in determining both lyotropism and mesomorphic phase properties as the chemical structure of the lipid headgroup, interface and hydrocarbon chains are systematically altered. For GGLs of a given chain length, interactions between the headgroup/interface and water determine whether or not a highly ordered, lamellar crystalline phase is formed, the number of such phases and their rate of formation and, in some cases, the nature of the molecular packing of those phases. In the liquid crystalline phases, the hydrocarbon chains determine the area per molecule in the lamellar liquid crystalline phase, but it is the cross-sectional area of the hydrated headgroup and the penetration of water into the interface which determines the nature of the non-lamellar phases, probably through small changes in interfacial geometry as the lateral stresses in the headgroup region increase.
Current Opinion in Colloid & Interface Science 04/2004; 8(6-8):426-447. DOI:10.1016/j.cocis.2004.01.009 · 5.84 Impact Factor
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