- Synthesis and antimicrobial activity of (?)-cleistenolide and analogues
-
Using the “chiral pool” approach, two modified total syntheses of the biologically active δ-lactone cleistenolide (1) have been achieved starting from D-glucose. These approaches also enabled the preparation of novel analogues and derivatives of natural product 1. The applied strategy for the synthesis of 1 involves: the initial degradation of the chiral precursor for a single C-atom, C2-fragment chain extension using Z-selective Wittig reaction, and the final δ-lactonization. All tested cleistenolide analogues displayed antimicrobial activity against a panel of nine microbial strains, most of them superseding the activity of cleistenolide itself, and, in some cases, coming close in value to the observed minimal inhibitory concentrations of chloramphenicol. Increased lipophilicity of the derivatives and the non-sterically congested conjugated lactone moiety were a prerequisite for analogues with high inhibitory activity against S. aureus and, in general, Gram-positive bacteria.
- Benedekovi?, Goran,Popsavin, Mirjana,Radulovi?, Niko S.,Stojanovi?-Radi?, Zorica,Farkas, Sándor,Francuz, Jovana,Popsavin, Velimir
-
-
- A Warburg effect targeting vector designed to increase the uptake of compounds by cancer cells demonstrates glucose and hypoxia dependent uptake
-
Glycoconjugation to target the Warburg effect provides the potential to enhance selective uptake of anticancer or imaging agents by cancer cells. A Warburg effect targeting group, rationally designed to facilitate uptake by glucose transporters and promote cellular accumulation due to phosphorylation by hexokinase (HK), has been synthesised. This targeting group, the C2 modified glucose analogue 2-(2-[2-(2-aminoethoxy)ethoxy]ethoxy)-D-glu-cose, has been conjugated to the fluorophore nitrobenzoxadiazole to evaluate its effect on uptake and accumulation in cancer cells. The targeting vector has demonstrated inhibition of glucose phosphorylation by HK, indicating its interaction with the enzyme and thereby confirming the potential to facilitate an intracellular trapping mechanism for compounds it is conjugated with. The cellular uptake of the fluorescent analogue is dependent on the glucose concentration and is so to a greater extent than is that of the widely used fluorescent glucose analogue, 2-NBDG. It also demonstrates selective uptake in the hypoxic regions of 3D spheroid tumour models whereas 2-NBDG is distributed primarily through the normoxic regions of the spheroid. The increased selectivity is consistent with the blocking of alternative uptake pathways.
- Glenister, Alexandra,Simone, Michela I.,Hambley, Trevor W.
-
-
- New antitumour agents with α,β-unsaturated δ-lactone scaffold: Synthesis and antiproliferative activity of (?)-cleistenolide and analogues
-
A stereoselective total synthesis of (?)-cleistenolide (1) from D-glucose has been achieved. This new approach for the synthesis of (?)-cleistenolide and analogues involves a one-C-atom degradation of the chiral precursor, (Z)-selective Wittig olefination, followed by the final δ-lactonisation. Synthesized compounds showed potent growth inhibitory effects against selected human tumour cell lines, especially 2,4,6-trichlorobenzoyl derivative 12, which in the culture of MDA-MB 231 cells displayed the highest activity (IC500.02?μM) of all compounds under evaluation. A preliminary SAR study reveals the structural features that are beneficial for antiproliferative activity of synthesized δ-lactones, such as presence of either electron-withdrawing or electron-donating substituents in the aromatic ring, as well as the presence of cinnamoyl functionality instead of benzoyl group at the O-7 position.
- Benedekovi?, Goran,Kova?evi?, Ivana,Popsavin, Mirjana,Francuz, Jovana,Koji?, Vesna,Bogdanovi?, Gordana,Popsavin, Velimir
-
supporting information
p. 3318 - 3321
(2016/07/12)
-
- Chemical Approach to Positional Isomers of Glucose-Platinum Conjugates Reveals Specific Cancer Targeting through Glucose-Transporter-Mediated Uptake in Vitro and in Vivo
-
Glycoconjugation is a promising strategy for specific targeting of cancer. In this study, we investigated the effect of d-glucose substitution position on the biological activity of glucose-platinum conjugates (Glc-Pts). We synthesized and characterized all possible positional isomers (C1α, C1β, C2, C3, C4, and C6) of a Glc-Pt. The synthetic routes presented here could, in principle, be extended to prepare glucose conjugates with different active ingredients, other than platinum. The biological activities of the compounds were evaluated both in vitro and in vivo. We discovered that varying the position of substitution of d-glucose alters not only the cellular uptake and cytotoxicity profile but also the GLUT1 specificity of resulting glycoconjugates, where GLUT1 is glucose transporter 1. The C1α- and C2-substituted Glc-Pts (1α and 2) accumulate in cancer cells most efficiently compared to the others, whereas the C3-Glc-Pt (3) is taken up least efficiently. Compounds 1α and 2 are more potent compared to 3 in DU145 cells. The α- and β-anomers of the C1-Glc-Pt also differ significantly in their cellular uptake and activity profiles. No significant differences in uptake of the Glc-Pts were observed in non-cancerous RWPE2 cells. The GLUT1 specificity of the Glc-Pts was evaluated by determining the cellular uptake in the absence and in the presence of the GLUT1 inhibitor cytochalasin B, and by comparing their anticancer activity in DU145 cells and a GLUT1 knockdown cell line. The results reveal that C2-substituted Glc-Pt 2 has the highest GLUT1-specific internalization, which also reflects the best cancer-targeting ability. In a syngeneic breast cancer mouse model overexpressing GLUT1, compound 2 showed antitumor efficacy and selective uptake in tumors with no observable toxicity. This study thus reveals the synthesis of all positional isomers of d-glucose substitution for platinum warheads with detailed glycotargeting characterization in cancer.
- Patra, Malay,Awuah, Samuel G.,Lippard, Stephen J.
-
supporting information
p. 12541 - 12551
(2016/10/07)
-
- First synthesis of 4a-carba-β-d-galactofuranose
-
The synthesis of 4a-carba-β-d-galactofuranose is described starting from diacetone glucose. The key ring-closure step was carried out by metathesis to form a cyclopentene. Catalytic hydrogenation of the C{double bond, long}C double bond gave the galacto configured saturated carbahexofuranose with excellent diastereoselectivity.
- Frigell, Jens,Cumpstey, Ian
-
p. 9073 - 9076
(2008/03/27)
-
- Synthesis of 1,4-anhydro-d-fructose and 1,4-anhydro-d-tagatose
-
1,4-Anhydro-d-fructose and 1,4-anhydro-d-tagatose were prepared from 1,2-O-isopropylidene-d-glucofuranose via the common intermediate 3,5,6-tri-O-benzyl-d-glucitol. The title compounds may be interesting anti-oxidants and feature activities akin to their natural pyranoid counterpart, 1,5-anhydro-d-fructose.
- Dekany, Gyula,Lundt, Inge,Steiner, Andreas J.,Stuetz, Arnold E.
-
p. 1737 - 1742
(2007/10/03)
-
- Preparation of sugar-derived α-acetoxy-aldehydes
-
A convenient method for conversion of sugar diols (2a-2d) into a-acetoxy-aldehydes: 5-O-acetyl-3-O-benzyl-1,2-O-isopropylidene-α-D-glucofuranos-6-ulose (5a), 5-O-acetyl-3-O-benzyl-1,2-O-isopropylidene-α-D-allofuranos-6-ulose (5b), methyl 6-O-acetyl-2,3,4-tri-O-benzyl-D-glycero-α-D-gluco- and L-glycero-α-D-gluco-heptopyranosid-7-uloses (5c and 5d respectively) is presented. This involves the protection (as TBDMS ether) of the primary hydroxyl group, acetylation of the remaining secondary one and desilylation followed by a Swern oxidation. Partial migration of the acetyl group during desilylation (with Bu4NF) was observed for compound 4a and complete migration for 4f. α-Acetoxy-aldehydes 5a-5d were characterized as adducts with Ph3P = CH-CO2Me (12a-12d).
- Jarosz,Kozlowska
-
-
- Synthesis and glycosidic reaction of 1,2-anhydromanno-, lyxo-, gluco-, and xylofuranose perbenzyl ethers
-
Stereospecific synthesis of 1,2-anhydromanno-, lyxo-, gluco-, and xylofuranose perbenzyl ethers was successfully achieved via intramolecular SN2 reaction of the corresponding C-1 alkoxide with C-2 bearing tosyloxy group. The key intermediates, furanose 2-sulfonates, were prepared from the corresponding 1,2-diols and tosyl chloride under phase transfer conditions in good yields. Condensation of the anhydro sugars with 1,2:3,4-di-O-isopropylidene-α-D-galactopyranose or N-benzyloxycarbonyl L-serine methyl ester in the absence of catalyst gave 1,2-trans-linked glycofuranosides in high yield.
- Du, Yuguo,Kong, Fanzuo
-
p. 797 - 817
(2007/10/03)
-
- A convenient preparation of 5-benzyl ethers of D-gluco- and D-manno-furanose derivatives
-
Keywords: Glucofuranose; Mannofuranose; Selective benzylation; Two-phase benzylation
- Stepowska, Halszka,Zamojski, Aleksander
-
p. 133 - 138
(2007/10/02)
-
- Benzylation of sugar polyols by means of the PTC method
-
Studies on benzylation of hydrophilic carbohydrate derivatives with benzyl chloride, using a phase-transfer technique, have led to the conclusion that alkylation of a substrate can be greatly facilitated by the introduction of a "co-catalyst" (e.g. a tertiary alcohol) and/or a co-solvent (e.g.DMSO) to the reaction mixture.Efficient procedures for benzylation of sugar derivatives having three to eight hydroxyl groups per molecule, in two-phase system employing an almost stoichiometric amount of the alkylating agent, are presented.
- Szeja, W.,Fokt, I.,Grynkiewicz, G.
-
p. 224 - 226
(2007/10/02)
-
- Regioselective De-O-benzylation with Lewis Acids
-
Simple and highly regioselective de-O-benzylations of poly-O-benzylated monosaccharides and polyols with Lewis acids (SnCl4 and TiCl4) were developed.Spectral studies on intermediates complexes showed that three appropriately situated metal chelating functional groups were necessary for the selective de-O-benzylation.
- Hori, Hiroshi,Nishida, Yoshihiro,Ohrui, Hiroshi,Meguro, Hiroshi
-
p. 1346 - 1353
(2007/10/02)
-
- Synthesis of the antibiotic 1,5-dideoxy-1,5-imino-D-glucitol; concomitant formation of the D-mannitol analogue
-
The easy accessible 1,2-O-isopropylidene-3-O-benzyl-α-D-glucofuranose was converted in six steps into 1,2-O-isopropylidene-3,6-di-O-benzyl-5-deoxy-5-azido-α-D-glucofuranose.The latter afforded, after acidolysis followed by hydrogenolysis, 1-deoxynojirimicine and a small quantity of 1-deoxymannonojirimicine.The antibiotic thus obtained had an inhibitory effect on the trimming of N-linked carbohydrates in IgM.
- Broxterman, H. J. G.,Marel, G. A. van der,Neefjes, J. J.,Ploegh, H. L.,Boom, J. H. van
-
p. 571 - 576
(2007/10/02)
-
- ACID-CATALYZED CONVERSION OF 2-O-(2-HYDROXYPROPYL)-D-GLUCOSE DERIVATIVES INTO 1,2-O-(1-METHYL-1,2-ETHANEDIYL)-D-GLUCOSE ACETALS. STUDIES RELATED TO O-(2-HYDROXYPROPYL)CELLULOSE
-
The acid-catalyzed solvolysis of methyl 3,5,6-tri-O-benzyl-2-O-(2-hydroxypropyl)-α-D-glucofuranoside (1) in chloroform involves a neighboring-group attack on C-1 by the hydroxypropyl substituent, and opening of the furanoside ring to yield a diastereomeric pair of 3,5,6-tri-O-benzyl-1-Omethyl-1,2-O-(1-methyl-ethanediyl)-D-glucose acetals (2 and 3).The latter, which differ in configuration at C-8,represent a resolution of the enantiomeric forms of the original 2-O-(2-hydroxypropyl) group.In a succeeding reaction, the 1-methoxyl group of each acetal undergoes an intramolecular displacement by O-4, leading to the formation of the corresponding biycyclic acetals, i.e., the two diastereomers (4 and 5) of 3,5,6-tri-O-benzyl-1,2-O-(1-methyl-1,2-ethanediyl)-α-D-glucofuranose.Solvolysis of 6, the β anomer of 1, proceeds in an analogous manner, although more rapidly, to yield a corresponding pair of acyclic-aldose acetals (7 and 8), as well as bicyclic acetals 4 and 5.Similar results are observed for solvolysis in the 2-O-(2-hydroxyethyl) series, whereas the reaction of the 2-O-(2,3-epoxypropyl) counterpart of 1 (or 6) with hydrogen chloride affords the corresponding chloromethyl analogs of 4 and 5.In all of these series, one of each diastereomeric pair of products is more stable than the other, and reasons for this are considered.Evidence based on n.m.r.-spectral data and steric factors is presented to show that the configuration of the chiral center C-8 of 2, 4, and 7 is (S), whereas it is (R) in 3, 5, and 8.Also, conformational characteristics of the various solvolysis products are assessed, and mechanisms possibly involved in their formation are discussed.
- Lee, Dae-Sil,Perlin, Arthur S
-
p. 265 - 282
(2007/10/02)
-
- 1,6-Anhydrofuranoses, XI. - 1,6-Anhydro-α-L-idofuranose
-
The title compound 13 is prepared on different routes from suitable benzyl derivatives with gluco-configuration.Preparations use the susceptibility of axial 5-O-benzyl groups in this compounds to selective hydrogenolysis, thus allowing subsequent inversion of configuration in this position from D-gluco to L-ido by an oxidation/reduction sequence.Only 0.08percent of 13 are found in the equilibrium mixture of idose in acidic medium.It is shown with 4-C-methyltalose as example, that the amount of 1,6-anhydrofuranoses in these equilibria rises significantly by changing the hydroxy groups in 4-position from secondary to tertiary ones.
- Koell, Peter,John, Hans-Georg,Schulz, Juergen
-
p. 613 - 625
(2007/10/02)
-