A non-hydrogen-bonding role for the 4-hydroxyl group of D-Galactose in its reaction with D-Galactose oxidase

Several 4-deoxy analogs of methyl β-D-galactopyranoside are oxidized by D-galactose oxidase. The rates associated with their various, axially attached 4-substituents follow the sequence OH>NH₂>F?>Cl> H; these differences are attributed mainly to variations in K_m. Other 4-deoxy analogs, namely, the 4-azido-4-deoxy, 4-bromo-4-deoxy-, 4-deoxy-4-iodo, and 4-thio derivatives were found to be inactive. These observations indicate that the axial 4-hydroxyl group of D-galactopyranose does not play a hydrogen-bonding role primarily, but constitutes a substituent of a size optimal for interaction with the enzyme.     

Scammonins I and II, the resin glycosides of radix scammoniae from Convolvulus scammonia.

The ether-soluble resin glycoside ('jalapin') fraction obtained from scammony roots, on alkaline hydrolysis, gave a glycosidic acid, scammonic acid A, together with isobutyric, 2S-methylbutyric and tiglic acids. In addition, two kinds of resin glycosides, named scammonin I and II, were isolated and characterized, respectively, as (11S)-hydroxyhexadecanoic acid, 11-[( O-6-deoxy-4-O-(2(E)-methyl-1-oxo-2- butenyl)-beta-D-glucopyranosyl-(1----4)-O-6-deoxy-2-O-(2-methyl-1-oxobut yl)- alpha-L-mannopyranosyl-(1----2)-O-beta-D-glucopyranosyl-(1----2)-6-deoxy -beta- D-glucopyranosyl]oxy)-, intramol. 1,3"'-ester and (11S)-hydroxyhexadecanoic acid, 11-[( O-beta-D-glucopyranosyl-(1----4)-O-6-deoxy-2-O-(2-methyl-1-oxobutyl)- alpha-L-mannopyranosyl-(1----2)-O-beta-D-glucopyranosyl-(1----2)-6-deoxy -beta-D - glucopyranosyl]oxy)-, intramol. 1,3"'-ester.     

Transition metal-catalysed A-ring C–H activations and C(sp2)–C(sp2) couplings in the 13α-oestrone series and in vitro evaluation of antiproliferative properties

Facile syntheses of 3-O-carbamoyl, -sulfamoyl, or -pivaloyl derivatives of 13α-oestrone and its 17-deoxy counterpart have been carried out. Microwave-induced, Ni-catalysed Suzuki–Miyaura couplings of the newly synthesised phenol esters with phenylboronic acid afforded 3-deoxy-3-phenyl-13α-oestrone derivatives. The carbamate and pivalate esters proved to be suitable for regioselective arylations. 2-(4-Substituted) phenyl derivatives were synthesised via Pd-catalysed, microwave-assisted C–H activation reactions. An efficient, one-pot, tandem methodology was elaborated for the introduction of the carbamoyl or pivaloyl group followed by regioselective C-2-arylation and subsequent removal of the directing group. The antiproliferative properties of the novel 13α-oestrone derivatives were evaluated in vitro on five human adherent cancer cell lines of gynaecological origin. 3-Sulfamate derivatives displayed substantial cell growth inhibitory potential against certain cell lines. The newly identified antiproliferative compounds having hormonally inactive core might be promising candidates for the design of more active anticancer agents.     

Structural determination of an exocellular mannan from Rhodotorula mucilaginosa YR-2 using ab initio assignment of proton and carbon NMR spectra

The synthesis of 3-azido-3-deoxy, 3-amino-3-deoxy and 3-N-tert-butyloxycarbonyl-3-deoxy derivatives of 2-acetamido-2-deoxy-alpha,beta-D-mannose (N-acetyl-alpha,beta-D-mannosamine, ManNAc), is presented. The 3-azido-3-deoxy- and 3-N-tert-butyloxycarbonyl compounds were further characterised as their peracetates. A preliminary study has found that these C-3 nitrogen-substituted derivatives of ManNAc not to be substrates for Neu5Ac aldolase.     

Crystal structures and thermal analyses of alkyl 2-deoxy-α-d-arabino-hexopyranosides

The crystal structures of alkyl 2-deoxy-α-d-arabino-hexopyranosides, with the alkyl chain lengths from C₈ to C₁₈, are established by the single crystal X-ray structural determination. The even-alkyl chain length derivatives crystallized orthorhombic, with space group P2₁2₁2₁, whereas the odd-alkyl chain length derivatives crystallized monoclinic, with space group P2₁. The sugar moieties retained a ⁴C₁ chair conformation and the conformation of the alkyl chains was all-trans. The molecules formed a bilayer structure, in which alkyl chains were interdigitated. The hydrogen bonds, originating from the sugar moieties, were observed in adjacent layers and also within the same layer, resulting in the formation of infinite chains. The alkyl chains arranged parallel to each other and formed planar structures. The thermal properties of the alkyl 2-deoxy glucosides were analyzed further. It was observed that none of the derivatives exhibited mesomorphism. This study establishes that the absence of the hydroxyl group at C-2 of the sugar moiety results in a non-mesogenic nature of the alkyl 2-deoxy-α-d-glycosides, as opposed to the profound mesogenic nature of the normal alkyl glycosides.     

Deoxy and deoxyfluoro analogues of acetylated methyl beta-D-xylopyranoside--substrates for acetylxylan esterases

Four modified substrates for acetylxylan esterases, 2-deoxy, 3-deoxy, 2-deoxy-2-fluoro, and 3-deoxy-3-fluoro derivatives of di-O-acetylated methyl beta-D-xylopyranoside were synthesized via 2,3-anhydropentopyranoside precursors. Methyl 2,3-anhydro-4-O-benzyl-beta-D-ribopyranoside was transformed into methyl 2,3-anhydro-4-O-benzyl-beta-D-lyxopyranoside in three steps. The epoxide ring opening of 2,3-anhydropentopyranosides was accomplished either by hydride reduction or hydrofluorination. Methyl beta-D-xylopyranoside 2,3,4-tri-O-, 2,4-di-O-, and 3,4-di-O-acetates, and the prepared diacetate analogues were tested as substrates of acetylxylan esterases from Schizophyllum commune and Trichoderma reesei. Measurement of their rate of deacetylation pointed to unique structural requirements of the enzymes for the substrates. The enzymes differed particularly in the requirement for the trans vicinal hydroxy group in the deacetylation at C-2 and C-3 and in the tolerance to the presence of trans vicinal acetyl groups esterifying the OH group at C-2 and C-3.     

Synthetic receptor analogues: preparation and calculated conformations of the 2-deoxy, 6-O-methyl, 6-deoxy, and 6-deoxy-6-fluoro derivatives of methyl 4-O-alpha-D-galactopyranosyl-beta-D-galactopyranoside (methyl beta-D-galabioside)

The 2-deoxy (7), 6-O-methyl (15), 6-deoxy (22), and 6-deoxy-6-fluoro (31) derivatives of methyl beta-D-galabioside (1) have been synthesised. Thus, 7 was prepared by xanthate reduction using tributyltin hydride, whereas 22 was obtained by catalytic hydrogenation of a 6-deoxy-6-iodogalabioside. Regioselective monofluorination of methyl 2,3-di-O-benzoyl-beta-D-galactopyranoside with Et2NSF3 and subsequent alpha-D-galactosylation provided 31. Molecular mechanics calculations yielded similar conformations for 1, 7, 15, 22, and 31 with differences in phi H and psi H of less than 5 degrees. No indications of intramolecular hydrogen bonds, as displayed by 1 in the crystal, were found for 7, 15, 22, or 31.     

Synthesis of Amide-Linked [(3′)CH2CO-NH(5′)] Nucleoside Analogues of Small Oligonucleotides

Abstract

We report syntheses of new amide-linked (di-penta)nucleoside analogues of antisense oligonucleotide components. Solution-phase coupling of 3′-(carboxymethyl)-3′-deoxy- and 5′-amino-5′-deoxynucleoside derivatives provides amide dimers. Activated [3′-(carboxymethyl)-3′-deoxy] units with a 5′-azido-5′-deoxy function provide “masked” 5′-amino-5′-deoxy residues for chain extension, and a 5′-O-DMT-protected unit provides the 5′-terminus for attachment to a phosphodiester linkage.     

Synthesis of analogues of 3-deoxy-D-manno-octulosonic acid (KDO) as potential inhibitors of CMP-KDO synthetase

A series of derivatives of the 2-deoxy analogue of beta-KDO (2,6-anhydro-3-deoxy-D-glycero-D-talo-octonic acid; ammonium salt, 2) has been synthesised as potential inhibitors of CMP-KDO synthetase, starting from methyl 2,6-anhydro-3-deoxy-4,5:7,8-di-O-isopropylidene-D-glycero-D-talo- octonate and replacing the CO2Me group attached to C-2 variously by CONH2, CONHOH, CH2OH, CH2PO(OH)(O-NH4+), COCH2PO(OH)(O-H3N+pheny), CH2CO2-NH4+, CON-HCH2CO2-NH4+, CONHBn, CONHHexyl, CO2Bn, and CO2Hexyl. Of these derivatives, the hydroxamic acid (CONHOH) was the best inhibitor of CMP-KDO synthetase, but was less potent than 2.     

Biological activities of a specific ecdysteroid dimer and of selected monomeric structural analogues in the B(II) bioassay.

The biological activities of selected specific ecdysteroids obtained by photochemical or chemical transformation are compared in the B(II) bioassay, in which the potency reflects the affinity of binding to the ligand-binding site of the Drosophila melanogaster ecdysteroid receptor. The compounds tested represent 14-deoxy, 14-dehydroxy, 14-hydroperoxy and 14-epi derivatives of 20-hydroxyecdysone and were selected on the basis of their close structural relationship to elucidate the contribution of the 14-hydroxy group and the stereochemical configuration at C-14 to ecdysteroid agonist activity. The structure-activity relationship shows that a 14-hydroxy group is not required for activity. However, the alpha-configuration of -H, -OH or -OOH at C-14, which determines the C/D rings trans-annelation, is very significant for activity; it is as important for activity as the well studied A/B rings cis-annelation. Compounds containing a double bond involving C-14 showed low activity with the exception of the specific, and so far unique, ecdysteroid dimer 7,7'-bis-[14-deoxy-8(14)-ene-20-hydroxyecdysone], which was obtained as the main product of the photochemical transformation of 20-hydroxyecdysone. The relatively high biological activity of this dimeric compound is discussed.     

Synthesis of 5′-Fluoro-5′-deoxy-and 5′-Amino-5′-Deoxytoyocamycin and Sangivamycin and Some Related Derivatives

Abstract

A series of 5′-substituted analogs of toyocamycin were prepared by condensation of silylated 4-amino-6-bromo-5-cyanopyrrolo[2,3-d]pyrimidine with protected 5-azido-5-deoxy- or 5-fluoro-5-deoxyribofuranose followed by debromination and deblocking. Alternatively, 5′-azido-5′-deoxytoyocamycin was prepared by azidation of toyocamycin. Conversion of the 5-nitrile function of the toyocamycin derivatives into a carboxamide or a thiocarboxamide gave the corresponding analogs of sangivamycin or thiosangivamycin while reduction of the 5′-azido-5′-deoxy nucleosides provided 5′-amino-5′-deoxy derivatives.     

Preparation of glycosides of 2-deoxy-2-methylamino-D-mannose, 2-deoxy-2-methylamino-D-glucose,and 2-deoxy-2-methylamino-D-galactose: observations on N-methylation of amides

Benzyl 2-[(benzyloxycarbonyl)methylamino]-2-deoxy-α-D-mannopyranoside (10) and its furanose isomer (9), the derived N-methyloxazolidinones 11 and 6, benzyl 2-[(benzyloxycarbonyl)methylamino]-2-deoxy-β-D-glucofuranoside (15) and methyl 2-deoxy-2-methylacetamido-β-D-galactofuranoside (20), were prepared from appropriate diethyl dithioacetals. They were considered the most suitable starting materials for synthesis of O-methyl-2-deoxy-2-methylamino-hexoses because of their ease of preparation and the presence of suitable blocking groups. Oxazolidinones were prepared from N-benzyloxycarbonyl derivatives of 2-amino-2-deoxy-D-mannose by using methanolic sodium methoxide. Their use in preparation of 2-deoxy-2-methyl-amino derivatives is discussed. The Kuhn reagent was used in these syntheses for N-methylating amides. However, certain amides containing comparatively bulky substituents in the vicinity of the NH group are resistant to methylation.     

The 13C-n.m.r. spectra of peracetylated cello-oligosaccharides

The reaction of 1,4-anhydro-2-deoxy-5,6-O-isopropylidene-d-arabino-hex-1-enitol (1) with m-chloroperbenzoic acid in ethanol gives 2,3-unsaturated ethyl glycosides together with saturated ethyl glycosides formed by trans-ring opening of 1,2-epoxide intermediates. Similar results are obtained on peroxidation of 1,4-anhydro-2-deoxy-3-O-(2,3:5,6-di-O-isopropylidene-α-d-mannofuranosyl)-5,6-O-isopropylidene-d-arabino-hex-1-enitol (2). Products resulting from osmylation of 1 and 2 and cleavage of the osmate esters are also described. 2-Deoxy derivatives are prepared from 1 and 2 by methoxymercuration-demercuration and also by reduction of 2-bromo-2-deoxy derivatives obtained by ethoxybromination.     

Equimolar oxymercuration of D-glucal triacetate with mercuric perchlorate and its application to the synthesis of 2′-deoxy disaccharides

A search for appropriate reaction conditions for the equimolar methoxymercuration of D-glucal triacetate was made by using various mercuric salts, bases, and reaction solvents. Under optimum conditions with mercuric perchlorate, sym-collidine, and acetonitrile, D-glucal triacetate underwent methoxymercuration with an equimolar amount of methanol to afford methyl 3,4,6-tri-O-acetyl-2-deoxy-2-perchloratomercuri-β-D-glucopyranoside (1, 26%) and its α-D-manno isomer (2, 49%). Equimolar oxymercuration of D-glucal triacetate with partially protected sugars, followed by subsequent demercuration of the products with sodium borohydride, afforded α- and β-linked 2′-deoxy disaccharide derivatives in moderate yields. The partially protected sugars used were 1,2,3,4-tetra-O-acetyl-β-D-glucopyranose and 1,2:3,4-di-O-isopropylidene-α-D-galactopyranose, and the corresponding products were O-(3,4,6-tri-O-acetyl-2-deoxy-α-D-arabino-hexopyranosyl)-(1→6)-1,2,3,4-tetra-O-acetyl-D-glucopyranose(4, 23%) and its β-linked isomer (5, 11%) from the former, and O-(3,4,6-tri-O-acetyl-2-deoxy-α-D-arabino-hexapyranosyl)-(1→6)-1,2:3,4-di- O-isopropylidene-α-D-galactopyranose (9, 29%) and its β-linked isomer (10, 10%) from the latter. Deacetylation of these 2′-deoxy disaccharides was effected with methanolic sodium methoxide, but deacetonation was unsuccessful owing to simultaneous cleavage of the glycosidic linkage.     

New highly active taxoids from 9beta-dihydrobaccatin-9,10-acetals. Part 2

To investigate structure-activity relationships of the 9,10-acetal-9beta-dihydro taxoids, we modified the 7-hydroxyl groups of the 9,10-acetonide-3'-(4-pyridyl) analogue to deoxy, methoxy, alpha-F, and 7beta,8beta-methano group. As a result of this study, we found that the 7-deoxy analogue was the strongest among these analogues. In addition, we found that the 7-deoxy-3'-(4-pyridyl) and 7-deoxy-3'-(2-pyridyl) analogues showed stronger activity against cell lines expressing P-glycoprotein than the corresponding 3'-phenyl analogue.     

Convenient synthesis of 3- and 6-deoxy-D-myo-inositol phosphate analogues from (+)-epi- and (-)-vibo-quercitols

Starting from (+)-epi- and (-)-vibo-quercitols readily produced by bioconversion of myo-inositol, some biologically interesting phosphate and polyphosphate analogues, including the Ins(1,4,5)P(3) derivatives of 3-deoxy- and 6-deoxy-D-myo-inositol, could be readily prepared in a conventional manner. In addition, chemical modification at C-2 of the 3-deoxy Ins(1,4,5)P(3) provided 2-epimer, and 2-deoxy and 2-deoxy-2-fluoro forms. Eight polyphosphate analogues obtained were assayed for biological activity against PDH-Pase and PDH-K, and G6Pase, but none proved positive.     

Synthesis of 5-deoxy-β-d-galactofuranosides as tools for the characterization of β-d-galactofuranosidases

Derivatives of 5-deoxy-β-d-galactofuranose (5-deoxy-α-l-arabino-hexofuranose) have been synthesized starting from d-galacturonic acid. The synthesis of methyl 5-deoxy-α-l-arabino-hexofuranoside (14α) was achieved by an efficient strategy previously optimized, involving a photoinduced electron transfer (PET) deoxygenation. Compound 14α was converted into per-O-acetyl-5-deoxy-α,β-l-arabino-hexofuranoside (16), an activated precursor for glycosylation reactions. The SnCl₄-promoted glycosylation of 16 led to 4-nitrophenyl (19α), and 4-methylthiophenyl 5-deoxy-α-l-arabino-hexofuranosides (20α). The oxygenated analog 4-methylphenyl 1-thio-β-d-galactofuranoside (23β) was also prepared. The 5-deoxy galactofuranosides were evaluated as inhibitors or substrates of the exo-β-d-galactofuranosidase from Penicillium fellutanum, showing that the absence of HO-5 drastically diminishes the affinity for the protein.     

Preparation and calculated conformations of the 2'-, 3'-, 4'-, and 6'-deoxy, 3'-O-methyl, 4'-epi, and 4'- and 6'-deoxy-fluoro derivatives of methyl 4-O-alpha-D-galactopyranosyl-beta-D-galactopyranoside (methyl beta-D-galabioside)

The glycosyl chlorides of the 3-O-methyl (6) and 4-deoxy-4-fluoro (8) O-benzylated derivatives of D-galactopyranose and 2,3,4,6-tetra-O-benzyl-D-glucopyranose were condensed with methyl 2,3,6-tri-O-benzoyl-beta-D-galactopyranoside to give, after deprotection, the 3'-O-methyl (23), 4'-deoxy-4'-fluoro (25), and 4'-epi (27) derivatives, respectively, of methyl beta-D-galabioside (1). The glycosyl fluorides of 2,3,4-tri-O-benzyl-D-fucopyranose and the 3-deoxy (12) and 4-deoxy (16) O-benzylated derivatives of D-galactopyranose were condensed with methyl 2,3,6-tri-O-benzyl-beta-D-galactopyranoside (21), to give, after deprotection, the 6'-deoxy (31), 3'-deoxy (34), and 4'-deoxy (37) derivatives of 1, respectively. The 2'-deoxy (41) derivative of 1 was prepared by N-iodosuccinimide-induced condensation of 3,4,6-tri-O-acetyl-D-galactal and 21 followed by deprotection. Treatment of methyl 2,3,6-tri-O-benzoyl-4-O-(2,3-di-O-benzoyl-alpha-D-galactopyranosyl)-beta -D- galactopyranoside with Et2NSF3 (DAST), followed by deprotection, provided the 6'-deoxy-6'-fluoro (46) derivative of 1. Molecular mechanics calculations yielded conformations for 23, 25, 27, 31, 34, 37, 41, and 46 with small deviations from the calculated conformation for 1 (phi H/psi H: -40 degrees/-6 degrees).     

Stereocontrolled Facile Synthesis and Biological Evaluation of (3′S) and (3′R)-3′-Amino (and Azido)-3′-Deoxy Pyranonucleosides

This article describes the synthesis of (3 ′S) and (3 ′R)-3 ′-amino-3 ′-deoxy pyranonucleosides and their precursors (3 ′S) and (3 ′R)-3 ′-azido-3 ′-deoxy pyranonucleosides. Azidation of 1,2:5,6-di-O-isopropylidene-3-O-toluenesulfonyl-α-D-allofuranose followed by hydrolysis and subsequent acetylation afforded 3-azido-3-deoxy-1,2,4,6-tetra-O-acetyl-D-glucopyranose, which upon coupling with the proper silylated bases, deacetylation, and catalytic hydrogenation, obtained the target 3 ′-amino-3 ′-deoxy-β-D-glucopyranonucleosides. The desired 1-(3 ′-amino-3 ′-deoxy-β-D-allopyranosyl)5-fluorouracil was readily prepared from the suitable imidazylate sugar after azidation followed by a protection/deprotection sequence and reduction of the unprotected azido precursor. No antiviral activity was observed for the novel nucleosides. Moderate cytostatic activity was recorded for the 5-fluorouracil derivatives.     

Structural requirements for active intestinal transport. Spatial and bonding requirements at C-3 of the sugar

Analogues of d-glucose modified at C-3, and in some cases at a second position, were prepared and tested for active accumulation by everted segments of hamster intestine. Their relative affinity for the sugar carrier was measured by tissue/medium ratio, Michaelis-Menten kinetics and competitive inhibition of d-galactose or methyl alpha-d-glucoside transport. d-Glucose and its 3-deoxy-3-fluoro, 3-chloro-3-deoxy and to a smaller extent its 3-bromo-3-deoxy derivatives, bound and were transported more strongly than 3-deoxy-d-glucose and other sugars not containing an electronegative atom in the gluco configuration at C-3. 3-Deoxy-d-galactose, 3,6-dideoxy-d-glucose and d-gulose, which have two alterations from the d-glucose structure, were not, or only very weakly, transported. The results are interpreted as indicating the presence of a hydrogen bond from the carrier to the hydroxyl group at C-3 of d-glucose. Spatial requirements are also discussed. New syntheses are reported for 3-chloro-3-deoxy- and 3-bromo-3-deoxy-d-glucose and 3,6-dideoxy-d-glucose.