Deoxy Function Research Articles

Design, synthesis and SAR analysis of antitumour styryl lactones related to (+)-crassalactones B and C

A series of styryl lactones containing the cinnamic acid ester groups such as (+)-crassalactones B (3a) and C (4a), 5,7-di-O-cinamoyl derivative 6, the corresponding 7-epimers and 7-deoxy derivatives have been synthesized, characterized and evaluated for their in vitro antitumour activity against a panel of several human tumour cell lines. Twelve new analogues such as 5-O- or 7-O-(4-methoxycinnamoyl), 5-O- or 7-O-(4-nitrocinnamoyl) and 5-O- or 7-O-(4-fluorocinnamoyl) esters of (+)-goniofufurone (3b–d), 7-epi-(+)-goniofufurone (epi-3b–d), as well as 7-deoxy derivatives 5b–d have been prepared to correlate all compounds in a SAR study. Some of the analogues displayed powerful antiproliferative effects on selected human tumour cell lines, but none of them demonstrated cytotoxicity towards the normal foetal lung fibroblasts (MRC-5). Thus, for the 7-epi-crassalactone B (epi-3a) was found to be a potent inhibitor of HL-60 cells growth, with an IC50 value that is approximately 46-fold lower than that observed for the commercial antitumour drug doxorubicin in the culture of the same cells. A SAR analysis performed on these lactones reveals the main structural features that affect their antiproliferative activity, such as nature of the substituents at the C-4 in the aromatic rings of cinnamoyl moieties, the absolute stereochemistry, as well as the presence of a deoxy function at the C-7 position.

Heteroannelated and 7-deoxygenated goniofufurone mimics with antitumour activity: Design, synthesis and preliminary SAR studies

Cytotoxic (+)-goniofufurone mimic such as benzoxepane 2 was preferentially formed after the treatment of 7-O-benzoyl-5-O-benzyl (+)-goniofufurone derivative 6 with titanium(IV) fluoride. However, the corresponding 7-epimer 5 (derivative of 7-epi-goniofufurone) under the similar reaction conditions gave mainly 7-deoxy derivative 7 as a result of an unexpected 1,5-hydride shift. Extension of this methodology to the enantiomer ent-6 provided cytotoxic (−)-goniofufurone mimics ent-2 and ent-7. Synthesized compounds showed diverse growth inhibitory effects against selected tumour cell lines, but were devoid of any significant toxicity towards the normal foetal lung fibroblasts (MRC-5). A SAR study reveals the structural features of these lactones that are beneficial for their antiproliferative activity, such as presence of an additional oxepane ring, the absolute stereochemistry and the presence of a deoxy function at the C-7 position.

Synthesis of monodeoxy analogues of the trisaccharide α- d-Glc p-(1→3)-α- d-Man p-(1→2)-α- d-Man pOMe recognised by Calreticulin/Calnexin

Six (3,4,4′,6′,3″ or 6″)-monodeoxy analogues of the title trisaccharide ( 1– 6) have been prepared utilising monodeoxy monosaccharide precursors. The reducing end deoxy derivatives were synthesised by N-iodosuccinimide/silver trifluoromethanesulfonate (NIS/AgOTf)-promoted couplings of a common disaccharide thioglycoside donor 10 to suitably protected monodeoxy acceptors 9 and 12, affording trisaccharides, which after deprotection yielded target structures 1 and 2. The non-reducing end deoxy derivatives could similarly be produced by halide-assisted glycosylations of a common disaccharide acceptor 17 with monodeoxy glycosyl bromide donors (obtained from thioglycosides 18 and 20) to yield, after removal of protecting groups, target trisaccharides 3 and 4. The analogues with the deoxy function in the middle mannose residue, were obtained through orthogonal halide-assisted coupling of tetrabenzyl-glucopyranosyl bromide to monodeoxy thioglycoside acceptors to give thioglycoside disaccharides, which subsequently were used as donors in NIS/AgOTf-promoted couplings to a common 2-hydroxy-mannose acceptor 15 to afford trisaccharides; deprotection yielded the final target compounds 5 and 6.

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

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.

The Synthesis of Four Dideoxygenated Analogues of β-Maltosyl-(1→4)-Trehalose

Four derivatives of β-maltosyl-(1→4)-trehalose were prepared, each with two deoxy functions in one of the constitutive disaccharide building blocks. 2,3-Di-O-acetyl-4,6-dideoxy-4,6-diiodo-α-D-galactopyranosyl- (1→4) −1,2,3,6-tetra-O-acetyl-D-glucopyranose (3) was employed as a precursor for the 4‴,6‴-dideoxygenated tetrasaccharide 9: coupling of 3 with 2,3,6-tri-O-benzyl-α-D-glucopyranosyl 2,3,6-tri-O-benzylidene-α-D-glucopyranoside (4) furnished the tetrasaccharide 5 which was deiodinated and deprotected to yield the target tetrasaccharide 9. Secondly, the dideoxygenated maltose derivative 3-deoxy-4,6-O-isopropylidene-2-O-pivaloyl-β-D-glucopyranosyl- (1→4) −1,6-anhydro-3-deoxy-2-O-pivaloyl-β-D-glucopyranose (10) was ring-opened to the anomeric acetate 11. A [2+2] block synthesis with 4 in TMS triflate mediated glycosylation gave a tetrasaccharide which was deprotected to the 3″,3‴-dideoxygenated analogue of β-maltosyl-(1→4)-trehalose. For the third tetrasaccharide, 2,3,2″,3′-tetra-O-benzyl-α,α-trehalose was iodinated at the primary positions and deiodinated in the presence of palladium-on-carbon, then this acceptor was selectively glycosylated with hepta-O-acetyl-maltosyl bromide (20). Removal of protective groups furnished the maltosyl trehalose tetrasaccharide deoxygenated at positions C-6 and C-6′. to prepare a 3,3′-dideoxygenated trehalose, the free hydroxyl groups of 2-O-benzyl-4,6-O-(R)-benzylidene-α-D-glucopyranosyl 2-O-benzyl-4,6-O-(R)-benzylidene-α-D-glucopyranoside (25) were reduced by Barton-McCombie deoxygenation. One of the benzylidene groups was opened reductively with sodium cyanoborohydride. The resulting free hydroxyl group at the 4′-position was glycosylated in a Koenigs-Knorr reaction with 20 to yield the 3,3′-dideoxygenated tetrasaccharide 32, the fourth target oligosaccharide, after deprotection.

The Synthesis of the 3′- and 3′′′-Monodeoxygenated Derivatives of β-Maltosyl-(1→4)-Trehalose

Two derivatives of β-maltosyl-(1→4)-trehalose monodeoxygenated at C-3′ or C-3′′′ have been synthesized in [2+2] block syntheses. Starting from 4,6;4′,6′-di-O-benzylidene-trehalose (3) the 3′-hydroxyl group was singled out by selective pivaloylation and reduced by a Barton-McCombie reaction. The benzylidene group in the vicinity of the deoxy function could be reductively opened to supply a suitable monodeoxygenated glycosyl acceptor (8). Standard glycosylation with hepta-O-acetylmaltosyl bromide and deprotection led to 3′-deoxymaltosyl-(1→4)-trehalose 13. For the synthesis of a 3′-deoxygenated derivative of maltose we used 1,6-anhydromaltose as starting material. From the tributyltin hydride reduction of the 3,3′-bis-thiocarbonylimidazole derivative 18, the 3′-monodeoxygenated derivative 20 was obtained in low yield. After opening of the 1,6-anhydro ring, the maltosyl derivative was activated as trichloroacetimidate 24. Glycosylation followed by standard deprotection furnished the 3′′′-deoxymaltosyl-(1→4)-trehalose 28.

Selectively Deoxygenated Derivatives of β-Maltosyl-(1→4)-Trehalose as Biological Probes. II. the Synthesis of the 4- and 4′″-Monodeoxygenated Analogues

ABSTRACT Two derivatives of β-maltosyl-(1→4)-trehalose monodeoxygenated at positions 4 or 4′″ have been synthesized in [2+2] block syntheses. After the preparation of precursors with only one free hydroxyl group the deoxy function was introduced by a Barton-McCombie reaction. Thus, glycosylation of 2,3,6-tri-O-benzyl-α-D-glucopyranosyl 2,3,6-tri-O-benzyl-α-D-glucopyranoside (4) with octa-O-acetyl-β-maltose (3) gave tetrasaccharide 5 with only one free hydroxyl group at the 4-position. The 4′-position of an allyl maltoside was available selectively after removal of a 4′,6′-cyclic acetal and selective benzoylation of the 6′-position. Reduction of this derivative 11 afforded allyl O-(2,3-di-O-acetyl-6-O-benzoyl-4-deoxy-α-D-glucopyranosyl)-(1→4)-2,3,6-tri-O-acetyl-β-D-glucopyranoside (14), which was deallylated, activated as an trichloroacetimidate, and coupled to 2,3-di-O-benzyl-4,6-O-benzylidene-α-D-glucopyranosyl 2′,3′,6′-tri-O-benzyl-α-D-glucopyranoside (20). Several compounds were fully characterized by ...

Syntheses of deoxy analogues of methyl [formula omitted] for studies of the binding site of Concanavalin A

All of the monodeoxy analogues of methyl 3,6- di-O-α- d-mannopyranosyl-α- d-mannopyranoside have been synthesized together with two dideoxy (2,3′- and 4,3′-) analogues. The 2′- and 2″-deoxy functions were introduced by NIS-promoted couplings with 2,3,4- tri-O- acetyl- d-glucal as donor, followed by reduction of the resulting 2′- and 2″-iodo derivatives, whereas the 3′-, 3″-, 4′-, 4″-, 6′-, and 6″-deoxy functions were introduced by using known deoxyglycosyl chlorides as donors in coupling reactions promoted by silver trifluoromethanesulfonate. The 2- and 4-deoxy functions on the central mannose residue were introduced by displacement, using triiodoimidazole and triphenylphosphine, of a hydroxyl group by iodine on suitably protected derivatives followed by reduction of the resulting iodo analogues.

Bausteine von Oligosacchariden, CIII. Synthese von modifizierten Derivaten des Disaccharides β‐D‐Gal‐(1 → 3)‐α‐D‐GalNAc zur Untersuchung der Substratspezifität der Core‐2‐β6‐GlcNAc‐Transferase und α‐3‐Sialyltransferase der Biosynthese von O‐Glycoproteinen

Building Units of Oligosaccharides, CIII. — Synthesis of Modified Derivatives of the Disaccharide β‐D‐Gal‐(→3)‐α‐D‐GalNAc for the Examination of Substrate Specificities of Core 2‐β6‐GlcNAc‐Transferase and α‐3‐Sialyltransferase Involved in the Biosynthesis of O‐GlycoproteinsDerivatives of benzyl β‐D‐galactopyranosyl‐(1→3)‐2‐acet‐amido‐2‐deoxy‐α‐D‐galactopyranoside have been synthesized. The 6′‐, 4′‐ and 3′‐OH group of the galactose moiety as well as the 6‐ and 4‐OH and the 2‐acetamido group of the 2‐acet‐amido‐2‐deoxy‐D‐galactose moiety have been selectively substituted by the corresponding deoxy function. The compounds are useful in studies of the substrate specificities of the core 2‐β6‐GlcNAc‐transferase and the α3‐sialyltransferase involved in the biosynthesis of O‐glycoproteins.

Formation of disaccharides related to heparin and heparan sulfate by chemical modification of maltose

Maltose has been converted into 4- O-(2-amino-2-deoxy-α- d-glucopyranosyl)- l-idopyranuronic acid, 4- O-(2-amino-2-deoxy-α- d-glucopyranosyl)- d-glucopyranose, and 4- O-α- d-glucopyranosyl- l-idopyranose, the first two disaccharides being related structurally to biose sequences in heparin and heparan sulfate. Used as the starting material was a major product of the kinetic acetonation of maltose, namely, 2,3:5,6-di- O-isopropylidene-4- O-(4,6- O-isopropylidene-α- d-glucopyranosyl)- aldehydo- d-glucose dimethyl acetal. It was subjected to a sequence of transformations that included the introduction of a 2′-amino-2′-deoxy function into the glucosyl group, the inversion of C-5 in the glucose residue to give the l- ido configuration, oxidation at position 6, and cyclisation of the acyclic dimethyl acetal to give the desired pyranuronic acid. In the formation of the latter, the 5- O-levulinoyl substituent was found to be less prone to acyl migration to O-6 than more conventional ester groups. The relative acid labilities of the O-isopropylidene and dimethyl acetal groups are compared, and conformations of the acyclic residues of some disaccharide derivatives are discussed.

Stereoselective synthesis of s-(2-deoxy-α-D-glycosyl)- phosphorodithioates 1 and of their (2R)-2-deoxy-2-deuterio- analogues. Novel route to C-2 d

Addition of 0,0-dialkylphosphorodithioic acids to fully protected 1,2-unsaturated hexo- and pentopyranoses gives S-(2-deoxy-glycosyl)-phosphorodithioates in quantitative yield and high stereoselectivity with respect to the α-isomer. The stereochemistry of this reaction is “cis” as demonstrated by the addition of deuterated 0,0-dialkylphosphorodithioic acids to 3,4,6-tri-O-acetyl-D-glucal which gives exclusively the α-dithiophosphates of (2R)-2-deoxy-2-deuterio-D-arabinohexopyranose. This result provides an efficient and fully stereoselective method of labeling of the deoxy function in 2-deoxy monosaccharides and their glycosylic derivatives.

Identification of 2-keto-3-deoxy-1,7-dicarboxyheptonic acid as a constituent of the lipopolysaccharide of Acinetobacter calcoaceticus NCTC 10305.

A 3-deoxyaldulosonic acid, not previously described, was identified as a component of the lipopolysaccharide of Acinetobacter calcoaceticus NCTC 10305: 2-keto-3-deoxy-1,7-dicarboxyheptonic acid. This compound, whose steric configuration has not been determined, was released from lipopolysaccharide after acid hydrolysis as monosaccharide and in the form of a glucose-substituted disaccharide. It was identified by combined gas-liquid chromatography/mass spectrometry using various derivatization procedures. The presence of a 2-keto-3-deoxyaldulosonic acid was established from the typical fragmentation pattern of the C1-C6 moiety which was identical to that of similarly derivatized authentic 2-keto-3-deoxy-D-mannooctonic acid (dOclA). Location of the keto and deoxy function at C2 and C3, respectively, was deduced from the fragmentation pattern of the deuterolabelled derivatives after reduction of the keto and carboxy groups. The presence of two carboxy groups was ascertained after carboxy reduction with sodium boro-(2H)hydride of the carbonyl-reduced and permethylated derivative whereby the molecular masses were found to differ by 4 Da. Further proof for the presence of two carboxy groups was obtained by alkaline transesterification of the carbonyl-reduced and permethylated derivative with ethanolic sodium ethylate: it was shown that two methyl ester groups had been transesterified since the molecular mass was shifted higher by 28 Da. Substitution by a D-glucopyranosyl residue in position 4 was established by methylation analysis performed on the carbonyl- and carboxyl-reduced and permethylated disaccharide. The D-configuration of the glucosyl residue was determined by its reactivity with D-glucose oxidase. Thus, the structure of the disaccharide is 4-O-glucopyranosyl-2-keto-3-deoxy-1,7-dicarboxyheptonic acid.

Stereochemical dependence of the mechanism of deoxygenation, with lithium triethylborohydride, in 4,6-O-benzylidenehexopyranoside p-toluenesulfonates

Lithium triethylborohydride was shown to react with methyl 4,6-O-benzylidene-α-D-hexopyranoside 2- and 3-tosylates, and 2,3-ditosylates, in the manno, allo, and altro configurational series both by O—S fission (O-desulfonylation) and by C—O fission (C-desulfonyloxylation), to produce carbinol and deoxy functions, respectively. The results were compared with those previously obtained with the corresponding gluco and galacto isomers, and the degree of facility of the cleavage reactions was seen to depend on the position of the sulfonic ester groups and the overall configuration of the molecules. The mechanism of reductive desulfonyloxylation also depended on configuration and was demonstrated to involve intermediary epoxide formation or displacement by internal hydride shift as the principal paths; competing elimination and direct nucleophilic displacement were found to occur in the allo series, whereas reduction accompanied by ring contraction has thus far been encountered only in the conformationally less constrained, cis-fused acetal system of the galacto series. Like the borohydride reagent, lithium aluminum hydride was found to react (though much more slowly) with the altro 2,3-ditosylate by the epoxide-mediated mechanism, although the latter hydride is known to desulfonyloxylate the α-D-gluco-isomer by a different, intramolecular reduction mechanism.