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Biomedical subjects

D Horton

Publications and source records attributed to D Horton.

At least 91 records · Page 5Linked to original sources
PubMed1979

New daunorubicin analogs. 3-Amino-2,3,6-trideoxy-alpha- and beta-D-arabino- and 3,6-diamino-2,3,6-trideoxy- alpha-D-ribo-hexopyranosides of daunomycinone.

Glycosidation of 2,3,6-trideoxy-3-trifluoroacetamido-4-O-trifluoroacetyl-alpha-D-arabino-hexopyranosyl chloride (19) (or the corresponding 4-p-nitrobenzoate, 20) with daunomycinone under Koenigs-Knorr conditions afforded, after separation of the anomers and removal of the protecting groups, the individual target glycosides 8 (alpha anomer; major product) and 9 (beta; minor) in acceptable yields. In contrast, the title diamino sugar, suitably protected with N-trifluoroacetyl and O-acetyl (or O-p-nitrobenzoyl) groups, underwent stereospecific coupling to the anthracycline aglycon by the glycal procedure to give, after deprotection, the alpha glycoside 12. All three analogs were assayed in vivo against P388 lymphocytic leukemia. They showed little (T/C 125 for 8; T/C 115 for 9) or no (compound 12) activity, but were essentially devoid of toxicity at the dose-levels tested.

Animals↗
PubMed1979

Preparatively useful reactions involving nitrogenous sugars and some applications with carbohydrate-containing antibiotics.

This work describes the development of useful synthetic methodology with simple sugars, practical applications for conversion of abundant precursors into modified sugars (especially amino and deoxy sugars) of importance in various groups of natural products, and the conversion of such products into compounds of biological or pharmacological interest, especially carbohydrate antibiotics and their analogs. Examples of synthetic methodology illustrate various routes to deoxygenated (saturated, alkenic, and acetylenic), and oxidized (carbonylic, aldehydic, and carboxylic) functionality from hydroxyl and amino precursors. Unusual modes of sugar protection by such procedures as kinetic acetonation are discussed, together with the use of diazo and hydrazino groups for access to novel structures, including extended carbon-chain sugars and sugar--heterocycle conjugates. The broad utility of 5-membered benzylidene acetals in regiospecific routes to alpha, beta-deoxycarbonyl sugars is the basis of general methodology for practical, large-scale synthesis of aminopolydeoxy sugars, with daunosamine as the prototype, of widely varied substitution-mode and stereochemistry. Implications of the foregoing are discussed in relation to several classes of antibiotics, especially the anthracyclines and analogs thereof. A range of 7-O-(amino sugar-substituted)daunomycinones have been synthesized, together with 3'-hydroxy-daunorubicin and adriamycin, and their antitumor and toxicological properties evaluated; prospects for useful total synthesis will be mentioned.

Amino Sugars↗
PubMed1977

Preparation of derivatives of L-idose and L-iduronic acid from 1,2-O-isopropylidene-alpha-D-glucofuranose by way of acetylenic intermediates.

The products (1) from the periodate oxidation of 1,2-O-isopropylidene-alpha-D-glucofuranose were converted by ethynylmagnesium bromide into a separable, 14:11 mixture of 6,7-dideoxy-1,2-O-isopropylidene-beta-L-ido-hept-6-ynofuranose (2) and its alpha-D-gluco analog 3. These crystalline products were further characterized as their respective 3,5-diacetates (5 and 7) and 3,5-dibenzoates (4 and 6). Ozonolysis of 2 and 3 led to 1,2-O-isopropylidene-beta-L-idofuranurono-6,3-lactone (8) and its alpha-D-gluco analog 9, respectively; similar ozonolysis of the dibenzoates 4 and 6, followed by treatment with diazomethane, gave methyl 3,5-di-O-benzoyl-1,2-O-isopropylidene-alpha-L-idofuranuronate (10) and its alpha-D-gluco analog 11, respectively. Diborane reduction of the ozonolysis products from 4 gave 1,2-O-isopropylidene-beta-tl-idofuranose (13) as its 3,5-dibenzoate (12), and a similar sequence was performed with 6. The propargylic alcohols 2 and 3 were reduced by lithium aluminum hydride, in high yield, to the allylic alcohol analogs 15 and 16, further characterized as their 3,5-dibenzoates 17 and 18; compounds 15 and 16 were also obtainable by vinylation of compounds 1. The two series of derivatives in this work, epimeric at C-5, were examined comparatively by polarimetry and p.m.r. spectroscopy.

Acetylene↗
PubMed1977

Photochemical conversion of sugar dimethylthiocarbamates into deoxy sugars.

Protected sugar derivatives having one free hydroxyl group may be deoxygenated at the alcoholic position by ultraviolet irradiation of the corresponding dimethylthiocarbamic esters; a concomitant process leads also to the original alcohol. Thus, on photolysis, the 6-dimethylthiocarbamate (1) of 1,2:3,4-di-O-isopropylidene-alpha-D-galactopyranose (3) gives 6-deoxy-1,2:3,4-di-O-isopropylidene-alpha-D-galactopyranose (2) together with 3. Likewise, the 4-dimethylthiocarbamate (6) of 1,6-anhydro-2,3-O-isopropylidene-beta-D-mannopyranose (8) gives a mixture of the 4-deoxy derivative 7 and the alcohol 8. 3-Deoxy-1,2:5,6-di-O-isopropylidene-alpha-D-ribo-hexofuranose (10) was obtained by irradiation of 3-O-(dimethylthiocarbamoyl)-1,2:5,6-di-O-isopropylidene-alpha-D-glucofuranose (9), and was accompanied by 1,2:5,6-di-O-isopropylidene-alpha-D-glucofuranose (11). The 3-deoxy-3-iodo analog (14) of 11 underwent conversion into 10 by photolysis, and the deoxy sugar 10 was also prepared from 3,3'-dithiobis(1,2:5,6-di-O-isopropylidene-alpha-D-glucofuranose) (12) by the action of Raney nickel. Photolysis of the 2-dimethylthiocarbamate (16) of methyl 3,4-O-isopropylidene-beta-L-arabinopyranoside (18 gave the 2-deoxy derivative (17), together with the parent alcohol 18, and the same pair of products was obtained by the action of tributylstannane on the 2-(methylthio)thiocarbonyl derivative (19) of 18, although the dimethylthiocarbamate 16 was unreactive toward tributylstannane.

Arabinose↗
PubMed1977

Preparation of 3-amino-2,3,6-trideoxy-D-arabino-hexose hydrochloride and its N-trifluoroacetyl derivative.

Methyl 3-acetamido-4,6-O-benzylidene-2,3-dideoxy-alpha-D-arabino-hexopyranoside (5) was converted by treatment with N-bromosuccinimide into the 4-O-benzoyl-6-bromo derivative 6. Reduction with Raney nickel followed by catalytic transesterification of the resultant 4-benzoate 7 afforded methyl 3-acetamido-2,3,6-trideoxy-alpha-D-arabino-hexopyranoside (8), which could readily be converted into the 4-acetate 11. N-Decetylation of 7 and subsequent acid hydrolysis furnished 3-amino-2,3,6-trideoxy-D-arabino-hexose hydrochloride (9), the D enantiomorph of acosamine. The 3-benzamido analog (12) of 8 was prepared from 8 by N-deacetylation and subsequent benzoylation. Hydrolysis of 8 and 12 gave the 3-acetamido (10) and 3-benzamido (13) analogs of 9, which crystallized in the alpha anomeric form. 2,3,6-Trideoxy-3-trifluoro-acetamido-alpha-D-arabino-hexopyranose (15), a key intermediate for the synthesis of glycosidically coupled derivatives of 9, was obtained from 7 by saponification with barium hydroxide followed by N-trifluoracetylation of the resultant glycoside 14 and subsequent selective hydrolysis.

Amino Sugars↗
PubMed1977

Preparative syntheses of 2,6-dideoxy-alpha-L-lyxo-hexose (2-deoxy-alpha-L-fucose) and its D-ribo epimer (digitoxose).

Methyl 4,6-O-benzylidene-2-deoxy-alpha-D-ribo-hexopyranoside (1) is converted into methyl 3,4-di-O-benzoyl-6-bromo-2,6-dideoxy-alpha-D-ribo-hexopyranoside (3) via the 3-O-benzoyl derivative (2) of 1 by subsequent treatment with N-bromosuccinimide. Compound 3 is the key intermediate in high-yielding, preparative syntheses of the title dideoxy sugars, which are constituents of many antibiotics, Dehydrohalogenation of 3 affords the 5,6-unsaturated glycoside 7, which undergoes stereospecific reduction by hydrogen with net inversion at C-5 to give methyl 3,4-di-O-benzoyl-2,6-dideoxy-beta-L-lyxo-hexopyranoside (8), whereas reductive dehalogenation of 3 provides the corresponding D-ribo derivative 4. The unprotected glycosides 9 (L-lyxo) and 5 (D-ribo) are readily obtained by catalytic transesterification, and mild, acid hydrolysis gives the crystalline title sugars 10 (L-lyxo) and 6 (D-ribo) in 45 and 57% overall yield from 1 without the necessity of chromatographic purification at any of the steps.

Chemical Phenomena↗
PubMed1977

Characterization of 2-amino-2,6-dideoxy-D-glucose as a constituent of the lipopolysaccharide antigen of Pseudomonas aeruginosa immunotype 4.

The title lipopolysaccharide was freed from its lipid A component by mild, acid hydrolysis, to give a polysaccharide fraction that was subsequently hydrolyzed completely to afford a mixture of neutral sugars and amino sugars. The amino sugars were separated, and identified as 2-amino-2-deoxy-D-galactose, 2-amino-2,6-dideoxy-galactose as a 2:1 mixture of the D and L enantiomers, and 2-amino-2,6-dideoxy-D-glucose. A reference sample of 2-amino-2,6-dideoxy-D-glucose was synthesized by an improved preparative route. Among the lipopolysaccharide antigens of the seven recognized immunotypes of Pseudomonas aeruginosa, 2-amino-2,6-dideoxyglucose is also characterized as a constituent of two others, types 3 and 5.

Deoxyglucose↗
PubMed1977

Analytical characterization of lipopolysaccharide antigens from seven strains of Pseudomonas aeruginosa.

Lipopolysaccharide antigens from seven different serotype strains (antigen immunotypes Nos. 1-7 in the classification of Fisher et al.3) of Pseudomonas aeruginosa have been analyzed for neutral carbohydrate, amino sugars, lipid, protein, 3-deoxy-manno-octulosonic acid, and phosphorus. The individual amino sugars were determined for each antigen type; all contained 2-amino-2-deoxy-D-glucose and -D-galactose, together with 2-amino-2,6-dideoxygalactose; the latter as isolated from the type 2 antigen was identified as the DL form. In addition, 2-amino-2,6-dideoxy-D-glucose was present in the types 3, 4, and 5 antigens. Mild, acid hydrolysis of the antigens gave the lipid A component containing all of the lipid and 2-amino-2-deoxy-D-glucose, together with lipid A-free polysaccharides that contained principally carbohydrate. The lipid A-free polysaccharides all contained L-rhamnose and D-glucose, together with 2-amino-2,6-dideoxygalactose in all except those from types 1, 5, and 7; that from type 6 also contained D-xylose.

Amino Sugars↗
PubMed1976

Reaction of derivatives of methyl 2,3-O-benzylidene-6-deoxy-alpha-L-mannopyranoside with butyllithium: synthesis of methyl 2,6-dideoxy-4-O-methyl-alpha-L-erythro-hexopyranosid-3-ulose.

Methyl 2,3-O-benzylidene-6-deoxy-alpha-L-mannopyranoside (2) reacted with butyllithium to give a mixture of 1,5-anhydro-3-C-butyl-1,2,6-trideoxy-L-ribo-hex-1-enitol (3) and its L-arabino analogue (4), together with methyl 2,3,6-trideoxy-alpha-L-erythro-hex-2-enopyranoside (5). In contrast, the 4-O-methyl-analogue (8) of 2 was converted by butyllithium into methyl 2,6-dideoxy-4-O-methyl-alpha-L-erythro-hexo-pyranosid-3-ulose (9), which was further characterized as its oxime 10. The 4-O-benzyl analogue of 8, obtained as two separate diastereoisomers (6 and 7) differing in configuration at C-2 of the dioxolane ring gave a complex misture of products on treatment with butyllithium.

Daunorubicin↗
PubMed1976

Synthesis of 3-amino-2,3,6-trideoxy-D-ribo-hexose hydrochloride.

The title sugar, the 5-epimer of daunosamine, was prepared in a sequence of high-yielding steps from methyl alpha-D-mannopyranoside (1). Conversion of 1 into methyl 3-acetamido-4-O-benzoyl-6-bromo-2,3,6-trideoxy-alpha-D-ribo-hexopyranoside (2), followed by reduction with hydrogen and Raney nickel, gave the 4-benzoate (3) of methyl 3-acetamido-2,3,6-trideoxy-alpha-D-ribo-hexopyranoside (4). Saponification of 3 gave 4 as an oil that gave a crystalline 4-acetate (8). N-Deacetylation of 4 was effected with barium hydroxide, and the resultant glycoside was hydrolyzed to give 3-amino-2,3,6-trideoxy-D-ribo-hexose hydrochloride (7). The 3-benzamido analogue (5) of 4 was prepared from 4 by N-deacetylation and subsequent benzoylation, and hydrolysis of 5 gave crystalline 3-benzamido-2,3,6-trideoxy-D-ribo-hexose (6). The crystalline 3-acetamido analogue (9) of 6 was obtained by acid hydrolysis of the glycoside 4.

Deoxy Sugars↗
PubMed1975

Synthesis and evaluation of acyclic sugar nucleosides.

Acylated aldose dialkyl dithioacetals with bromine undergo replacement of one alkylthio group by bromine. These unstable bromides react, as by fusion with 2,4-bis(trimethylsilyloxy)pyrimidine, to give acylated 1-(pyrimidin-1-yl) derivatives that upon saponification afford acyclic sugar nucleoside analogues, some as separable mixtures of 1-epimers. Systemic stereochemical variants have been conducted. Pmr conformational studies show that the sugar chain is extended in certain examples, whereas others favor folded ("sickle") conformations, in line with a general rationale developed for acyclic-sugar derivatives. Condensation of the bromides with purines gives 9-substituted acyclic-sugar nucleoside analogues; synthesized systematically for various series, these include the D-pentoses in combination with 6-mercaptopurine. In vitro and in vivo biological activities vary according to stereochemistry of the sugar. The position of substitution of the sugar chain, the chirality at C-1', and the tautomeric form of the heterocycle, were established by x-ray crystallography of the product from D-arabinose and 6-mercaptopurine. The x-ray data permit correlation of C-1 chirality throughout the series and pmr data indicate the favored conformations.

Arabinose↗
PubMed1975

A preparative synthesis of 3-amino-2,3,6-trideoxy-L-lyxo-hexose (daunosamine) hydrochloride from D-mannose.

A simple, preparative route in nine steps from methyl alpha-D-mannopyranoside (1) is described that affords, in 40% overall yield, the title amino sugar 11, the sugar constituent of the antitumor antibiotics adriamycin and daunorubicin. The 2,3:4,5-dibenzylidene acetal (2) of 1 is converted by butyllithium into the 2-deoxy-3-ketone 3, whose oxime 4 is reduced with high stereoselectivity to the D-ribo amine, isolated as its N-acetyl derivative 5 and converted by action of N-bromosuccinimide into the 4-O-benzoyl-6-bromide 7. Dehydrohalogenation of gives the 5,6-unsaturated glycoside 8, which, after O-debenzoylation to 9, undergoes stereospecific reduction by hydrogen with net C-5 inversion to give the crystalline, N-acetylated methyl beta-glycoside (10) of daunosamine, readily converted into daunosamine hydrochloride (11) and into the crystalline N-benzoyl (14) and N-acetyl(15) derivatives. No chromatographic procedures for isolation are required in any of the steps.

Deoxy Sugars↗