Acetonation of 2-(acylamino)-2-deoxy-d-glucoses

2-Acetamido-2-deoxy-d-glucose and 2-(benzyloxycarbonylamino)-2-deoxy-d-glucose were each treated with 2,2-dimethoxypropane in N,N-dimethylformamide containing a trace of p-toluenesulfonic acid. The new 5,6-O-isopropylidene derivatives 2-acetamido-2-deoxy-5,6-O-isopropylidene-d-glucofuranose, 2-acetamido-1,4-anhydro-2-deoxy-5,6-O-isopropylidene-d-arabino-hex-1-enitol, 2-acetamido-2-deoxy-3,4:-5,6-di-O-isopropylidene-aldehydo-d-glucose-dimethyl acetal, and 2-(benzyloxycarbonylamino)-2-deoxy-5,6-O-isopropylidene-d-glucofuranose were isolated. The formation of these furanoid acetals may be important in ascertaining the mechanism of this unique acetonation accompanied by glycosidation.     

Enantiospecific synthesis of carbocyclic (+)-(E)-5-(2-bromovinyl)-2'-deoxyuridine

(+)-1-[(1R, 3S, 4R)-3-hydroxy-4-hydroxymethylcyclopentyl]-5-[(E)-2- bromovinyl]-1H,3H-pyrimidin-2,4-dione 10 was synthesized starting from (+)-endo-5-norbornen-2-yl acetate. This chiral educt was obtained by enzymatic hydrolysis of racemic esters of endo-5-norbornen-2-ol.     

The Synthesis and Antiviral Activity of (E)-5-(2-Nitrovinyl)uridine and (E)-5-(2-Nitrovinyl)-2′-deoxyuridine

Abstract

The protection of the sugar moiety of a 5-formyluracil nucleoside with acid-labile protecting groups allows for the deprotection of the sugar of a subsequently formed nucleoside possessing a 5-nitrovinyl side-chain. The synthesis and antiviral activity of (E) -5-(2-nitrovinyl)-uridine and (E)-5-(2-nitrovinyl)-2′-deoxyuridine are reported.     

Salicylate poly(vinyl chloride) membrane electrode based on (2-[(E)-2-(4-nitrophenyl) hydrazono]-1-phenyl-2-(2-quinolyl)-1-ethanone) Cu(II)

A new salicylate-selective electrode based on the complex of (2-[(E)-2-(4-nitrophenyl)hydrazono]-1-phenyl-2-(2-quinolyl)-1-ethanone) Cu(II) as the membrane carrier was developed. The electrode exhibited a good Nernstian slope of -59.6+/-1.0 mV/decade and a linear range of 1.0 x 10(-6) to 1.0M for salicylate. The limit of detection was 5.0 x 10(-7) M. The electrode had a fast response time of 10 s and can be used for more than 3 months. The selective coefficients were determined by the fixed interference method and could be used in the pH range of 4.0 to 10.5. The electrode was employed as an indicator electrode for direct determination of salicylate in pharmaceutical and biological samples.     

2-(Aminomethyl)-2-decarboxyprostaglandin F2 alpha type analogs

The 2-(aminomethyl)-2-decarboxy analogs of prostaglandin F2 alpha (PGF2 alpha), (15S)-15-methyl-PGF2 alpha, 16-phenoxy-omega-tetranor-PGF2 alpha and 16,16-dimethyl-PGF2 alpha were synthesized. The amino analogs closely resemble the parent PGF2 alpha compounds as antifertility agents in the hamster.     

(E)-2-(2-(2-hydroxyphenyl)hydrazono)-1-phenylbutane-1,3-dione: Tautomery and coordination to copper(II)

(E)-2-(2-(2-hydroxyphenyl)hydrazono)-1-phenylbutane-1,3-dione (H₂L) was synthesized by azocoupling of diazonium salt of 2-hydroxyaniline with 1-phenylbutane-1,3-dione and characterized by IR, ¹H and ¹³C NMR spectroscopies and X-ray diffraction analysis. In solution, H₂L exists as a mixture of the enol-azo and hydrazone tautomeric forms and a decrease of temperature and of solvent polarity shifts the tautomeric balance to the hydrazone form. In the solid state, H₂L crystallizes from ethanol-water in the monohydrate hydrazone form, as shown by X-ray analysis. The dissociation constants of H₂L (pK₁ = 5.98 ± 0.04, pK₂ = 9.72 ± 0.03) and the stability constants of its copper(II) complex (log β₁ = 11.01 ± 0.07, log β₂ = 20.19 ± 0.08) were determined by the potentiometric method in aqueous-ethanol solution. The copper(II) complex [Cu₂(μ-L)₂]_n was isolated in the solid state and found by X-rays to be a coordination polymer of a binuclear core with a distorted square pyramidal metal coordination geometry.     

Synthesis of (S)-2-fluoro-L-daunosamine and (S)-2-fluoro-D-ristosamine

Derivatives of (S)-2-fluoro-L-daunosamine and (S)-2-fluoro-D-ristosamine were synthesized, starting ultimately from 2-amino-2-deoxy-D-glucose which was converted, according to the literature, into methyl 2-benzamido-4, 6-O-benzylidene-2-deoxy-3-O-(methylsulfonyl)-alpha-D-glucopyranoside (2). Treatment of 2 with tetrabutylammonium fluoride gave a 63% yield of (known) methyl 3-benzamido-4,6-O-benzylidene-2,3-dideoxy-2-fluoro-alpha-D-altropyran oside (4), together with a 6% yield of its 2-benzamido-2,3-dideoxy-3-fluoro-alpha-D-gluco isomer. From 4, the corresponding 6-bromo-2,3,6-trideoxyglycoside 4-benzoate (6) was obtained by Hanessian-Hullar reaction. Dehydrobromination of 6, followed by catalytic hydrogenation of the resulting 5-enoside, and subsequent debenzoylation and N-trifluoroacetylation, afforded the fluorodaunosaminide, methyl 2,3,6-trideoxy-2-fluoro-3-trifluoroacetamido-beta-L-galactopyranos ide. Reductive debromination of 6, followed by debenzoylation and N-trifluoroacetylation, gave the fluororistosaminide, methyl 2,3,6-trideoxy-2-fluoro-3-trifluoroacetamido-alpha-D-altropyran oside. The 1H-n.m.r. spectra of the new aminofluoro sugars are discussed with respect to the effects of neighboring amino and acylamido substituents on geminal and vicinal 1H-19F coupling constants, in comparison with the reported effects of oxygen substituents.     

Synthesis and antimetabolite properties of 5-substituted 2'-deoxyuridines. Anomeric 5-(2-aminohexafluoroprop-2-yl)- and 5-(2-trifluoroacetylaminohexafluoroprop-2-yl)-2'-deoxyuridine

Alkylation of 2,4-bis-O-(trimethylsilyl)uracil with hexafluoroacetone trifluoroacetylimine gave 5-(2-trifluoroacelylaminohexafluoroprop-2-yl)uracil, which was transformed by alkaline hydrolysis to 5-(2-aminohexafluoroprop-2-yl)uracil. The latter was glycosytated with 2-deoxy-3,5-di-O-p-toluoyl-alpha-D-ribofyranosyl chloride by means of various modifications of the silyl method leading to the predominant formation of beta-deoxynucleoside; after deacylation 1-(2-deoxy-beta-D-ribofuranosyl)-5-(2-aminohexafluoroprop-2-yl)ura cil was obtained. Interaction of silylated 5-(2-trifluoroacetylaminohexafluoroprop-2-yl)uracil with acylgalogenose gave anomeric O-substitutet deoxynucleosides, which were deblocked to give 5-(2-trifluoroacetylaminohexafluoroprop-2-yl)-2'-deoxyuridine and corresponding alpha-anomer. Alkaline hydrolysis of N-trifluoroacetyl group in both individual anomers produced 1-(2-deoxy-alpha-D-ribofuranosyl)-5-(2-aminohexafluoroprop-2-yl)ur acil and the abovementioned beta-anomer. Of all compounds synthesised only 1-(2-deoxy-beta-D-ribofuranosyl)-5-(2-aminohexafluoroprop-2-yl)ura cil has a moderate inhibitory effect on replication of vaccinia virus in vitro.     

(E)-2-(2-Hydroxyethylidene)-6-methyl-5-heptenal (alpha-acariolal) and (E)-2-(2-hydroxyethyl)-6-methyl-2,5-heptadienal (beta-acariolal), two new types of isomeric monoterpenes from Caloglyphus polyphyllae (Acari: Acaridae)

The opisthonotal gland secretion of the acarid mite, Caloglyphus polyphyllae, contained two new monoterpenes, (E)-2-(2-hydroxyethylidene)-6-methyl-5-heptenal (1) and (E)-2-(2-hydroxyethyl)-6-methyl-2,5-heptadienal (2), to which we have given the trivial names alpha- and beta-acariolal in relation to alpha- and beta-acaridial (3 and 4), respectively. Elucidation of the structure of 1 was established mainly from 1H-NMR and GC/MS spectral data after partial purification, together with the fact that 1 was recovered in the more-polar fraction from a silica gel column than alpha- and beta-acaridial (3 and 4) present in the secretion. Compound 2 was obtained in the same fraction as a mixture with 1. Based on the facts that 2 had the same molecular weight by GC/MS and the same polarity as that of 1, compound 2 was assumed to be a structural analog of 1. The structures of compounds 1 and 2 were confirmed by their synthesis in nine and ten respective steps starting from alpha-bromo-gamma-butyrolactone.     

Synthesis and antibacterial activity of N-[2-[5-(methylthio)thiophen-2-yl]-2-oxoethyl] and N-[2-[5-(methylthio)thiophen-2-yl]-2-(oxyimino)ethyl]piperazinylquinolone derivatives

A number of N-substituted piperazinylquinolone derivatives were synthesized and evaluated for antibacterial activity against Gram-positive and Gram-negative bacteria. Preliminary results indicated that most compounds tested in this study demonstrated comparable or better activity against Staphylococcus aureus and Staphylococcus epidermidis than their parent piperazinylquinolones as reference drugs. Among these derivatives, ciprofloxacin derivative 5a, containing N-[2-[5-(methylthio)thiophen-2-yl]-2-oxoethyl] residue, showed significant improvement of potency against staphylococci, maintaining Gram-negative coverage.     

Chiral synthesis of (2S,3S)-2-(2-morpholin-2-yl-2-phenylmethoxy)phenol

Resolution of (2RS,3RS)-2-[alpha-(2-methoxymethoxyphenoxy)phenylmethyl]morpholine, 11, with (+) mandelic acid led to the formation of (+)-(2S,3S)-2-[alpha-(2-methoxymethoxyphenoxy)phenyl methyl] morpholine (11a). Compound 11 was synthesized in seven steps from (2RS,3RS)-cinnamyl alcohol-2,3-epoxide (4), with an overall yield of 17%. Cleavage of the methoxymethyl group of the Fmoc derivative 12 with catalytic amounts of p-toluenesulfonic acid in methanol afforded (+)-(2S,3S)-2-(2-morpholin-2-yl-2-phenylmethoxy)phenol 2. The synthetic utility as well as the configuration of compound 2 has been demonstrated by converting (S,S)-2-(2-morpholin-2-yl-2-phenylmethoxy)phenol 2 to (2S,3S)-2-[alpha-(2-ethoxyphenoxy)phenylmethyl]morpholine (1) and (2S,3S)-2-(2-methoxyphenoxy) benzyl)morpholine (16), two potential norepinephrine reuptake inhibitors under clinical evaluation.     

Potent inhibitory effects of the 5'-triphosphates of (E)-5-(2-bromovinyl)-2'-deoxyuridine and (E)-5-(2-bromovinyl)-1-beta-D-arabinofuranosyluracil on DNA polymerase gamma

(E)-5-(2-Bromovinyl)-2'-deoxyuridine 5'-triphosphate (BrVdUTP) and (E)-5-(2-bromovinyl)-1-beta-D-arabinofuranosyluracil 5'-triphosphate (BrVarafUTP), which are known as specific inhibitors of herpes simplex viral (type 1 and 2) DNA polymerase, were found to be strong inhibitors of DNA polymerase gamma from human KB and murine myeloma cells. In fact BrVdUTP and BrVarafUTP were found to be stronger inhibitors of DNA polymerase gamma than of other DNA polymerases having viral (herpes simplex virus or retrovirus) origin or cellular (eukaryotic alpha and beta, or prokaryotic) origin. The mode of inhibition of DNA polymerase gamma by BrVdUTP and BrVarafUTP was competitive with respect to dTTP, the normal substrate. Whereas BrVdUTP was an efficient substrate for DNA polymerase gamma and other DNA polymerases that were examined, BrVarafUTP failed to serve as a substrate for DNA synthesis. Ki values for BrVdUTP (40 nM) and BrVarafUTP (7 nM) with DNA polymerase gamma, as determined with (rA)n.(dT) as the template.primer, were much smaller than the Km values for dTTP (0.16 microM and 0.71 microM for murine and human DNA polymerase gamma, respectively). Thus, the affinity of BrVdUTP or BrVarafUTP for DNA polymerase gamma was much stronger than that of dTTP.     

Enantioconvergent synthesis of (-)-(S)- and (+)-(R)-2-acetyl-3,6-dihydroxycyclohex-2-enone starting from rac-6-hydroxy-3-methoxycyclohex-2-enone

The synthesis of enantiomerically pure (-)-(S)- and (+)-(R)-2-acyl-3,6-dihydroxycyclohex-2-enone starting from diastereomerically pure N-tosyl-(S)-proline esters 3-methoxy-6-hydroxycyclohex-2-enone 1 is presented. An enantioconvergent synthesis of either (-)-(S)- and (+)-(R)-2-acyl-3,6-dihydroxycyclohex-2-enone starting with the racemic alpha-ketol 1 through a conversion of ( approximately 1:1) mixture of diastereomeric esters into one diastereomer by a repeated crystallization, followed by dimethylaminopyridine-catalyzed equilibration as key steps is described.     

Isolation and identification of urinary metabolites of AF-2 (3-(5-nitro-2-furyl)-2-(2-furyl)acrylamide) in rabbits

After oral administration of AF-2 (3-(5-nitro-2-furyl)-2-(2-furyl)acrylamide) to rabbits, the two unique metabolites, M-I and M-II, were isolated from the urine. M-I, yellow needles of mp 117°, was identified as a new type metabolite of nitrofuran derivative, 2-(β-carboxypropionyl)-3-(5-methylthio-2-furyl) acrylamide by its mass, ir and nmr spectrometries. M-II, yellow solid, appears to be cis-trans isomer of M-I considering from its uv and mass spectral data, and the behavior on tlc.     

Synthesis of P-Thioadenylyl (2′-5′) Adenosine and P-Thioadenylyl (2′-5′)-P-Thioadenylyl-(2′-5′)-Adenosine

Abstract

Dimer and trimer adenylates with 2′-5′ phosphorothioate linkages were synthesized via the phosphoramidite method using p-nitrophenyl-ethyl group for phosphate protection and followed by sulfur oxidation. The various diastereoisomers were separated and characterized.     

Synthesis, cytostatic, and antiviral activity of novel 6-[2-(dialkylamino)ethyl]-, 6-(2-alkoxyethyl)-, 6-[2-(alkylsulfanyl)ethyl]-, and 6-[2-(dialkylamino)vinyl]purine nucleosides

An efficient and facile synthesis of a large series of diverse 6-[2-(dialkylamino)vinyl]-, 6-[2-(dialkylamino)ethyl]-, 6-(2-alkoxyethyl)-, and 6-[2-(alkylsulfanyl)ethyl]purine nucleosides (35 examples of both ribo- and 2'-deoxyribonucleosides) was developed. The key transformations involved conjugate nucleophilic additions of amines, alcoholates, or thiolates to Tol-protected 6-alkylylpurine or 6-vinylpurine nucleosides. 6-[(2-Dialkylamino)vinyl]- and some 6-[(2-dialkylamino)ethyl]purine ribonucleosides exerted significant cytostatic effects and some anti-HCV activity with low selectivity.     

Inhibition of terminal deoxynucleotidyltransferase by (E)-5-(2-bromovinyl)-2'-deoxyuridine 5'-triphosphate

(E)-5-(2-bromovinyl)-2'-deoxyuridine 5'-triphosphate (BVdUTP), known as a specific inhibitor of herpes simplex virus (type 1)-DNA polymerase, was found to be a potent inhibitor of the activity of terminal deoxynucleotidyltransferase (TdT) from calf thymus. BVdUTP was not an efficient substrate of TdT, but it inhibited the incorporation of normal deoxynucleotide substrates in competitive fashion at the nucleotide binding site of TdT molecule. The Ki value for BVdUTP (5 microM) was much less than the Km value for dGTP (83 microM), indicating stronger affinity of the inhibitor to TdT than that of the substrate. These results indicate the usefulness of BVdUTP as a potent inhibitor of TdT for elucidation of the reaction mechanism of this enzyme.