Derivatives of 1-(2-Deoxy-2-fluoro-β-D-arabinofuranosyl)-5-phenyluracil and 5-Benzyluracil. Synthesis and Biological Properties

Abstract

A number of 1-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)uracil and -cytosine nucleosides substituted at the 5 position with a nitrophenyl or nitrobenzyl group were synthesized from 5-phenyl- and 5-benzyluracil via condensation of the fluorinated sugar, followed by nitration. The corresponding amino analogues were also prepared by reduction of the nitro nucleosides. The uracil nucleosides were converted into the corresponding cytosine nucleosides by way of the triazole intermediates. None of these nucleosides exhibited significant activity against herpes simplex virus type 1 in Vero cells. However, cytosine nucleosides containing the o-nitrophenyl, p-nitrophenyl, p-nitrobenzyl or p-aminobenzyl substituent were found to be toxic (even at 1 μM) to uninfected Vero cells, although they were essentially nontoxic in HL-60 cells. The 5′-monophosphates of the uracil nucleosides were inhibitors of the reaction catalyzed by purified Ehrlich ascites carcinoma thymidylate synthase, the 5-phenyluracil nucleotides causing a strong inhibition, competitive vs dUMP, described by the K_i value of 0.01 μM.     

Synthesis of 9-(2-Deoxy-β-D-ribofuranosyl)purine-2-thione

Abstract

A synthesis of 9-(2-deoxy-β-D-ribofuranosyl)purine-2-thione was performed by desulfurization of 2′-deoxy-6-thioguanine to give 2-amino-9-(2-deoxy-β-D-ribofuranosyl)purine, diazotization with chloride replacement to give 2-chloro-9-(2-deoxy-β-D-ribofuranosyl)purine, and the replacement of chloride with sulfur using thiolacetic acid and deacetylation.     

Stereoselective Synthesis of 6-Methyl-9-(2-Deoxy-β-D-Erythro-Pentofuranosyl)purine

Abstract

The coupling of the sodium salt of 6-methylpurine with 2-deoxy-3,5-di-O-p-toluoyl-α-D-erythro-pentofuranosyl chloride in acetonitrile gives the di -O-p-toluoyl protected 9-β nucleoside regio- and stereo-selectively in good yield. Methoxide deprotection followed by preparative hplc then affords pure 6-methyl-9-(2-deoxy-β-D-erythro-pentofuranosyl)purine.     

Synthesis of 8-(2-Deoxy-β-D-Ribofuranosyl)-Isoxanthopterins New Fluorescent Analogs of 2′-Deoxyguanosine

Abstract

We have synthesized isoxanthopterin and 6-phenylisoxanthopterin nucleosides in form of their 5′-O-dimethoxytritylated 3′-phosphoramidites to be used as fluorescence markers directly in the synthesis of oligonucleotides by a machine-aided solid-support approach. The preparation of the monomers and some results of the oligonucleotide synthesis will be described.     

Synthesis and Properties of Modified Oligodeoxyribonucleotides Containing 9-(2-Amino-2-deoxy-β-D-arabinofuranosyl)adenine

Abstract

The synthesis of modified oligodeoxyribonucleotides# This publication is dedicated to Professor Tsujiaki Hata, who made a valuable contribution to the chemistry of nucleosides and nucleotides. containing 2′-amino-2′-deoxyarabinoadenosine residues (aAⁿ) was carried out by means of the standard phosphoramidite chemistry. A high reactivity of such compounds to electrophilic reagents was shown. The cross-link formation between 2′-amino group of aAⁿ and carboxyl function introduced into complementary strands occurs with 55% yield. The aAⁿ residues was shown to induce the increased resistance of modified oligomers towards the enzymatic cleavage and provide the insignificant destabilization of DNA duplexes.

     

Synthesis of 9-(β-d-arabinofuranosyl)guanine using whole cells of Escherichia coli

Summary Synthesis of 9-(-d-arabinofuranosyl)guanine (ara-G) from 1-(-d-arabinofuranosyl)cytosine (ara-C) and guanine, guanosine or 2-deoxyguanosine (dG) by glutaraldehyde-treated Escherichia coli BM-11 cells is described. It is shown that the concentration of phosphate ions, molar ratio of substrates and pH of the reaction medium are factors affecting product yield. Under optimum conditions ara-G was produced in the reaction mixture in a yield of 63%–65% based on dG as the best source of guanine base. The yield of isolated ara-G was 48%–53%.Offprint requests to: A. I. Zinchenko     

Synthesis and Some Properties of Modified Oligonucleotides. II. Oligonucleotides Containing 2′-Deoxy-2′-fluoro-β-D-arabinofuranosyl Pyrimidine Nucleosides

Abstract

In order to find the effects of unnatural nucleosides on the stability of duplex, several oligonucleotides containing 1-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-uracil(FAU),-cytosine (FAC) and -thymine (FMAU) were synthesized by two alternative approaches: phosphoramidite method on an ABI 392 synthesizer and H-phosphonate procedure on our GeneSyn I universal module synthesizer. It was shown from the melting profiles that the presence of FMAU has a large stabilizing effect on the duplex. Replacement of thymidine with FAU, or deoxycytidine with FAC resulted in the formation of less stable duplexes. Temperature-dependent CD spectroscopy demonstrated that the structures of the fluorine containing oligomers are very similar to those of unmodified oligomers.     

Synthesis of 1-(2-Deoxy-β-D-ribofuranosyl)benzimidazole via Cyclonucleosides

Abstract

Starting from 2-chlorobenzimidazole and 1-O-acetyl-2,3,5-tri-O-benzoylribofuranose a β-D-ribonucleoside of 2-chlorobenzimidazole was obtained using Vorbrüggen's procedure. This compound was derivatized to a 2,2′-S-cyclonucleoside via 2′-O-tosylation and thiourea treatment. The cyclonucleoside was converted to 1-(2-deoxy-β-D-ribo-furanosyl) benzimidazole by Raney nickel desulfurization.     

Synthesis of (2′S)-1-(2-C-Azidomethyl-2-deoxy and 2-C-Cyanomethyl-2-deoxy-β-D-arabinofuranosyl)cytosines

Abstract

2′-C-Cyanomethyl-2′-deoxy-arabinosylcytosine 3 and 2′-C-azidomethyl-2′-deoxy-arabinosylcytosine 4 were synthesized from uridine. The antineoplastic activities of these compounds were evaluated.     

A Convenient and Stereoselective Synthesis of 2′-Deoxy-β-L-Ribonucleosides

Abstract

2′-Deoxy-β-L-ribonucleosides containing usual bases which are useful as synthons for modified oligodeoxyribonucleotides, were conveniently synthesized by a stereoselective glycosylation procedure. The method is suitable for large-scale preparations.     

Synthesis of 2-(3-Deoxy-β-D-erythropentofuranosyl)-thiazole-4-carboxamide (3′-Deoxytiazofurin)

Abstract

2-(3-Deoxy-β-D-erythropentofuranosyl)-thiazole-4-carboxamide was synthesized in four steps from its β-D-ribofuranosyl nucleoside precursor.     

Synthesis and Antiviral Evaluation of 2′,3′-Dideoxy-2′-fluoro-3′-C-hydroxymethyl-β-D-arabinofuranosyl Pyrimidine Nucleosides

Abstract

The synthesis and anti-HBV and anti-HIV activity of a number of 2′,3′-dideoxy-2′-fluoro-3′-C-hydroxymethyl-β-D-arabinofuranosyl pyrimidine nucleosides are reported.     

Evaluation of the Kinetics of Hydrolysis of Monoamino Analogues of 2′- or 3′-Deoxyadenosine and of 9-(2-Deoxy-β-D-Threo-pentofuranosyl)Adenine or 9-(3-Deoxy-β-D-threo-pentofuranosyl)Adenine by Liquid Chromatography

Abstract

Liquid chromatography was used to follow the degradation of monoamino analogues of 2′- or 3′-deoxyadenosine and of 9-(2-deoxy-β-D-threo-pentofuranosyl) adenine or 9-(3-deoxy-β-D-threo-pentofuranosyl) adenine in buffers of different pH and constant ionic strength (μ). Comparison of stabilities of some of the compounds under study with those of corresponding hydroxyl analogues showed that at acid pH the aminated compounds are more stable than the corresponding hydroxyl compounds. The higher stability associated with the presence of an amino group in the sugar is explained in function of pK_a values, which were determined by ¹³C NMR.     

A New Synthesis of (—)-exo-Brevicomin

Rubusoside derivatives by transgalactosylation of various β-galactosidases were isolated and their structures were analyzed. Escherichia coli β-galactosidase produced mainly 13-O-β-d-glucosyl-19-O-[β-d-galactosyl-(1→6)-β-d-glucosyl]-steviol (RGal-2). Bacillus circulans β-galactosidase produced mainly 13-O-β-d-glucosyl-19-O-[β-d-galactosyl-(1→4)-β-d-glucosyl]-steviol (RGal-1a) in the early stage of the reaction and then produced 13-O-[β-d-galactosyl-(1→4)-β-d-glucosyl]-19-O-β-d-glucosyl-steviol (RGal-1b). With decreasing the amount of these products (RGal-1a and RGal-1b), RGal-2 was produced.     

A Stereoselective Synthesis of α - and β-2′-Deoxy-2-thiouridine

Abstract

A stereoselective glycosylation procedure is described for the synthesis of protected α- and β-2′-deoxy-2-thiouridine (dS²U) in 68% and 94% yield, respectively. Evidence is presented that suggests the reaction proceeds through a silylated thio-glycoside intermediate. This intermediate undergoes an efficient S² → N¹ rearrangement mediated by SnCl₄. The phosphoramidite and phosphodiester synthons and a dS²U dinucleotide are also synthesized and the X-ray structure of β-dS²U is presented.     

Synthesis of 1-β-L-Arabinofuranosylcytosine (β-L-Ara-C) and 2′-Deoxy-2′-methylene-β-L-cytidine (β-L-DMDC) as Potential Antineoplastic Agents

Abstract

1-β-L-Arabinofuranosylcytosine (β-L-Ara-C, 7) and 2′-deoxy-2′-methylene-β-L-cytidine (β-L-DMDC, 14) have been synthesized via a multi-step synthesis from L-arabinose. These compounds were tested in vitro against L1210, P388, Sarcoma 180, and CEM cells, and found not to be active at a concentration up to 100 μM. β-L-Ara-C and β-L-DMDC were also tested against HSV-1 and HSV-2 and yielded ID₅₀ values of 100 μM.     

A New Synthesis of (±)-9-Demethylmunduserone Thermal Rearrangement of Phenyl 2-Propynyl Ether and Its Application

A new synthesis of (±)-9-demethylmunduserone (2) is described. Thermal rearrangement of l-(4-benzyloxy-2-hydroxyphenyl)-4-(3′,4′-dimethoxyphenoxy)-2-butyn-1-one (7) afforded 4-(4-benzyloxy-2-hydroxybenzoyl)-6,7-dimethoxy-2H-chromene (8), 3-(4-benzyloxy-2-hydroxyberrzoyl)-5,6-dimethoxy-2-methylbenzofuran (9) and 9-benzyloxy-2,3-dimethoxy-6a,12a-dihydrorotoxen-12(6H)-one (3). 4-Aroyl-2H-chromene (8) was smoothly converted to 3 in quantitative yield by the treatment with sodium acetate. The structure of 3 was confirmed by an alternative synthesis from methyl tephrosate (10). Debenzylation of 3 with aluminum bromide afforded (±)-9-demethylmunduserone (2) in high yield.     

Synthesis and Biological Activity of the Mono- and Diamino Analogues of 2′-Deoxyadenosine,Cordycepin, 9-(3-Deoxy-α-D-Threo-Pentofuranosyl)-Adenine (A Structural Component of Agrocin 84) and 9-(2-Deoxy-α-D-Threo-Pentofuranosyl)Adenine

Abstract

The mono- and diamino analogues of 9-(2-deoxy-α-D-erythro-pen-tofuranosyl)adenine la, 9-(2-deoxy-α-D-threo-pentofuranosyl)adenine 4a, 9-(3-deoxy-α-D-erythro-pentofuranosyl)adenine 2a and 9-(3-deoxy-α-D-threo-pentofuranosyl)adenine 3a were synthesized by triphenylphosphine reduction of the corresponding azido compounds. The azido group was introduced by a substitution reaction with lithium azide on mesylates or, more directly, by reaction with lithium azide, triphenylphosphine and carbon tetrabromide. Of the newly synthesized compounds, only 3′-amino-2′,3′-dideoxyadenosine proved, albeit slightly, inhibitory to murine leukemia L1210 and mammary carcinoma FM3A, and human B-lymphoblast Raji, T-lymphoblast Molt/4F and T-lymphocyte MT-4 cell proliferation in vitro (50 % inhibitory dose : 43.1-323 μM). None of the compounds inhibited human immunodeficiency virus-induced cytopathogenicity in MT-4 cells.     

A Convenient Method for the Synthesis of 2-(β-D-Glycopyranosylthio) Pyridines

Abstract

Treatment of piperidinium salts of dihydropyridinethiolates 3 with glycosyl bromides 4 in dry acetone provides a convenient and high yielding synthesis of 1,4-dihydro-3-cyanopyridine thioglycosides 5. The structures of 5 were confirmed by oxidation as well as by ¹H NMR and ¹³C NMR spectral analysis.     

Synthesis of Isochroman-1,3-diones A New Synthesis of (±)Sclerin

(±)Sclerin (4,5,6,7-tetramethyl-8-hydroxyisochroman-1,3-dione), a mycerial extracts of Sclerotinia libertiana, and related compounds were synthesized. Alkylated-7-hydroxyindanones were obtained from alkylated phenols and α-bromobutyrylbromide, and these indanone derivatives were treated with benzaldehyde to give 2-benzylidene-7-hydroxyindanone derivatives. By ozonolysis of these benzylidene-indanones were obtained 8-hydroxyisochroman-1,3-diones.