Deamination of Cyclaradine by Adenosine Deaminase Under High Pressure#

Abstract

The deamination of cyclaradine corresponding to a carbocyclic analogue of ara-A having anti-HSV activity by adenosine deaminase was examined under various pressure. The deamination of (+)- and (±)-cyclaradine was remarkably facilitated by high pressure, and the rate was increased with increasing of pressure. However, (-)-cyclaradine was not deaminated even under high pressure.

     

A Facile Synthesis of cis-9-[4-(1,2-Dihydroxyethyl)-cyclopent-2-enyl]guanine and Its Derivative

Abstract

The synthesis of carbocyclic nucleosides, cis-9-[4-(1,2-dihydroxyethyl)-cyclopent-2-enyl]guanine (3) and cis-2-amino-6-cyclopropylamino-9-[4-(1,2-dihydroxyethyl)-cyclopent-2-enyl]guanine (4), was achieved from cyclopentadiene (5) in five and six steps, respectively. This route involves a hetero Diels-Alder reaction and a Pd(0)-catalyzed coupling reaction.     

Synthesis and Biological Properties of (+) and (-)-(E)-5-(2-bronovinyl)-21 -deoxy-11 a-Carbauridine

Abstract

Carbocyclic (+)- and (-)-(E)-5- (2-bromovinyl)-2′-deoxyuridlne have been prepared from (+)- and (-)-endo-norborn-5-en-2-y1 butyrate. In cell cultures both (+)- and (-)-C-BVDU showed activity against herpes simplex virus types 1 and 2, (+)-C-BVDU being only slightly less active than BVDU itself. (-)-C-BVDU gave a smaller but still significant antiviral effect. A nomenclature for carbocyclic nucleosides is proposed.     

Synthesis and Antiviral Activities of Enantiomeric 1-[2-(Hydroxymethyl) Cyclopropyl] Methyl Nucleosides

Abstract

Cyclopropyl carbocyclic nucleosides have been synthesized from the key intermediate 2 which was converted to the mesylated cyclopropyl methyl alcohol 3. Condensation of compound 3 with various purine and pyrimidine bases gave the desired nucleosides. All synthesized nucleosides were evaluated for antiviral activity and cellular toxicity. Among them adenine 22 and guanine 23 derivatives showed moderate antiviral activity against HIV-1 and HBV. None of the other compounds showed any significant antiviral activities against HIV-1, HBV, HSV-1 and HSV-2 in vitro up to 100μM.     

Cis (IS,3R)-1-(9-Adenyl)-3-Hydroxycyclopentane Inhibits the Respiratory Burst from Polymorphonuclear Leukocytes and Has In Vivo Efficacy in an Acute and Chronic Model of Inflammation

Abstract

The adenine-containing carbocyclic nucleosides 1 and 2 were synthesized in optically active form and have been shown to effectively inhibit interferon-gamma priming of Lewis (LEW/N) rat air pouch-derived PMNs. Compound 2 was also shown to have in vivo activity in a LEW/N rat antigen-induced arthritis model which assesses acute and chronic inflammation.     

Deamination of 4-Aminopyrimidine Nucleosides by Extracts of Rye Grass (Lolium perenne)

A deaminase specific for 4-aminopyrimidine nucleosides has been found in rye grass. Lolium perenne. The pH optimum, temperature stability, Km values and specificity was determined.

A new and more accurate method for following the course of deamination is reported. This method depends on the shift in maximum absorbance wavelength of the mixture containing the 4-aminopyrimidine nucleoside and its deaminated product.

     

The Controlled Stereospecific Reduction of Cyclopentenyl Cytosine (CPE-C) to Carbodine and Isocarbodine

Abstract

The preferential cis-addition of hydrogen to either face of the carbocyclic double bond of enantiomerically pure cyclopentenyl cytosine (1) was achieved. The resulting saturated carbocyclic nucleosides carbodine (2) and isocarbodine (3) were evaluated against human influenza virus. Carbodine showed the greater potency against this virus but the activity of isocarbodine was still substantial.     

Asymmetric Synthesis of Cyclopropyl Carbocyclic Nucleosides

Abstract

A number of nucleosides have been synthesized as potential antiviral and antitumor agents.¹ More recently, various dideoxynucleosides have been synthesized and found to be potent anti-HIV agents.² As a part of our drug discovery program for the treatment of HIV and HBV, we have initiated to synthesize cyclopropyl carbocyclic nucleosides as potential antiviral agents. Several papers regarding the synthesis of cyclopropyl carbocyclic nucleosides have appeared in the literature.^3–5 However, they are all reported as racemic mixtures. In this abstract, we wish to report the asymmetric synthesis of cylopropyl carbocyclic nucleosides from optically active common intermediates, 6 and 11.     

Synthesis of Carbocyclic 1-[4-(Hydroxymethyl)cyclopent-2-enyl]-1,2,4-triazole-3-carboxamide and Its Derivatives

Abstract

The synthesis of carbocyclic 1-[4-(hydroxymethyl)cyclopent-2-enyl]-1,2,4-triazole-3-carboxamide (6a) and its derivatives was achieved from triol 10 in excellent overall yield. This route involves a Pd(0)-catalyzed coupling reaction as a key step.     

Protection of the Lactam Function of 2′-Deoxyinosine with A 2-(4-Nitrophenyl)-Ethyl Moiety

Abstract

The reaction of O-protected inosine with p-nitrophenyl ethanol under Mitsunobu conditions yields a mixture of the 1- and 0° -alkylated derivatives. 2′-Deoxyinosine protected on 0⁶ -, can be synthesized fairly easy from deoxyguanosine with a Mitsunobu reaction followed by reductive deamination.     

Synthesis of Some Purine Carbocyclic Isosteres of 2′,3′-Dideoxy-3′-C-Hydroxymethyl Nucleosides as Potential Inhibitors of HIV

Abstract

The synthesis of some enantiomerically pure carbocyclic 2′,3′-dideoxy-3′-C-hydroxymethyl derivatives of adenine, inosine and guanine is described. The Mitsunobu reaction was used in the coupling procedure giving exclusively N⁹-coupling. The nucleosides were tested for inhibition of HIV multiplication in vitro and were found to be inactive in the assay.     

Carbocyclic Nucleosides: Synthesis of Analogues of Cyclobut-G

Abstract

Several carbocyclic nucleosides structurally related to Cyclobut-G have been synthesized from pinonic acid.     

Synthesis of Carbocyclic Analogues of MECA and NECA 1,2-Disubstituted as Potential Adenosine Receptor Agonists

Abstract

A new class of 1,2-disubstituted carbocyclic nucleosides of MECA and NECA analogues was synthesized in gool yield starting from (±) 6-azabicyclo[3.2.0]heptan-7-one.     

HPLC as a Tool to Study the Kinetics of Parallel and Consecutive Reactions: Competitive Interconversion,Dephosphorylation, Deamination and Depyrimidination of Cytidine 2′- and 3′-Monophosphates in Aqueous Acid

Abstract

The applicability of HPLC as a method to study the kinetics of complicated reaction systems of nucleosides and nucleotides has been demonstrated by using the hydrolytic reactions of cytidine 2′- and 3′-monophosphates as an example.     

Synthesis of (±)-cis-3-Aminomethyl-1-indanylmethanol as a Precursor of Carbocyclic Analogues of Nucleosides

Abstract

Aminoalcohol precursor of carbocyclic analogues of nucleosides (±)-cis-3-aminomethyl-1-indanylmethanol was efficiently synthesized starting from benzonorbornadiene (5) previously prepared by addition of cyclopentadiene to 1-bromo-2-fluorobenzene.     

Synthesis and Biological Evaluation of 3-Chloro-4-(D-Ribofuranosyl)-Pyridine and 3-(D-Ribofuranosyl)-2- Pyridone

Abstract

Condensation of 2-fluoro-3-lithio pyridine and 3-chloro-4-lithio pyridine with 2,4:3,5-di-O-benzylidene-alde-hydo-D-ribose gives the corresponding D-allo- and D-altro-addition products. These were converted into the corresponding mesylates and cyclized to the ribofuranosyl nucleosides with an overall yield of 60–70 %. Both nucleosides did not show any inhibitory effect on L-₁₂₁₀-cells.     

Carbovir: A Carbocyclic Nucleoside with Potent and Selective Activity Against Human Immunodeficiency Virus (HIV) in Vitro

Abstract

Carbocyclic 2′, 3′-didehydro-2′,3′-dideoxyquanosine (carbovir), a novel nucleoside analog, emerged as a potent and selective anti-HIV agent from a primary screen of a large number of carbocyclic nucleosides.¹ Carbovir inhibited the infectivity and replication of HIV in T-cells at concentrations 200 to 400-fold below toxicity to host cells. Carbovir was also evaluated for its Inhibitory effects on the expression of viral antigen in HIV-infected CEM cells. Production of p 24 core antigen at optimal inhibitory concentrations of the antiviral agents indicated comparable results for AZT, ddA and carbovir.     

Synthesis of Novel Carbocyclic Nucleosides with a Modified Cyclopentane Ring and Evaluation of Their Antiviral Activity

Abstract

New carbocyclic nucleosides with purine (compounds 2a-2c), 8-azapurine (compounds 2d and 2e) or pyrimidine (compound 3) as base were prepared and assayed for in vitro activity.     

Enantioselective Synthesis of Carbocyclic Nucleosides by Enzymatic Approach and the Anticancer Activities

Abstract

Enantioselective synthesis of carbocyclic nucleosides, aristereomycin, neplanomycin A and their homologues has been completed by a combination of enzymatic and non-enzymatic procedures starting with a bicyclic meso-diester 2. The study on anticancer activities of them showed that the cytosine homologue exhibits most remarkable activity against L1210 leukemia in mice.