Enzymatic Recognition of Acyclic Universal Base Analogues in Oligonucleotides

Abstract

The effects of the acyclic analogues 3 and 4 on recognition by commonly used enzymes in recombinant DNA work have been investigated. This report shows that acyclic sugars can function in place of the normal 2′- deoxyribose moiety with some enzymes, expanding the range of possible manipulations.     

Acyclic Nucleosides other than Acyclovir as Potential Antiviral Agents

Abstract

In the past few years interest in the synthesis and biological properties of acyclic nucleosides has been generated based largely upon the development of acyclovir [9-[(2-hydroxyethoxy)methyll guanine, 1a] as an antiviral agent for the treatment of certain herpesvirus infections. The literature in the area covers a variety of different heterocycles, a variety of different side chains, and spans research that is strictly synthetic to research that is strictly biological. Two compounds, 9-[(2-hydroxy-l-(hydroxymethyl)ethoxy)methyl] guanine (1b) and 9-(S)-(2,3-dihydroxypropyl)adenine (2), have received the most attention, but many others have been made.     

Novel Acyclic Analogues of Purine Nucleosides: 2,3-Dihydroxy-1-Methoxypropyl and 3-Hydroxy-1-Methoxypropyl Derivatives

Abstract

Novel purine nucleoside analogues in which the N-9 ribosyl moiety is replaced by a 2,3-dihydroxy-1-methoxypropyl or 3-hydroxy-1-methoxypropyl substituent and their N-7 substituted isomers have been synthesized and tested for antiviral activity.     

2-Hydroxyethoxyethylated Bases as Acyclic Analogues of 1,5-Anhydrohexitol Nucleoside Derivatives

Abstract

The synthesis and antiviral activity of a new series of acyclic nucleoside analogues containing a (2-hydroxyethoxy)ethyl moiety is discussed.     

Novel Acyclic Analogues of Pyrimidine Nucleosides: 1-Methoxy-2, 3-Dihydroxypropyl and 1-Methoxy-3-hydroxypropyl Derivatives

Abstract

The preparation of a series of novel pyrimidine nucleoside analogues in which the N-1 ribosyl moiety is replaced by 1-methoxy-2, 3-dihydroxypropyl and 1-methoxy-3-hydroxypropyl substituents is described.     

1,2-Disubstituted Carbocyclic Analogues of Thymine Nucleosides

Abstract

A series of o ne t wo c arbonucleoside (OTC) analogues of thymine was synthetized and their conformation was studied by AM1 theoretical calculations. The low-energy conformations of Compound 1 and 2′,3′-dideoxythymidine, showed a degree of steric congruity.     

Synthesis and In Vitro Antitumor Activity of New Substituted Thiopyrimidine Acyclic Nucleosides and Their Thioglycoside Analogs

Some new thiopyrimidine acyclic nucleosides and thioglycoside derivatives 3a-c, 4a-c, 6a,b, and 7a,b were synthesized. The cytotoxicity and antitumor evaluation of all prepared compounds have been tested in vitro against Ehrlich's ascites carcinoma cell line and their activity against glutathione peroxidase and catalase were reported. The role of the prepared compounds as free radical regulators and the therapeutic antitumor effect of a balanced generation of free radicals are discussed. Compounds 2, 3b, 3c, 4a, and 4c inhibited significantly in a dose dependent manner the growth of Ehrlich ascites carcinoma cells while the other compounds did not show any antitumor activity even at higher concentrations.     

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 Novel Difluoro-Cyclopropyl Guanine Nucleosides and Their Phosphonate Analogues as Potent Antiviral Agents

The synthesis of new rigid guanine analogues with anti-HIV-1 and anti-herpes viral activities is described. The phosphonate of difluorocyclopropane nucleoside analogue 26 exhibits in vitro anti-HIV-1 activity similar to that of PMEA in MT-4 cells. Further, analogue 20 shows moderate anti-HCMV activity in MRC cells.     

Purine Derivatives of 1,2-Disubstituted Cyclohexane Analogues of Nucleosides

Abstract

Starting from (±)-cis-2-hydroxymethylcyclohexylamine, a series of cyclohexane-derived cis-1,2-disubstituted carbonucleoside analogues with a 6- or 2,6-purine or 8-azapurine base were synthesized. The antiviral and antitumoral in vitro effects of the new compounds were evaluated.     

Synthesis of Novel Acyclic Nucleoside Analogues with Anti-Retroviral Activity

A series of novel acyclic thymine nucleoside analogues were prepared by the Mitsunobu reaction from appropriately protected chiral triols. The enantiomeric triols were obtained from substituted γ-lactone acids, prepared by asymmetric oxidation of 3-substituted-1,2-cyclopentanediones. The cytotoxic activity of new analogues was evaluated on MCF-7 human breast cancer and HeLa cells, and antiviral activities on human immunodeficiency virus type 1 and hepatitis C virus models. The synthesized compounds revealed specific anti-retroviral activity and no cytotoxic side effects.     

Synthetic Studies on the Acyclic Nucleosides of 5-Substituted-6-Azauracils

Abstract

A number of acyclic nucleosides have been prepared. 5-substituted-6-azauracils were persilylated with HMDS and then alkylated with aliphatic side chains e.g., (2-acetoxyethoxy)methyl bromide, 1,3-dibenzuloxy-2-chloromethoxypropane, (1-benzyloxy-3-phthalimido-2-propoxy)methyl chloride, and 1-benzyloxy-2-chloro-methoxybutane to yield protected acyclic nucleosides which were deprotected by Lewis acid or palladium to give various 6-azauracil acyclonucleosides.     

Synthesis and Antiherpetic Activities of Several Acyclic Analogues Of Guanosine

Abstract

Several acyclic analogues of guanosine, 2′-deoxy-2′, 3′-secoguanosine(3), 3′-deoxy-2′, 3′-secoguanosine (4), and 2′-, 3′-dideoxy-2′-, 3′-secoguanosine were synthesized from guanosine. In addition, the 3′-, 5′-cyclic phosphate (21) and 3′-, 5′-cyclic methylphosphonates (22a, b) of 3 were also prepared. At concentrations up to 300 μM none of these compounds had significant antiherpetic activity in antiviral assays in vitro.     

Synthesis of Cyclobutane Nucleosides 2-Preparation of Thymine and Uracil Analogues

1-(2-Oxocyclobutyl-4-benzoyloxymethyl)-2,4(1H,3H)-pyrimidinedione and 1-(2-oxocyclobutyl-4-benzoyloxymethyl)-5-methyl-2,4(1H,3H)-pyrimidinedione can be prepared by reaction of uracil and thymine, respectively, with 3-benzoyloxymethyl-2-bromocyclobutanone. The N-alkylation gave both cis and trans isomers with the trans isomer predominating for uracil whereas the trans isomer was the only product which could be isolated for thymine. Both series were subjected to borohydride reduction followed by transesterification with methoxide giving the corresponding uracil and thymine nucleoside analogues. The uracil derivative 1-(2-oxocyclobutyl-4-benzoyloxymethyl)-2,4(1H,3H)-pyrimidinedione was irradiated in aqueous acetonitrile to generate isonucleoside analogues.     

Application of the Transpuriation Reaction to Synthesis of Acyclic Guanosine Analogues

Abstract

A novel transpurination reaction of tetraacetylguanosine was successfully applied for the preparation of 9-(2-hydroxyethoxymethyl)-and 9-(1,3-dihydroxy-2-propoxymethyl)guanines (compounds 1 and 2, respectively). Yield of the desired 9-isomers was significantly increased by application of the thermal 7=9 transglycosylation.     

Synthesis and Biological Activity of 2-Aminopurine Methylenecyclopropane Analogues of Nucleosides

Abstract

Synthesis and biological activity of 7- and 9-isomers (Z+E) of methylenecyclopropane analogues of 2-aminopurine nucleosides is described. The (S,Z)-9-isomer is a substrate for xanthine oxidase.     

Short Synthesis and Antiviral Activity of Acyclic Phosphonic Acid Nucleoside Analogues

An efficient route for synthesizing novel allylic and cyclopropanoid phosphonic acid nucleoside analogues is described. The condensation of the bromine derivatives 6 and 18 with nucleoside bases (A, U, T, C, G) under standard nucleophilic substitution and deprotection conditions, afforded the target phosphonic acid nucleoside analogues. These compounds were evaluated for their antiviral properties against various viruses. Cyclopropanoid phosphonic adenine nucleoside analogue 23 showed significant anti-HIV activity.     

Synthetic and Antiviral Studies on Certain Acyclic Nucleosides of 5-Benzyl-6-Azauracil Derivatives

Abstract

Several 5-(4-substituted benzyl)-6-azauracils have been synthesized from the corresponding benzaldehydes. The 5-benzyl-6-azauracils were silylated with hexamethyldisilazane and then glycosylated with aliphatic halides, e.g., (2-acetoxyethoxy)methyl bromide and 1,3-dibenzyloxy-2-chloromethoxypropane, to give protected acyclic nucleosides which were deprotected to afford acyclonucleosides of 5-(4-substituted benzyl)-6-azauracils. None of the compounds exhibited significant antiviral activity against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) in vitro.     

Phosphoralaninate Pronucleotides of Pyrimidine Methylenecyclopropane Analogues of Nucleosides: Synthesis and Antiviral Activity

The Z- and E-thymine and cytosine pronucleotides 3d, 4d, 3e, and 4e of methylenecyclopropane nucleosides analogues were synthesized, evaluated for their antiviral activity against human cytomegalovirus (HCMV), herpes simplex virus 1 and 2 (HSV-1 and HSV-2), varicella zoster virus (VZV), Epstein-Barr virus (EBV), human immunodeficiency virus type 1 (HSV-1), and hepatitis B virus (HBV) and their potency was compared with the parent compounds 1d, 2d, 1e, and 2e. Prodrugs 3d and 4d were obtained by phosphorylation of parent analogues 1d or 2d with reagent 8. A similar phosphorylation of N⁴-benzoylcytosine methylenecyclopropanes 9a and 9b gave intermediates 11a and 11b. Deprotection with hydrazine in pyridine–acetic acid gave pronucleotides 3e and 4e. The Z-cytosine analogue 3e was active against HCMV and EBV. The cytosine E-isomer 4e was moderately effective against EBV.     

Nucleic Acid Components and Their Analogues: New Synthesis of Bicyclic Thiopyrimidine Nucleosides

Abstract

A novel synthesis of condensed bicyclic thiopyrimidine glycosides utilising 1H-cyclopentapyrimidine-2(3H)-thiones and α-bromoglucose or α-bromogalactose tetraacetate as starting components is described.