ABSTRACT
Synthesis of 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)uracils containing a vinyl (4a), 2-halovinyl (4b-d), or ethyl substituent at C-5 was achieved. These nucleosides were found to be about a log order less active than 2'-fluoro-5-iodo-ara-C (FIAC) against HSV-1, but they are much less cytotoxic against normal human lymphocytes than FIAC. Nucleosides 4a and 4e showed good activity against HSV-1 (ED50 = 0.16 and 0.24 microM, respectively) and HSV-2 (ED50 = 0.69 and 0.65 microM) with very little cytotoxicity (ID50 greater than 100 microM).
Subject(s)
Antiviral Agents/chemical synthesis , Arabinofuranosyluracil/analogs & derivatives , Simplexvirus/drug effects , Uridine/analogs & derivatives , Animals , Arabinofuranosyluracil/chemical synthesis , Arabinofuranosyluracil/therapeutic use , Cell Line , Chlorocebus aethiops , Drug Evaluation, Preclinical , Humans , Indicators and Reagents , Kidney , Lymphocyte Activation/drug effects , Lymphocytes/drug effects , Lymphocytes/immunology , Magnetic Resonance Spectroscopy , Structure-Activity RelationshipSubject(s)
Cytarabine/analogs & derivatives , Animals , Chromatography, High Pressure Liquid , Cytarabine/chemical synthesis , Cytarabine/metabolism , Cytarabine/pharmacology , Deamination , Feces/analysis , Injections, Intravenous , Mice , Rats , Tetrahydrouridine/administration & dosage , Time Factors , Tissue DistributionABSTRACT
Syntheses of five pairs of cytosine and 5-fluorocytosinexylofuranosyl nucleosides in which the 3'-hydroxyl group is replaced by Cl, Br, OMs, or OTs are described. Those xylosyl nucleosides with a good leaving group at the 3' position exhibit good inhibitory activity against L5178Y and P815 mouse leukemic cells in vitro at rather low concentrations, and like that of ara-C this cytotoxicity is reversed by 2'-deoxycytidine but not by thymidine. Xylosylcytosines are not active against ara-C resistant lines of L5178Y and P815 cells; however, the corresponding 5-fluorocytosine analogues exhibit significant cytotoxicity against these ara-C resistant leukemic cell lines, and this activity is reversed by thmidine but not by deoxycytidine. These data support the "double-barreled" masked precursor hypothesis in that xylosyl-5-fluorocytosines substituted at the 3' position by a good leaving group exhibit activity akin to that of ara-C in the ara-C sensitive lines, while these nucleosides act as 5-fluoropyrimidines in the ara-C resistant lines.
Subject(s)
Antineoplastic Agents/chemical synthesis , Cytosine Nucleotides/chemical synthesis , Animals , Cell Line , Cytosine Nucleotides/metabolism , Cytosine Nucleotides/pharmacology , Leukemia, Experimental/drug therapy , Mice , Structure-Activity RelationshipABSTRACT
A series of 5-substituted 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)cytosines 7a-d and their corresponding uracils 9a-d,f were prepared by condensation of 3-O-acetyl-5-O-benzoyl-2-deoxy-2-fluoro-D-arabinosyl bromide (5) with appropriately trimethylsilylated pyrimidines followed by saponification of the protected nucleosides 6 or 8. 1-(2-Deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-iodocytosine (7e) was obtained by iodination of 7a. Iodination of 8a followed by removal of the protecting acyl-protecting groups afforded the 5-iodo nucleoside 9e. Several of these 2'-fluoro-substituted nucleosides completely obviated replication of herpes simplex virus type 1 (HSV-1) in monolayers of Vero cells at concentrations of 10-100 microgram/mL. The 5-iodocytosine analogue 7e was the most effective, showing 99.5% suppression of viral replication even at concentrations of 0.1 microgram/mL. The cytotoxicity of 7e to L5178Y or P815 cells in culture was minimal. A comparison of the efficacy of 7e against HSV-1 with other known nucleoside antiviral agents indicates that further in vitro and in vivo evaluation of 7e is warranted.
Subject(s)
Antiviral Agents/chemical synthesis , Arabinonucleosides/chemical synthesis , Pyrimidine Nucleosides/chemical synthesis , Simplexvirus/drug effects , Arabinonucleosides/pharmacology , Pyrimidine Nucleosides/pharmacology , Structure-Activity Relationship , Virus Replication/drug effectsSubject(s)
Cytarabine/analogs & derivatives , Animals , Arabinofuranosyluracil/analogs & derivatives , Arabinofuranosyluracil/chemical synthesis , Arabinofuranosyluracil/pharmacology , Cells, Cultured , Cytarabine/chemical synthesis , Cytarabine/pharmacology , Isomerism , Leukemia L1210/pathology , MethodsABSTRACT
Very recently, 1-N-methyl-psi-uridine was isolated from the culture filtrate of Streptomyces platensis var. clarensis along with an antibacterial and antiviral antibiotic, U-44590. We achieved chemical syntheses of 1-N-methyl-psi-uridine by selective methylation of psi-uridine in two different routes and established the identity of the synthetic nucleoside with the natural product.
Subject(s)
Uridine/analogs & derivatives , Chemical Phenomena , Chemistry , Chemistry, Physical , Methods , Streptomyces/metabolism , Uridine/biosynthesis , Uridine/chemical synthesisSubject(s)
Acetamides , Epoxy Compounds , Ethers, Cyclic , Nucleosides , Arabinose , Chemical Phenomena , ChemistryABSTRACT
A seven-step synthesis of 1,3-di-O-acetyl-5-O-benzoyl-2-deoxy-2-fluoro-D-arabinofuranose, a versatile intermediate in the synthesis of chemotherapeutically important nucleosides, was achieved from 1,2:5,6-di-O-isopropylidene-3-O-tosyl-alpha-D-allofuranose. The crucial steps were the fluorination by use of potassium fluoride in acetamide and the conversion of 6-O-benzoyl-3-deoxy-3-fluoro-D-glucofuranose into 5-O-benzoyl-2-deoxy-2-fluoro-3-O-formyl-D-arabinofuranose by periodate oxidation. Also described is the synthesis of 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)cytosine. This procedure affords good overall yields of products without formation of undesirable, isomeric intermediates and is suitable for large-scale preparations.
