Orotic acid is decarboxylated with a half-time (t1/2) of 78 million years in neutral aqueous solution at room temperature, as indicated by reactions in quartz tubes at elevated temperatures. Spontaneous hydrolysis of phosphodiester bonds, such as those present in the backbone of DNA, proceeds even more slowly at high temperatures, but the heat of activation is less positive, so that dimethyl phosphate is hydrolyzed with a t1/2 of 130,000 years in neutral solution at room temperature. These values extend the known range of spontaneous rate constants for reactions that are also susceptible to catalysis by enzymes to more than 14 orders of magnitude. Values of the second-order rate constant kcat/Km for the corresponding enzyme reactions are confined to a range of only 600-fold, in contrast. Orotidine 59-phosphate decarboxylase, an extremely proficient enzyme, enhances the rate of reaction by a factor of 10(17) and is estimated to bind the altered substrate in the transition state with a dissociation constant of less than 5 x 10(-24) M.

https://science.sciencemag.org/content/sci/267/5194/90.full.pdf

A proficient enzyme

A new pyrimidine antimetabolite, 2',2'-difluorodeoxycytidine, Gemcitabine (LY188011, dFdCyd) has been synthesized and evaluated in experimental tumor models. dFdCyd is a very potent and specific deoxycytidine analogue. The concentration required for 50% inhibition of growth is 1 ng/ml in the CCRF-CEM human leukemia cell culture assay. Concurrent addition of deoxycytidine to the cell culture system provides about a 1000-fold decrease in biological activity. The inhibition of growth of human leukemia cells in culture led to the in vivo evaluation of this compound as a potential oncolytic agent. Maximal activity in vivo was seen with dFdCyd when administered on an every third day schedule. 1-beta-D-Arabinofuranosylcytosine, administered on a daily for 10-day schedule, was directly compared to dFdCyd in this evaluation. dFdCyd demonstrated good to excellent antitumor activity in eight of the eight murine tumor models evaluated. 1-beta-D-Arabinofuranosylcytosine was substantially less active or had no activity in these same tumor models. This in vivo activity against murine solid tumors supports the conclusion that dFdCyd is an excellent candidate for clinical trials in the treatment of cancer.

https://cancerres.aacrjournals.org/content/canres/50/14/4417.full.pdf

Evaluation of the Antitumor Activity of Gemcitabine (2′,2′-Difluoro-2′-deoxycytidine)

Mechanism of interaction of thymidylate synthetase with 5-fluorodeoxyuridylate.

This invention is directed to novel purine-based compounds for inclusion into oligonucleotides. The compounds of the invention, when incorporated into oligonucleotides are especially useful as 'antisense' agents -- agents that are capable of specific hybridization with a nucleotide sequence of an RNA. The compounds of the invention may also be used for cross-linking oligonucleotides. Oligonucleotides are used for a variety of therapeutic and diagnostic purposes, such as treating deseases, regulating gene expression in experimental systems, assaying for RNA and for RNA products through the employment of antisense interactions with such RNA, diagnosing diseases, modulating the production of proteins, and cleaving RNA in site specific fashions. The compounds of the invention include novel heterocyclic bases, nucleosides, and nucleotides. When incorporated into oligonucleotides, the compounds of the invention can be useful for modulating the activity of RNA.

Substituted purines and oligonucleotide cross-linking

This review describes the various manifestations of the pyrimidine system (alkylated, glycosylated, benzo-annelated.). These comprise pyrimidine nucleosides as well as alkaloids and antibiotics – some of them have been discovered and isolated from natural sources already long time ago, others have been reported very recently. A short overview on pyrimidine syntheses (prebiotic synthesis, biosynthesis, and metabolism) is given. The biological activities of most of the pyrimidine analogs are briefly described, and, in some cases, syntheses are formulated.

Pyrimidine as constituent of natural biologically active compounds.

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.

Nucleosides. 110. Synthesis and antiherpes virus activity of some 2'-fluoro-2'-deoxyarabinofuranosylpyrimidine nucleosides.

Nucleosides. 120. Syntheses of 2'-Deoxy-ψ-isocytidine and 2'-Deoxy-1-methyl-ψ-uridine from ψ-Uridine

2'-Deoxy-2'-fluoro-β-D-arabinofuranosyl nucleosides of the following structure are disclosed: ##STR1## wherein X and Y are the same or different and are hydrogen, OR 3 , SR 3 , NR 3 R 4 or NHacyl wherein R 3 and R 4 are the same or different and are hydrogen, lower alkyl of 1 to 7 carbon atoms, aralky, or aryl; NHacyl is alkanoyl or aroylamide; R 1 and R 2 are the same or different and are hydrogen, acyl or aroyl.

2'-fluoro-arabinofuranosyl purine nucleosides

Pyrimidine nucleosides exhibiting anti-viral and anti-tumor effects have the formula ##STR1## wherein A is OR3, SR3, NR3 R4 or NHacyl wherein R3 and R4 are the same or different and are hydrogen, lower alkyl of 1 to 7 carbon atoms, aralkyl, or aryl; NHacyl is alkanoyl or aroyl amide; B is oxygen or sulfur; X is halogen, alkylsulfonyl or arylsulfonyl; Y is halogen, amino, monoalkyl- or monoaralkylamino, dialkylamino, aminomethyl, hydroxymethyl, lower alkyl, aryl, aralkyl, vinyl and substituted vinyl or ethynyl and substituted ethynyl; Z is methyne or nitrogen; R1 and R2 are the same or different and are hydrogen acyl or aroyl.

5-Substituted 1-(2'-Deoxy-2'-substituted-β-D-arabinofuranosyl)pyrimidine nucleosides

Spectrophotometric studies of nucleic acid derivatives and related compounds as a function of pH. IV. On the structure of orotidine. A study of N-methylated orotic acids.

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