Ara-cytidine

Deoxy-2 -C-methyl-ara-cytidine (27) has been synthesized from a keto-nucleoside precursor as shown in Scheme 6. ... 

Cytarabine (cytosine arabinoside, ara-C, Cytosar-U) is an analogue of the pyrimidine nucleosides cytidine and deoxycytidine. It is one of the most active agents available for the treatment of acute myelogenous leukemia. Cytarabine kills cells in the S-phase of the cycle by competitively inhibiting DNA polymerase. The drug must... 

Increased cytidine deaminase activity, converting Ara-C to inactive Ara-U... 

Pharmacokinetics Ara-C is not effective when given orally because of its deamination to the noncytotoxic uracil arabinoside (ara-U) by cytidine deaminase in the intestinal mucosa. Given IV, it distributes throughout the body, but does not penetrate the CNS in sufficient amounts to be effective against meningeal leukemia. However, it may be injected intrathecally. Ara-C undergoes exten-... 

The distribution and disposition of a drug in the body result from a complex set of physiological processes and biochemical interactions. In principle, it is possible to describe these processes and interactions in mathematical terms and, if sufficient data are available, to predict the time course of drug and metabolite(s) in different species and at specific anatomic sites (15). A physiological pharmacokinetic model was developed to predict the deamination of cytosine arabinoside (ARA-C) in humans from enzyme parameters determined from homogenates of human tissue (16). ARA-C is converted to its inactive metabolite, uracil arabinoside (ARA-U) by cytidine deaminase, the activity of which varies substantially among tissues. 

Cytidine deaminase had been reported to vary greatly among mammalian species, both in its kinetic characteristics and in its dominant location (17). In humans, the highest levels (pg ARA-C/min-g) were found in the liver with smaller amounts in the kidney and heart. By comparison, the highest levels in the mouse were found in the kidney, while the dog had very low enzyme activities and the monkey... 

Cytamen cyanocobalamin. cytarabine [ban, inn. jan, usan] (cytarabine hydrochloride [usan] Ara C Cytosar Cytosar-U ) is an antimetabolite cytotoxic ANTICANCER and ANTIVIRAL AGENT isolated from the mushroom Xerocomm nigromaculatus. It works by interfering with pyrimidine synthesis. Clinically, it can be used sys-temically in anticancer treatment mainly of acute leukaemia, cytidine diphosphate choline dticoline. cytidine diphosphocholine dticoline. cytisine is an alkaloid with CNS STIMULANT, RESPIRATORY STIMULANT and psychoactive properties. It has been used clinically as a respiratory stimulant in Russia. It is a common cause of poisoning by the seeds of Cytisus laburnum. 

The syntheses of carbocyclic analogs of phosphononucleosides (29) and (30a-c) have been reported. Phosphonic acid (29) was obtained by introduction of the benzoylated thymine on the 2(4-hydroxycyclopent-2-enyl)ethyl phosphonic acid diisopropyl ester under Mitsunobu conditions while (30a-c) were prepared by building-up the base around a phosphono-cyclopentylamine moi-ety. The vinylphosphonate derivatives of uridine, cytidine and cytosine ara-binoside (31a-c) have been prepared by Wittig condensation of [(diethoxyphos-phinyl)methylidene]triphenylphosphorane with the appropriately protected 5-aldehydic nucleoside derivatives. Dihydroxylation of the novel vinyl phosphon-ates offered the dihydroxylated phosphonate derivatives (32a-c). Each of these novel compounds was evaluated as substrates for the enzyme nucleotide monophosphate kinase, and their toxicity to K562 cells. All analogues were found to be poorly phosphorylated by the kinase and exhibited poor in vivo toxicity. ... 

Cytarabine (ara-C) is an arabinose analog of cytosine. Cytarabine was originally isolated from sponges, but is now produced synthetically. Ara-C is phosphorylated to its active triphosphate form (ara-CTP) within tumor cells. Ara-CTP inhibits DNA polymerase, an enzyme responsible for strand elongation. It is also incorporated directly into DNA, where it inhibits the replication of DNA and acts as a chain terminator to prevent DNA elongation. Activation of ara-C is opposed by deaminase enzymes, particularly cytidine deaminase, which degrades ara-C to an inactive form, ara-U. " " ... 

Cytosine arabinoside is used in the treatment of acute granulocytic leukemia. Doxorubicin, daunorubicin and cytarabine cytarabine and thioguanine or cytarabine, vincristine, and prednisone are the combinations of agents employed. Resistance to cytosine arabinoside may stem from the deletion of deoxycytidine kinase, an inaeased intracellular pool of dCTP, a nucleotide that competes with Arp-CTP, or increased cytidine deaminase activity, converting Ara-C to inactive Ara-U. 

Conventional reversed phase HPLC is unable to separate ara-cyti-dine, ara-uridine, ribo-cytidine and ribo-uridine whereas a dual column procedure utilising an Ultrasphere ODS column in series with a Partisil PXS 10/25 SCX column gave excellent separation of these compounds (Sinkule and Evans, 1983). The accuracy of the method allowed comparative pharmacokinetic and pharmacodynamic studies to be carried out. 

Vidarabine 4.16) differs from adenosine in the same way that cytarabine differs from cytidine, namely the natural sugar has been replaced by arabinose. However, the anti-viral properties of vidarabine are more to the fore than any anti-cancer power, the exact opposite of cytarabine s properties. Vidarabine, also known as Ara A, is 9-j8-D-arabinofuranosyladenine and it has a reasonably high therapeutic index (Muller et al., 1977). Its most successful and spectacular application has been in herpes virus encephalitis, of which several thousands of cases break out in the United States each year, killing 70% of the sufferers... 

Pyrimidines - The leukocytes of patients responding to l- -D-arabino-furanosylcytosine (ara-C) exhibited reduced DNA and elevated RNA and protein contents, whereas the normal bone marrow cells of these patients exhibited increased DNA, RNA, and protein contents. Despite extensive intracellular conversion of ara-C to nucleotides, only limited incorporation of the compounds into nucleic acids occurred. 2-Deoxy-cytidine reverses the effects of ara-C by inhibiting its phosphorylation, an anabolic step that must occur before it can inhibit DNA polymerase and, consequently, cell proliferation. Uridine exerts a sparing action on ara-C, and the effective level of this drug can be prolonged by coadministration of tetrahydrouridine, a potent inhibitor of deoxycytidyl-ate aminohydrolase. ... 

We next examined in vivo antileukemic activity of SMDC compared with ara-C against implanted mouse leukemia P388 (10 ) in CDFl mice, with doses indicated in Table 3 given ip once each day on days 1-5. As described in Table 3, ara-C was much more potent than SMDC at every dose. We found that SMDC was not a substrate for cytidine deaminase from... 

The in vitro cytotoxicity of DMDC against L1210 cells was prevented dose depen-dently by 2 -deoxycytidine, suggesting that DMDC is phosphorylated by deoxycytidine kinase. Unlike ara-C, DMDC was not a substrate of cytidine deaminase from mouse kidney.33 Together with these characteristics, chemically synthesized DMDCTP was a potent inhibitor of DNA polymerase a, P, and y from calf thymus with Ki values of 0.42, 2.52, and 1.00 pM, respectively, in a manner competitive with dCTP, while ara-CTP inhibited only DNA polymerase a with a K of 1.10 pM.32 it was also found that DMDCTP was incorporated into DNA molecules at the site complementary to guanine by the action of DNA... 

The following symbols are used throughout all tables =data converted to fiM from literature values in /xg/ml --=data not reported in reference ara=arabinosyl Az=azido C=cytidine d=2 -deoxy dd=2 ,3 -dideoxy d4=2 ,3 -didehydro-2 ,3 -dideoxy Et=ethyl Me=methyi NA=not active Pr=propyl T=thymidine U=uridine. 

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