Deoxycytidine derivatives

In summary, decitabine (1), a deoxycytidine derivative, is a potent antileukemic that is able to induce in vitro gene activation and cellular differentiation by a mechanism involving DNA hypomethylation. It is generally most beneficial in patients with high-risk MDS or in MDS patients with intermediate-2 or high-risk features. Its process synthesis and academic synthetic approaches have been summarized in this chapter. 

Antitumor activity of 2 -deoxy-2 -methylidenecytidine, a new 2 -deoxycytidine derivative. Cancer Res. 51 2319 (1991). 

The first etCCR application has been reported for a partially C— N-labeled phosphotyrosine peptide derived from interleukin-4 receptor ligated to STAT-6 [107] and subsequent studies involve nucleotide cofactors ligated to human recombinant deoxycytidine kinase [108] and epothilone A bound to tubulin [109]. Since etCCR usually involves isotope-labeling schemes for the ligand, its applicability is limited to specific molecular classes. 

The formation of 5-hydroxy-2 -deoxycytidine (22) and 5-hydroxy-2 -de-oxyuridine (23) that arise from dehydration of dCyd glycols 20 and related dUrd derivatives 21, respectively, was assessed by HPLC-electrochemical detection within calf thymus DNA upon exposure to photoexcited menadione and subsequent enzymatic hydrolysis [57]. The latter two oxidized nucleo-... 

S. G. Kerr, T. I. Kalman, Highly Water-Soluble Lipophilic Prodrugs of the Anti-HIV Nucleoside Analogue 2, 3 -Dideoxycytidine and Its 3 -Fluoro Derivative , J. Med. Chem. 1992, 35, 1996 - 2001 S. G. Kerr, T. I. Kalman, V4-(Dialkylaminomelhylcnc Derivatives of 2 -Deoxycytidine and Arabinocytidine Physicochemical Studies for Potential Prodrug Applications , J. Pharm. Sci. 1994, 83, 582 - 586. 

Hudarabine phosphate is a fluorinated nucleotide analog of the antiviral agent vidarabine. Its cytotoxicity is not well understood. It is rapidly dephospho-rylated at the cell membrane level and then rephos-phorylated intracellularly by deoxycytidine kinase to the active triphosphate derivative. It inhibits DNA polymerase and DNA primase. It is also incorporated into DNA and RNA. Hudarabine is administered intravenously by infusion over 30-120 min. It is eliminated by renal excretion with a terminal half life 10 hours. Adverse effects include myelosuppres-sion, nausea, vomiting, chills and fever. The number of CD4 positive cells is reduced and the incidence of opportunistic infections is increased. 

The most important pyrimidine derivatives are those upon which biological organisms depend. Cytosine 1018 and uracil 1019 are found in ribonucleic acid (RNA) in the form of their ribonucleotides, cytidine 1020 and uridine 1021, while in deoxyribonucleic acid (DNA), cytosine and thymine 1022 are found in the form of their 2 -deoxyribonucleotides, 2 -deoxycytidine 1023 and thymidine 1024. 5-Methylcytosine 1025 is also found to a small extent (c. 5%) in human DNA in the form of its 2 -deoxyriboside 1026, and 5-(hydroxymethyl)cytosine-2 -deoxyriboside 1027 has also been detected in smaller amounts <2005CBI1>. Many variants of cytosine and uracil can be found in RNA including orotic acid 1028 in the form of its ribonucleotide orotidine 1029. Other pyrimidine derivatives to have been isolated from various biological sources include 2 -deoxyuridine 1030, alloxan 1031, and toxopyrimidine (pyramine) 1032 (Figure 2). 

For a ribosyl derivative if the sugar is deoxyribose, these names are prefixed by deoxy-, i.e., deoxycytidine. However, by custom, thymidine and thymidylic acid always refer to the deoxy derivative. 

Bianchini F, Hall J, Donato F, Cadet J (1996) Monitoring urinary excretion of 5-hydroxymethyluracil for assessment of oxidative DNA damage and repair. Biomarkers 1 178-184 Bienvenu C, Wagner JR, Cadet J (1996) Photosensitized oxidation of 5-methyl-2 -deoxycytidine by 2-methyl-1,4-naphthoquinone characterization of 5-(hydroperoxymethyl)-2 -deoxycytidine and stable methyl group oxidation products. J Am Chem Soc 118 11406-11411 Bothe E, Behrens G, Schulte-Frohlinde D (1977) Mechanism of the first order decay of 2-hydroxypro-pyl-2-peroxyl radicals and of O2 formation in aqueous solution. Z Naturforsch 32b 886-889 Bothe E, Deeble DJ, Lemaire DGE, Rashid R, Schuchmann MN, Schuchmann H-P, Schulte-Frohlinde D, Steenken S, von Sonntag C (1990) Pulse-radiolytic studies on the reactions of S04 with uracil derivatives. Radiat Phys Chem 36 149-154... 

Yamamoto O (1973) Radiation-induced binding of nucleic acid constituents with protein constituents and with each other. Int J Radiat Phys Chem 5 213-229 Yamamoto O, Mandal PC (1988) Radiation-induced fluorescence changes of 2 -deoxycytidine and cytidilyl-cytidine in aqueous solution. Comparison with radiolytic behaviors of other nudeo-base derivatives. J Radiat Res 131-143... 

Anabolic steroids, antidepressants and drugs of abuse affect libido, potency, and ejaculatory function. Anabolic steroids are derivatives of testosterone, and have strong genitotropic effects. There is published evidence indicating that anabolic steroids increases sexual desire however, the frequency of erectile dysfunction is also increased. Treatment with the antidepressant fluoxetine has been associated with sexual side effects including delayed or nonexistent ejaculation and hyposexuality. Mice treated in utero with the anideukemic agent 5-aza-2/-deoxycytidine exhibit abnormal reproductive behavior and low reproductive capacity. 

Essentially similar results144 were obtained from the 3-0-acetyl-5-0-tosyl derivative of deoxycytidine (and deoxyadenosine). Although the expected 2, 5-anhydro-2-deoxycytidine tosylate was unstable and was not isolated, it broke down, upon heating in acetone, to several components, including cytosine and deoxycytidine. The lability of the Cl—Nl and C5—02 linkages was explained by the supposed presence of a positive charge on Nl ... 

Decitabine (1) was first synthesized in 1964 by a multistep procedure described by Pliml and Sorm.17 In this preliminary communication, 5-aza-2 -deoxycytidine was prepared via cyclization of the peracylglycosyl isocyanate 5, which was prepared from silver cyanate and chloride 4.18,19 Addition of 2-methylisourea to 5 afforded the crystalline intermediate 6. Condensation of isobiuret derivative 6 with ethyl orthoformate resulted in the formation of crystalline triazine 7. Prolonged treatment with methanolic ammonia at room temperature afforded 1 -(2-deoxy-D-ribofiiranosyl)-5-azacytosine (8) as a mixture of a and (3 anomers. No yield was reported as the authors did not separate or distinguish between decitabine (1) and its a-anomer. 

In a similar biochemically oriented vein, several papers were published during 2003 in the journal Chemical Research in Toxicology, representing yet another area of applicability of 3 mm NMR probe capabilities. In the first of these reports, Hankin et al.159 described the results of an investigation into the covalent binding of leukotriene A4 to DNA and RNA. Later in 2003, Blair and co-workers160 reported on the characterization of 2 -deoxycytidine adducts derived from 4-oxo-2-nonenal, a novel lipid peroxidation product. Two of the adducts characterized, Ai and A2, were consistent with substituted ethano-deoxycytidine structures. The third adduct, B, was characterized as a 7-heptanone-etheno-deoxycytidine adduct (78). 

However, under similar reaction conditions the N-benzoyl-cytidine derivative furnished a mixture of N-benzoyl-3 -0-DMTr-deoxycytidine and the corresponding N-unprotected nucleoside. However, this limitation was avoided using the corresponding levuUnic derivative because the protecting group was easily removed using hydrazine (Scheme 10.8). 

Another type of photochemical reaction involving a pyrimidine base is the addition of a molecule of water across the 5,6 double bond of C to yield a 5,6-dihydro-6-hydroxy derivative called the cytosine hydrate. The quantum yield for the formation of cytosine hydrates in UV-irradiated DNA is greater in single-stranded than in duplex-DNA (45). Hydrates of cytosine, deoxycytidine, CMP, or dCMP are unstable, readily reverting to the parent form by rehydration (45). However, their half-life is dramatically increased in DNA, and cytosine hydrate may be the major nondimer C photoproduct. Cytosine hydrate can undergo deamination and dehydration to yield uracil (1). The hydrate of 5-methylcytosine may undergo deamination to yield 5-thymine hydrate, which can convert to thymine upon dehydration (1). 

Lastly, electron transfer in D—[H]—A assemblies is not a perquisite of the excited states of metal complexes. Organic ensembles 38 and 39 (R = SiMe2 Bu), containing a dimethylaniline-anthracene redox pair, have been synthesized recently [124]. Preliminary time-resolved and steady-state fluorescence experiments indicate the occurrence of photoinduced electron transfer. In work related to Watson Crick base-paired systems, the excited state of the fluorescent pyrene derivative 40 is efficiently quenched (94-99 %) by 2 -deoxyguanosine (dG), 2 -deoxycytidine (dC), or 2 -deoxythymidine (dT) in aqueous solution [125]. A PCET mechanism is thought to be responsible for this process, as the thermodynamics of electron transfer are unfavorable unless coupled to a rapid proton-transfer step. The quenched lifetime of 40 in the presence of dC and dT in H2O is significantly extended by a factor of 1.5-2.0 in D2O this isotope effect is similar to that observed in the kinetics studies of 1 [70]. The invoked PCET reaction mechanism also accounts for the inability of dC and dT to quench the fluorescence of 40 in the aprotic organic solvent DMSO. 

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