Cytotoxic nucleoside

Capecitabine (Xeloda ) Cytotoxic nucleoside Breast (then colorectal) Phase II. On the basis of response rate. Then randomized Phase III for survival... 

The chemical modification of the cytotoxic nucleosides ara-C, 5-FdU, ETC, and correspondingly of the antiviral nucleosides azidothymidine (AZT), dideoxycytidine (ddC) and dideoxyinosine (ddl) and their formulation in liposomes render these new heterodinucleoside compounds interesting candidates for further developments. 

Repta, A. J., B. J. Rawson, R. D. Shaffer, K. B. Sloan, N. Bodor, andT. Higuchi. 1975. Rational development of a soluble prodrug of a cytotoxic nucleoside preparation and properties of arabinosylad ohrraeflie. 

Vinogi adov SV, Zeman AD, Bati akova EV, Kabanov AV (2005b) Polyplex Nanogel fonnuladons for drug delivery of cytotoxic nucleoside analogs. J Conti ol Release 107 143-157. 

Mojavarion, R. Repta, A. Development of an intravenous formulation for the unstable investigational cytotoxic nucleosides 5-azacytosine arabinoside (NSC 281272) and 5-azacytidine (NSC 102816). J. Pharm. Pharmacol. 1984, 36 (11), 728-733. 

In previous studies performed with similar heterodinucleoside phosphate dimers composed of the antivirally active nucleosides azidothymidine, dideoxycytidine and dideoxyinosine and formulated in liposomes we found significantly different pharmacokinetic properties and superior antiviral effects in comparison to the parent hydrophilic nucleosides (33, 34). Thus, the chemical modification of cytotoxic nucleosides and their formulation in liposomes render these new hetero-dinucleoside compounds interesting candidates for further developments. 

C11H14N4O4, Mr 266.26, cryst., mp. 247°C (decomp.), cytotoxic nucleoside antibiotic from Streptomyces tu-bercidicus, LD50 (rat p. o.) 16 mg/kg, with antitumor, antifungal, and antiviral activities. T. was also isolated as one of the main cytotoxins from Tolypothrix bys-soidea. Known derivatives of T. are the 5 -0-sulf-amoyl compound (CnHisNsO S, Mr 345.34, herbicide) isolated from Streptomyces mirabilis as well as the cytotoxic and antifungal S -O-a-D-glucopyranosyl compound C,7H24N40, Mr 428.40, [aJo +10° (HjO) isolated from Plectonema radiosum and Tolypothrix distorta. 

The highly cytotoxic nucleoside antibiotic tubercidin likewise appears to adopt an abnormal conformation in single-stranded homopolymers. However, present data are inadequate to permit a specific assignment of the syn conformation to the individual residues in single-stranded poly-tubercidin. 

Vinogradov, S.V., Mitin, A., and Warren, G. 2008. Folate-targeted polyformulations of cytotoxic nucleoside triphosphates and paclitaxel. Polymer Prepr. 49 1050-1051. 

Another natural product, mizoribiae (39), a nucleoside antibiotic produced by the fungus Eupenicillium brefeldianum has cytotoxic and immunosuppressive activity. It has been evaluated for use ia renal transplantation and neoplasia (68). 

Amino-5-iodo-2, 5 -dideoxyuridine [56045-73-9] (13) C2H22IN2O4, was synthesized ia 1975 (27) and was found effective against herpes keratitis ia rabbits (28). This compound is markedly less cytotoxic than IdU, iadicating that it may have a safer and more specific mode of antiviral activity. A potential limitation of this group of nucleosides is their specificity, for they fail to inhibit all strains of herpes vimses. The specific antiviral activity of (13) is considered to be a result of the incorporation of the 5 -Ai-phosphate into both viral and host DNA in infected cells, but not into the DNA of normal cells. Phosphorylation of (13) occurs only in herpes vims-infected cells, brought about by a vims-induced thymidine kinase (29). 

Cladribine (2-Chlordeoxyadenosine) is a synthetic purine nucleoside that is converted to an active cytotoxic metabolite by the deoxycytidine kinase. The drug is relatively selective for both normal and malignant lymphoid cells. 

Decitabine (5-aza-deoxycytosine) is an analog of the nucleoside 2 -deoxycytidine. It is believed to exert its antineoplastic effects after phosphorylation and direct incorporation into DNA and by inhibition of the enzyme DNA methyltransferase, causing hypomethylation of DNA and cellular differentiation or apoptosis. DNA hypomethylation is achieved at concentrations below those required to significantly inhibit DNA synthesis, which may promote restoration of function to genes associated with control of cellular differentiation and proliferation. Cytotoxicity in rapidly dividing cells may also result from covalent adducts between DNA methyltransferase and decitabine. 

The 2 -chloro and 2 -bromo congeners of either 748 (FIAC) or 758 (FMAU) are more cytotoxic than FIAC and FMAU, suggesting that these chloro and bromo nucleosides, in contrast to the 2 -fluoro compounds, are comparatively better substrates for deoxycytidine kinase of human lymphocytes than the substrates for viral-specific thymidine kinase. The disposition of the 2 -fluoro group may also be important from the biological viewpoint. It should be noted that the structural difference between RNA and DNA is at the 2 -position. The ribo type of analog (738) of FIAC is 10 times less effective in suppression of HSV replication than is FIAC. Thus Fox, and Watanabe and coworkers concluded that the 2 - up fluorine disposition and the species of the substituent at C-5 are the two important factors influencing antiviral activity. Nevertheless, the mechanism of action of 2 -deoxy-2 -fluorocytidine (737) on certain herpes viruses, including HSV-1... 

Lu, X., et al. Correlation of nucleoside and nucleobase transporter gene expression with antimetabolite drug cytotoxicity. J. Exp. Ther. Oncol. 2002,... 

Mata, J. F., et al. Role of the human concentrative nucleoside transporter (hCNTl) in the cytotoxic action of 5[Prime]-deoxy-5-fluorouridine, an active intermediate metabolite of capecitabine, a novel oral anticancer drug. Mol. Pharmacol. 2001, 59, 1542— 1548. 

MRP4 is an ubiquitously expressed transporter with highest expression in the prostate where it can be localized to the basolateral membrane of tubuloacinar cells [149]. Schuetz and colleagues [150] demonstrated that high copy number and overexpression of MRP4 in a human T-lymphoid cell line was associated with cytotoxic resistance and increased cell efflux of an acyclic nucleoside phosphonate drug PMEA. Furthermore, these cells were more resistant to nucleoside analog... 

Gemcitabine - nucleoside analogue antimetabolite S-phase specific cytotoxicity -bone marrow suppression—most commonly thrombocytopenia -nausea and vomiting -fever during administration -elevated transaminases -rash... 

Allenic nucleoside analogs are currently of high interest as cytotoxic and antiviral agents. Prototypes of this class of compounds (Scheme 18.50) are the nucleoside analogs cytallene (154) and adenallene (155), which were developed by Zemlicka [143]. 

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