Nucleic Acids. II. Cytotoxicity Studies with Nucleotides and Dinucleoside Phosphates Containing <i>ara</i>-Cytidine

Smith, Charles G.; Buskirk, Harold H.; Lummis, William L.

doi:10.1021/jm00317a004

Cited by 18 publications

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“…98,99 The reversal of activity of the dimers by deoxycytidine and the lack of cytotoxicity against the kinase-de®cient Ara-C resistant mutant of L5178Y murine leukemia cells suggested that the dimers probably undergo hydrolysis to release the nucleosides rather than the nucleotides. 98,99 Likewise, incubation of human erthyrocytes with 5 H 3 3 H linked bisphosphate FUdR dimer was postulated to release two Figure 13. Dinucleosidyl phosphodiesters.…”

Section: D I N U C L E O S I D Y L P H O S P H a T E D E R I V A T mentioning

confidence: 99%

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Pronucleotides: Toward thein vivo delivery of antiviral and anticancer nucleotides

Wagner¹,

Iyer²,

McIntee³

2000

Med. Res. Rev.

264

215

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To overcome the many hurdles preventing the use of antiviral and anticancer nucleosides as therapeutics, the development of a prodrug methodology (i.e., pronucleotide) for the in vivo delivery of nucleotides has been proposed as a solution. The ideal pronucleotide should be non‐toxic, stable in plasma and blood, capable of being i.v. and/or orally dosed, and intracellularly convertible to the corresponding nucleotide. Although this goal has yet to be achieved, many clever and imaginative pronucleotide approaches have been developed, which are likely to be important pharmacological tools. This review will discuss the major advances and future directions of the emerging field of antiviral and anticancer pronucleotide design and development. © 2000 John Wiley & Sons, Inc. Med Res Rev, 20, No. 6, 417–451, 2000

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Section: D I N U C L E O S I D Y L P H O S P H a T E D E R I V A T mentioning

confidence: 99%

“…88,93^96,98^100, 102, 162 equivalents of FUdR-MP by phosphodiesterase-mediated hydrolysis. 99 However, further conversion to FUdR and FU was also observed.…”

Section: D I N U C L E O S I D Y L P H O S P H a T E D E R I V A T mentioning

confidence: 99%

Pronucleotides: Toward thein vivo delivery of antiviral and anticancer nucleotides

Wagner¹,

Iyer²,

McIntee³

2000

Med. Res. Rev.

264

215

View full text Add to dashboard Cite

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“…We thought that combining a glycine residue with a protonated arginine residue would confer water solubility on the derivative, while the arginylamido Calculated from median survival times of treated and control groups. 6 Compound 1 was given as the free base, compounds 2-9 as hydrochloride salts, and compound 10 as the dihydrochloride salt. c Vehicle A = 0.9% (w/v) aqueous NaCl (saline).…”

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confidence: 99%

“…The compounds were also tested for immunosuppressive activity in a standard hemagglutinin assay in the mouse. 6 The dosage was 400 µ /kg/day given on days 1-5.…”

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confidence: 99%

Nucleic acids. 16. Orally active derivatives of ara-cytidine

Wj¹,

Dt²,

Me³

et al. 1976

J. Med. Chem.

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Water-soluble derivatives of ara-cytidine (cytarabine, Cytosar) were prepared and tested for antitumor, immunosuppressive, and antiarthritic activities in animals after oral administration. The compounds tested included the 5'-palmitate, 5'-benzoate, and 5'-adamantoate esters of ara-cytidine, made water soluble by use of their hydrochloride salts of peptidyl derivatives, and two basic 5' esters (5'-nicotinoate and 5'-quinuclidinate) as their hydrochloride salts. Five of the compounds had antitumor activity superior to that found with ara-cytidine itself after oral administration in the L1210 leukemic mouse assay. One of these, 5'-adamantoyl-ara-cytidine hydrochloride, had antitumor activity after oral administration approaching that achieved with parenterally administered ara-cytidine.

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“…16 The nucleotides and dinucleoside phosphates displayed activity against KB carcinoma cells in culture, but were cross-resistant with ara-C against an ara-C-resistant mutant (kinaseless). 17 It was suggested that the nucleotides and dinucleoside phosphates were cleaved to free ara-C, which was then converted to the metabolically active form. 18 The introduction of a fluorine atom into the 5 position of ara-C produced a new nucleoside possessing more activity19 against transplanted mouse leukemia P-815 and P-388 and approximately equal activity20 with ara-C against leukemia L-1210.…”

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confidence: 99%

Synthesis and antitumor antiviral activities of 1-.beta.-D-arabinofuranosylpyrimidine 3',5'-cyclic phosphates

Long¹,

Szekeres²,

Khwaja³

et al. 1972

J. Med. Chem.

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Ring closure of 1-ß-D-arabinofuranosylcytosine 3'-phosphate was accomplished by treatment with dicyclohexylcarbodiimide in refluxing pyridine to yield 1-ß-D-arabinofuranosylcytosine 3',5'-cyclic phosphate (cyclic-ara-CMP). Treatment of this product with sodium nitrite in aqueous acetic acid furnished -ß-Darabinofuranosyluracil 3',5'-cyclic phosphate. Conversion of cyclic-ara-CMP into l^-D-arabinofuranosyl-4thiouracil 3',5'-cyclic phosphate was accomplished with hydrogen sulfide in pyridine-water. -ß-D-Arabinofuranosyl-4-methylthio-2-p|yrimidone 3 ,5'-cyclic phosphate was obtained by methylation of -ß-Darabinofuranosyl-4-thiouracil 3 ,5'-cyclic phosphate. Antiviral studies in cell culture reveal cyclic-ara-CMP to be as active as ara-C in inhibiting the growth of DNA viruses. Cyclic-ara-CMP shows considerable toxicity against leukemia L-1210 in vivo. Five daily doses of 300 mg/kg produced a 52% increase in the survival time of the mice bearing L-1210 leukemia. In vitro studies with partially purified cAMP phosphodiesterase show that the arabinosylpyrimidine 3',5'-cyclic phosphates are slowly hydrolyzed to the monophosphates.The inhibitory activity of 1 -ß-D-arabinofuranosylcytosine (cytosine arabinoside, ara-C) against leukemias, lymphomas, and DNA viruses in vitro and in vivo is well documented.1 The antitumor activity of ara-C against leukemia L-5178Y cells in culture was found to be due to the prevention of the conversion of cytidine nucleotides to deoxycytidine nucleotides.2'3 Inhibition of DNA synthesis at the DNA polymerization level by ara-C has also been established.4"7 Ara-C is converted to the triphosphate (ara-CTP), with the phosphorylation of ara-C being mediated by deoxycytidine kinase.8 Resistance to ara-C has been found when the activ-

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Nucleic Acids. II. Cytotoxicity Studies with Nucleotides and Dinucleoside Phosphates Containing ara-Cytidine

Cited by 18 publications

References 0 publications

Pronucleotides: Toward thein vivo delivery of antiviral and anticancer nucleotides

Pronucleotides: Toward thein vivo delivery of antiviral and anticancer nucleotides

Nucleic acids. 16. Orally active derivatives of ara-cytidine

Synthesis and antitumor antiviral activities of 1-.beta.-D-arabinofuranosylpyrimidine 3',5'-cyclic phosphates

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