Analogs of 1-β-d-arabinofuranosylcytosine. Studies on mechanisms of action in Burkitt's cell culture and mouse leukemia, and in vitro deamination studies

Dollinger, Malin R.; Burchenal, Joseph H.; Kreis, Willi; Fox, Jack J.

doi:10.1016/0006-2952(67)90082-2

Cited by 36 publications

(18 citation statements)

References 15 publications

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“…The results of the present study corroborate these previous findings. In our target-organ herpesvirus experiments, Ara-C was less active than Ara-A and TFT, possibly owing to its rapid deamination to the inactive uracil arabinoside (3,5,7). TFT has marked antiviral activity against herpes and vaccinia infections in rabbit eyes (10,11) and in vitro against vaccinia virus (22).…”

Section: Resultsmentioning

confidence: 80%

Target-Organ Treatment of Neurotropic Virus Diseases: Efficacy as a Chemotherapy Tool and Comparison of Activity of Adenine Arabinoside, Cytosine Arabinoside, Idoxuridine, and Trifluorothymidine

Allen¹,

Sidwell²

1972

Antimicrob Agents Chemother

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A sensitive in vivo system was studied for use in evaluating relatively small quantities of antiviral compounds. Swiss mice were injected intracerebrally with 10 LD50 of type 1 herpes simplex virus (HSV) or vaccinia virus. Test compounds were injected intracerebrally into mice at a standard time interval after virus inoculation. Significant increases in the number of survivors in drug-treated, infected animals as compared to saline-treated virus controls was the criterion for evaluation of antiviral activity. 9-f3-D-Arabinofuranosyladenine (Ara-A) was used to determine an optimal time of therapy for this system. Significant survival increases occurred when the drug was injected 3, 6, 12, and 48 hr after HSV inoculation, with maximal effect occurring after the 6-hr treatment interval. Determination of brain virus titer of 6-hr Ara-A-and saline-treated mice at various intervals indicated that treatment with the drug delayed development of detectable levels of HSV by 1 day. 1-f3-D-Arabinofuranosylcytosine (Ara-C), trifluorothymidine (TFT), and 5-iodo-2'-deoxyuridine (IDU) were also evaluated with the use of the 6-hr treatment time against HSV and vaccinia virus. Ara-A and TFT increased the number of survivors among mice infected with either virus, whereas Ara-C increased the survivors among HSVinfected, but not vaccinia virus-infected, mice. IDU was inactive against both viruses.A need exists for a method whereby small quantities of potential antiviral substances can bereproducibly evaluated in vivo for antiviral activity. A system having possible efficacy is the intracerebral or target-organ treatment of neurotropic virus infections. Renis et al. (13)

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Section: Resultsmentioning

confidence: 80%

Target-Organ Treatment of Neurotropic Virus Diseases: Efficacy as a Chemotherapy Tool and Comparison of Activity of Adenine Arabinoside, Cytosine Arabinoside, Idoxuridine, and Trifluorothymidine

Allen¹,

Sidwell²

1972

Antimicrob Agents Chemother

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“…The low order of toxicity of both substances is in contrast to the rather marked effects (50% inhibition at < 1 .O pg/ml) reported by other investigators when these substances were tested against proliferating malignant cells in culture (2, 3). Dollinger et al reported that the highly sensitive Burkitt's tumor and leukemia L-1210 cells lack the ability to deaminate CA in vitro, whereas both CA and FCA are rapidly deaminated to the corresponding inactive uracil nucleosides by both human liver and mouse kidney enzyme systems in vitro (14). The disparity between high cytotoxicity for malignant cells in vitro, and the low degree of cytotoxicity for normal resting mammalian cells reported here, may possibly be explained by either the preferential lethality of these antimetabolites for rapidly growing cells and/or inactivation by normal cells through deamination of the cytosine moiety in both molecules.…”

Section: The Results Summarized Inmentioning

confidence: 98%

A Comparative Study of the Antitumor and Antiviral Activity of 1- -D-Arabinofuranosyl-5-fluorocytosine (FCA) and 1- -D-Arabinofuranosylcytosine (CA)

Prince

Grünberg

Buck

et al. 1969

Experimental Biology and Medicine

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“…The residue was dissolved in MeOH (25 mL) and the solution absorbed on a Dowex-50 (sulfate form) column; the column was eluted with MeOH (30 mL). The UV-absorbing fractions were combined and evaporated to dryness to provide 10 as a pale solid: yield, 52 mg, 72%; UV Xmal (MeOH) 278 nm (e 6900); Xmax (pH 1) 278 nm (e 7050); XmM (pH 14) 1 -ß--Arabinofuranosyl-2-amino-1,4(2H)-iminopyrimidine nofuranosyl-5-chIorocytosine hydrochloride (6,76.5 mg, 0.25 mmol)…”

Section: Methodsmentioning

confidence: 99%

Synthesis and antitumor and antiviral activities of 1-.beta.-D-arabinofuranosyl-2-amino-1,4(2H)-iminopyrimidine, and its derivatives

Mian¹,

Long²,

Allen³

et al. 1979

J. Med. Chem.

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1-beta-D-Arabinofuranosyl-2-amino-1,4(2H)-imino-5-fluoropyrimidine (10), 1-beta-D-arabinofuranosyl-2-amino-1,4(2H)-imino-5-fluoropyrimidine 3'-phosphate (9), and 1-beta-D-arabinofuranosyl-2-amino-1,4(2H)-imino-5-chloropyrimidine (11) have been synthesized from 2,2'-anhydro-1-beta-D-arabinofuranosyl-5-fluorocytosine (5), 2,2'-anhydro-1-beta-D-arabinofuranosyl-5-fluorocytosine 3'-phosphate (4), and 2,2'-anhydro-1-beta-D-arabinofuranosyl-5-chlorocytosine (6), respectively. 2,2'-Anhydro-1-beta-D-arabinofuranosylcytosine 3'-phosphate (7), 1-beta-D-arabinofuranosyl-2-amino-1,4-(2H)-iminopyrimidine (13), 1-beta-D-arabinofuranosyl-2-amino-1,3(2H)-iminopyrimidine 3'-phosphate (12), and compounds 4, 5, and 9 showed significant in vitro activity against a number of DNA viruses. Compounds 7 and 12 were also effective in vivo against type 1 herpes simplex virus. Compounds 7, 12, and 13 were extremely effective in the treatment of mice bearing leukemia L1210.

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Analogs of 1-β-d-arabinofuranosylcytosine. Studies on mechanisms of action in Burkitt's cell culture and mouse leukemia, and in vitro deamination studies

Cited by 36 publications

References 15 publications

Target-Organ Treatment of Neurotropic Virus Diseases: Efficacy as a Chemotherapy Tool and Comparison of Activity of Adenine Arabinoside, Cytosine Arabinoside, Idoxuridine, and Trifluorothymidine

Target-Organ Treatment of Neurotropic Virus Diseases: Efficacy as a Chemotherapy Tool and Comparison of Activity of Adenine Arabinoside, Cytosine Arabinoside, Idoxuridine, and Trifluorothymidine

A Comparative Study of the Antitumor and Antiviral Activity of 1- -D-Arabinofuranosyl-5-fluorocytosine (FCA) and 1- -D-Arabinofuranosylcytosine (CA)

Synthesis and antitumor and antiviral activities of 1-.beta.-D-arabinofuranosyl-2-amino-1,4(2H)-iminopyrimidine, and its derivatives

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