Initial studies on the cellular pharmacology of 2′,3′-dideoxycytidine, an inhibitor of HTLV-III infectivity

Cooney, David A.; Dalal, Maha; Mitsuya, Hiroaki; McMahon, James B.; Nadkarni, Moreshwar V.; Balzarini, Jan; Broder, Samuel; Johns, David G.

doi:10.1016/0006-2952(86)90571-x

Cited by 237 publications

(67 citation statements)

References 5 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…1, compound 1) (Mitsuya, 1985). Although the free Sf-phosphates of AZT are known (Cooney, 1986), Sf-phosphate triesters have not been reported. Thus, the aforementioned route was employed in the direct synthesis of compounds 8a-8c (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…1, compound 2). AlT was first prepared by HOrwitz(1964)and displays promising anti-AIDS activity in initial clinical trials (yarchoan, 1986).Along with ddCyd, and the other nucleoside analogues; AlT acts following metabolic conversion to its 5' -triphosphate (Furman, 1986;Cooney, 1986). This may lead to the problem, common among nucleoside analogues, of a poor clinical response resulting from poor cellular phosphorylation (york, 1966;Furman, 1979).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Synthesis of Some Novel Dialkyl Phosphate Derivatives of 3′-Modified Nucleosides as Potential Anti-AIDS Drugs

McGuigan

Nicholls

O’Connor

et al. 1990

Antivir Chem Chemother

View full text Add to dashboard Cite

SummaryThe reaction of thymidine with diethyl, dipropyl, and dibutyl phosphorochloridates yields novel 5/-(dialkyl phosphates), characterized by spectroscopic and analytical data. These are readily mesylated at the 3'-position. Similar reaction of 3'-0-acetyl and 3'-0-ethyl thymidine with dialkyl phosphorochloridates gives an analogous series of compounds. Lastly, reaction of the anti-AIDS drug AZT with these phosphorylating agents gives the corresponding 3'-azido products. It was hoped that these might act as membrane-soluble pro-drugs of the bio-active free nucleotides of AZT and that the alternative 3/ -substituents might also confer similar activity. In fact, none of the compounds studied displayed any anti-HIV activity in vitro. This is attributed to the metabolic stability of the trialkyl phosphate moiety.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Synthesis of Some Novel Dialkyl Phosphate Derivatives of 3′-Modified Nucleosides as Potential Anti-AIDS Drugs

McGuigan

Nicholls

O’Connor

et al. 1990

Antivir Chem Chemother

View full text Add to dashboard Cite

show abstract

“…Indeed, dogs tolerated up to 3.53 mg/kg (per hr) intravenous injections of ddCyd (plasma concentration of up to 50 AM) for 5 days and oral dosing yielded peak plasma levels of over 50 ,uM for 28 days; in fasting dogs, ddCyd had virtually 100% bioavailability by the oral route (C. Grieshaber, personal communication). In addition, ddCyd is a poor substrate for cytidine aminohydrolase (deaminase) (20). Finally, ddCyd has been shown to rapidly penetrate into the cerebrospinal fluid of monkeys, although the overall amount was 2-6% (as determined by calculating the area under the curve) of that in plasma (27).…”

Section: Methodsmentioning

confidence: 99%

Long-term inhibition of human T-lymphotropic virus type III/lymphadenopathy-associated virus (human immunodeficiency virus) DNA synthesis and RNA expression in T cells protected by 2',3'-dideoxynucleosides in vitro.

Mitsuya

Jarrett

Matsukura

et al. 1987

Proc. Natl. Acad. Sci. U.S.A.

180

View full text Add to dashboard Cite

We report that 2',3'-dideoxyadenosine and 2',3'-dideoxycytidine inhibit retroviral DNA synthesis and mRNA expression in T cells exposed to the virus that causes acquired immunodeficiency syndrome, and afford such cells long-term protection in vitro under conditions of substantial viral excess. Both 2',3'-dideoxyadenosine and 2',3'-dideoxycytidine appear to completely block reverse transcription from viral RNA to viral DNA. Viral mRNA expression is also not detected in cells protected by the drugs throughout 30 days of culture following exposure to the virus. Purine and pyrimidine analogues as 2',3'-dideoxynucleoside-5'-triphosphate serve as substrates for the human T-lymphotropic virus type III/lymphadenopathy-associated virus reverse transcriptase to elongate a DNA chain by one residue, after which the chain is terminated. Cloned normal helper/inducer T cells exposed to a cytopathic dose of the virus, but protected by the drugs, respond normally to specific antigen in vitro. These results suggest that the drugs could be promising agents for further studies in the experimental treatment of patients infected with retroviruses.

show abstract

“…2) (Fig. 4) (4,10,18,23) and then anabolized to 5'-triphosphate (20). This conversion is contingent upon cell division and is severalfold higher in the early exponential growth phase than at the beginning of G2 in the cell cycle (3).…”

Section: Mortalitymentioning

confidence: 99%

Hematological Effects of 2',3'-Dideoxycytidine in Rabbits

et al. 1992

View full text Add to dashboard Cite

The antiviral nucleoside analogue 2',3'-dideoxycytidine (ddC) is a DNA chain terminator and/or inhibitor of human immunodeficiency virus (HIV) reverse transcriptase. We evaluated the effects of ddC in 36 New Zealand white rabbits. Three/sex were assigned to a control group and 5 treatment groups (10-250 mg/kg/ day) for 13 or 18 weeks. Blood samples were taken 1 week prior to treatment and weekly thereafter to termination with the exception of the 2 highest dose groups, where blood sample collection was terminated at week 13. Selected hematological analytes were measured weekly with the exception of prothrombin time (PT) and activated partial thromboplastin time (APTT). PT and APTT and selected biochemical analytes were measured prior to treatment, at 7 weeks, and after 13 weeks of treatment. All rabbits were necropsied. Giemsa and hematoxylin and eosin sections were prepared from methacrylate-embedded marrow. Hematological effects included decreases in red blood cell count, hemoglobin, hematocrit, and white blood cell count and increases in mean corpuscular volume and red cell distribution width. Platelets, platelet volume, PT, APTT, and mean corpuscular hemoglobin concentration values were variable or unchanged. Effects were dose-related, most were seen at 1 week, and they persisted to term. Bone marrow histopathologic changes included megalocytosis, erythroid hypoplasia, bizarre erythroid nuclear morphology, nuclear-cytoplasmic asynchrony, and increased mitotic figures. Lymphopenia caused by ddC plateaued at 2 weeks and persisted until termination. Heteropenia (neutropenia) was sporadic. Biochemical values for serum analytes were unchanged by treatment. The principal hematological effect of ddC upon the erythron was characterized as a nonregenerative macrocytic anemia with erythroid hypoplasia and megaloblastic erythropoiesis. We consider the anemia to be of bone marrow origin because of the morphologic changes observed here and produced by the effect of ddC on DNA synthesis in erythroid precursors and/or stromal cells.

show abstract

Initial studies on the cellular pharmacology of 2′,3′-dideoxycytidine, an inhibitor of HTLV-III infectivity

Cited by 237 publications

References 5 publications

Synthesis of Some Novel Dialkyl Phosphate Derivatives of 3′-Modified Nucleosides as Potential Anti-AIDS Drugs

Synthesis of Some Novel Dialkyl Phosphate Derivatives of 3′-Modified Nucleosides as Potential Anti-AIDS Drugs

Long-term inhibition of human T-lymphotropic virus type III/lymphadenopathy-associated virus (human immunodeficiency virus) DNA synthesis and RNA expression in T cells protected by 2',3'-dideoxynucleosides in vitro.

Hematological Effects of 2',3'-Dideoxycytidine in Rabbits

Contact Info

Product

Resources

About