Lipophilic halogenated congeners of 2',3'-dideoxypurine nucleosides active against human immunodeficiency virus in vitro.

Shirasaka, Takuma; Murakami, Kunio; Ford, Harry; Kelley, James A.; Yoshioka, Hidetoshi; Kojima, Eiji; Aoki, Shizuko; Broder, Samuel; Mitsuya, Hiroaki

doi:10.1073/pnas.87.23.9426

Cited by 54 publications

(37 citation statements)

References 25 publications

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“…The 6-Cl-ddG is a highly lipophilic antiretroviral prodrug [22]. In a study now being done, we found that the values of area under the concentration time curve (AUC 1 ) in inguinal lymph nodes or mesenteric lymph nodes after intrasubcutaneous inoculation of 6-Cl-ddG to rats were 1.3 to 2 times higher than that of ddG (manuscript in preparation).…”

Section: Discussionmentioning

confidence: 99%

“…The 6-chloro-2', 3'-dideoxyguanosine (6-Cl-ddG) is a highly lipophilic antiretroviral drug [9,15,22], whose antiretroviral activity is as high as that of ddG or that of AZT in vitro [22]. Manouilov et al demonstrated that lipophilicity is a key element in the targeting of antiretroviral drug to lymph nodes [14].…”

Section: Animalsmentioning

confidence: 99%

“…The unique structure of 6-Cl-ddG (i.e., the chlorine at portion 6 of 2', 3'-dideoxyguanosine) increases lipophilicity [22], and may promote efficacy of ddG in lymph nodes.…”

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confidence: 99%

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Effects of 6-Chloro-2',3'-Dideoxyguanosine (6-Cl-ddG) in Surface Lymph Nodes of Rhesus Monkeys (Macaca mulatta) Chronically Infected with Simian Immunodeficiency Virus (SIVmac239).

Otani

Fujii

Akari

et al. 1997

The Journal of Veterinary Medical Science

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ABSTRACT. We studied the effects of 6-chloro-2', 3'-dideoxyguanosine (6-Cl-ddG), an antiretroviral drug, in surface lymph nodes of rhesus monkeys (Macaca mulatta) chronically infected with simian immunodeficiency virus (SIV). The rhesus monkeys were treated with 25 mg/kg of 6-Cl-ddG every 8 hr for 2 weeks. We performed sequential biopsies of the surface lymph nodes three times: before, during, and after the drug treatment. The 6-Cl-ddG dramatically decreased the number of infectious virus (measured by limiting dilution assay) in lymph node mononuclear cells. This decrease was consistent with the decrease in the number of viral RNA-positive cells in lymph nodes (analyzed by in situ hybridization). Histopathological analysis revealed that hyperplastic lymphoid follicles were reduced in size, especially, enlarged areas of centroblasts in lymphoid follicles (the so-called dark areas of germinal centers) were declined. Our results demonstrated that 6-Cl-ddG decreased the viral burden concomitantly with reduced hyper-activation of germinal centers in lymphoid follicles of SIV-infected rhesus monkeys. -KEY WORDS: antiretroviral drug, 6-chloro-2', 3'-dideoxyguanosine, histopathological change, lymph node, simian immunodeficiency virus.

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Section: Discussionmentioning

confidence: 99%

Section: Animalsmentioning

confidence: 99%

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Effects of 6-Chloro-2',3'-Dideoxyguanosine (6-Cl-ddG) in Surface Lymph Nodes of Rhesus Monkeys (Macaca mulatta) Chronically Infected with Simian Immunodeficiency Virus (SIVmac239).

Otani

Fujii

Akari

et al. 1997

The Journal of Veterinary Medical Science

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“…Jones et a/., 1987; Lindsay et a/.3~T991) and adenosine deaminase ( Van der Weyden and Kelley, 1976;Shirasaka et a/., 1990;Morgan et a/., 1992). In efforts to design this type of prodrug, we have synthesized the prodrug 2'-f1uoro-ara-dideoxypurine (2'-F-ara-ddP), which can be converted to the active nucleoside 2'-fluoro-aradideoxyinosine (2'-F-ara-ddl).…”

Section: Discussionmentioning

confidence: 99%

“…6-CI-ddP was stable in phosphate buffer, pH 7.4. Degradation of 6-CI-ddP, however, was observed in serum, mouse brain homogenate and mouse liver homogenate, suggesting that the degradation was enzyme-mediated.~-CI-ddP has been shown to be a substrate for the enzyme adenosine deaminase, resulting in the formation of ddl (Shirasaka et al, 1990(Shirasaka et al, , 1991. In vitro studies examining this enzyme showed rapid and complete biotransformation of 6-CI-ddP to ddl (data not only up to 5 min after prodrug administration.…”

mentioning

confidence: 99%

Brain Targeting of anti-HIV Nucleosides:in vitro and in vivoEvaluation of 6-chloro-2′,3′-dideoxypurine, a Lipophilic Prodrug of 2′,3′-dideoxyinosine

Doshi

Boudinot

Gallo

et al. 1994

Antivir Chem Chemother

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Lipophilic 6-halo-2′,3′-dideoxypurine nucleosides may be useful prodrugs for the targeting of 2′,3′-dideoxyinosine (ddl) to the central nervous system. The purpose of this study was to evaluate the potential effectiveness of 6-chloro-2′,3′-dideoxypurine (6-CI-ddP) for the targeting of ddl to the brain. In vitro studies indicated that the adenosine deaminase-mediated biotransformation of 6-CI-ddP to ddl was more rapid in mouse brain homogenate than in mouse serum. The brain distribution of 6-CI-ddP and ddl was assessed in vivo in mice following intravenous and oral administration of the prodrug or parent drug. Brain concentrations of ddl were similar after intravenous administration of 6-CI-ddP or ddl. However, after oral administration of the 6-CI-ddP prodrug, significantly greater concentrations of ddl were seen in the brain compared to those found after oral administration of ddl. The brain:serum AUG ratio (expressed as a percentage) of ddl after intravenous administration of 50 mg kg−1 of the active nucleoside was 3%. Following oral administration of 250 mg kg−1 ddl, low concentrations of ddl were detected in the brain. Brain:serum AUC ratios following intravenous and oral administration of the prodrug 6-CI-ddP were 19–25%. Thus, brain:serum AUC ratios were 6- to 8-fold higher after prodrug administration than those obtained after administration of the parent nucleoside. Oral administration of 6-CI-ddP yielded concentrations of ddl in the brain similar to those obtained following intravenous administration. The results of this study provide further evidence that 6-CI-ddP may be a useful prodrug for delivering ddl to the central nervous system, particularly after oral administration.

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In Vitro Evaluation of Experimental Agents for Anti‐HIV Activity

et al. 1993

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This unit presents an assay that has proven useful as an initial screening test is an HIV cytopathic effect (CPE) inhibition assay in which immortalized T cell lines (e.g., ATH8 or MT2) that are profoundly sensitive to the cytopathic effect of certain strains of HIV are utilized as target cells. Additional protocols assess the anti-HIV activity of certain candidate agents by measuring inhibition of syncytium formation or p24 gag protein production by ELISA. Calculation of the 50% inhibitory concentration (IC(50)) is also presented.

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Lipophilic halogenated congeners of 2',3'-dideoxypurine nucleosides active against human immunodeficiency virus in vitro.

Cited by 54 publications

References 25 publications

Effects of 6-Chloro-2',3'-Dideoxyguanosine (6-Cl-ddG) in Surface Lymph Nodes of Rhesus Monkeys (Macaca mulatta) Chronically Infected with Simian Immunodeficiency Virus (SIVmac239).

Effects of 6-Chloro-2',3'-Dideoxyguanosine (6-Cl-ddG) in Surface Lymph Nodes of Rhesus Monkeys (Macaca mulatta) Chronically Infected with Simian Immunodeficiency Virus (SIVmac239).

Brain Targeting of anti-HIV Nucleosides:in vitro and in vivoEvaluation of 6-chloro-2′,3′-dideoxypurine, a Lipophilic Prodrug of 2′,3′-dideoxyinosine

In Vitro Evaluation of Experimental Agents for Anti‐HIV Activity

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