AEGiS-06IAC: Halogenated congeners of 2',3'-dideoxypurine nucleosides active against HIV in vitro: a new class of lipophilic prodrug.

6th International AIDS Conference


San Francisco, California, USA — June 20-23, 1990

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Halogenated congeners of 2',3'-dideoxypurine nucleosides active against HIV in vitro: a new class of lipophilic prodrug.

Int Conf AIDS 1990 Jun 20-23; 6:186 (abstract no. Th.A.267)
Shirasaka T, Murakami K, Ford H, Kelley J, Yoshioka H, Kojima E, Aoki S, Driscoll JS, Broder S, Mitsuya H; National Cancer Institute, Bethesda, MD, USA

OBJECTIVE: Lipophilicity of 2',3'-dideoxypurine (ddP) nucleosides is generally low and their penetration into the central nervous system is not likely to be efficient. Generation of lipophilic antiretroviral drugs may have direct clinical relevance to the therapy of HIV infection.

METHODS: Four 2-amino-6-halo-ddP and four 6-halo-ddP were synthesized and tested for in vitro activity to suppress the infectivity, cytopathic effect, gag protein expression, and DNA synthesis of HIV in various cells. Octanol-water partition coefficients and enzymatic deamination kinetics were defined.

RESULTS: Of the above compounds, 2-amino-6-fluoro- and 2-amino-6-chloro-ddP possessed in vitro anti-HIV activity comparable to that of 2',3'-dideoxyinosine (ddI) and dideoxyguanosine (ddG). The comparative order of lipophilicity was: 2-amino-6-iodo greater than 2-amino-6-bromo greater than 2-amino-6-chloro greater than 2-amino-6-fluoro greater than ddG greater than ddI, while the relative rate of deamination by adenosine deaminase (ADA) was: ddA, 2-amino-6-fluoro much greater than 2-amino-6-chloro greater than 2-amino-6-bromo greater than 2-amino-6-iodo. In the presence of 2'-deoxycoformycin, a potent ADA-inhibitor, all 6-halo ddP analogs failed to exert in vitro antiretroviral effect.

CONCLUSION: All eight 6-halo 2',3'-dideoxypurine nucleosides were active against HIV in vitro and were substrates for ADA. In addition, all compounds except 6-fluoro ddPs were more lipophilic than 2',3'-dideoxynucleosides (AZT included) presently under clinical trials. These nucleosides represent a potential new class of lipophilic prodrugs for ddI and ddG.

Keywords: AEGIS, HIV, Prodrugs, Dideoxynucleosides, Didanosine, Dideoxyadenosine, Antiviral Agents, Zidovudine, Adenosine Deaminase, Enzyme Inhibitors, HIV Infections, Anti-HIV Agents, Pentostatin, Solubility, In Vitro, ICA6KWDaegis,hiv,prodrugs,dideoxynucleosides,didanosine,dideoxyadenosine,antiviralagents,zidovudine,adenosinedeaminase,enzymeinhibitors,hivinfections,anti-hivagents,pentostatin,solubility,invitro,ica6

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ThA267

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