title: Novel 6-alkoxypurine 2',3'-dideoxynucleosides as inhibitors of the cytopathic effect of the human immunodeficiency virus.
abstract: Twenty-one 6-alkoxypurine 2',3'-dideoxynucleosides were enzymatically synthesized with nucleoside phosphorylases purified from E. coli. Eighteen analogs exhibited anti-HIV-1 activity in MT4 cells. Two analogs, 6-(hexyloxy)-(17) and 6-(heptyloxy)-(18) purine 2',3'-dideoxynucleoside, were as potent as 2',3'-dideoxyinosine (ddI, didanosine, Videx). Although the antiviral activities of 17 and 18 were equivalent, 18 was more cytotoxic. Analogs containing less than four carbons in the 6-alkoxypurine substituent exhibited weak anti-HIV-1 activity. Analogs containing more than seven carbons in the 6-alkoxypurine substituent were too cytotoxic to be effectively evaluated for antiviral activity. Several 6-alkoxypurine 2',3'-dideoxynucleosides were evaluated for substrate activity with calf intestinal adenosine deaminase (ADA). Increasing the carbon chain length of the 6-alkoxypurine substituent decreased the rate of dealkoxylation. The best substrate in this series was 6-methoxypurine 2',3'-dideoxynucleaside (1); however, the rate of dealkoxylation of 100 microM 1 was 0.17% of the rate of deamination of 100 microM 2',3'-dideoxyadenosine. Compound 17, the most potent anti-HIV-1 analog, was not a substrate for ADA. EHNA (erthro-9-(2-hydroxy-3-nonyl)adenine), a potent inhibitor of ADA, had little effect on the antiviral activities of 17 and ddI. In contrast, coformycin, a potent inhibitor of both ADA and AMP deaminase, dramatically decreased the antiviral activity of 17, but not the antiviral activity of ddI. Thus, AMP deaminase appeared to be involved in the anabolism of 17. The pharmacokinetic profile of 17, the most promising analog in this series, was determined in the rat. At least seventeen metabolites of 17, including ddI, were detected in plasma samples. This analog also had poor oral bioavailability.
authors.affiliation: Division of Experimental Therapy, Burroughs Wellcome Co., Research Triangle Park, North Carolina 27709.
authors.forename: C L
authors.initials: CL
authors.lastname: Burns
authors.forename: M H
authors.initials: MH
authors.lastname: St Clair
authors.forename: L W
authors.initials: LW
authors.lastname: Frick
authors.forename: T
authors.initials: T
authors.lastname: Spector
authors.forename: D R
authors.initials: DR
authors.lastname: Averett
authors.forename: M L
authors.initials: ML
authors.lastname: English
authors.forename: T J
authors.initials: TJ
authors.lastname: Holmes
authors.forename: T A
authors.initials: TA
authors.lastname: Krenitsky
authors.forename: G W
authors.initials: GW
authors.lastname: Koszalka
mesh_terms: D000243:Adenosine Deaminase / Q000378:metabolism; D000818:Animals; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D015224:Dideoxynucleosides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D011684:Purine Nucleosides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011683:Purine-Nucleoside Phosphorylase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013939:Thymidine Phosphorylase / Q000378:metabolism
chemical_list: D015224:Dideoxynucleosides; D011684:Purine Nucleosides; D011683:Purine-Nucleoside Phosphorylase; D013939:Thymidine Phosphorylase; D000243:Adenosine Deaminase