Effects of chirality in 9-(2-hydroxy-3-nonyl)adenine upon deoxyribonucleic acid synthesis in herpes simplex virus-infected cells

North, Thomas W.; O'Connor, Lorraine; Abushanab, Elie; Panzica, Raymond P.

doi:10.1016/0006-2952(83)90300-3

Cited by 7 publications

(3 citation statements)

References 21 publications

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“…However, the ADA inhibitory activity does not account for the antiviral potency, as already reported for other adenosine deaminase inhibitors. 25 One can anticipate that the anti-HIV-1 activity of these nucleoside analogues generally rests on an inhibition of reverse transcriptase (RT). The observation that our compounds possess a modest anti-HSV-1 effect, which merely reflects cytotoxicity, argues against the possibility that they are selectively phosphorylated by the HSV-1 thymidine kinase or that they discriminate between cell DNA polymerase a and the herpes virus replicase.…”

Section: Discussionmentioning

confidence: 99%

“…Results (Table 3) showed that none of the tested derivatives were substrates of the enzyme, and some of them were good inhibitors, 2'-deoxy-l-deazaadenosine (25) being the most potent in the series (Ki = 0. and apparently more active than 1-deazaadenosine itself (9; Ki = 0.66 µ ). Interestingly, 2',3'-dideoxy-1 -deazaadenosine (41; Ki = 2.5 µ ) is the first dideoxy nucleoside reported so far to show ADA inhibitory activity in the micromolar range.…”

Section: Biological Evaluationmentioning

confidence: 99%

“…® Abstract published in Advance ACS Abstracts, September 1, 1995. 0022-2623/95/1838-4019$09.00/0 [4,[5][6]pyridine,n and the more versatile base 5,7dichloro-3I/-imidazo [4,[5][6]pyridine (50)11 with ribose and 2-deoxyribose derivatives to obtain 6-amino-,4 6-(hydroxyamino)-,12'13 and 6-(cycloalkylamino)-l-deazapurine nucleosides.614 Our approach is now to use 5011 as the starting base to obtain the new nucleoside 2',3'dideoxy-l-deazaadenosine (41) and a number of novel 2',3'-dideoxy-6-(cycloalkylamino)-l-deazaadenosine analogues. In particular, the present study was aimed at direct comparison of the activity as anti-HIV-1 and anti-HSV-1 (herpes simplex virus type-1) agents and ADA inhibitors of a series of 1-deazapurine nucleosides with the N6 nitrogen unsubstituted or bearing methyl or cycloalkyl substituents, with or without a chloro group in the 2-position, and with the glycosylic moiety being ribose (1-16), 2'-deoxyribose (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32), or 2',3'-dideoxyribose (33-48) (Figure 1).…”

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confidence: 99%

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Synthesis and Biological Evaluation of N6-Cycloalkyl Derivatives of 1-Deazaadenine Nucleosides: A New Class of Anti-Human Immunodeficiency Virus Agents

Cristalli¹,

Vittori²,

Eleuteri³

et al. 1995

J. Med. Chem.

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A series of 1-deazaadenine nucleosides with the N6 nitrogen unsubstituted or bearing methyl or cycloalkyl substituents, with or without a chloro group in the 2-position, and with the glycosylic moiety being ribose (1-16), 2'-deoxyribose (17-32), or 2', 3'-dideoxyribose (33-48) were designed and synthesized starting from 5,7-dichloro-3H-imidazo[4,5-b] pyridine (50). These compounds were evaluated for their in vitro activity against human immunodeficiency virus type-1 (HIV-1) and herpes simplex virus type-1 (HSV-1). In addition they were tested for their ability to inhibit adenosine deaminase (ADA) from calf intestine. While the parent compounds 1-deazaadenosine (9), 2'-deoxy-1-deazaadenosine (25), and 2',3'-dideoxy-1- deazaadenosine (41) and the corresponding 2-chloro derivatives were inactive, nucleosides bearing cycloalkyl substituents on N6 exhibited moderate to good anti-HIV-1 activity, compared to 2',3'-dideoxyadenosine, with the degree and pattern of improvement depending on the structure of the sugar moiety. In general, 2'-deoxy- and 2',3'-dideoxy derivatives were more potent compounds than the corresponding ribose nucleosides. Compounds bearing a 6-cycloheptyl or cyclooctylamine were the most active in every series. The presence of a chloro group in the 2-position improved both activity and therapeutic index in every series, the most active compound being 2'-deoxy-2-chloro-N6-cycloheptyl-1-deazaadenosine (23; ED50 = 0.2 microM). On the other hand, most of these derivatives were inactive as anti-HSV-1 agents, showing a high degree of virus selectivity. The 1-deazaadenine derivatives were not substrates of adenosine deaminase, and some of them proved to be good inhibitors of the enzyme. However, the ADA inhibitory activity does not account for the antiviral potency since increased lipophilicity and steric hindrance of substituents resulted in derivatives much less active than the parent compounds.

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Section: Discussionmentioning

confidence: 99%

Section: Biological Evaluationmentioning

confidence: 99%