Structure of the anti-human immunodeficiency virus agent 3'-fluoro-3'-deoxythymidine and electronic charge calculations for 3'-deoxythymidines.

Camerman, Norman; Mastropaolo, Donald; Camerman, Arthur

doi:10.1073/pnas.87.9.3534

Cited by 23 publications

(11 citation statements)

References 6 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The 3'-azido group has generally been held responsible for the chain-terminating properties of AZT, but other groups at C(12), as fluorine (F-ddT, 3'-fluoro-3'-deoxythymidine, has proven to be as potent an inhibitor of HIV replication as is AZT [38]) seem to be effective. There has been a suggestion that antiviral activity of all AZT-like molecules may be associated with an electronegative atom attached to C(12) [39]. Our calculations show that all stable conformations of AZT present a net negative charge of about the same magnitude at N(17) (see Table IV).…”

Section: Biological Implicationsmentioning

confidence: 68%

On the implications of the structure of 3′‐azido‐3′‐deoxythymidine and related compounds to antiviral activity

Neto

Zerner

Alencastro³

1992

Int J of Quantum Chemistry

View full text Add to dashboard Cite

We report structure-activity relation studies on 3'-azido-3'-deoxythymidine (AZT) and the implications to the biological activity of this class of compounds. The adiabatic potential surface (APS) of the title compound has been examined with the LCAO-MO-SCF method within the A M I approximation. This study has shown at least 13 minima, all separated by small energy differences and barriers. We have found that the equilibrium favors the antigg conformations, in variance to previous studies that predicted the syn,gg conformers to be the most stable forms. The most stable conformation (A) is favored by about 0.5 kcal/mol. However, calculations simulating a bulk-water environment suggest that the three lowest energy conformations (A, B, and C) become almost degenerate in solution. We suggest that the crystallographic conformation (L), characterized by a high dipole moment, and analogous to C, undergoes a strong stabilization upon rotation of the 3 '-azido group and that these two conformers, C and L, are the only ones in which the hydroxyl proton is free of steric hindrance. This last point has some relevance from the biological point of view since it is generally accepted that this site must be phosphorylated in order for AZT to achieve its therapeutic effects. The above results suggest that, once in solution, conformer L isomerizes to C, which is the bioactive form of AZT. 8 1992 John Wiley & Sons, Inc.

show abstract

Section: Biological Implicationsmentioning

confidence: 68%

On the implications of the structure of 3′‐azido‐3′‐deoxythymidine and related compounds to antiviral activity

Neto

Zerner

Alencastro³

1992

Int J of Quantum Chemistry

View full text Add to dashboard Cite

show abstract

“…One of the interesting consequences of our work is that we have shown that this point must be examined further: All the drugs studied in the present paper could bind HIV-I RT in the same active site. The second point to be stressed is that it has been repeatedly quoted [23,45] that negative charges at the 3'-position are likely to be related to antiviral activity. In this series of studies, we have shown that this point is probably an error, since only AZT, among the drugs that we have examined, has such a substitution.…”

Section: Discussionmentioning

confidence: 99%

A possible mechanism of molecular recognition for the reverse transcriptase of HIV-1

Neto

Zerner

Alencastro³

1992

Int. J. Quantum Chem.

View full text Add to dashboard Cite

The reverse transcriptase (RT) of human immunodeficiency Virus type-I (HIV-I) is still a pivotal target for anti-AIDS therapy research. We examine in this paper "classical" RT inhibitors, the chain-terminating deoxynucleosides, as well as recently developed synthetic drugs. Comparison of their structures and electronic properties allowed us to speculate on a mechanism of inhibition of RT with three different recognition schemes. The first one consists of in-plane H-bond interactions of the CONH binding site. The second one is related to out-of-plane interactions and Seems to be favored by charge delocalization. It is also observed that a completely different chemical, Bl-RG-587, has a binding site exhibiting remarkable similarity to those of the dideoxynucleosides. Also important is the observation that all drugs that we have examined present two nearly perpendicular planes, one of which is likely to be associated to hydrophobic interactions. This picture provides a simple basis for discussing the antiretroviral activity of the most potent inhibitors of HIV-1 RT. It also reveals that ddI is a poor inhibitor (relative to AZT) and ddU is inactive against HIV-1 replication for completely different reasons. The low-energy conformation of ddI gives rise to unfavorable van der Waals contacts. On the other hand, ddU cannot assume a conformation suitable for phosphorylation of its hydroxyl moiety. All these features are discussed in detail. 0

show abstract

“…group substitution, limits the efficient inhibition of RT activity, and the retroviral inhibitory effects of tricyclic molecules (Mitsuya et al 1986;Camerman et al, 1990). Acyclic compounds are either not cytotoxic, or are slightly so, and only two compounds induced a cellular toxicity for the promonocytic cell-line U937.…”

Section: Discussionmentioning

confidence: 99%

Anti-HIV Activities of Novel Nucleoside Analogues: Acyclic and Tricyclic Base Nucleosides

Clayette

Merrouche

Gharbaoui

et al. 1991

Antivir Chem Chemother

View full text Add to dashboard Cite

Two series of new nucleoside derivatives, acyclic nucleosides and tricyclic base nucleosides, were screened for cellular toxicity and against HIV-1. Compounds were tested on MT4, MT2, U937 cell lines and PBMCs in multiwell tissue culture plates. Cells were infected in vitro with 2 TCID50/105 cells or 0.2 TCID50/105 cells of HIV-1-LAV-1. Two out of eight tricyclic derivatives showed little cytotoxicity; at 100μM, only two acyclic compounds exhibited cellular toxicity in U937 cells. In vitro, none of these 19 compounds demonstrated any efficient activity against the lentiviral HIV infection and replication. Furthermore, combinations of these acyclonucleosides with ddC or AZT did not inhibit HIV-1-LAV-1 replication additively or synergistically. Because acyclonucleosides did not induce any cytotoxic effect, other compounds of this family should be investigated.

show abstract

Structure of the anti-human immunodeficiency virus agent 3'-fluoro-3'-deoxythymidine and electronic charge calculations for 3'-deoxythymidines.

Cited by 23 publications

References 6 publications

On the implications of the structure of 3′‐azido‐3′‐deoxythymidine and related compounds to antiviral activity

On the implications of the structure of 3′‐azido‐3′‐deoxythymidine and related compounds to antiviral activity

A possible mechanism of molecular recognition for the reverse transcriptase of HIV-1

Anti-HIV Activities of Novel Nucleoside Analogues: Acyclic and Tricyclic Base Nucleosides

Contact Info

Product

Resources

About