PMID:15598076
| Citation |
Doughty, MB, Aboudehen, K, Anderson, G, Li, K, Moore, B 2nd and Poolson, T (2004) Side-chain conformational restriction in template-competitive inhibitors of E. coli DNA polymerase I Klenow fragment: synthesis, structural characterization and inhibition activity. Nucleosides Nucleotides Nucleic Acids 23:1751-65 |
|---|---|
| Abstract |
Nucleotide triphosphate alpha-(4-azidophenyl)-1,N6-etheno-dATP 3 and its monophosphate 3m were synthesized by condensation of 2-halo-2-(4-azidophenyl)acetaldehyes with dATP and dAMP, respectively. Structure analysis shows that the azidophenyl side chain is attached to the alpha-position of the etheno ring (i.e., the carbon attached to N1 of the purine), and conformation calculations show minima in the etheno-phenyl bond rotation at 50 and 130 degrees where the bulk of the phenyl ring projects out from the plane of the etheno group. Like DNA Pol inhibitor 2-(4-azidophenacyl)thio-2'-deoxyadenosine 5'-triphosphate 1, nucleotide 3 is a template-competitive DNA polymerase inhibitor (TCPI), with a competitive Ki for Pol I KF of 3.41 microM, but has only weak activity as an HIV RT inhibitor relative to the template-competitive reverse transcriptase inhibitor 2-(4-azidophenacyl)thio-1,N6-etheno-2'-deoxyadenosine 5'-triphosphate 2. Additionally, 3 photoinactivates KF in a time-dependent manner, confirming the kinetic data that 3 binds to the free form of KF. The TCPI activity of 3 provides evidence for an extended side chain conformational preference in the combined substrate polymerase inhibitors. |
| Links |
PubMed Online version:10.1081/NCN-200034042 |
| Keywords |
Adenosine/analogs & derivatives; Azides/chemistry; Azides/metabolism; Binding, Competitive; DNA Polymerase I/antagonists & inhibitors; DNA Polymerase I/chemistry; Enzyme Inhibitors/chemical synthesis; Enzyme Inhibitors/chemistry; Enzyme Inhibitors/pharmacology; Escherichia coli/enzymology; HIV Reverse Transcriptase/antagonists & inhibitors; Humans; Phenol/chemistry; Phenol/metabolism; Protein Conformation; Reverse Transcriptase Inhibitors/chemical synthesis; Reverse Transcriptase Inhibitors/chemistry; Reverse Transcriptase Inhibitors/pharmacology |
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