Side-chain conformational restriction in template-competitive inhibitors of E. coli DNA polymerase I Klenow fragment: Synthesis, structural characterization and inhibition activity

Michael B. Doughty; Karam Aboudehen; Garland Anderson; Ke Li; Bob Moore; Tina Poolson

doi:10.1081/NCN-200034042

Side-chain conformational restriction in template-competitive inhibitors of E. coli DNA polymerase I Klenow fragment: Synthesis, structural characterization and inhibition activity

Michael B. Doughty, Karam Aboudehen, Garland Anderson, Ke Li, Bob Moore, Tina Poolson

Medicine - Renal and Hypertension Division

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Abstract

Nucleotide triphosphate α-(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 α-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° 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 μM, 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.

Original language	English (US)
Pages (from-to)	1751-1765
Number of pages	15
Journal	Nucleosides, Nucleotides and Nucleic Acids
Volume	23
Issue number	11
DOIs	https://doi.org/10.1081/NCN-200034042
State	Published - 2004

Bibliographical note

Funding Information:
Nucleotide triphosphate a-(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 a-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° 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 µM, but has only weak activity as an HIV RT inhibitor relative to the template-competitive reverse #This work was funded in part by the Louisiana Board of Regents 044UG-02 and the National Institutes of Health GM067686. *Correspondence: Michael B. Doughty, Department of Chemistry and Physics, Southeastern Louisiana University, SLU Box 10878, Hammond, LA 70402, USA; Fax: (985) 549-5126; E-mail: mdoughty@selu.edu.

Keywords

DNA polymerase inhibitors
Klenow fragment
Reverse transcriptase inhibitors

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Side-chain conformational restriction in template-competitive inhibitors of E. coli DNA polymerase I Klenow fragment: Synthesis, structural characterization and inhibition activity. / Doughty, Michael B.; Aboudehen, Karam; Anderson, Garland et al.
In: Nucleosides, Nucleotides and Nucleic Acids, Vol. 23, No. 11, 2004, p. 1751-1765.

Research output: Contribution to journal › Article › peer-review

Doughty, MB, Aboudehen, K, Anderson, G, Li, K, Moore, B & 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 and Nucleic Acids, vol. 23, no. 11, pp. 1751-1765. https://doi.org/10.1081/NCN-200034042

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title = "Side-chain conformational restriction in template-competitive inhibitors of E. coli DNA polymerase I Klenow fragment: Synthesis, structural characterization and inhibition activity",

abstract = "Nucleotide triphosphate α-(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 α-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° 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 μM, 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.",

keywords = "DNA polymerase inhibitors, Klenow fragment, Reverse transcriptase inhibitors",

author = "Doughty, {Michael B.} and Karam Aboudehen and Garland Anderson and Ke Li and Bob Moore and Tina Poolson",

note = "Funding Information: Nucleotide triphosphate a-(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 a-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° 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{\textquoteright}-deoxyadenosine 5{\textquoteright}-triphosphate 1, nucleotide 3 is a template-competitive DNA polymerase inhibitor (TCPI), with a competitive Ki for Pol I KF of 3.41 µM, but has only weak activity as an HIV RT inhibitor relative to the template-competitive reverse #This work was funded in part by the Louisiana Board of Regents 044UG-02 and the National Institutes of Health GM067686. *Correspondence: Michael B. Doughty, Department of Chemistry and Physics, Southeastern Louisiana University, SLU Box 10878, Hammond, LA 70402, USA; Fax: (985) 549-5126; E-mail: mdoughty@selu.edu.",

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T1 - Side-chain conformational restriction in template-competitive inhibitors of E. coli DNA polymerase I Klenow fragment

T2 - Synthesis, structural characterization and inhibition activity

AU - Doughty, Michael B.

AU - Aboudehen, Karam

AU - Anderson, Garland

AU - Li, Ke

AU - Moore, Bob

AU - Poolson, Tina

N1 - Funding Information: Nucleotide triphosphate a-(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 a-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° 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 µM, but has only weak activity as an HIV RT inhibitor relative to the template-competitive reverse #This work was funded in part by the Louisiana Board of Regents 044UG-02 and the National Institutes of Health GM067686. *Correspondence: Michael B. Doughty, Department of Chemistry and Physics, Southeastern Louisiana University, SLU Box 10878, Hammond, LA 70402, USA; Fax: (985) 549-5126; E-mail: mdoughty@selu.edu.

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N2 - Nucleotide triphosphate α-(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 α-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° 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 μM, 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.

AB - Nucleotide triphosphate α-(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 α-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° 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 μM, 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.

KW - DNA polymerase inhibitors

KW - Klenow fragment

KW - Reverse transcriptase inhibitors

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Side-chain conformational restriction in template-competitive inhibitors of E. coli DNA polymerase I Klenow fragment: Synthesis, structural characterization and inhibition activity

Abstract

Bibliographical note

Keywords

UN SDGs

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