α-Keto phosphonoacetates

McKenna, Charles E.; Levy, Jeffrey N.

doi:10.1039/c39890000246

Cited by 21 publications

(7 citation statements)

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“…Foscarnet ( phosphonoformic acid) [17][18][19] 14 acts by trapping the pre-translocational state of HIV-1 RT, and while phosphonoacetic acid (PAA) 15 is a potent anti-herpetic agent, it is virtually ineffective against HIV. [20][21][22] Oxophosphonoacetate 16 is an inhibitor of some nucleic acid polymerases. 22,23 Carbonylbisphosphonate (COBP) 17, first isolated by Quimby 24 and further investigated by McKenna, is efficient at inhibiting HIV-1 RT.…”

Section: Introductionmentioning

confidence: 99%

Exploring the role of the α-carboxyphosphonate moiety in the HIV-RT activity of α-carboxy nucleoside phosphonates

et al. 2016

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As α-carboxy nucleoside phosphonates (α-CNPs) have demonstrated a novel mode of action of HIV-1 reverse transcriptase inhibition, structurally related derivatives were synthesized, namely the malonate 2, the unsaturated and saturated bisphosphonates 3 and 4, respectively and the amide 5. These compounds were evaluated for inhibition of HIV-1 reverse transcriptase in cell-free assays. The importance of the α-carboxy phosphonoacetic acid moiety for achieving reverse transcriptase inhibition, without the need for prior phosphorylation, was confirmed. The malonate derivative 2 was less active by two orders of magnitude than the original α-CNPs, while displaying the same pattern of kinetic behavior; interestingly the activity resides in the “L”-enantiomer of 2, as seen with the earlier series of α-CNPs. A crystal structure with an RT/DNA complex at 2.95 Å resolution revealed the binding of the “L”-enantiomer of 2, at the polymerase active site with a weaker metal ion chelation environment compared to 1a (T-α-CNP) which may explain the lower inhibitory activity of 2.

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Section: Introductionmentioning

confidence: 99%

Exploring the role of the α-carboxyphosphonate moiety in the HIV-RT activity of α-carboxy nucleoside phosphonates

et al. 2016

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“…The following compounds were prepared as described: 1, 6, and 17 (McKenna et al, 1989a); 3 and 13-15 (McKenna et al, 1987);7, 12, 16, and 20-23 (McKenna et al, 1988); 5 (McKenna & Levy, 1989); 10 and 11 (McKenna et al, 1989b). 2 was prepared by titration of the corresponding acid (McKenna et al, 1987) with NaOH (Ye & McKenna, unpublished results).…”

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confidence: 99%

Carbonyldiphosphonate, a selective inhibitor of mammalian DNA polymerase .delta.

Talanian

Brown²,

McKenna³

et al. 1989

Biochemistry

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Twenty-three pyrophosphate analogues were screened as inhibitors of proliferating cell nuclear antigen independent DNA polymerase delta (pol delta) derived from calf thymus. Carbonyldiphosphonate (COMDP), also known as alpha-oxomethylenediphosphonate, inhibited pol delta with a potency (Ki = 1.8 microM) 20 times greater than that displayed for DNA polymerase alpha (pol alpha) derived from the same tissue. Characterization of the mechanism of inhibition of pol delta indicated that COMDP competed with the dNTP specified by the template and was not competitive with the template-primer. In the case of pol alpha, COMDP did not compete with either the dNTP or the polynucleotide substrate. COMDP inhibited the 3'----5' exonuclease activity of pol delta weakly, displaying an IC50 greater than 1 mM.

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“…They have IR bands at 2126, 2085 (sh) cm À1 (3) and 2113 cm À1 (4) attributed to the azido group. The present study and our previous interest in diazo transfer chemistry 23,24 prompted us to reinvestigate a reported azido transfer to triethyl phosphonoacetate using triflyl azide in the presence of triethyl amine. 25 Triflyl azide is known to be a powerful diazo transfer reagent 9 and attempts by other authors to extend the procedure to benzocyclic β-keto esters were unsuccessful; 8 nevertheless, the original reaction has been cited as a viable azido transfer reaction in recent reviews.…”

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confidence: 87%