Isolation and identification of a metabolite of cidofovir from rat kidney

Eisenberg, Eugene; Lynch, Geoffrey; Bidgood, Alison M.; Krishnamurty, Krish; Cundy, Kenneth C.

doi:10.1016/s0731-7085(97)00162-3

Cited by 11 publications

(10 citation statements)

References 8 publications

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“…The 1 H and 13 C chemical shifts of the drug are in good agreement with previously published chemical shifts for CDV-phosphocholine extracted from rat kidney 36. Of particular interest are the resonances of C4′, H4′ and H4″.…”

Section: Resultssupporting

confidence: 86%

Solution Structure of a DNA Duplex Containing the Potent Anti-Poxvirus Agent Cidofovir

et al. 2011

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Cidofovir (1-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]cytosine, CDV) is a potent inhibitor of orthopoxvirus DNA replication. Prior studies have shown that when CDV is incorporated into a growing primer strand, it can inhibit both the 3′-to-5′ exonuclease and the 5′-to-3′ chain extension activities of vaccinia virus DNA polymerase. This drug can also be incorporated into DNA, creating a significant impediment to trans-lesion DNA synthesis in a manner resembling DNA damage. CDV and deoxycytidine share a common nucleobase but CDV lacks the deoxyribose sugar. The acyclic phosphonate bears a hydroxyl moiety that is equivalent to the 3′-hydroxyl of dCMP and permits CDV incorporation into duplex DNA. To study the structural consequences of inserting CDV into DNA, we have used 1H NMR to solve the solution structures of a dodecamer DNA duplex containing a CDV molecule at position 7 and of a control DNA duplex. The overall structures of both DNA duplexes were found to be very similar. We observed a decrease of intensity (>50%) for the imino protons neighboring the CDV (G6, T8) and the cognate base G18, and a large chemical shift change for G18. This indicates higher proton exchange rates for this region, which was confirmed using NMR monitored melting experiments. DNA duplex melting experiments monitored by circular dichroism revealed a lower Tm for the CDV DNA duplex (46°C) compared to the control (58°C) in 0.2 M salt. Our results suggest that the CDV drug is well accommodated and stable within the dodecamer DNA duplex, but the stability of the complex is less than the control suggesting increased dynamics around the CDV.

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Section: Resultssupporting

confidence: 86%

Solution Structure of a DNA Duplex Containing the Potent Anti-Poxvirus Agent Cidofovir

et al. 2011

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“…The kinetics and metabolic half-life of the prodrug were determined, and the prodrug was fully metabolized to T 12 phosphorothioate [31]. An unknown metabolite of the antiviral acyclic nucleotide analogue cidofovir was isolated from rat kidney and confirmed by MALDI and NMR to be cidofovirphosphocholine [32]. Olson and Fabris have shown that MALDI can be used as a tool to determine in vitro metabolites, via CYP 450 enzymes in liver microsomes, of tamoxifen, promethazine and diphenhydramine [33].…”

Section: Qualitative Characterization Of Lmw Compoundsmentioning

confidence: 99%

Small molecule analysis by MALDI mass spectrometry

2002

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This review focuses on the application of matrix assisted laser desorption/ionization (MALDI) mass spectrometry to the characterization of molecules in the low mass range (<1500 Da). Despite its reputation to the contrary, MALDI is a powerful technique to provide both qualitative and quantitative determination of low molecular weight compounds. Several approaches to minimize interference via sample preparation and matrix selection are discussed, as well as coupling of MALDI to liquid and planar chromatographic techniques to extend its range of applicability.

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“…The 1 H and 13 C chemical shifts of the drug are in good agreement with previously published chemical shifts for CDV-phosphocholine extracted from rat kidney. 36 Of particular interest are the resonances of C4′, H4′ and H4″. Since 13 P decoupling was not used during the acquisition of the HSQC spectra, the 13 C4′ nucleus showed a splitting of 153 Hz characteristic of a 13 C-31 P coupling constant ( 1 J 13C-31P ).…”

Section: Chemical Shift Assignments Of the CDV And Incorporation Intomentioning

confidence: 99%

Solution Structure of a DNA Duplex Containing the Potent Anti-Poxvirus Agent Cidofovir

2011

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Cidofovir (1-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]cytosine, CDV) is a potent inhibitor of orthopoxvirus DNA replication. Prior studies have shown that when CDV is incorporated into a growing primer strand, it can inhibit both the 3′-to-5′ exonuclease and the 5′-to-3′ chain extension activities of vaccinia virus DNA polymerase. This drug can also be incorporated into DNA, creating a significant impediment to trans-lesion DNA synthesis in a manner resembling DNA damage. CDV and deoxycytidine share a common nucleobase but CDV lacks the deoxyribose sugar. The acyclic phosphonate bears a hydroxyl moiety that is equivalent to the 3′-hydroxyl of dCMP and permits CDV incorporation into duplex DNA. To study the structural consequences of inserting CDV into DNA, we have used 1 H NMR to solve the solution structures of a dodecamer DNA duplex containing a CDV molecule at position 7 and of a control DNA duplex. The overall structures of both DNA duplexes were found to be very similar. We observed a decrease of intensity (>50%) for the imino protons neighboring the CDV (G6, T8) and the cognate base G18, and a large chemical shift change for G18. This indicates higher proton exchange rates for this region, which was confirmed using NMR monitored melting experiments. DNA duplex melting experiments monitored by circular dichroism revealed a lower T m for the CDV DNA duplex (46°C) compared to the control (58°C) in 0.2 M salt. Our results suggest that the CDV drug is well accommodated and stable within the dodecamer DNA duplex, but the stability of the complex is less than the control suggesting increased dynamics around the CDV.

show abstract

Isolation and identification of a metabolite of cidofovir from rat kidney

Cited by 11 publications

References 8 publications

Solution Structure of a DNA Duplex Containing the Potent Anti-Poxvirus Agent Cidofovir

Solution Structure of a DNA Duplex Containing the Potent Anti-Poxvirus Agent Cidofovir

Small molecule analysis by MALDI mass spectrometry

Solution Structure of a DNA Duplex Containing the Potent Anti-Poxvirus Agent Cidofovir

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