Interactions of 2′-fluoro-substituted dUMP analogues with thymidylate synthase

Ziemkowski, Przemysław; Felczak, Krzysztof; Poznański, Jarosław; Kulikowski, Tadeusz; Zieliński, Zbigniew; Cieśla, Joanna; Rode, Wojciech

doi:10.1016/j.bbrc.2007.07.097

Cited by 7 publications

(9 citation statements)

References 34 publications

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“…[15] More recently, Ziemkowski and colleagues used a procedure similar to Hertel's procedure for hydrolytic deamination of gemcitabine (1) in which they used hydrochloric acid in 1,4-dioxane in the presence of isoamyl nitrite. [16] Though this strategy resulted in a much improved 83 % yield relative to Hertel's original protocol, the purification strategy was based on extraction followed by a lengthy preparative TLC procedure. For all three of these procedures, dFdU (2) was formed as an oil.…”

Section: Resultsmentioning

confidence: 99%

“…Though this strategy resulted in a much improved 83 % yield relative to Hertel’s original protocol, the purification strategy was based on extraction followed by a lengthy preparative TLC procedure. For all three of these procedures, dFdU ( 2 ) was formed as an oil 14–16. Hence, an improved purification procedure was needed to obtain sufficiently pure compound for biological experiments.…”

Section: Resultsmentioning

confidence: 99%

“…For all three of these procedures, dFdU (2) was formed as an oil. [14][15][16] Hence, an improved purification procedure was needed to obtain sufficiently pure compound for biological experiments.…”

Section: Chemistrymentioning

confidence: 99%

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Combinatorial Pharmacologic Effects of Gemcitabine and its Metabolite dFdU

et al. 2011

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Recent evidence has shown that the gemcitabine metabolite, dFdU, is pharmacologically active. Though less potent, dFdU has a longer half-life and could potentiate or antagonize the activity of gemcitabine. Hence, studies were undertaken to evaluate the combined effects. Following chemical synthesis, an improved purification procedure for dFdU was developed (80 % yield; >99 % purity). Zebrafish phenotype-based embryo screens revealed no acute toxicity after gemcitabine or dFdU treatment. Only gemcitabine affected zebrafish development in a dose-dependent manner. Synergy or antagonism for the combination was not observed. Antitumor effects for dFdU were dose dependent. Antagonism was tumor cell-line dependent and did not depend on formation of the intracellular active metabolite of gemcitabine, suggesting that the drug-metabolite interaction occurs later. These studies highlight a platform for testing the pharmacologic activity for anticancer agent and metabolite combinations. Such analyses are expected to provide insight into the beneficial or harmful effect(s) of metabolites towards parent drug activity.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Combinatorial Pharmacologic Effects of Gemcitabine and its Metabolite dFdU

et al. 2011

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“…Of these 2 enzymes, thymidylate kinase catalyses the transformation of dUDP and dUMP. However, generating dUMP did not translate to dTMP efficiently [14]. Thymidine phosphorylase (EC 2.4.2.4), which was responsible for dTMP salvage synthesis was not an enzyme at this stage.…”

Section: Discussionmentioning

confidence: 86%

Improving Mycoplasma ovipneumoniae culture medium by a comparative transcriptome method

2020

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Mycoplasma ovipneumoniae (Mo) is difficult to culture, resulting in many difficulties in related research and application. Since nucleotide metabolism is a basic metabolism affects growth, this study conducted a "point-to-point" comparison of the corresponding growth phases between the Mo NM151 strain and the Mycoplasma mycoides subsp. capri (Mmc) PG3 strain. The results showed that the largest difference in nucleotide metabolism was found in the stationary phase. Nucleotide synthesis in PG3 was mostly de novo, while nucleotide synthesis in NM151 was primarily based on salvage synthesis. Compared with PG3, the missing reactions of NM151 referred to the synthesis of deoxythymine monophosphate. We proposed and validated a culture medium with added serine to fill this gap and prolong the stationary phase of NM151. This solved the problem of the fast death of Mo, which is significant for related research and application.

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“…Their metabolite 5‐FdUMP, which is also formed after 5‐FdC administration, covalently binds to TS causing inhibition () [57,58]. dUaMP analogs fluorinated at the 2′‐position of the sugar moiety also show interactions with TS [59]. Some of these molecules were substrates, but others, among which was dFdUMP, were shown only to be competitive inhibitors.…”

Section: Pharmacological Activity Of Deoxyuridine Analog Nucleotidesmentioning

confidence: 99%

Deoxyuridine analog nucleotides in deoxycytidine analog treatment: secondary active metabolites?

Jansen

Rosing

Schellens

et al. 2011

Fundamemntal Clinical Pharma

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Deoxycytidine analogs (dCa's) are nucleosides widely used in anticancer and anti (retro) viral therapies. Intracellularly phosphorylated dCa anabolites are considered to be their main active metabolites. This article reviews the literature on the formation and pharmacological activity of deaminated dCa nucleotides. Most dCa's are rapidly deaminated into deoxyuridine analogs (dUa's) which are only slowly phosphorylated and therefore relatively inactive. dUa nucleotides are, however, also formed via deamination of dCa monophosphates by deoxycytidine monophosphate deaminase (dCMPD). dUa-monophosphates can interact with thymidylate synthase (TS), whereas dUa-triphosphates are incorporated into nucleic acids and interfere with polymerases. Administration of dCa's as monophosphate prodrugs or co-administration of the cytidine deaminase inhibitor tetrahydrouridine (THU) does not prevent dUa nucleotide formation which is, on the other hand, influenced by the dose and dCMPD activity. Taken together, these observations show that the formation of dUa nucleotides is a common phenomenon in treatment with dCa's and these compounds may play a role in treatment outcome. We conclude that more attention should be given to these relatively unknown, but potentially important metabolites.

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Interactions of 2′-fluoro-substituted dUMP analogues with thymidylate synthase

Cited by 7 publications

References 34 publications

Combinatorial Pharmacologic Effects of Gemcitabine and its Metabolite dFdU

Combinatorial Pharmacologic Effects of Gemcitabine and its Metabolite dFdU

Improving Mycoplasma ovipneumoniae culture medium by a comparative transcriptome method

Deoxyuridine analog nucleotides in deoxycytidine analog treatment: secondary active metabolites?

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