Enzymatic cleavage of 5-substituted-2'-deoxyuridines by pyrimidine nucleoside phosphorylases

Veres, Zsuzsa; Szabolcs, Anna; Szinai, I.; Dénes, Géza; Jeney, A.

doi:10.1016/0006-2952(86)90101-2

Cited by 26 publications

(13 citation statements)

References 10 publications

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“…The basis for selective antiherpes activity of 5-alkyl-2'-deoxyuridines is primarily due to the specific interaction with two virus-induced enzymes, the deoxythymidine-deoxycytidine (dThd/dCyd) kinase (viral-K) and the DNA polymerase. Cleavage of the N-glycosidic bond of many of these 5-substituted-2'-deoxyuridines by nucleoside phosphorylases rapidly leads to loss of biological activity (4)(5)(6). Thymidine phosphorylase (EC 2.4.2.4) is specific for the 2'-deoxyribosyl moiety of the nucleosides whereas uridine phosphorylase (EC 2.4.2.3) has broader substrate specificity (7)(8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

Structure and conformation of 5-methoxymethyl-2′-deoxycytidine

Jia¹,

Tourigny²,

Delbaere³

et al. 1990

Can. J. Chem.

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Can. J. Chem. 68,836 (1990).The three-dimensional structure of the antiviral agent 5-methoxymethyl-2'-deoxycytidine (MMdCyd) was deduced by X-ray crystallographic analysis. MMdCyd crystallized in space group P2, with a = 7.9255(6) A; b = 16.1505(15) A, c = 10.1861 (5) A, P = 103.801(5)", and Z = 4 (2 molecules per asymmetric unit); R = 0.044 (R, = 0.046) for 2560 observed reflections with net I > 3u(I). The furanose ring adopts the C(3')-exo envelope conformation (3E) in molecule A and the C(2')-endo envelope conformation ( 2~) in molecule B. In the sugar ring of both crystallographically independent molecules A and B, the side chain at C(5') has the gi conformation. This appears to be a preferred geometry required for antiherpes activity in 2'-deoxyribonucleosides.The glycosyl linkage is anti with x = 213.7' for the A molecule and 222.2" for the B molecule. With respect to this anti conformation, the methoxy group at C(5) in molecules A and B exhibits different conformations; it is on the same side of the pyrimidine plane as the deoxyribofuranose ring oxygen (04') in molecule B and on the opposite side in molecule A.Key words: antiherpes agent, conformation, 5-methoxymethyl-2'-deoxycytidine, crystal structure. IntroductionThe discovery of 5-substituted-2'-deoxyuridines with selective activity against Herpes simplex virus was a major development in the area of viral chemotherapy (for reviews see refs. 1-3). The basis for selective antiherpes activity of 5-alkyl-2'-deoxyuridines is primarily due to the specific interaction with two virus-induced enzymes, the deoxythymidine-deoxycytidine (dThd/dCyd) kinase (viral-K) and the DNA polymerase. Cleavage of the N-glycosidic bond of many of these 5-substituted-2'-deoxyuridines by nucleoside phosphorylases rapidly leads to loss of biological activity (4-6). Thymidine phosphorylase (EC 2.4.2.4) is specific for the 2'-deoxyribosyl moiety of the nucleosides whereas uridine phosphorylase (EC 2.4.2.3) has broader substrate specificity (7-10). One possible approach to overcome this limitation is to use deoxycytidine analogs. The rationale for this hypothesis is (i) dCyd analogs are not substrates for thymidine and (or) uridine phosphorylase and (ii) in HSV-infected cells, dCyd analogs will be metabolized primarily by the virus-induced dCyd kinase -deoxycytidylate kinase pathway. Our findings on the biological activity of (E)-5-

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Section: Introductionmentioning

confidence: 99%

Structure and conformation of 5-methoxymethyl-2′-deoxycytidine

Jia¹,

Tourigny²,

Delbaere³

et al. 1990

Can. J. Chem.

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“…We have found that TP is identical to an angiogenic factor, platelet-derived endothelial cell growth factor (PD-ECGF), and the enzymatic activity of TP is need for the angiogenesis by TP (14)(15)(16). TP is also considered to activate some pyrimidine antimetabolites (17)(18)(19). 5-Fluorouracil (5-FU) was developed as a potential anti-tumor drug (20), and reportedly activated through three alternative routes.…”

Section: Introductionmentioning

confidence: 99%

The role of thymidine phosphorylase in the induction of early growth response protein-1 and thrombospondin-1 by 5-fluorouracil in human cancer carcinoma cells

Akiyama¹

2010

Int J Oncol

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Abstract. Thymidine phosphorylase (TP) is an enzyme involved in reversible conversion of thymidine to thymine. TP is identical to an angiogenic factor, pletelet-derived endothelial cell growth factor (PD-ECGF) and the expression levels of TP in a variety of malignant tumors were higher than the adjacent non-neoplastic tissues. To investigate the molecular basis for the effect of TP on the metabolic process and the anticancer effect of 5-fluorouracil (5-FU), human gastric carcinoma AZ521 cells and epidermoid carcinoma KB cells were transfected with TP cDNA, and AZ521/TP and KB/ TP were cloned. AZ521/TP and KB/TP cells overexpressed TP and were more sensitive to 5-FU than the counterpart parental cells. TPI, a newly synthesized inhibitor for TP (Ki=2.36x10 -9 M), decreased the sensitivity to 5-FU of the TP expressing cells but not of the parental cells. 5-Formyltetrahydrofolate (leucovorin; LV) stabilized the complex of thymidylate synthase (TS) and 5-fluoro-deoxyuridinemonophosphate (FdUMP), increased the sensitivity to 5-FU of TP expressing AZ521 cells, but not of the parental cells. The levels of FdUMP in TP expressing cells were significantly higher than in parental cells and TPI considerably decreased FdUMP to the level comparable to that in the parental cells. 5-FU increased the expression of early growth response protein-1 (Egr-1) and an angiogenesis inhibitor, thrombospondin-1 (TSP-1), in KB/TP cells but only slightly in KB/CV cells, if any. TPI attenuated the induction of Egr-1 and TSP-1 mRNA by 5-FU, while LV increased the expression of Egr-1 and TSP-1 mRNA in KB/TP cells. These findings demonstrate that the TP has a principal role in the production of FdUMP and the enhanced responses to 5-FU by leucovorin in TP-overexpressing KB and AZ521 cells, and FdUMP but not FUTP is implicated in the induction of Egr-1 and TSP-1 in KB cells. IntroductionThymidine phosphorylase (TP) catalyzes the reversible phosphorolysis of thymidine, deoxyuridine, and their analogues to their respective bases and 2-deoxyribose-1-phosphate (1-3). It also catalyzes deoxyribosyltransfer from one deoxynucleotide to another base, to form a second deoxyuridine (4-6). Recent studies showed that TP is expressed in a wide variety of solid tumors (7-13), but the role of TP in tumor proliferation was unknown. We have found that TP is identical to an angiogenic factor, platelet-derived endothelial cell growth factor (PD-ECGF), and the enzymatic activity of TP is need for the angiogenesis by TP (14-16). TP is also considered to activate some pyrimidine antimetabolites (17-19). 5-Fluorouracil (5-FU) was developed as a potential anti-tumor drug (20), and reportedly activated through three alternative routes. It may be converted to FUMP either directly by orotate phosphoribosyltranferase or by the sequential actions of uridine phosphorylase and uridine kinase. FUMP may be converted to FUDP and then to FUTP, INTERNATIONAL JOURNAL OF ONCOLOGY 36: 1193-1200, 2010 The role of thymidine phosphorylase in the induction of early growth response protein-1...

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“…Some of the difficulties in the search for new antiviral and neoplastic chemotherapeutic agents have included lack of selectivity, DNA misreading and resultant tumor formation, metabolic breakdown and production of inactive metabolites. Cleavage of the N-glycosidic bond in pyrimidine analogues with chemotherapeutic activity results in the reduction or loss of biological activity of the parent compounds (2)(3)(4)(5).…”

Section: Introductionmentioning

confidence: 99%

Metabolism of anti-herpes agent 5-(2-chloroethyl)-2′-deoxyuridine in mice and rats

Szlnai

Veres

Ganzler

et al. 1991

European Journal of Drug Metabolism and Pharmacokinetics

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The enzymatic splitting and metabolic elimination of anti-viral agent 5-(2-chloroethyl)-2'-deoxyuridine [CEDU] have been studied. For elucidation of structures of metabolites, several different kinds of extraction, purification and spectroscopic methods were used (Extrelut LC, TLC, HPLC, MS, NMR, IR, UV and CD). For mass spectral analysis, various ionization techniques (EI, CI and FAB-MS) were performed as complementary methods. After oral administration of [14C]-CEDU to mice and rats, the parent compound, 5-(2chloroethyl) uracil [CEU] and hydroxylated CEU metabolites were isolated and identified from urine and faeces by the above mentioned methods. The CEDU showed rapid phosphorolysis in vitro with thymidine phosphorylase Km 41.0 +/- 5.0; and uridine phosphorylase Km 10.0 +/- 1.5. The cleavage of the N-glycosidic bond of the nucleoside analogue and a new metabolic pathway of CEDU [stereoselective oxidation of 5-(2-chloroethyl) uracil] was observed in both species.

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Enzymatic cleavage of 5-substituted-2'-deoxyuridines by pyrimidine nucleoside phosphorylases

Cited by 26 publications

References 10 publications

Structure and conformation of 5-methoxymethyl-2′-deoxycytidine

Structure and conformation of 5-methoxymethyl-2′-deoxycytidine

The role of thymidine phosphorylase in the induction of early growth response protein-1 and thrombospondin-1 by 5-fluorouracil in human cancer carcinoma cells

Metabolism of anti-herpes agent 5-(2-chloroethyl)-2′-deoxyuridine in mice and rats

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