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Benzylacyclouridine Sale

(Synonyms: BAU; 5-Benzylacyclouridine) 目录号 : GC63665

Benzylacyclouridine (BAU) 是一种有效且特异性的尿苷磷酸化酶抑制剂,尿苷磷酸化酶是尿苷分解代谢中的第一种酶。Benzylacyclouridine 可以调节 5-氟尿嘧啶 (5-FU) 及其衍生物的细胞毒副作用。

Benzylacyclouridine Chemical Structure

Cas No.:82857-69-0

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5 mg
¥1,350.00
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10 mg
¥2,250.00
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25 mg
¥4,950.00
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50 mg
¥8,100.00
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100 mg
¥13,050.00
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产品描述

Benzylacyclouridine (BAU) is a potent and specific inhibitor of uridine phosphorylase, the first enzyme in the catabolism of uridine. Benzylacyclouridine can modulate the cytotoxic side effects of 5-fluorouracil (5-FU) and its derivatives[1][2][3].

Benzylacyclouridine increases 5-FU-induced cytotoxicity in a number of human cancer cell lines[1].Benzylacyclouridine (20-100 μM) reduces the rapid clearance of trace amounts of either [14C]uridine or hyperphysiologic concentrations of non-labeled uridine by the isolated rat liver perfused with an artificial oxygen carrier[2].

Benzylacyclouridine (p.o. or i.v.) arrests the rapid degradation of a tracer dose of uridine into uracil in dogs and pigs[1].Benzylacyclouridine exhibits the t1/2 of 1.8-3.6 h in dogs, with bioavailability levels of 85% (30 mg/kg) and 42.5% (120 mg/kg)[1].Benzylacyclouridine (120 mg/kg) exhibits the t1/2 of 1.6-2.3 h, with a bioavailability of 40% in pigs[1].

[1]. Pizzorno G, et, al. Phase I clinical and pharmacological studies of benzylacyclouridine, a uridine phosphorylase inhibitor. Clin Cancer Res. 1998 May;4(5):1165-75.
[2]. Monks A, et, al. Effect of 5-benzylacyclouridine, a potent inhibitor of uridine phosphorylase, on the metabolism of circulating uridine by the isolated rat liver. Biochem Pharmacol. 1983 Jul 1;32(13):2003-9.
[3]. Roosild TP, et, al. Implications of the structure of human uridine phosphorylase 1 on the development of novel inhibitors for improving the therapeutic window of fluoropyrimidine chemotherapy. BMC Struct Biol. 2009 Mar 16;9:14.

Chemical Properties

Cas No. 82857-69-0 SDF
别名 BAU; 5-Benzylacyclouridine
分子式 C14H16N2O4 分子量 276.29
溶解度 DMSO : 100 mg/mL (361.94 mM; Need ultrasonic) 储存条件 Store at -20°C
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1 mg 5 mg 10 mg
1 mM 3.6194 mL 18.0969 mL 36.1939 mL
5 mM 0.7239 mL 3.6194 mL 7.2388 mL
10 mM 0.3619 mL 1.8097 mL 3.6194 mL
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Research Update

Benzylacyclouridine reverses azidothymidine-induced marrow suppression without impairment of anti-human immunodeficiency virus activity

Blood 1990 Dec 1;76(11):2210-5.PMID:2257294doi

Increased extracellular concentrations of uridine (Urd) have been reported to reduce, in vitro, azidothymidine (AZT)-induced inhibition of human granulocyte-macrophage progenitor cells without impairment of its antihuman immunodeficiency virus (HIV) activity. Because of the clinical toxicities associated with chronic Urd administration, the ability of Benzylacyclouridine (BAU) to effect, in vivo, AZT-induced anemia and leukopenia was assessed. This agent inhibits Urd catabolism and, in vivo, increases the plasma concentration of Urd in a dose-dependent manner, without Urd-related toxicity. In mice rendered anemic and leukopenic by the administration of AZT for 28 days in drinking water (1.5 mg/mL), the continued administration of AZT plus daily BAU (300 mg/kg, orally) partially reversed AZT-induced anemia and leukopenia (P less than .05), increased peripheral reticulocytes (to 4.9%, P less than .01), increased cellularity in the marrow, and improved megaloblastosis. When coadministered with AZT from the onset of drug administration, BAU reduced AZT-induced marrow toxicity. In vitro, at a concentration of 100 mumol/L, BAU possesses minimal anti-HIV activity and has no effect on the ability of AZT to reverse the HIV-induced cytopathic effect in MT4 cells. The clinical and biochemical implications of these findings are discussed.

Benzylacyclouridine enhances 5-fluorouracil cytotoxicity against human prostate cancer cell lines

Pharmacology 1998 Feb;56(2):80-91.PMID:9494066DOI:10.1159/000028185.

At a nontoxic growth inhibitory concentration benzyloxyacyclouridine (BAU), a potent and specific inhibitor of uridine phosphorylase (UrdPase), enhanced 5-fluorouracil (5-FU) cytotoxic activity against human prostate cancer PC-3 and DU-145 cell lines. The BAU/5-FU combination exhibited greater antitumor activity in vivo using PC-3 human xenografts compared to 5-FU alone, with no associated increase in animal host toxicity. The mechanism(s) responsible for the enhanced in vitro and in vivo activity of this combination may involve enhanced formation of the 5-FU nucleotide metabolites FdUMP, FdUTP, and FUTP resulting in enhanced inhibition of thymidylate synthase (TS) and increased incorporation of fluoropyrimidine metabolites into tumoral RNA and DNA.

Benzylacyclouridine. Pharmacokinetics, metabolism and biochemical effects in mice

Biochem Pharmacol 1988 Jul 1;37(13):2613-8.PMID:3390221DOI:10.1016/0006-2952(88)90254-7.

The pharmacokinetics, tissue distribution and urinary excretion of the uridine (Urd) phosphorylase (EC 2.4.2.3) inhibitor 5-benzylacyclouridine (BAU) were studied in C57BL/6 female mice by reverse-phase HPLC. The plasma clearance of BAU after i.v. administration followed first-order kinetics with a half-life of approximately 36 min. Other pharmacokinetic parameters such as volume of distribution (17 ml), clearance rate (0.3 ml/min) and the elimination rate constant (0.019 hr-1) were relatively constant over a dose range of 5 to 240 mg/kg when based on a first-order clearance model. Following oral administration, BAU was rapidly absorbed from the gut; peak plasma concentrations occurred within 30 min and were approximately 60% of equivalent i.v. doses. The distribution of BAU between plasma and most major organs was rapid and efficient, the exceptions being spleen and brain, which maintained only 40% and 10%, respectively, of the plasma BAU concentration. Approximately 41% of the injected dose of BAU was recovered intact in urine within 24 hr. Another 27% appeared as a more polar metabolite which, at a concentration of 50 microM, did not inhibit murine Urd phosphorylase. A near linear relationship was observed between the injected dose of BAU and its ability to increase the plasma concentration of Urd; i.v. injections of 30, 120 and 240 mg/kg increased plasma Urd 3-, 7- and 15-fold respectively. The utility of these data in the design of combination chemotherapy regimens containing BAU and related compounds is discussed.

Different effect of Benzylacyclouridine on the toxic and therapeutic effects of azidothymidine in mice

Blood 1990 Dec 1;76(11):2216-21.PMID:2257295doi

It has been reported that in vitro uridine (Urd) can reverse azidothymidine (AZT) cytotoxicity without decreasing anti-human immunodeficiency virus (HIV) activity. Our studies in mice have shown that daily oral doses of Benzylacyclouridine (BAU), an inhibitor of Urd breakdown, also reduces AZT hematologic toxicity, presumably by elevating the plasma concentration of Urd. We now extend these murine studies and report the effect of various doses of exogenous Urd, various doses of BAU, or the combination of BAU and Urd, administered daily, on AZT-induced toxicity. In mice receiving concomitant AZT, daily doses of Urd of 1,000 to 2,000 mg/kg increase peripheral reticulocytes and slightly reduce AZT-induced hematologic toxicity. However, the range of effective doses is narrow, and higher doses of Urd (greater than 3,000 mg/kg/d) significantly enhance hematologic toxicity. At its most effective dose, (2,000 mg/kg/d), Urd produces 28% mortality. In contrast, BAU doses up to 300 mg/kg/d reduced AZT-related hematologic toxicity in a dose-dependent manner without mortality. Higher daily doses of BAU and the combination of BAU with low doses of Urd were not more effective. Studies conducted in mice infected with the Rauscher murine leukemia virus (RLV) indicate that BAU does not impair the antiretroviral effect of AZT when administered at doses that reduce AZT-induced anemia and leukopenia. These findings may be significant for the treatment of patients with acquired immunodeficiency syndrome (AIDS) and AIDS-related complex.

Tissue-specific expansion of uridine pools in mice. Effects of Benzylacyclouridine, dipyridamole and exogenous uridine

Biochem Pharmacol 1991 Jun 15;41(12):2031-6.PMID:2039551DOI:10.1016/0006-2952(91)90146-v.

The concentration of uridine (Urd) in murine tissues appears to be controlled by Urd catabolism, concentrative Urd transport, and the non-concentrative, facilitated diffusion of Urd. Previous reports document the tissue-specific disruption of these processes, and subsequently intracellular pools of free Urd in mice, by the administration of exogenous Urd (250 mg/kg) or the Urd phosphorylase (EC 2.4.2.3; uracil:ribose-1-phosphate phosphotransferase) inhibitor 5-benzylacyclouridine (BAU) (240 mg/kg). We now report the effect of combinations of BAU (120 mg/kg, p.o.), the nucleoside transport inhibitor dipyridamole (DP) (25 mg/kg, i.p.), and exogenous Urd (250 mg/kg, i.v.) on Urd pools in mice. This dose of BAU increased Urd pools 2- to 6-fold, in a tissue-specific manner, for up to 5 hr. DP increased Urd pools 3-fold in spleen, over a 4-hr period, but did not affect other tissues. Administration of BAU 1 hr prior to exogenous Urd resulted in a 50- to 100-fold expansion of tissue normal after 6 hr. Administration of DP 1 hr prior to exogenous Urd caused a tissue-specific 40- to 100-fold increase in Urd pools which, except in spleen, returned to normal within 2 hr. The marked additive effects of these combinations were in contrast to those obtained following the administration of BAU 1 hr prior to DP. This regimen increased Urd pools from 4- to 9-fold, in a tissue-specific manner. In addition, Urd pools remained elevated for up to 9 hr, except in spleen where the Urd concentration was elevated for up to 15 hr. Analysis of enzyme activities indicated that DP does not enhance the inhibitory effect of BAU against murine liver Urd phosphorylase. However, DP did inhibit plasma clearance of BAU, and this effect may partially explain the apparent synergistic effect of this combination. In spite of the prolonged and dramatic expansion of tissue Urd pools produced by BAU + DP, the total Ura nucleotide content in spleen, gut and colon tumor 38 (CT38) increased by less than 70% over a 12-hr period following administration of this combination. These findings are discussed in light of their biochemical and therapeutic implications.