Synthesis of 5-Fluorouracil Derivatives Containing an Inhibitor of 5-Fluorouracil Degradation.

Hirohashi, M.; Kido, Masaru; Yamamoto, Yoshihito; Kojima, Yutaka; Jitsukawa, Koichiro; Fujii, Setsuro

doi:10.1248/cpb.41.1498

Cited by 12 publications

(7 citation statements)

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“…Emitefur (BOF-A2, Figure 1) is a newly developed anticancer agent which consists of 1-ethoxymethyl-5-fluorouracil (EM-FU) and 3-cyano-2,6-dihydroxypyridine (CNDP) (Fujii et al, 1989;Hirohashi et al, 1993). EM-FU is a masked form of 5-fluorouracil (5-FU) and is gradually converted to 5-FU in the microsomal fraction of the liver; CNDP is a potent inhibitor of 5-FU degradation (Tatsumi et al, 1993;Okayasu et al, 1994).…”

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confidence: 99%

Combined effect of clinically relevant doses of emitefur, a new 5-fluorouracil derivative, and radiation in murine tumours

Shibamoto

Murata²,

Miyauchi³

et al. 1996

Br J Cancer

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Summary We investigated the combined effect of radiation and clinically relevant doses of emitefur (BOF-A2), a newly developed anti-cancer agent consisting of a masked form of 5-fluorouracil (5-FU) and a potent inhibitor of 5-FU degradation, in two types of murine tumours. In preliminary pharmacokinetic studies, the area under the curve for 5-FU in plasma, after administration of 12.5 mg kg-1 and 25 mg kg-1 emitefur in mice, appeared to be similar to that obtained on the first day and that on the seventh day, respectively, after starting administration of 400-600 mg day 'in humans. These doses (12.5 and 25 mg kg-1) of emitefur were evaluated either alone or in combination with single (15 Gy), five-fraction (4 Gy each) or ten-fraction (2.8 Gy each) irradiation using a tumour growth delay assay for SCCVII tumours and in combination with fourfraction (5 Gy each) irradiation using an in vivo -in vitro assay for EMT6 tumours. The anti-tumour and radiation-enhancing effects of 12.5 mg kg-' emitefur were not significant in any except the ten-fraction experiment. On the other hand, multiple doses of 25 mg kg-' emitefur given either alone or in combination with radiation produced marked effects. The mean tumour growth delay time (the time to double in volume for treated tumours minus that for untreated tumours) was 8.1 days for five administrations of 25 mg kg-' emitefur, 10.4 days for five fractions of 4 Gy and 22.1 days for five treatments with the combination of the two. Thus, the increase in growth delay afforded by this combination was at least additive. The effect of four fractions of 5 Gy with 25 mg kg-1 emitefur in EMT6 tumours was lower than that of four fractions of 7.5 Gy, but the effect of five fractions of 4 Gy with this dose of emitefur in SCCVII tumours was similar to the effect of five fractions of 6 Gy, and the effect of ten fractions of 2.8 Gy with 25 mg kg-emitefur was much higher than that of ten fractions of 4.2 Gy. In conclusion, emitefur given either alone or in combination with radiation appears to have a significant anti-tumour effect even at clinically relevant dose levels, although a threshold dose exists between 12.5 and 25 mg kg-'. Further clinical studies of this compound are warranted.

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confidence: 99%

Combined effect of clinically relevant doses of emitefur, a new 5-fluorouracil derivative, and radiation in murine tumours

Shibamoto

Murata²,

Miyauchi³

et al. 1996

Br J Cancer

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“…Starting from 1-ethoxymethyl-5-fluorouracil 143 emitefur 144 was prepared in 25% yield (Scheme 86) 163,164 by reaction with the isophthaloyl chloride 145 followed by reaction with 6-benzoyloxy-3-cyano-2-pyridone 146. Emitefur 144 is degraded in vivo into 1-ethoxy-715 methyl-5-fluorouracyl 143, a prodrug of 5-FU, and 3-cyano-2,6-dihydroxypyridine (CNDP) 147, a competitive inhibitor of DPD, the enzyme responsible for rapid degradation of 5-FU 1.…”

Section: Synthesis Of Antitumor Fluorinated Pyrimidine Nucleosidesmentioning

confidence: 99%

Synthesis of Antitumor Fluorinated Pyrimidine Nucleosides

Ferraboschi

Ciceri

Grisenti

2017

Organic Preparations and Procedures International

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5-Fluorouracil35 Interest in the fluoropyrimidines stemmed from studies of the metabolism of uracil in rat hepatoma cells. The observation that these cells utilize uracil more avidly than normal rat intestinal mucosa prompted the preparation of fluorinated pyrimidines in order to improve disruption of tumor DNA biosynthesis. 3 In 1957 5-fluorouracil (5-FU) 1 was synthesized by Heidelberger et al., 4 with the aim of 40 blocking metabolism in malignant cells. The replacement of a hydrogen atom at C-5 by the fluorine atom modifies the interaction with the active sites of enzymes involved in metabolism. This antimetabolite, although toxic, is still one of the most widely used agents against solid tumors. Its action is due to two different mechanisms: 5 after penetration into the cell, 5-FU 1 is transformed into the 5-fluorouridine triphosphate that mimics UTP, is recognized by RNA 45 polymerase and consequently incorporated into RNA. The most significant action, however, is due to the 5-FU conversion into 5-fluoro-2 0 -deoxyuridine (FdUMP) 2, a known inhibitor of thymidylate synthetase (TS), a key enzyme in the DNA synthesis. 6,7 TS, in the presence of methylene tetrahydrofolate and deoxyuridine monophosphate (dUMP) 3 forms a ternary complex that catalyzes the substitution of 5-H uracil with a methyl group, affording thymine. If FdUMP 50 2 is present, the above ternary complex is not able to carry out this reaction, due to the presence of fluorine in the 5-position: the formation of TMP 4 (2 0 -deoxythymidine 5 0 -monophosphate), the only nucleotide precursor specific to DNA, is, therefore, blocked (Scheme 1), decreasing the availability of TTP (2 0 -deoxythymidine 5 0 -triphosphate) for DNA synthesis.Scheme 1 2 Ferraboschi, Ciceri, and GrisentiLater two additional mechanisms were proposed for 5-FU 1 antitumor activity: the 55 incorporation of 5-FU into DNA and the alteration of the membrane function of 5-FU 1 treated cells. Recent studies indicate that the TS-direct mechanism predominates when 1 is administered at low doses for a prolonged time, whereas the RNA-mediated process is more active following a bolus administration. 8-10 Synthesis of 5-FU 1, by construction of the pyrimidine ring, was first realized by Hei-60 delberger et al. in 1957 4,11,12 by reaction of a thiourea derivative 5 with the enolate of ethyl a-fluoro, a-formyl acetate 6 which, in turn, was obtained from methyl formate and ethyl fluoroacetate (Scheme 2). Depending on the chosen a-fluoro-b-ketoester the method is also applicable to the synthesis of other 5-fluoropyrimidines.An alternative method for the total synthesis is the direct fluorination of the pyrimi-65 dine ring of compound 7 by means of trifluoromethyl hypofluorite (CF 3 OF) 13 proposed by Robins in 1971. In the case of CF 3 OF in methanol/fluorotrichloromethane an intermediate was formed that, after treatment with triethylamine, afforded 5-FU 1 in 84% yield. 13 If the reaction was carried out with CF 3 OF in trifluoroacetic acid 1 was directly isolated in 85% yield. 14 The meth...

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“…BV-araU was pro vided by Yamasa Shoyu Co., Ltd., Chiba. The method of BOF-A2 synthesis is described elsewhere (6), and the structures of all drugs applied are shown in Fig. 2.…”

Section: Animalsmentioning

confidence: 99%

“…1, CNDP (3-cyano-2,6-dihydroxypyridine) is a more potent inhibitor of 5-FU degradation than uracil (5). BOF-A2 (3-{3-[6-benzoyloxy-3-cyano-2-pyridyloxycar bonyl]benzoyl}-1-ethoxymethyl-5-fluorouracil), a novel 5-FU-derived antineoplastic drug, was developed by conjugating CNDP and EM-FU (1-ethoxymethyl-5 fluorouracil), a 5-FU precursor that steadily releases 5-FU via liver microsomes (6).…”

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Leukopenia-Inducing Effect of a Combination of a New 5-Fluorouracil (5-FU)-Derived Drug, BOF-A2 (Emitefur), with Other 5-FU-Derived Drugs or BV-araU (Sorivudine) in Rats

Miyauchi

Imaoka

Okada

et al. 1996

Japanese Journal of Pharmacology

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ABSTRACT-BOF-A2(emitefur: 3-{3-[6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl]benzoyl}-1-ethoxy methyl-5-fluorouracil), a novel 5-FU (5-fluorouracil)-derived drug, was co-administered with other conventional 5-FU-derived drugs or BV-araU [sorivudine:for 8 con secutive days to rats. BOF-A2 (6 or 8 mg/kg, p.o.) co-administered with other 5-FU-derived drugs elevated the plasma 5-FU concentration 3 to 23.3-fold and decreased the peripheral white blood cell (WBC). The .3%, 32.0%, 58.6% and 30.0%, respectively, compared with each drug alone. On the other hand, these phenomena did not occur with BV-araU. These findings can be at tributed to the fact that the inhibitory activity of CNDP (3-cyano-2,6-dihydroxypyridine)for 5-FU degra dation (IC50: 6.3 x 10-9 M) is potent and 6000 times greater than that of BVU [(E)-5-(2-bromovinyl) uracil], another inhibitor of 5-FU degradation.

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Synthesis of 5-Fluorouracil Derivatives Containing an Inhibitor of 5-Fluorouracil Degradation.

Cited by 12 publications

References 1 publication

Combined effect of clinically relevant doses of emitefur, a new 5-fluorouracil derivative, and radiation in murine tumours

Combined effect of clinically relevant doses of emitefur, a new 5-fluorouracil derivative, and radiation in murine tumours

Synthesis of Antitumor Fluorinated Pyrimidine Nucleosides

Leukopenia-Inducing Effect of a Combination of a New 5-Fluorouracil (5-FU)-Derived Drug, BOF-A2 (Emitefur), with Other 5-FU-Derived Drugs or BV-araU (Sorivudine) in Rats

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