Studies on antitumor agents. V. Syntheses and antitumor activities of 5-fluorouracil derivatives.

Yamashita, Jun‐ichi; Yamawaki, Ichiro; Ueda, Shuichi; Yasumoto, M.; Unemi, Norio; Hashimoto, Susumu

doi:10.1248/cpb.30.4258

Cited by 18 publications

(7 citation statements)

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“…1-Ethoxymethyl-5-fluorouracyl 143 was synthesized in 1978 in very poor yield (4%) by reaction of ethoxychloromethane with 5-FU 1 160 or by reaction of the silylderivative 710 of 5-FU 47 with diethoxymethane and sodium iodide (44% yield) 161 or stannic chloride (14% yield), 162 as depicted in Scheme 85.…”

Section: Galocitabinementioning

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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Section: Galocitabinementioning

confidence: 99%

Synthesis of Antitumor Fluorinated Pyrimidine Nucleosides

Ferraboschi

Ciceri

Grisenti

2017

Organic Preparations and Procedures International

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“…Many new 5-FU derivatives, e.g., the glycosides of 5-FU, were synthesized to develop more effective and more selective drugs. 4−6 These glycosides are deemed promising as both sugar and 5-FU units are well-known biologically important compounds.…”

Section: Introductionmentioning

confidence: 99%

O-Regioselective Synthesis with the Silver Salt Method

Wang

Barnes

2018

ACS Omega

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The excellent O-regioselectivity of the glycosidation of the ambident 2-O-substituted 5-fluorouracil (5-FU) via the silver salt method is computationally investigated at the MP2/6-311++G(2d,p):DZP//B3LYP/6-31+G(d):DZP level of theory. The reactions studied are those between 1-bromo-1-deoxy-2,3,4,6-tetra- O -acetyl-α- d -glucopyranose and the silver salts of 5-FU, 2- O -butyl-5-FU, and 2- O -benzyl-5-FU. Two pathways are considered as follows: (A) one where the silver and bromide ion do not interact, and (B) another where the silver and bromide ion interact in the transition states. Because the O-reaction barriers are much lower (by 13.3–22.2 kcal/mol) than N-reaction barriers in both pathways, the O-regioselectivity of the silver salt method can be satisfactorily explained by either path A or path B. Furthermore, path B, where Ag and Br interact consistently, has lower activation barriers than the corresponding path A (by 6.8–17.4 kcal/mol) in both N- and O-reactions. This computational result can be attributed to the following reasons: (1) the speeding-up effect in Koenigs–Knorr reactions due to the addition of silver carbonate into the reaction mixture; (2) the halogens being pulled away by silver ions from halides, as proposed by Kornblum and co-workers; and (3) the oxocarbenium ion involvement in the glycosidation reactions. The large energy difference between N- and O-transition states originates from the association between Ag and N–(O−) of the ambident unit (−N3–C4=O4) that shows significant covalent character so that the O-reaction transition states of the silver salt method benefit from favorable ionic interaction (C + ···O – ) and favorable covalent interaction (Ag···N). These two favorable interactions are in agreement with the hard and soft acids and bases principle; the former is a hard–hard interaction and the latter is a soft–soft interaction.

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“…In addition, it is known that modified nucleosides and nucleotides reduce the cell mitotic activity resulting in antineoplastic [11][12][13][14][15][16] and antiviral [17] activity. 5-fluorouracil, a pyrimidine analogue and representative antimetabolite drug, is currently used as a first-line chemotherapeutic agent for the treatment of different solid tumours [18][19][20][21]. However, the clinical efficacy of 5-fluorouracil is compromised by its propensity to cause several types of dose-dependent toxicity [20,21].…”

Section: Introductionmentioning

confidence: 99%

“…5-fluorouracil, a pyrimidine analogue and representative antimetabolite drug, is currently used as a first-line chemotherapeutic agent for the treatment of different solid tumours [18][19][20][21]. However, the clinical efficacy of 5-fluorouracil is compromised by its propensity to cause several types of dose-dependent toxicity [20,21].…”

Section: Introductionmentioning

confidence: 99%

In vivo toxicity study of N-1-sulfonylcytosine derivatives and their mechanisms of action in cervical carcinoma cell line

et al. 2011

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New N-1-sulfonylpyrimidines showed potent growth inhibitory activity against human and mouse tumour cells of different origin. 1-(p-toluenesulfonyl)cytosine (TsC) and 1-(p-toluenesulfonyl)cytosine hydrochloride (TsC × HCl) inhibited the growth of human cervical carcinoma cells (HeLa), and had no significant cytotoxic effects on normal human foreskin fibroblasts (BJ). TsC and TsC × HCl interfered with the HeLa cell cycle progression bringing about the accumulation of G1 phase cells and the induction of apoptosis. Antiproliferative effects of TsC and TsC × HCl were additionally confirmed by investigating de novo synthesis of RNA, DNA and proteins in HeLa cells. Monitoring gene expression using DNA Chip Analysis and quantitative PCR showed that TsC × HCl affects the expression of several cell-cycle regulating genes implying that cell cycle arrest and DNA damage-induced apoptosis might account for the observed cellular effects. In vivo experiments revealed low toxicity of TsC × HCl, as demonstrated by unaltered haematological and metabolic blood parameters. In conclusion, potent antitumour efficacy and low toxicity of new compounds in comparison with the common chemotherapy drug 5-FU make them promising anticancer agents. Additional pre-clinical and clinical studies are warranted to illuminate the mode of action of these newly synthesized compounds in vivo, which would lay the groundwork for their further optimization.

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Studies on antitumor agents. V. Syntheses and antitumor activities of 5-fluorouracil derivatives.

Cited by 18 publications

References 0 publications

Synthesis of Antitumor Fluorinated Pyrimidine Nucleosides

Synthesis of Antitumor Fluorinated Pyrimidine Nucleosides

O-Regioselective Synthesis with the Silver Salt Method

In vivo toxicity study of N-1-sulfonylcytosine derivatives and their mechanisms of action in cervical carcinoma cell line

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