Synthesis of Antitumor Fluorinated Pyrimidine Nucleosides

Abstract

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...

Synthesis and Conformational Analysis of Fluorinated Uridine Analogues Provide Insight into a Neighbouring-Group Participation Mechanism

“…Fluorinated nucleosides and nucleotide analogues have attracted much attention as antiviral and anticancer drugs or mechanistic probes [ 1 , 2 , 3 , 4 ]. Since the development of the first fluorine-containing drug in 1957, the research in the field of fluorine chemistry has flourished, leading to noteworthy industrial applications [ 5 ].…”

Therapeutic Use of Fluorinated Nucleosides – Progress in Patents

“…Introduction of fluorine into nucleosides can be achieved either via nucleophilic or electrophilic fluorination using fluorinating agents such as Olah's reagents, DAST and XtalFluor-E or Selectfluor [42][43][44]. An extensive review on synthetic methodologies for the preparation of antitumour fluorinated nucleobase 5-fluorouracil (1), and its nucleoside-derivatives including FUDR (2), capecitabine (3), as well as pyrimidine nucleosides fluorinated at the sugar moiety such as gemcitabine (4) and related non-clinical nucleosides, was recently published by Ferraboschi and colleagues [45].…”

“…As depicted inFigure 5, the novel compounds exemplified include the natural thymidine, adenine, cytosine and guanosine nucleobases, along with 2-amino-6-(4-methoxythiophenol)purine, 7-deaza-guanine, 7-deaza-7-fluoroguanine and 7-deaza-7-cyano-guanine. Once the nucleobase is functionalised with the acyclic fluorinated phosphonate ester 41 and the two ester groups are cleaved to yield the corresponding free phosphonic acids, as shown inFigure 5, the free acids are then converted into the corresponding aryloxyphosphonamidates(42)(43)(44)(45)(46)(47)(48)(49)(50).…”

Fluorinated Nucleosides: Synthesis, Modulation in Conformation and Therapeutic Application

“…In the last twelve years, radical fluorination has become the choice of method for organic chemists [16] but still, we are waiting for a general method of fluorination. There are few reviews available that are specifically dedicated to fluoro‐nucleoside analogs synthesis and their biological study [2,3c,10,13b,d,e,f] . But none is available which also summarizes the influence of fluoro substituent on the conformation of the nucleoside.…”