Fluoropyrimidines

FLUOROPYRIMIDINES Fluoropyrknidines find diverse use in cancer chemotherapy and other dmg appHcations, as well as in fiber-reactive dyes. Table 13 fists physical properties of representative fluoropyrknidines. 

Likewise, 4-amino-5-fluoropyrimidin-2(l/f)-one 3-oxide (496) and acetic anhydride give 4-acetoxyamino-5-fluoropyrimidin-2(l/f)-one (497) (68M847). 

Reaction of tetrafluoropyrimidine with anhydrous HC1 set up an equilibrium in which the outcome was determined by the reaction conditions. It allowed the isolation of 2,4,6-trichloro-5-fluoropyrimidine, an isomer not accessible by KF exchange. Hydrogenolysis and hydrolysis of the 2,5-difluoroisomer provided a convenient route to 5-fluorouracil [89JFC(45)417],... 

C21H27CIFN7O2 32566-14-6) see Flurazepam 4-amino-2-chloro-5-fluoropyrimidine (C4H2CIFN3 155-10-2) see Flucytosine 4-amino-6-chloro-S-methoxypyrimidine (CjHdClNjO 5018-41-7) see Sulfadoxine... 

The chemical shifts for fluoropyrimidines, a quinoxoline, and for 5-fluorouracil are also provided in Scheme 3.61. 

Thymidylate synthase (TS) is the rate-limiting enzyme in the DNA synthetic pathway and the target for 5-FU and folate analogs (Figure 14.3). Compared to normal tissues, TS is often overexpressed in tumor cells, probably as a result of tumor suppression loss of function, gene amplification or other mechanisms. Acute induction of TS protein as well as stable amplification of TS-specific genes may be associated with resistance to fluoropyrimidine derivatives [118, 119], and an inverse correlation between tumor TS expression and clinical response was found [120-122]. 

Guo, Y., Kotova, E., Chen, Z.S., Lee, K., Hopper-Borge, E., Belinsky M.G. and Kruh, G.D. (2003) MRP8, ATP-binding cassette Cll (ABCC11), is acyclic nucleotide efflux pump and a resistance factor for fluoropyrimidines 2, 3 -dideoxycytidine and 9 -(2 -phosphonylmethoxyethyljadenine. Journal of Biological Chemistry, 278, 29509-29514. 

T. Ishikawa, M. Utoh, N. Sawada, M. Nishida, Y. Kukase, F. Sekiguchi, H. Ishitsuka, Tumor Selective Delivery of 5-Fluorouracil by Capecitabine, a New Oral Fluoropyrimidine Carbamate, in Human Cancer Xenografts , Biochem. Pharmacol. 1998, JJ, 1091 - 1097. 

The aminodefluorination occurs to a considerably lesser extent according to the Sn(ANRORC) mechanism (40%) apparently, the competitive addition on C-2, leading to the Sn(AE) substitution, is more favored. This preference for Sn(AE) reactions is characteristic of the fluoro atom it has been also observed in aminodefluorinations of 2-fluoropyrimidines (Section II,C,l,c). 

Fluoro-5-phenyl-l,2,4-triazine (109, X = F) reacts much faster than the 3-chloro-, 3-bromo-, or 3-iodo-compound. Moreover, the reaction mixture obtained is cleaner than that from the corresponding 3-chloro- or 3-bromo compounds 3-amino-5-phenyl-l,2,4-triazine (110) is formed in good yield. This conversion takes place to only a small extent (18%) via the ANRORC process the main part of the aminodefluorination seems to involve the Sn(AE) mechanism. This result is consistent with the observation that the aminodefluorination of 4,6-diphenyl-2-fluoropyrimidine follows the Sn(AE) process, whereas 2-fluoro-4-phenylpyrimidine (position 6 is vacant for addition of the nucleophile) reacts for the most part according to the Sn(ANRORC) mechanism (see Section II,C,l,c). 

Fluoropyrimidines and fluoropyrazines must also be metaUated with LDA or LiTMP to avoid ring addition. Replacing F with CF3 also allows metallation, but side-reactions are more of a problem (Scheme 117). 

Fluorouracil Fluorouracil, 4-fluorouracil (30.1.3.3), is made by condensing the ethyl ester of fluoroacetic acid with ethylformate in the presence of potassium ethoxide, forming hydroxy-methylenfluoroacetic ester (30.3.1), which cyclizes by reacting it with S-methyl-isothiourea to 2-methylthio-4-hydroxy-5-fluoropyrimidine, which is subsequently hydrolyzed by hydrochloric acid to fluorouracil (30.1.3.3) [21,22]. An alternative method of synthesizing... 

Flucytosine Flucytosine, 5-fluorocytosine (35.4.4), is synthesized from fluorouracil (30.1.3.3). Fluorouracil is reacted with phosphorous oxychloride in dimethylaniline to make 2,4-dichloro-5-fluoropyrimidine (35.4.2), which is reacted with ammonia to make a product substituted with chlorine at the fourth position of the pyrimidine ring—4-amino-2-chloro-5-fluoropyrimidine (35.4.3). Hydrolysis of the chlorovinyl fragment of this compound in a solution of hydrochloric acid gives the desired flucytosine [52-55]. 

Fluoropyrimidine-Radiation Interactions Mechanisms of Radiosensitization by Fluoropyrimidines Pharmacological and Scheduling Requirements for Obtaining Effective Radiosensitization with Fluoropyrimidines... 

The recent availability of oral formulations of 5-FU, may provide not only an improvement in the ease of administration and the efficacy of fluoropyrimidine therapy, but also alleviate complications related to the catheters. Such agents include uracil tegafur (UFT) and capecitabine (Xeloda). 

The fluoropyrimidines as a group can affect the synthesis and function of both deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), and both of these two mechanisms... 

Fig. 3. Metabolism of the fluoropyrimidines dTMP = deoxythymidine monophosphate, dUMP = deoxyuridine monophosphate, FdUDP = fluorodeoxyuridine diphosphate, FdUMP - fluoro-deoxyuridine monophosphate, FdUTP = fluorodeoxyuridine triphosphate, FU-DNA= fluorouracil-deoxyribonucleic acid, FUDP = fluorouracil diphosphate, FUMP = fluorouracil monophosphate, FU-RNA = fluorouracil-ribonucleic acid, FUTP = fluorouracil triphosphate.

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