Halogenated pyrimidines

Franken NA, Van Bree CV, Kipp JB, et al. Modification of potentially lethal damage in irradiated Chinese hamster V79 cells after incorporation of halogenated pyrimidines. Int J Radiat Biol 1997 72(1) 101-109. 

Kinsella TJ, Dobson PP, Mitchell JB, et al. Enhancement of X ray induced DNA damage by pretreatment with halogenated pyrimidine analogs. Int J Radiat Oncol Biol Phys 1987 13(5) 733-739. 

Idoxuridine is a halogenated pyrimidine derivative. Any efficacy of topical application of idoxuridine for the treatment of cutaneous and mucocutaneous herpes simplex lesions is dubious. An improvement of therapeutic efficacy of idoxuridine entrapped in liposomes in treatment of HSV-1 and HSV-2 patients has been reported. 

The development of monoclonal antibodies which recognize halogenated pyrimidines such as 5-bromo-2-deoxyuridine (BrdU) incorporated into DNA (1) and of flow cytometric (FCM) techniques to simultaneously measure BrdU uptake and total DNA content (2) have led to a renaissance in cell kinetic studies. The speed and quantitative power of the flow cytometer, m conjunction with the specificity and sensitivity of monoclonal antibody techniques, provide the basis for the adoption and success of the BrdU technique in experimental and clinical investigations. 

Dolbeare, F. and Gray, J. W. (1988) Use of restriction endonuclease and exonuclease III to expose halogenated pyrimidines for immunochemical staining Cytometry 9, 631-635... 

Halogenated pyrimidines. There is a considerable interest in the reactions of 5-halourucils, notably 5BrUra. The latter can substitute Thy in DNA without... 

The first class of radiation sensitizer alluded to above, namely the halogenated pyrimidines, includes such materials as 5-bromodeoxyuridine (BUdR) [122], 5-iododeoxyuridine (ludr), and 5-fluorouracil (5-FU). These compounds have shown a certain degree of efficacy due, presumably, to the fact that they are incorporated into DNA [113,114,123]. Indeed, a new drag application (NDA) for one member of this class, BUdr (also known as Broxine ), has recently been filed by Neopharm with the FDA [124]. 

Halopurines are valuable intermediates for conversion to other purines. The halogen substituents show selectivity for positions 2, 6 and 8. The chloropurines are usually obtained by displacement reactions on hydroxy- or sulfanylpurines (see Sections 7.1.1.3.4.5.2. and 7.1.1.3.4.5.3.). However, they are also accessible by Traube synthesis care must be taken that the reactive halogen substituents are not displaced during the condensation reaction. 2-Chloro-purine (la), 6-chloropurine (lb), and 2,6-dichloropurine (Ic) are obtained from appropriately halogenated pyrimidine-4,5-diamines and ethyl orthoformate. ... 

Ehas L, Crissman HA. Interferon effects upon the adenocarcinoma 38 and HL-60 cell lines antiproliferative responses and synergistic interactions with halogenated pyrimidine antimetabolites. Cancer Res 1988 48(17) 4868-73. 

For halogenated pyrimidines, dehydrohalogenation competes with elimination of the hydride ion, as shown for 5-bromopyrimidine (173) in Scheme 64 (82JHC1285). Other examples are the amination of 4-tert-butyl-5-chloropyrimidine (174) and 2,4-di-fert-butyl-5-chloropyrimidine (175) with potassium amide in liquid ammonia (78RTC288). Some cine-substitution products (176 and 177) were also obtained (Scheme 65). From isotopic labeling studies, it was determined that the Sn(ANRORC) mechanism was not involved. 

In further reactions of N-phenylbenzimidoyl chloride (56), methyl isothiocyanate and stannic chloride, in nitrobenzene at 110°C, gave 2-phenyl-4-methylthioquinazoline in moderate yield JV-phenyltrichloroacetimidoyl chloride reacted similarly.41 Then, in one of the few reactions that produce a halogenated pyrimidine ring, the chloride (56) with cyanogen bromide and stannic chloride (in nitrobenzene at 150°C) gave 4-bromo-2-phenylquinazo-line in excellent yield.41... 

The best-characterized agents in this class are the halogenated pyrimidines, a group that includes... 

Grignard reactions involving halogenated pyrimidines 13JHC735. Lithiations and Grignard reactions on pyrimidine and quinazoline 13THC (31)21. 

There are many commercial sources of monodonal antibodies recognizing the halogenated pyrimidines. The choice of antibody often depends on individual preference to one or other company. However, several points should be taken into account as the quality of the measurement will depend on the purity, affinity, and spedfidty of the antibody. For instance high affinity antibodies such as IU-4 (Caltag) will be required if low levels of BrdUrd are to be detected. 

The development of antibodies to the halogenated pyrimidines combined with the attributes of FCM have led to a revolution in the study of cell kinetics and a resurgence of interest in their clinical apphcation. The techniques are reproducible and relatively straightforward and can be tailored to individual experimental requirements. 

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