Fluoro-orotic acid

Fluoro-orotic acid was found to be an effective insect chemosterilant. When fed at a 1 per cent concentration (w/w in milk powder) for 24 h, it induced complete and permanent sterility in female adult houseflies (Musca domesticd) [205,206]. Other biological activities of 5-fluoro-orotic acid have been discussed in Part I of this review. 

Cycloheximide (CYH), 4-nitroquinoline-oxide (4-NQO), sulfomethuron methyl (SMM), and 5-fluoro-orotic acid (5FOA) (BioMol, PA). 

Aminopterin, methotrexate, S-fluorouracil, 5-fluoro-orotic acid, tepa, metepa, and apholate all sterilized at the higher concentration, but only the antimetabolites sterilized at the lower concentration. Whenever a compound induces sterility, a second series of tests is run to determine the range of effective concentrations. Some antimetabolites sterilized at concentrations as low as 0.0025%, whereas the minimum for alkylating agents was 0.25%. In the third series of tests, the specific sex sterilized is determined. The chemosterilants are presented in the food at sterilizing concentrations to individual sexes of flies. These flies are then mated with normal flies of the opposite sex. All the chemicals mentioned above sterilized the females, but aminopterin and methotrexate failed to sterilize the male flies, and 5-fluorouracil produced male sterility in only a few tests. Tepa, 5-fluoro-orotic acid, metepa, and apholate, when included in the food, regularly sterilized both sexes. Because of the inability of aminopterin, methotrexate, and 5-fluorouracil to sterilize males, these compounds were not considered further. 

Tepa, metepa, apholate, and 5-fluoro-orotic acid were then evaluated as contact sterilants. In these tests individual sexes of houseflies were exposed to residues of 10 to 250 mg. per sq. foot of the chemosterilant on glass. After exposure for 2 to 4 hours, the flies were mated with virgin flies. Sterility was obtained in both sexes with tepa and metepa, but apholate and 5-fluoro-orotic acid were ineffective as residues. 

Fluoro-orotic acid undergoes in the liver the same conversion as orotic acid [269,270]. The 5-fluoro analogue serves as a substrate for orotate phosphoribosyltransferase [270] and the anomalous nucleoside 5 -phosphate so produced inhibits orotidylic acid decarboxylase. A number of... 

However, 5-fluoro-orotic and orotic acids are utilized differentially for the synthesis of cytoplasmic liver RNA. 5-Fluoro-orotate is incorporated preferentially into a fraction of non-ribosomal RNA which has several properties in common with messenger RNA [271]. Analysis of microsomal RNA showed Uttle or no incorporation of 5-fluoro-orotic acid into either 18 S or 28 S ribosomal RNA. The analogue is rapidly incorporated into 45 S ribosomal precursor RNA but its subsequent processing into mature 18 S and 28 S RNA is inhibited [272]. The analogue also greatly inhibits the incorporation of orotic acid into ribosomal RNA but has little effect on its incorporation into messenger RNA [273]. 

Boeke, J.D., LaCroute, F. and Fink, G.R. 1984, A positive selection for mutants lacking orotidine-5 -phosphate decarboxylase activity in yeast 5-fluoro-orotic acid resistance. Mol. Gen. Genet., 197 345. 

Fluorine has the closest atomic dimensions to the hydrogen atom, and pyrimidine analogues where hydrogen is substituted by fluorine are powerful antimetabolites. 5-fluoro-orotic acid (Fig. 12), for instance, prevents the conversion of orotic acid to orotidylic acid (Fig. 2) and the methylation of deoxyuridylic acid to form thymi-dylic acid (Fig. 9). 

These two groups of compounds have different mechanisms for inducing sterility. The antimetabolites have been considered as compounds wherein a metabolite essential to cell development has been changed in one or several ways and, when introduced into an animal, will elicit signs associated with a specific lack of the metabolite (10y 11). Some of the more promising are methotrexate, aminopterin (N- p- [ (2,4-diamino-6-pteridyl)methyl]amino benzoyl glutamic acid), 5-fluorouracil, and S-fluoro-orotic acid. 

OCH3, SH, NH2, CHg, or COOH,205 adenine-thymine base pair171,175,184, 185 and its cationic and anionic forms209 (for the charge densities at C-5 and C-6 positions in uracil, thymine, 5-amino- 5-nitro- and 6-methyl-uracil, 6-azathymine and orotic acid, see refs. 187, 188) it-HMO + a-Del Re calculations on uracil,369,397 5-fluoro- and 5-bromouracil,397 5,6-dihydrouracil and its anionic form369 n-SCF MO + a-Del Re... 

By analogy with 5-fluoro-orotate, [270] 5-azaorotate was found to react with PRPP blocking simultaneously and in a competitive manner the phosphoribosyltransferase reaction. The newly formed 5-azaorotate 5 -phosphate and/or 5-azauridine 5 -phosphate then inhibit orotidylic acid... 

C5H4FN20sRb, Rubidium 5-fluoro-orotate monohydrate, 29, 712 C5H4N4, Purine, 30B, 173 C5H4N4O, Allopurinol, 38B, 420 C5H4N4O3, Uric acid, 31B, 162... 

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