CHEMOTHERAPY OF CANCER,III.SYNTHESIS OF FLUORO-CONTAINING AMINO-ACIDS

Since it is known that some organo-fluorine compounds such as fluoro pyrimidines, are capable of inhibiting the growth of rat tumor,it will be of interest to synthesize and study fluoro-containing amino-acids for the carcinostatic action. ω-Fluoro-a-amino butyric,-valenic and caproic acids are the only fluoro-containing aliphatic amino-acid recorded in literature.We have synthesized β-fluoro-α-amino-propionic acid by the following sequence of reactions: When 2-phenyl-4-chloromethylene-5-azlactone (Ⅰ) was treated with anhydrous potassium fluoride in acetylacetone by UV irradiation,the corresponding fluoro-substituted azlactone (Ⅱ)was formed.The latter was hydrolyzed in aqueous alkali to the acrylic acid deri- vative,which was then hydrogenated in the presence of Adam’s catalyst and subsequently hydrolyzed with hydrochloric acid and formic acid mixture.As shown by paper chroma- tography,the product was contaminated with alanine.The latter was completely removed by azobenzene-p-sulfonic acid and followed by treatment with alumina.The β-fluoro-α- amino-propionic acid hydrochloride thus obtained was chromatographically pure.Raasch was unable to get this amino acid by malonic ester synthesis.We have made attempts to synthesize this compound by treating β-bromo-α-benzoylamido-,β-p-tosylhydroxy-α-benzoyl- amido-propionic acid or diethyl α-acetamido-α-dimethylamino-methyl malonate methyl iodide with anhydrous potassium fluoride in various solvents but the attempts was unsuccessful. A series of fluoro-containing aromatic amino-acids with the general formula given were prepared from p-fluorobenzaldehyde. R=H,OH,SH,SR′ 2-Phenyl-4-(p-fluorobenzylidene)-5-azlactone (Ⅳ) was resulted from p-fluorobenzal- dehyde via Erlenmeyer azlactone synthesis underwent an addition reaction with ethyl-or benzylmercaptans in the presence of sodium methoxide with formation of the corresponding β-(p-fluorophenyl)-S-alkyl-N-benzoylcysteine methyl ester (Ⅵ).The latter was hydrolyzed into the free amino acid in the usual way.In the case of addition of ethylmercaptan, the expected Threo-and Erythreo-isomers were separated.β-(p-Fluorophenyl)cysteine (Ⅷ)was synthesized by subsequent debenzylation of β-(p-fluorophenyl)-S-benzylcysteine (Ⅶb)with metallic sodium in liquid ammonia. A modification of the preparation of p-fluorobenzoldehyde,the key intermediate in our synthesis,has been developed. Biological tests of the indicated compounds showed that p-fluorophenyl serine prolonged the life of rat transplanted with Erhlich Ascites but with no effect toward Sarcoma 180. β-Fluoro-α-amino-propionic acid possessed some inhibiting action on the growth of Sarcoma 180 in rats.The biological tests were carried out in the laboratories of Institute of Ex- perimental Biology and Institute of Materia Media,Academia Sinica.