Antineoplastic agents. 1. N-Protected vinyl, 1,2-dihaloethyl, and cyanomethyl esters of phenylalanine

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Abstract
A series of N-protected vinyl, 1,2-dihaloethyl and cyanomethyl esters of phenylalanine was synthesized and these compounds were evaluated for antitumor activity against the growth of Ehrlich ascites carcinoma in CF1 male mice (33 mg/kg per day), Walker 256 carcinosarcoma in Sprague-Dawley male rats (2.5 mg/kg per day) and P388 lymphocytic leukemia in DBA/2 mice (20 mg/kg per day). Structure-activity relationships were evaluated and acute toxicity studies (LD50 determinations) in male CF1 mice were also done on selected compounds. Carbobenzoxy-L-phenylalanine vinyl ester (5), N-carbobenzoxy-L-phenylalanine 1,2-dibromoethyl ester (12) and N-carbobenzoxy-L-phenylalanine cyanomethyl ester (8) were potent inhibitors of Ehrlich ascites tumor growth at nontoxic doses cited above. Compounds 5 and 12 also tripled survival time in the Walker 256 system. LD50 values for compounds 5, 12, and 8 were > 2000 mg/kg (> 6.15 mmol/kg), 74 mg/kg (0.15 mmol/kg and 150 mg/kg (0.44 mmol/kg), respectively.