HUI-PO WANG^1*, MIN-FANG WU², CHIN-YU SHU², ON LEE², SU-JUAN LEE² AND CHI-HUA SUNG¹　　

(Received: March 22, 2000; Accepted: May 25, 2000)

   A large number of human prostate cancer cases has been proven to be genetically associated with ras-mutation. A series of a-azatyrosinamides prepared in this laboratory demonstrated selective cytotoxicity against ras-mutated NIH3T3 cells while with little toxicity on wild type NIH3T3 cells. The compounds also proved to be active in inhibiting human prostate cancer cell lines. Using a-azatyrosinamides as the leads, we prepared another series of novel b-azatyrosinamides for the purpose of treating human prostate cancer. Preparation of the b-azatyrosinamides starts from 5-benzyloxypyridin-2-ylaldehyde (1), which upon reaction with malonic acid and ammonium acetate afforded 5-benzyloxy-b-azatyrosine (2). This intermediate was allowed to react with benzyloxycarbonic anhydride followed by coupling with a variety of amines to form the desired b-azatyrosinamides 4-15. The compounds exhibited an inhibitory effect on the growth of ras-mutated NIH3T3 cells with IC₅₀ ranged between 0.13±0.01 mM and 3.16±1.45 mM, which were with activities 2-57 fold higher than that of azatyrosine, but were much less active than their a-amino acid analogues. The selective toxicity, in terms of the ratio of IC₅₀ against wild type NIH3T3 to that against ras-transformed NIH3T3 cell lines, is at the range of 0.7-11.9. The IC₅₀'s of b-azatyrosinamides 4-15 on PC-3 human prostate cancer cell line ranged between 0.15±0.02 mM and 13.05±9.41 mM, which were 0.4-33 fold lower than that of azatyrosine.