N,N'-disubstituted L-isoglutamines as novel cancer chemotherapeutic agents.

Previous studies carried out in the authors' Institute revealed that one of the active metabolites of Antineoplaston A10 is phenylacetylisoglutamine. The objective of this study is screening of N,N'-disubstituted L-isoglutamine derivatives for selection of novel anticancer agents. A series of seven derivatives of L-isoglutamine was synthesized as potential chemotherapeutic agents. Antitumor activity studies were performed in tissue culture of breast carcinoma cells HBL-100. The acute toxicity study was carried out on a group of 60 HA/ICR Swiss mice. Among the compounds tested N alpha-(phenylacetylamino)-gamma-(4-amino-N-benzyl-piperidinyl)-L-g lutamyl amide was found to have the best anticancer activity and no significant acute toxicity. The LD50 was calculated by the moving average method and determined as 4.5 g/kg i.p. in mice. It is concluded that the important structural features for good antineoplastic activity are lipophilic groups on both amine and amide nitrogen of isoglutamine. The activity is also increased when the phenyl group present at the side chain is at least two carbon atoms away from the amide nitrogen.