Khalid M, Burzynski S R
Drugs Exp Clin Res. 1987;13 Suppl 1:57-60.
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.
作者所在研究所之前开展的研究表明，抗肿瘤素A10的活性代谢产物之一是苯乙酰异谷氨酰胺。本研究的目的是筛选N，N'-二取代L-异谷氨酰胺衍生物，以选择新型抗癌药物。合成了一系列七种L-异谷氨酰胺衍生物作为潜在的化疗药物。在乳腺癌细胞HBL-100的组织培养中进行了抗肿瘤活性研究。对一组60只HA/ICR瑞士小鼠进行了急性毒性研究。在所测试的化合物中，发现Nα-（苯乙酰氨基）-γ-（4-氨基-N-苄基-哌啶基）-L-谷氨酰胺具有最佳的抗癌活性且无明显急性毒性。通过移动平均法计算出LD50，在小鼠腹腔注射时为4.5 g/kg。得出结论，异谷氨酰胺的胺氮和酰胺氮上存在亲脂性基团是具有良好抗肿瘤活性的重要结构特征。当侧链上的苯基与酰胺氮至少相隔两个碳原子时，活性也会增加。
