347. Cyto-active amino-acids and peptides. Part XI. Nitrogen mustard derivatives of glutamic acid and related compounds
347. Cyto-active amino-acids and peptides. Part XI. Nitrogen mustard derivatives of glutamic acid and related compounds
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DOI：
10.1039/jr9650001907
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发表时间：
1965
期刊：
影响因子：
--
通讯作者：
M. Szekerke;R. Wade;F. Bergel
中科院分区：
文献类型：
--
作者：
M. Szekerke;R. Wade;F. Bergel
The synthesis of a series of derivatives in which glutamic acid was linked by peptide bonds to various bases containing aromatic nitrogen mustard groups is described. Both L and D isomers of glutamic acid were joined in a and y peptide linkage. Basic nitrogen mustard derivatives used were melphalan* ethyl ester, NN-dichloroethylphenylenediamine, and NN-dichloroethylaminophenylethylamine. In addition a-and f3-aspartyl-and seryl-melphalan esters were prepared and a polyglutamylmelphalan ester. Comparative results of anti-tumour tests are briefly discussed.THE preparation of a series of peptide esters in which melphalan* ester was acylated with various amino-acids and peptides containing (with the exception of cystine) non-functional side chains, was described in Part VIII. 2 Part X1 included the synthesis of L-arginylmelphalan ester, representing basic side-chain derivatives, a compound which exhibited anti-tumour activity to a high degree. Considering amino-acids with other than basic functional side chains, we recall the work of Roberts and his co-workers3 among others; they have shown that glutamine plays a key role in the metabolism of tumour cells, being absorbed rapidly. This encouraged the supposition that some analogues of glutamine might share this property and possess high permeability into tumour cells. Accordingly a number of derivatives of glutamine and isoglutamine have been prepared in which variations have been made both in the configuration of the glutamic acid used and in the nature of the basic molecule carrying the nitrogen mustard group. Preliminary experiments carried out by JM Johnson in this Institute had indicated that a-benzyl N-benzyloxycarbonylglutamate prepared by the method of Bergmann, Zervas, and Salzmann5 was not a suitable intermediate for the preparation of pure y-glutamyl derivatives in this particular series. Coupling of the ester-acid with NN-dichloroethylphenylenediamine gave a mixture of a and y isomers which could not be separated by crystallisation (cf. preparation of glutamine 5). Consequently the analogues of glutamine were prepared using a-benzyl N-benzyloxycarbonyl-L-glutamate made as described by
