Synthesis and radioprotective properties of 4-[bis(2-chloroethyl)amino]phenylalanyl-L-glutamic acid derivatives

Abstract

A promising direction in the search for substances possessing radioprotective properties is the synthesis of compounds capable of inhibiting the metabolism of nucleic acids and proteins, in particular, on the basis of natural amino acid derivatives [1,2]. An interesting object for modification is Lglutamic acid which is known to play an important role in the organism. It was reported that some of the glutamic acid derivatives possess radioprotective activity [3,4].The purpose of this work was to synthesize a diethyl ester and salts of a dipeptide of L-glutamic acid with 4-bis(2-chloroethyl)amino]phenylalanine (sarcolysine) and study their radioprotective properties.Diesters were obtained by condensation of N-acetyl-4-[bis(2-chloroethyl)amino]-DL-phenylalanine (I) with the diethyl ester hydrochloride (I) of L-glutamic acid, followed by separation of the resulting diethyl ester of N-acetyl-4-[bis(2- chloroethyl)amino]-DL-phenylalanyl-L-glutamic acid (HI) into diastereomers: diethyl ester of N-acetyl-4-[bis(2-chloroethyl)amino]-L-phenylalanyl-L-glutamic acid (IV) and Nacetyl-4-[bis(2-chloroethyl)amino]-D-phenylalanyl-L-gluta mie acid (V). The corresponding salts (VI and VII) were ob-9 tained by saponification of the ester groups of compounds IV and V with an alkali solution.An important factor is the stereo-purity of the resulting disodium salts of N-acetyl-4-[bis(2-chloroethyl)amino]-Lphenylalanyl-L-glutarnic acid and N-acetyl-4-[bis(2-ehloroethyl)amino]-D-phenylalanyl-L-glutamic acid, which determines the activity of compounds VI and VII. The individual diastereomers IV and V were isolated in analytical amounts by chromatography on a silica gel eohmm.Due to the close chromatographic mobility of the two diastereomers, the method of column chromatography did not