Selective cytotoxicity of a system L specific amino acid nitrogen mustard

Abstract

The synthesis and characterization of DL-2-amino-7-bis[(2-chloroethyl)amino]-1,2,3,4-tetrahydro-2-naphthoic acid (6) and DL-2-amino-5-bis[(2-chloroethyl)amino]-1,2,3,4-tetrahydro-2-naphthoic acid (7) were accomplished. The correct assignment of the site of attachment of the bis(2-chloroethyl)amino side chain was ascertained by selective proton decoupling of the 13C NMR spectra performed on the corresponding nitrospirohydantoin precursors 2 and 3, which were obtained from the nitration of .beta.-tetralone hydantoin. The two target compounds 6 and 7 were designed as tumor-specific agents capable of being selectively transported into tumor cells by the leucine-preferring transport system (system L). Inhibition analysis of the initial rate of transport of the system L specific substrate 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid (BCH) by 6 and 7 indicated that the 7-substituted isomer 6 was an extremely potent competitive inhibitor of that transport system in murine L1210 leukemic cells (Ki = 0.2 .mu.M). Evaluation of the selectivity of this compound indicated that it possessed enhanced in vitro antitumor activity and reduced myelosuppresion activity when compared to its prototype amino acid nitrogen mustard, L-phenylalanine mustard (L-PAM). In adidtion to being more selectively toxic to tumor cells, this compound differs from L-PAM in having a 2.sbd.3-fold shorter half-life (t1/2).