Selective cytotoxicity of a system L specific amino acid nitrogen mustard.
The synthesis and characterization of DL-2-amino-7-bis[(2-chloroethyl)amino]-1,2,3,4-tetrahydro-2-naphthoic acid and DL-2-amino-5-bis[(2-chloroethyl)amino]-1,2,3,4-tetrahydro-2-napthoic+ ++ acid 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-amino-bicyclo[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 microM). Evaluation of the selectivity of this compound indicated that it possessed enhanced in vitro antitumor activity and reduced myelosuppressive activity when compared to its prototype amino acid nitrogen mustard, L-phenylalanine mustard (L-PAM). In addition to being more selectively toxic to tumor cells, this compound differs from L-PAM in having a 2-3-fold shorter half-life (t1/2).
D015081:2-Naphthylamine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000627:therapeutic use / Q000633:toxicity; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D001692:Biological Transport; D001853:Bone Marrow / Q000187:drug effects; D006207:Half-Life; D007202:Indicators and Reagents; D007939:Leukemia L1210 / Q000188:drug therapy; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D009281:Naphthalenes / Q000138:chemical synthesis*; D009588:Nitrogen Mustard Compounds / Q000138:chemical synthesis* / Q000627:therapeutic use / Q000633:toxicity; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D007202:Indicators and Reagents; D009281:Naphthalenes; D009588:Nitrogen Mustard Compounds; C051625:2-amino-7-(bis(2-chloroethyl)amino)-1,2,3,4-tetrahydro-2-naphthoic acid; C051626:2-amino-5-(bis(2-chloroethyl)amino)-1,2,3,4-tetrahydro-2-naphthoic acid; D015081:2-Naphthylamine