Selective cytotoxicity of a system L specific amino acid nitrogen mustard

Journal of Medicinal Chemistry
1987.0

Abstract

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).

Knowledge Graph

Similar Paper

Selective cytotoxicity of a system L specific amino acid nitrogen mustard
Journal of Medicinal Chemistry 1987.0
Discovery and Optimization of Novel Hydrogen Peroxide Activated Aromatic Nitrogen Mustard Derivatives as Highly Potent Anticancer Agents
Journal of Medicinal Chemistry 2018.0
Synthesis and transport applications of 3-aminobicyclo[3,2,1]octane-3-carboxylic acids
Journal of Medicinal Chemistry 1983.0
Synthesis of nitrosourea derivatives of pyridine and piperidine as potential anticancer agents
Journal of Medicinal Chemistry 1980.0
Structure-activity relationship in a series of newly synthesized 1-amino-substituted ellipticine derivatives
Journal of Medicinal Chemistry 1980.0
1-Amino-substituted 4-methyl-5H-pyrido[3',4':4,5]pyrrolo[3,2-c]pyridines: a new class of antineoplastic agents
Journal of Medicinal Chemistry 1987.0
Amino acid and dipeptide derivatives of daunorubicin. 2. Cellular pharmacology and antitumor activity of L1210 leukemic cells in vitro and in vivo
Journal of Medicinal Chemistry 1980.0
Acetamidine Lysine Derivative, N-(5(S)-amino-6,7-dihydroxyheptyl)ethanimidamide Dihydrochloride:  A Highly Selective Inhibitor of Human Inducible Nitric Oxide Synthase
Journal of Medicinal Chemistry 1998.0
A Comparison of Chloroambucil- and Xylene-Containing Polyamines Leads to Improved Ligands for Accessing the Polyamine Transport System
Journal of Medicinal Chemistry 2008.0
Synthesis and Evaluation of Several New (2-Chloroethyl)nitrosocarbamates as Potential Anticancer Agents
Journal of Medicinal Chemistry 2000.0