Lysosomotropic agents. 4. Carbobenzoxyglycylphenylalanyl, a new protease-sensitive masking group for introduction into cells

• Published in: Journal of medicinal chemistry Vol. 25; no. 5; pp. 539 - 544
• Main Authors: Firestone, Raymond A, Pisano, Judith M, Bailey, Philip J, Sturm, Anita, Bonney, Robert J, Wightman, Paul, Devlin, Richard, Lin, C. Shirley, Keller, Doris L, Tway, Patricia C
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 01-05-1982
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - metabolism; Cells, Cultured; Detergents - pharmacology; Dipeptides - chemical synthesis; Dipeptides - metabolism; Dipeptides - pharmacology; Hydrogen-Ion Concentration; Leukemia L1210 - metabolism; Lysosomes - drug effects; Neoplasms, Experimental - drug therapy; Nitrogen Mustard Compounds - toxicity; Peptide Hydrolases - metabolism; Thymidine - metabolism
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00347a012

Bioactive primary and secondary amines, when acylated with the Z-Gly-Phe group, are transported into pinocytic cells, such as macrophages, P-815 mastocytoma, SV-40 3T3, and leukemia 1210, much faster than the parent compounds. Amines such as lysosomotropic detergents [R. A. Firestone, J. M. Pisano, and R. J. Bonney, J. Med. Chem., 22, 1130 (1979) and nitrogen mustard, which are deactivated by acylation, are unmasked by enzymic action intracellularly, probably in lysosomes because an acidic pH maximum in activity exists which acts only on the L isomer. The added polarity and molecular weight brought about by acylation prevents the amines' normally facile entry into cells by simple diffusion, restricting it to an active-transport mechanism.