Collagenase-sensitive peptidyl-nitrogen mustards as potential antitumor agents.
Attempts to design an agent which would release cytotoxic nitrogen mustards within collagenase-producing tumors led to the synthesis of Cbz-L-Pro-L-Leu-Gly-L-Pro-Gly-NHC6H4N(CH2CH2Cl)2 (10). 10 was cleaved in vitro by bacterial and tumor-associated collagenase as expected at the peptide bond joining L-leucine and glycine to give Gly-L-Pro-Gly-NHC6H4N(CH2CH2Cl)2 which was over six times more toxic, on a molar basis, than 10. In vivo tests of 10 against well-advanced Sarcoma-180 gave disappointing results. The lack of specific antitumor activity may be accounted for by the presence of competing cleavage reactions by collagenases in certain normal tissues.
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000627:therapeutic use / Q000633:toxicity; D001345:Autoradiography; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D051379:Mice; D003012:Microbial Collagenase / Q000378:metabolism*; D009588:Nitrogen Mustard Compounds / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D009842:Oligopeptides / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D012510:Sarcoma 180 / Q000188:drug therapy / Q000201:enzymology; D013552:Swine
D000970:Antineoplastic Agents; D009588:Nitrogen Mustard Compounds; D009842:Oligopeptides; D003012:Microbial Collagenase