title: N-phosphoryl derivatives of bisantrene. Antitumor prodrugs with enhanced solubility and reduced potential for toxicity.
abstract: The selective phosphorylation of bisantrene (1) affords bis(phosphonoguanidinic acid) 6, a prodrug with enhanced aqueous solubility (as sodium salt 7) at physiological pH. Unlike 1, in a rat tail vein model, no precipitation was observed when bis(phosphonoguanidinic acid) 6 was injected. While in rats 6 hydrolyzed to monophosphonoguanidinic acid 9 with a half-life of ca. 12 min., complete hydrolysis to bisantrene required several hours. The corresponding monophosphonoguanidinic acid 9 was synthesized from bisantrene and also showed good solubility and antitumor activity. While the antitumor activities of 6 in mice were comparable to bisantrene against B-16 melanoma and P-388 and L-1210 leukemias, it was inactive in vitro vs several tumor cell types. Thus, its activity in vivo resulted from its ability to serve as a prodrug for bisantrene.
authors.affiliation: American Cyanamid Company, Medical Research Division, Pearl River, New York 10965.
authors.forename: K C
authors.initials: KC
authors.lastname: Murdock
authors.forename: V J
authors.initials: VJ
authors.lastname: Lee
authors.forename: R V
authors.initials: RV
authors.lastname: Citarella
authors.forename: F E
authors.initials: FE
authors.lastname: Durr
authors.forename: G
authors.initials: G
authors.lastname: Nicolau
authors.forename: M
authors.initials: M
authors.lastname: Kohlbrenner
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000138:chemical synthesis / Q000494:pharmacology; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis*; D007941:Leukemia P388 / Q000188:drug therapy; D008546:Melanoma, Experimental / Q000188:drug therapy; D051379:Mice; D011355:Prodrugs / Q000138:chemical synthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000873:Anthracenes; D000903:Antibiotics, Antineoplastic; D011355:Prodrugs; C031404:bisantrene