N-phosphoryl derivatives of bisantrene. Antitumor prodrugs with enhanced solubility and reduced potential for toxicity.
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.
Murdock
K C
KC
American Cyanamid Company, Medical Research Division, Pearl River, New York 10965.
Lee
V J
VJ
Citarella
R V
RV
Durr
F E
FE
Nicolau
G
G
Kohlbrenner
M
M
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
D000873:Anthracenes; D000903:Antibiotics, Antineoplastic; D011355:Prodrugs; C031404:bisantrene