N-PHOSPHORYL DERIVATIVES OF BISANTRENE - ANTITUMOR PRODRUGS WITH ENHANCED SOLUBILITY AND REDUCED POTENTIAL FOR TOXICITY

The selective phosphorylation of bisantrene (1) affords bis(phosphonog uanidinic acid) 6, a prodrug with enhanced aqueous solubility (as sodi um salt 7) at physiological pH. Unlike 1, in a rat tail vein model, no precipitation was observed when bis(phosphonoguanidinic acid) 6 was i njected. While in rats 6 hydrolyzed to monophosphonoguanidinic acid 9 with a half-life of ca. 12 min., complete hydrolysis to bisantrene req uired several hours. The corresponding monophosphonoguanidinic acid 9 was synthesized from bisantrene and also showed good solubility and an titumor activity. While the antitumor activities of 6 in mice were com parable to bisantrene against B-16 melanoma and P-388 and L-1210 leuke mias, 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 b isantrene.