In the search for new anticancer drugs XII. Synthesis and biological evaluation of spin labeled nitrosoureas

Abstract

The spin labeled nitrosourea 1-(2-chloroethyl)-3-(1-oxyl-2, 2, 6, 6-tetramethyl-piperidinyl)-1-nitrosourea (SLCNU, 4 ) and its analogues 5 – 7 were synthesized either by a regio-selective method or by a conventional route via the nitrosation of the spin labeled intermediates ( 11a - e ). Nitrosation of the ureas 11a - e with dinitrogen tetraoxide resulted in better yields than those obtained with sodium nirite. The nitrosoureas 4 – 8 were tested for their anti-cancer activity against the lymphocytic leukemia P388 in mice. Thus, either at the equal molar dose or at the dose of equal toxicity level, the SLCNU ( 4 ) was found to be more active than the clinically used CCNU ( 1 ). Unlike CCNU ( 1 ) whose LD 50 is 56 mg/kg, the SLCNU ( 4 ) possesses a low toxicity (LD 50 123 mg/kg). Therefore, SLCNU ( 4 ) is a promising new entry into the nitrosourea class of anticancer drugs.