In the Search for New Anticancer Drugs: 28. Synthesis and Evaluation of Highly Active Aminoxyl Labeled Amino Acid Derivatives Containing the [N;‐(2‐chloroethyl)‐N′‐nitrosoamino]carbonyl group

Abstract

The aminoxyl (nitroxyl) labeled (2‐chloroethyl)nitrosocarbamoyl (CNC) derivatives of amino acids, i.e.,N‐[[N′‐(2‐chloroethyl)‐N′‐nitrosoamino]carbonyl]‐A‐(1‐oxy‐2,2,6,6‐tetramethylpiperidin‐4‐yl)amides, A = glycyl (10a), A =L‐alanyl (10b), A =L‐valyl (10c), A =L‐phenylalanyl (10d), were synthesized and evaluatedin vitrofor their anticancer activities against the murine lymphocytic leukemia P388. Compounds10a‐dpossessed activities ranging from 242 to 456% increase in life span (% ILS). All CDF1male mice treated with the highly active compounds10band10cat 12 mg/kg/day for 9 days were alive after 30 days. Compounds10a‐dwere then testedin vivoagainst the murine lymphoid leukemia L1210. Compounds10a‐dexhibited, on day 60, a % ILS of 496, 663, 663, and 581, respectively. All CDF1male mice treated with the highly active compounds10band10cat 12 mg/kg/day for 9 days were alive after 60 days. The lipophilicities of compounds10a‐dwere determined using the UV method. The % ILS parameters obtained against the P388 and L1210 tumor lines were correlated with the corresponding lipophilicities, and a trend was generally observed toward an increase in cytotoxicity with a concomitant decrease in hydrophobicity.