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.
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 evaluated in vitro for their anticancer activities against the murine lymphocytic leukemia P388. Compounds 10a-d possessed activities ranging from 242 to 456% increase in life span (%ILS). All CDF1 male mice treated with the highly active compounds 10b and 10c at 12 mg/kg/day for 9 days were alive after 30 days. Compounds 10a-d were then tested in vivo against the murine lymphoid leukemia L1210. Compounds 10a-d exhibited, on day 60, a %ILS of 496, 663, 663, and 581, respectively. All CDF1 male mice treated with the highly active compounds 10b and 10c at 12 mg/kg/day for 9 days were alive after 60 days. The lipophilicities of compounds 10a-d were 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.
Department of Chemistry, University of Wisconsin-Milwaukee 53201.
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D000596:Amino Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D009589:Nitrogen Oxides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D009607:Nitrosourea Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013055:Spectrophotometry, Infrared
D000596:Amino Acids; D000970:Antineoplastic Agents; D009589:Nitrogen Oxides; D009607:Nitrosourea Compounds; C039900:nitroxyl