In the search for new anticancer drugs. 27. Synthesis and comparison of anticancer activity in vivo of amino acids, carbohydrates, and carbohydrate-amino acid conjugates containing the [N'-(2-chloroethyl)-N'-nitrosoamino]carbonyl group.
The [N'-(2-chloroethyl)-N'-nitrosoamino]carbonyl [(2-chloroethyl)nitrosocarbamoyl, CNC] moiety containing compounds CNC-glycinamide 2d, CNC-amino acid derivatives 7a-d, and carbohydrate-CNC-amino acid conjugates 13, 18, 22, 23, 27, and 28 were synthesized and evaluated in vivo for their anticancer activities against the murine lymphocytic leukemia P388 using the National Cancer Institute (NCI) protocol. The most active compound was 2d with a 520% increase in life span (%ILS) and 6/6 survivors after 60 days. The CNC-amino acid analogs 7a-d possessed high to moderate activities with maximum %ILS values of 270, 174, 141 and 132, respectively. Among the carbohydrate-CNC-amino acid derivatives the alpha-methyl glycoside derivatives 22 and 23 were most active with maximum %ILS values of 277 and 137, respectively, followed by the hemiacetal carbohydrate analogs 13 and 18 with %ILS values of 93 and 149, respectively, and the tetra-O-acetyl derivatives 27 and 28 with %ILS of 110 and 111, respectively. Compounds 7b, 18, 23 and 28 were then tested in vivo against the murine lymphoid leukemia L1210 using the NCI protocol. In this case, the hemiacetal type carbohydrate-CNC-amino analog 18 had the highest activity with a maximum %ILS value of 477 and 4/6 survivors on day 60, followed by 7b (275% ILS), 23 (152% ILS) and 28 (106% ILS). The lipophilicities of all CNC compounds were determined by the partition coefficient using the UV method. A correlation of %ILS values with log P values indicated, in general, an increase in cytotoxicity with a decrease in hydrophilicity for the carbohydrate-CNC-amino acid conjugates 13, 18, 22, 23 and the clinical drugs streptozotocin (1e), chlorozotocin (1f), and cymerin (1g).
Department of Chemistry, University of Wisconsin-Milwaukee 53201.
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D000596:Amino Acids / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002241:Carbohydrates / Q000138:chemical synthesis* / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D007939:Leukemia L1210 / Q000188:drug therapy; D007941:Leukemia P388 / Q000188:drug therapy; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008811:Mice, Inbred DBA; D009607:Nitrosourea Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*
D000596:Amino Acids; D000970:Antineoplastic Agents; D002241:Carbohydrates; D009607:Nitrosourea Compounds