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'-NITRASOAMINO]CARBONYL GROUP

The [N'-(2-chloroethyl)-N'-nitrosoamino] carbonyl [(2-chloroethyl)nitr osocarbamoyl, CNC] moiety containing compounds CNC-glycinamide 2d, CNC -amino acid derivatives 7a-d, and carbohydrate-CNC-amino acid conjugat es 13, 18, 22, 23, 27, and 28 were synthesized and evaluated in vivo f or their anticancer activities against the murine lymphocytic leukemia P388 using the National Cancer Institute (NCI) protocol. The most act ive compound was 2d with a 520% increase in life span (%ILS) and 6/6 s urvivors 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 t he alpha-methyl glycoside derivatives 22 and 23 were most active with maximum %ILS values of 277 and 137, respectively, followed by the hemi acetal carbohydrate analogs 13 and 18 with %ILS values of 93 and 149, respectively, and the tetra-O-acetyl derivatives 27 and 28 with %ILS o f 110 and 111, respectively. Compounds 7b, 18, 23 and 28 were then tes ted in vivo against the murine lymphoid leukemia L1210 using the NCI p rotocol. In this case, the hemiacetal type carbohydrate-CNC-amino anal og 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 Ilpophilicities of all CNC compounds were determined by the partition coefficient using the UV method. A correlation of %IL S values with log P values indicated, in general, an increase in cytot oxicity with a decrease in hydrophilicity for the carbohydrate-CNC-ami no acid conjugates 13, 18, 22, 23 and the clinical drugs streptozotoci n (1e), chlorozotocin (1f), and cymerin (1g).