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

Abstract

The [N′‐(2‐chloroethyl)‐N′‐nitrosoamino]carbonyl [(2‐chloroethyl)nitrosocarbamoyl, CNC] moiety containing compounds CNC‐glycinamide2d, CNC‐amino acid derivatives7a‐d, and carbohydrate‐CNC‐amino acid conjugates13, 18, 22, 23, 27, and28were synthesized and evaluatedin vivofor their anticancer activities against the murine lymphocytic leukemia P388 using the National Cancer Institute (NCI) protocol. The most active compound was2dwith a 520% increase in life span (% ILS) and 6/6 survivors after 60 days. The CNC‐amino acid analogs7a‐dpossessed high to moderate activities with maximum % ILS values of 270, 174, 141 and 132, respectively. Among the carbohydrate‐CNC‐amino acid derivatives the α‐methyl glycoside derivatives22and23were most active with maximum % ILS values of 277 and 137, respectively, followed by the hemiacetal carbohydrate analogs13and18with % ILS values of 93 and 149, respectively, and the tetra‐O‐acetyl derivatives27and28with % ILS of 110 and 111, respectively. Compounds7b,18,23and28were then testedin vivoagainst the murine lymphoid leukemia L1210 using the NCI protocol. In this case, the hemiacetal type carbohydrate‐CNC‐amino analog18had the highest activity with a maximum % ILS value of 477 and 4/6 survivors on day 60, followed by7b(275% ILS),23(152% ILS) and28(106% ILS). The lipophilicities of all CNC compounds were determined by the partition coefficient using the UV method. A correlation of % ILS values with logPvalues indicated, in general, an increase in cytotoxicity with a decrease in hydrophilicity for the carbohydrate‐CNC‐amino acid conjugates13,18,22,23and the clinical drugs streptozotocin (1e), chlorozotocin (1f), and cymerin (1g).