Synthesis and Antineoplastic Evaluation of α-Substituted Alkanesulfonates: Analogues of Clomesone

Abstract

2-Chloroethyl (methylsulfonyl)methanesulfonate (clomesone) is highly effective against certain experimental neoplasma and is now undergoing initial clinical trials. Two groups of analogues have been prepared to explore further the anticancer activity of this type of sulfonates. The first group is comprised of several 2-chloroethyl sulfonates that have electron-attracting groups alpha to the sulfonate group; among these, the alpha-chloroethanesulfonate and the (trifluoromethyl)-methanesulfonate caused increases in lifespan of 45 and 72%, respectively, in tests against P388 leukemia in mice. The second group is comprised of several (methylsulfonyl)methanesulfonates that possess alkylating groups other than the 2-haloethyl groups. 2-Hydroxyethyl (methylsulfonyl)methanesulfonate was active against P388 leukemia (increases in lifespan, 66 and 94%), but was less effective than clomesone, which effects cures. The 3-chloropropyl and the propyl derivatives caused modest increases in lifespan. Therefore, several 2-chloroethyl alpha-substituted methanesulfonates are less effective against P388 leukemia than is the alpha-(methylsulfonyl) derivative (clomesone), and several substituted alkyl (methylsulfonyl)methanesulfonates are also less effective than is the 2-chloroethyl derivative (clomesone). The synthesis of clomesone was simplified to one operational step from methanesulfonyl chloride.