Synthesis of analogs of N-(2-chloroethyl)-N'-(trans-4-methylcyclohexyl)-N-nitrosourea for evaluation as anticancer agents

• Published in: Journal of medicinal chemistry Vol. 20; no. 2; pp. 279 - 290
• Main Authors: Johnston, Thomas P, McCaleb, George S, Clayton, Sarah D, Frye, Jerry L, Krauth, Charles A, Montgomery, John A
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 01-02-1977
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - therapeutic use; Chemical Phenomena; Chemistry; Isomerism; Leukemia L1210 - drug therapy; Mice; Mice, Inbred Strains; Nitrosourea Compounds - chemical synthesis; Semustine - analogs & derivatives; Semustine - chemical synthesis; Semustine - pharmacology; Semustine - therapeutic use; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00212a019

The superior activity of N-(2-chloroethyl)-N'-(trans-4-methylcyclohexyl)-N-nitrosourea (MeCCNU) against advanced murine Lewis lung carcinoma in comparisons with the cis form and other nitrosoureas prompted the synthesis of a number of MeCCNU analogues, including several cis-trans pairs. The methyl group was replaced by a variety of substituents (CO2H, CH2CO2H, CO2Me, CH2OAc, CH2Cl, OMe); the trans-3-methylcyclohexyl, cis-2-methyl-1,3-dithian-5-yl, cis- and trans-2-methyl-1,3-dithian-5-yl-tetraoxide, and 1-methylhexyl (open-chain) analogues were also prepared. Preliminary tests against murine leukemia L1210 revealed therapeutic indices (ED50/LD10) ranging from 0.26 to 0.79; all but three analogues effected 50% cure rates at nontoxic doses, the open-chain analogue being one of the least active. In terms of therapeutic index, diequatorial (trans-4) isomers were, with one exception, as active as or, in four of the eight examples, somewhat more active than the corresponding axial-equatorial (cis-4) isomers. In this series, four of the five 2-fluoroethyl analogues prepared were clearly inferior to the corresponding 2-chloroethyl analogues.