Synthesis of analogues of N-(2-chloroethyl)-N'-(trans-4-methylcyclohexyl)-N-nitrosourea for evaluation as anticancer agents.
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.
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000627:therapeutic use; D055598:Chemical Phenomena; D002621:Chemistry; D007536:Isomerism; D007939:Leukemia L1210 / Q000188:drug therapy; D051379:Mice; D008815:Mice, Inbred Strains; D009607:Nitrosourea Compounds / Q000138:chemical synthesis*; D012673:Semustine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D009607:Nitrosourea Compounds; D012673:Semustine