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

Abstract

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.

Neuronal and glial γ‐aminobutyric acid+ transporters are distinct proteins

“…Reagents for tissue culture, including Dulbecmo minimal essential medium, MEM HEPES, and fetal calf serum were from C.dbeo/BRL. ACHe was synthesized for u¢ by Erwin Gross, from the Pilot Plant at the School for Applied Science of the Hebrew University, according to the method of Johnston et al [14]. Valinomycin and fluorochromelabelled secondary antibodies were from Sigma; ni~ricin from C.albiochem.…”

Two pharmacologically distinct sodium- and chloride-coupled high-affinity gamma-aminobutyric acid transporters are present in plasma membrane vesicles and reconstituted preparations from rat brain.

“…We identify and characterize two distinct subtypes, one sensitive to ACHC, the other to ,B-alanine, possibly of neuronal and glial origin, respectively. (16). Sephadex G-50-80 was from Pharmacia, and nigericin was from Calbiochem.…”

A New and Practical Synthesis of Cariprazine through the Facile Construction of 2-[trans-4-(3,3-Dimethylureido)cyclohexyl]acetic Acid

“…11 However, the low yield (32%) and tedious operation was unsuitable for largescale preparation. We initially investigated the acetyl group as a protective group starting from N-(4-oxocyclohexyl)acetamide (5a).…”