N-Alkyl-N-Nitrosocarbamoyl-3alpha-Amino-와 3beta-Amino-5alpha-Cholestane 유도체들의 합성 및 항암작용 평가

Synthesis and Antitumor Evaluation of N-Alkyl-N-Nitrosocarbamoyl-3alpha-Amino- and 3beta-Amino-5alpha-Cholestane Derivatives

The isomeric intermediates, 3alpha- and 3beta-amino-5alpha-cholestane required for the synthesis of N-nitrosoureas, N-(2-chloroethyl)-N-nitrosocarbamoyl-3alpha-amino-5alpha-cholestane (9), N-methyl-N-nitrosocarbamoyl-3alpha-amino-5alpha-cholestane (10), N-(2-chloroethyl)-N-nitrosocarbamoyl-3beta-amino-5alpha-cholestane (7), and N-methyl-N-nitrosocarbamoyl-3beta-amino-5alpha-cholestane (8) were obtained through the LiAlH4 reduction of 5alpha-cholestan-3-one oxime, followed by the chromatographic separation: the assignment of the stereochemistry of both isomers were based on the shape and chemical shift of C3-proton resonances on their NMR spectra and on the elution mobility on the TLC. The urea intermediates, N-(2-chloroethyl)carbamoyl-3alpha-amino-5alpha-cholestane (13), N-methylcarbamoyl-3alpha-amino-5alpha-cholestane (14), N-(2-chloroethyl)carbamoyl-3beta-amino-5alpha-cholestane (11) and N-methyl-3beta-amino-5alpha-cholestane (12) were prepared by the treatment of each isomers (3alpha-amino- and 3beta-amino-5alpha-cholestane) with alkyl isocyanates in anhydrous CHCl3, and the corresponding nitrosoureas, 7~10 were obtained by the nitrosation of the ureas, 11~14, with AcOH (or HCOOH)/NaNO2 in ice-cold condition. The inhibitory activity of the nitrosoureas, 7~10, and their intermediates, 12~14 towards the growth of L1210 murine leukemia cells, were examined. Among them, the compounds 9 and 10 exhibited high activity having ED50 to be 5.5g/ml and 6.1g/ml, respectively.