Synthesis of Potentially Antineoplastic Derivatives of N‐[N‐(2‐Chloroethyl)‐N‐nitrosocarbamoyl]amino Acids

Abstract

The synthesis of N‐[N‐(2‐chloroethyl)‐N‐nitrosocarbamoyl]amino acids and their anilides, congeners of N‐(2‐chloroethyl)‐N‐nitrosoureas, as potential antineoplastic substances is reported. N‐[N‐(2‐chloroethyl)‐N‐nitrosocarbamoyl]amino acids are prepared by reaction of amino acids with N‐(2‐chloroethyl)‐N‐nitrosocarbamoyl azide. Corresponding anilides and toluidides are obtained by condensation of the primary reaction products with aniline and toluidine using dicyclohexylcarbodiimide (DCC).

Synthesis, DNA Binding, Topoisomerase Inhibition and Cytotoxic Properties of 2-Chloroethylnitrosourea Derivatives of Hoechst 33258

“…14) A solution of bromide 1 in absolute ethanol was saturated at 0°C with anhydrous ammonia and the mixture was stirred at room temperature for 48 h afforded the amine 2 in 78% yield. N-[N-(2-chloroethyl)-N-nitrosocarbamoyl]amino acids were prepared by the general method described by Eisenbrand et al 18,19) Finally, N-[N-(2-chloroethyl)-N-nitrosocarbamoyl]amino acids were conjugated with the amine 2 in the presence N,NЈ-dicyclohexylcarbodiimide (DCC) in DMF gave the final compounds 3-5 in moderate to good yields. These new chloroethylnitrosourea analogues of Hoechst 33258 (3-5) differ by the nature of amino acids side chains were isolated as the hydrochloride salts.…”

“…1) and N-[N-(2chloroethyl)-N-nitrosocarbamoyl]amino acids were synthesized as reported in the literature. 14,17,18) Synthesis of 2-[2-(4-((2-Aminoethyl)carbamoyloxy)phenyl)-6-benzimidazolyl]-6-(1-methyl-4-piperazinyl)benzimidazole Tetrahydrochloride (2) The compound 1 (2 mmol) was dissolved in 15 ml absolute ethanol and the mixture was cooled to 0°C. Anhydrous ammonia was slowly bubbled into the reaction mixture for 1 h. The reaction mixture was stirred for 48 h at ambient temperature and concentrated under reduced pressure.…”

“…The solution was cooled to 0°C before adding N-[N-(2-chloroethyl)-N-nitrosocarbamoyl]amino acid (1 mmol). 18,19) This provided a clear solution into which N,NЈ-dicyclohexylcarbodiimide (1 mmol) was added all at once. It was stirred at 0°C for 5 h, and then warmed to room temperature where it was kept for 24 h. The precipitate of dicyclohexylurea was removed by filtration.…”

Potential synthetic codeine substitutes: (-)-3-O-aryl-N-methylmorphinans

“…4 For example, treatment of 4 with bromobenzene in pyridine in the presence of potassium carbonate and copper gave 7 in 52% yield. The substituted O-aryl-TV-methylmorphinans (8)(9)(10)(11)(12)(13)(14)(15)(16) were prepared by this method from 4 and the appropriate aryl halides. O-Demethylation of the methoxyphenylsubstituted analogues [9][10][11] with pyridine hydrochloride at elevated temperature gave the hydroxyaryl ethers [17][18][19] without cleavage of the aryl ether bond.…”

“…/Numbers in parentheses are the 95% confidence limits obtained by the graphic11 or regression14 analysis. 8 Binding was performed with rat brain homogenate.…”