1. Potential inhibitors of L-asparagine biosynthesis. 4. Substituted sulfonamide and sulfonylhydrazide analogues of L-asparagine
S Brynes, G J Burckart, M Mokotoff J Med Chem. 1978 Jan;21(1):45-9. doi: 10.1021/jm00199a008.
Several N-substituted sulfonamides and N'-substituted sulfonylhydrazides have been prepared as sulfur analogues of L-asparagine with the potential of acting as inhibitors of L-asparagine synthetase (ASase, from Novikoff hepatoma). L-Cysteine was converted in known steps to N-carboxy-3-(sulfonylchloro)-L-alanine dibenzyl ester (1). Condensation of 1 with O-benzylhydroxylamine, p-(fluorosulfonyl)benzylamine, or monoethyl fumarylhydrazide (9), followed by deblocking with HF, gave 3-(hydroxysulfamoyl)-L-alanine (3a), 3-[p-(fluorosulfonylbenzyl)]sulfamoyl-L-alanine (3c), and 3-sulfo-L-alanine S-[2-[(E)-3-(ethoxycarbonyl)acryloyl]hydrazide] (3e), respectively. Similarly, 1 with 2-chloroethylamine and deblocking with H2-Pd gave 3-[(2-chloroethyl)sulfamoyl]-L-alanine (3b). tert-Butyl carbazate was allowed to react with 1 and the tert-butyl group was removed with HCl. The resulting sulfonylhydrazide 7 was condensed with p-(fluorosulfonyl)benzoyl chloride and then deblocked with HF to give 3-sulfo-L-alanine S-[2-[P-(fluorosulfonyl)benzoyl]hydrazide] (3d). The inhibition of ASase by 3a-e at 2 mM was 97, 0, 30, 43, and 37%, respectively, and 3a was competitive with L-aspartic acid. Neither 3a nor 3e was effective in increasing the life span of mice bearing P-388 lymphocytic leukemia.
2. Potential inhibitors of L-asparagine biosynthesis. 3. Aromatic sulfonyl fluoride analogs of L-asparagine and L-glutamine
M Mokotoff, S Brynes, J F Bagaglio J Med Chem. 1975 Sep;18(9):888-91. doi: 10.1021/jm00243a005.
The N-[p-(fluorosulfonyl)benzyl] derivatives of L-asparagine and L-glutamine (1a,b) were synthesized as potential inhibitors of L-asparagine synthetase (ASase). Condensation of p-(fluorosulfonyl)benzylamine (2) with the suitably protected amino acid in the presence of dicyclohexylcarbodiimide, followed by deblocking, afforded 1a and 1b. Derivatives 1a and 1b at 10 mM inhibit ASase isolated from Novikoff hepatoma (rats) by 60 and 46%, respectively. Preliminary results on inhibition of Jensen sarcoma (L-asparaginase sensitive) and JA-1 sarcoma (L-asparaginase resistant) tissue cultures by 0.3 mM 1a (139,90%) and 1b (101, 103%), respectively, are discussed.
3. Potential inhibitors of L-asparagine biosynthesis. 5. Electrophilic amide analogues of (S)-2,3-diaminopropionic acid
M Mokotoff, L W Logue J Med Chem. 1981 May;24(5):554-9. doi: 10.1021/jm00137a015.
Three electrophilic amide analogues of (S)-2,3-diaminopropionic acid (1, DAP) have been prepared as potential inhibitors of L-asparagine synthetase (ASase, from Novikoff hepatoma, EC 6.3.5.4). DAP was selectively blocked by the carbobenzoxy (Cbz) group to give 3-N-Cbz-DAP (2a). Esterification of 2a with isobutylene afforded tert-butyl 3-N-carbobenzoxy-(S)-2,3-diaminopropionate (3a), which was then blocked at the 2 position with the tert-butoxycarbonyl (Boc) group to give tert-butyl 2-[(S)-(tert-butoxycarbonyl)amino]-3-[(carbobenzoxy)amino]propionate (4). Selective cleavage of the Cbz group by H2/Pd gave the key intermediate tert-butyl 2-N-(tert-butoxycarbonyl)-(S)-2,3-diaminopropionate (5), which was acylated, via the N-hydroxysuccinimide esters, with bromoacetic acid, dichloroacetic acid, and fumaric acid monoethyl ester to give tert-butyl 2-[(S)-(tert-butoxycarbonyl)-amino]-3-(2-bromoacetamido)propionate (6a), tert-butyl 2-[(S)-(tert-butoxycarbonyl)amino]-3-(2,2-dichloroacetamido)propionate (6b), and tert-butyl 2-[(S)-(tert-butoxycarbonyl)amino]-3-(ethoxycarbonyl)acrylamido]-propionate (6c), respectively. Deblocking of 6a-c gave the corresponding amino acids (S)-2-amino-3-(2-bromoacetamido)propionic acid hydrobromide (7a), (S)-2-amino-3-(2,2-dichloroacetamido)propionic acid (7b), and ethyl N-[(S)-2-amino-2-carboxyethyl]fumarate (7c). By a slightly different procedure, 5 was converted in two steps to (S)-2-amino-3-acetamidopropionic acid hydrobromide (7d). The inhibition of ASase by 7a-c at 1 mM was 93, 19, and 37%, respectively, while 7d was without inhibition at 2 mM. Compounds 7a-c failed to increase the life span of mice infected with B16 melanoma.
