Antineoplastic agents. 2. Structure-activity studies on N-protected vinyl, 1,2-dibromoethyl, and cyanomethyl esters of several amino acids

Abstract

Previously reported work on N-protected activated esters of phenylalanine has been extended to include N-protected vinyl, dibromoethyl, and cyanomethyl esters of several other amino acids. These compounds have been synthesized and evaluated in Ehrlich ascites carcinoma, Walker 256 carcinosarcoma, and and P388 lymphocytic leukemia tests. Among compounds tested were derivatives of tyrosine, tryptophan, glycine, leucine, proline, aspartic acid, glutamic acid, 4-aminobutyric acid, and 6-aminocaproic acid. Compounds of greatest potential interest from this study are N-carbobenzoxyglycine 1,2-dibromoethyl ester and N-carbobenzoxy-L-leucine 1,2-dibromoethyl ester. Both compounds were highly active in Ehrlich ascites test systems (33 mg/kg/day). The glycine derivative was also active in the Walker 256 test (2.5 mg/kg/day. Values for LD50's in mice were 148 mg/kg (0.37 mmol/kg) and 225 mg/kg (0.50 mmol/kg) for glycine and leucine derivatives, respectively; therefore, these compounds do not appear to be toxic at effective dose levels.

Antineoplastic Agents III: Effects of Dibromoethyl and Vinyl Esters of N-Benzyloxycarbonyl-l-phenylalanine on Ehrlich Ascites Tumor Cell Metabolism

“…These analogs probably are acted on by tissue kinases, esterases, and proteases once they are introduced into the body. Previous studies indicated that an N-benzy1oxycarbonyl-Lphenylalanine ether analog is not active (1). Biotransformation according to Schemes I and I1 would result in the generation of a number of aldehyde derivatives.…”

“…Each compound was injected intraperitoneally (1 mg/day; ie., 33.3 mgkg) into CF1 male mice (-30 g). On the 7th day, the mice were sacrificed; the total volumes of ascites fluid and packed cells (ascites-crit) were determined, and the percentage inhibition was calculated (1). Phenylalanine mustard and mercaptopurine were used as positive controls.…”

Synthesis, Characterization and Optical Properties of a Novel Piperazine Derivative Microcrystal

“…4, 4'- (1, 4-piperazinediyl) bis (4-oxo-2-butenoic acid) and its derivative ester which have two unique plane structures (-CO-CH=CH-CO-) and are symmetric with respect to piperazine ring. literatures [6][7][8][9][10] reported that this -CO-CH=CH-CO-N-fragment may be responsible for antimitotic and cytostatic properties, so they could be used as a new useful method for treating cancer. However, as yet, there is no effective method for PBBA and its derivative ester to apply in biomedical field.…”

Substituted 4-hydroxyproline di- and tri-peptides as cytotoxic agents

“…These studies were extended to other amino acids, e.g. leucine, glycine, glutamic acid, aspartic acid and tyrosine which afforded similar activities (Loeffler et al, 1977b). Recently a series of N-cbz-hydroxyprolylglycinamides and related derivatives were synthesized and tested as anti-fibrotic agents, i.e.…”