Antineoplastic agents. 1. N-Protected vinyl, 1,2-dihaloethyl, and cyanomethyl esters of phenylalanine

Abstract

A series of N-protected vinyl, 1,2-dihaloethyl, and cyanomethyl esters of phenylalanine was synthesized and these compounds were evaluated for antitumor activity against the growth of Ehrlich ascites carcinoma in CF1 male mice (33 mg/kg/day), Walker 256 carcinosarcoma in Sprague-Dawley male rats (2.5 mg/kg/day), and P388 lymphocytic leukemia in DBA/2 mice (20 mg/kg/day). Structure-activity relationships were evaluated and acute toxicity studies (LD50 determinations) in male CF1 mice were also carried out on selected compounds. Carbobenzoxy-L0phenylalanine vinyl ester (5), N-carbobenzoxy-L-phenylalanine 1,2-dibromoethyl ester (12), and N-carbobenzoxy-L-phenylalanine cyanomethyl ester (8) were found to be very potent inhibitors of Ehrlich ascites tumor growth at nontoxic doses cited above. Compounds 5 and 12 also tripled survival time in the Walker 256 system. LD50 values for compounds 5, 12, and 8 were greater than 2000 mg/kg (greater than 6.15 mmol/kg), 74 mg/kg (0.15 mmol/kg), and 150 mg/kg (0.44 mmol/kg), respectively.

Amino acid vinyl esters: a new monomer palette for degradable polycationic materials

“…N-protected amino acid O-vinyl ester (AAVE) monomers were synthesized by Pd-catalyzed transvinylation of N-(tert-butoxycarbonyl) (Boc) protected amino acids with vinyl acetate (VAc). These vinyl ester monomers have been previously synthesized from either Boc or N-carboxybenzyl (CBz) protected amino acids and VAc with KOH and either PdCl 2 , 44 Pd(OAc) 2 , 45,46 or Na 2 PdCl 4 42,47 as catalysts. We found that these reported procedures typically produced low yields of the desired monomers (#30%), likely as a result of decomposition of the active Pd(II) catalysts to inactive Pd(0) black.…”

Synthesis of N-[5-alkoxy-2(5H)-furanonyl] amino acid propargyl esters

“…Condition optimization for substitution reaction Usually, amino acid propargyl esters were synthesized via condensation using N-protected amino acid and propargyl alcohol as materials, and the reported synthetic methods have many drawbacks, such as higher reaction temperature, multi-step reaction processes, more expensive reagents, longer reaction times, especially the tiresome condensing agents for their difficulty in the thorough separation from the products [32][33][34][35][36]. There are only a few reports on the synthesis of amino acid propargyl esters using N-protected amino acid and propargyl bromide as materials [37].…”

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

“…Carbobenzoxy [cbz]phenylalanine vinyl esters and 1,2-dibromoethyl esters have previously been shown to be potent anti-neoplastic and antiinflammatory agents in rodents (Loeffler et al, 1977a). These studies were extended to other amino acids, e.g.…”