Synthesis and evaluation of the antitumor properties of esters of 2-furoic acid and 2-furylacrylic acid.

A series of activated and nonactivated esters of 2-furoic and 2-furylacrylic acids were synthesized and examined for antineoplastic activity in the Ehrlich ascites carcinoma screen at 20 mg/kg/d. 2-Furoic acid and 2-furylacrylic acid demonstrated potent activity, as did the methyl and cyanomethyl esters of each series. The vinyl ester of 2-furoic acid possessed antineoplastic activity. However, the ethyl and D,L-tetrahydropyranyl esters of each series were inactive in the tumor screen.

Anti-inflammatory activity of diazomethyl ketone and chloromethyl ketone analogs prepared from N-tosyl amino acids.

A series of diazomethyl ketone and chloromethyl ketone analogs prepared from N-tosyl amino acids was shown to have anti-inflammatory activity in mice at 20 mg/kg and in rats at 10 mg/kg. N-Tosyl-L-alanine and N-tosyl-beta-alanine chloromethyl ketones demonstrated the most potent anti-inflammatory activity. The writhing reflex also was inhibited at 20 mg/kg in mice. In the tail flick test, N-tosyl-D,L-alanine and N-tosyl-D,L-isoleucine chloromethyl ketones demonstrated the highest increase in time. Toxicity studies indicated good therapeutic indexes for most of these agents.

Antitumor agents: diazomethyl ketone and chloromethyl ketone analogues prepared from N-tosyl amino acids.

Diazomethyl ketone and chloromethyl ketone analogues prepared from N-tosyl amino acids have been synthesized and tested for antitumor activity in Ehrlich ascites carcinoma and P-388 lymphocytic leukemia screens in mice. The N-tosyl chloromethyl ketone analogues prepared from glycine, L-alanine, beta-alanine, L-valine, and 6-(N-tosyl-amino)caproic acid were the most potent antineoplastic agents in the Ehrlich ascites carcinoma screen. The N-tosyl diazomethyl ketone analogues synthesized from glycine, L-leucine, and L-proline were the most active of this series in the Ehrlich ascites screen, along with 5-keto-1-tosyl-2-(diazoacetyl)pyrrolidine and the diazomethyl ketone analogues prepared from 6-(N-tosylamino)caproic acid. In the P-388 lymphocytic leukemia screen, the N-tosyl chloromethyl ketone prepared from glycine and the compound 5-keto-1-tosyl-2-(diazoacetyl)pyrrolidine were the most active.

Antitumor and antiinflammatory agents: N-benzoyl-protected cyanomethyl esters of amino acids.

A series of N-protected cyanomethyl esters of various amino acids was synthesized and tested for antineoplastic and antiinflammatory activity in rodents. Utilizing the L-phenylalanine cyanomethyl ester and varying the N-protecting moiety demonstrated that the N-tosyl and the N-Cbz analogues were the most active against Ehrlich ascites cell proliferation. The N-(carbobenzyloxy)- and N-benzoyl-L-phenylalanine cyanomethyl esters were the most active against carrageenan-induced inflammation. In the N-benzoyl series of cyanomethyl esters, L-alanine, DL-valine, and L-leucine amino acid analogues were the most active against Ehrlich ascites cell proliferation. The glycine and L-alanine analogues possessed the best inhibitor activity in the antiinflammatory screen. The cyanomethyl esters also demonstrated immunosuppressive activity and the ability to suppress the writhing reflex which is associated with inflammatory pain. However, no antipyretic or narcotic analgesic activity was demonstrated by these agents.

Antifertility and antiproteolytic activity of activated N-carbobenzoxy amino acid esters.

N-Carbobenzoxy L-phenylalanine, glycine, L-leucine, and L-proline derivatives, their vinyl esters, and their 1,2-dibromoethyl esters were tested for antifertility activity in mice. Intraperitoneal administration reduced the pregnancy percentage and the number of fetuses per litter. Intravaginal administration reduced the pregnancy percentage significantly, with N-carbobenzoxyglycine vinly ester, N-carbobenzoxyglycine-1,2-dibromoethyl ester, N-carbobenzoxyl-L-leucine-1,2-dibromoethyl ester, and N-carbobenzoxy-L-proline-1,2-dibromoethyl ester producing 100% inhibition at 10 mg/kg/day. Sperm enzyme hydrolysis of the nonspecific substrate azocasein was inhibited significantly by certain N-carbobenzoxy amino acid esters in vitro. Specific substrate N-benzoyl-L-arginine ethyl ester hydrolysis was also inhibited. Compounds that inhibited N-benzoyl-L-arginine ethyl ester hydrolysis also demonstrated in vivo intravaginal antifertility activity.

Antineoplastic agents III: effects of dibromoethyl and vinyl esters of N-benzyloxycarbonyl-l-phenylalanine on Ehrlich ascites tumor cell metabolism.

Evidence is presented that N-benzyloxycarbonyl-L-phenylalanine vinyl ester and 1,2-dibromoethyl ester are inhibitors of Walker 256 carcinosarcoma and Ehrlich ascites carcinoma tumor growth. The major effects of these two agents on Ehrlich ascites cell metabolism were the inhibition of deoxyribonucleic acid and protein synthesis and the alteration of cellular regulatory processes controlling cytokinetics. Deoxynucleotide (purine) kinase enzymes appeared to be the focal site for inhibition of deoxyribonucleic acid synthesis with marginal inhibition of thymidylate synthetase activity. Cyclic adenosine monophosphate levels were elevated by drug treatment whereas chromatin protein phosphorylation, cell respiration, and lysosomal activities were inhibited. N-Benzyloxycarbonyl-L-phenylalanine 1,2-dibromoethyl ester was a latent in vitro chymotrypsin inhibitor. Some preliminary evidence suggests that these activated esters may inhibit cellular enzymatic activity by alkylating imidazole and lysine residues of proteins.

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

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.

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

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.