Biomedical subjects

I H Hall

Publications and source records attributed to I H Hall.

At least 199 records · Page 11Linked to original sources

PubMed1981

Antitumor agents. 44. Bis(helenalinyl) esters and related derivatives as novel potent antileukemic agents.

Bis(helenalinyl), bis(plenolinyl), bis(2,3-dihydrohelenalinyl), and bis(2,3,11,13-tetrahydrohelenalinyl) esters have been synthesized in an effort to elucidate the role of the two enone alkylating centers, beta-unsubstituted cyclopentenone and alpha-methylene gamma-lactone, as well as the significance of the diester linkage with respect to the enhanced in vivo P-388 lymphocytic leukemia antileukemic activity of bis(helenalinyl) malonate (2) against P-388 lymphocytic leukemia in the mouse. The bisesters (2-5; 7, 8; 10, 11) are, in general, more potent and less toxic than their corresponding parent alcohols (1, 6; 9; 14). The beta-unsubstituted cyclopentenone ring and the alpha-methylene gamma-lactone moiety in the bisesters play important roles for the enhancement of the P-388 antileukemic activity. Removal of the enone double bonds in both alkylating centers of 2 gave rise to inactive compounds. Except for 2, the potent antileukemic activity of the bis(helenalinyl) esters (3-5) appears to be independent of the ester chain length.

Animals↗

PubMed1980

Antitumor agents XLI: Effects of eupaformosanin on nucleic acid, protein, and anaerobic and aerobic glycolytic metabolism of Ehrlich ascites cells.

The major effect of eupaformosanin as an antineoplastic agent on Ehrlich ascites cell metabolism was to inhibit deoxyribonucleic acid synthesis, specifically at deoxyribonucleic acid polymerase and thymidylate synthetase enzymatic sites. Both pyrimidine and purine systems of Ehrlich ascites were marginally inhibited. Ribonucleic acid synthesis and messenger and ribosomal polymerase activities also were suppressed. Cyclic adenosine monophosphate levels were increased significantly, which correlated with the drastic reduction of histone phosphorylation. Eupaformosanin also suppressed a number of glycolytic and Krebs cycle enzymes as well as oxidative phosphorylation in vitro. All of the inhibited enzymes are known thiol-bearing enzymes that can undergo a Michael-type addition with the alpha-methylene-gamma-lactone moiety of eupaformosanin, as shown with other sesquiterpene lactones.

Aerobiosis↗

PubMed1980

Mode of action of sesquiterpene lactones as anti-inflammatory agents.

Sesquiterpene lactones containing an alpha-methylene-gamma-lactone moiety were shown to be potent inhibitors of carrageenan-induced edema and chronic adjuvant-induced arthritis in rodents at 2.5 mg/kg/day. The mode of action of sesquiterpene lactones as anti-inflammatory agents appeared to be at multiple sites; for example, at 5 X 10(-4) M, the sesquiterpene lactones effectively uncoupled the oxidative phosphorylation of human polymorphonuclear neutrophils and elevated the cyclic adenosine monophosphate levels of rat neutrophils and rat and mouse liver cells. Free and total lysosomal enzymatic activity was inhibited by these agents at 5 X 10(-4) M in both rat and mouse liver and rat and human neutrophils. Furthermore, the structure-activity relationships for the stabilization of lysosomal membrane for rat liver cathepsin activity followed the same structural requirement necessary for anti-inflammatory activity; i.e., the alpha-methylene-gamma-lactone moiety contributed the most activity, whereas the beta-unsubstituted cyclopentenone and alpha-epoxycyclopentanone contributed only minor activity. Human polymorphonuclear neutrophil chemotaxis was inhibited at low concentrations (i.e., 5 X 10(-5) and 5 X10(-6) M), whereas prostaglandin synthetase activity was inhibited at a higher concentration (i.e., 10(-3) M) by the sesquiterpene lactones.

Acid Phosphatase↗

PubMed1980

Antihyperlipidemic activity of sesquiterpene lactones and related compounds.

Some naturally occurring pseudoguaianolides and germacranolides as well as synthetic related compounds were observed to be antihyperlipidemic agents in mice. Several of these compounds at a dose of 20 mg/kg/day resulted in lowering of serum cholesterol by approximately 30% and of serum triglycerides by approximately 25%. Thiol-bearing enzymes of lipid synthesis, i.e., acetyl-CoA, citrate-lyase, acetyl-CoA synthetase, and beta-hydroxy-beta-methylglutaryl-CoA reductase, were inhibited by these agents in vitro, supporting the premise that these agents alkylate thiol nucleophiles by a Michael-type addition. The alpha-methylene-gamma-lactone moiety, the beta-unsubstituted cyclopentenone ring, and the alpha-epoxycyclopentanone system of these compounds appeared to be responsible for the lowering of serum lipids.

Animals↗

PubMed1980

Anti-inflammatory activity of amine cyanoboranes, amine carboxyboranes, and related compounds.

Amine cyanoboranes and amine carboxyboranes (boron analogs of alpha-amino acids) were shown to inhibit inflammation. The analogs effectively blocked general inflammation, induced arthritis, and the writhing reflex associated with inflammation pain, while the inflammation associated with pleurisy was marginally inhibited. The boron analogs were shown in vitro to inhibit the release of lysosomal enzymes from liver and polymorphonuclear neutrophils. Furthermore, prostaglandin synthesis was blocked by these agents at a low concentration, i.e., 10(-6) M. Liver oxidative phosphorylation processes also were uncoupled by these agents, but the migration of polymorphonuclear neutrophils was unaltered at 10(-4) M. The elevation of cyclic adenosine monophosphate levels in polymorphonuclear neutrophils correlated positively with in vivo antiarthritic activity. Initial studies in rodents demonstrated that these boron analogs can be used at safe therapeutic doses.

Analgesics↗

PubMed1980

Antitumor agents XXXVI: Structural elucidation of sesquiterpene lactones microhelenins-A, B, and C, microlenin acetate, and plenolin from Helenium microcephalum.

The antitumor sesquiterpene lactones microhelenins-A, B, and C, microlenin acetate, and plenolin were isolated from Helenium microcephalum. The structures and stereochemistry of these lactones were determined by physical methods as well as by chemical transformations and correlations. Microlenin acetate appears to be the first novel dimeric sesquiterpene lactone demonstrated to have significant antileukemic activity.

Acetylation↗

PubMed1980

Antitumor agents XXXVIII: Isolation and structural elucidation of novel germacranolides and triterpenes from Elephantopus mollis.

The ethanolic extract of Elephantopus mollis yielded three novel cytotoxic antitumor germacranolides, molephantin, molephantinin, and phantomolin. The extract also yielded three inactive known triterpenes, beta-amyrin acetate, lupeol acetate, and epifriedelanol, as well as stigmasterol. The structure and stereochemistry of the cytotoxic antitumor agents molephantin, molephantinin, and phantomolin were determined on the basis of chemical transformations and spectral evidence. Preliminary in vivo tumor assays indicated that molephantinin and phantomolin were potent inhibitors of Ehrlich ascites carcinoma and Walker 256 carcinosarcoma. Molephantinin also showed significant antileukemic activity in the P-388 lymphocytic leukemia screen.

Animals↗

PubMed1980

Effects of cis-malonato-diammino platinum (II) on P-388 lymphocytic leukemia cell metabolism.

cis-Malonato-diammino platinum(II) significantly inhibited P-388 lymphocytic leukemia cell proliferation at 10 mg/kg/day. Incorporation studies showed that DNA synthesis was inhibited following in vivo drug therapy. The major inhibitory effects appeared to be on thymidine kinase and dihydrofolate reductase activities and on overall purine synthesis, with marginal effects on DNA polymerase and ribonucleotide reductase activities. In addition to the DNA inhibition, a marked increase in cyclic adenosine 3',5'-monophosphate levels was noted, which correlated with a rapid decrease in histone phosphorylation. Other minor effects of the drug included significant reduction of proteolytic activity, suppression of States 4 and 3 respiration, and an increase in adenosine triphosphatase and acid phosphatase activities of P-388 cells.

Animals↗

PubMed1980

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.

Amino Acids↗

PubMed1980

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.

Animals↗

PubMed1979

Anti-inflammatory activity of sesquiterpene lactones and related compounds.

Some sesquiterpene lactones and related compounds were tested for anti-inflammatory activity in rodents. In the edema-induced carrageenan inflammation screen, the alpha-methylene-gamma-lactone moiety of the sesquiterpene lactones was required for inhibitory activity. The 6-hydroxy group of helenalin also was required for potency. In the tenulin series, the 2,3-epoxy derivatives were marginally active. The same structure was required for inhibition of the writhing reflex. In the chronic adjuvant arthritic screen, compounds containing the alpha-methylene-gamma-lactone moiety, the beta-unsubstituted cyclopentenone ring, and the alpha-epoxy cyclopentenone system afforded significant inhibition at 2.5 mg/kg/day. The sesquiterpene lactones were marginally effective against induced pleurisy. The delayed hypersensitivity was suppressed by these agents whereas immunoglobulin synthesis was slightly stimulated. No delerious side effects were observed with these agents from the limited tests performed.

Anaphylaxis↗

PubMed1979

Boron betaine analogs: antitumor activity and effects on Ehrlich ascites tumor cell metabolism.

Several newly synthesized boron betaine analogs had antitumor activity in Ehrlich ascites, Walker 256 ascites carcinosarcoma, and Lewis lung screens and marginal activity in the B-16 melanotic melanoma screen. In vivo testing demonstrated that trimethylamine-cyanoborane inhibied Ehrlich ascites cell DNA and protein syntheses as well as gene modulation by chromatin protein phosphorylation and methylation. Trimethylamine-cyanoborane increased cyclic-AMP levels. In vitro testing showed that nuclear DNA polymerase, thymidylate synthetase, S-adenosylmethyltransferase, nonhistone chromatin methylation, deoxyribonuclease, ribonuclease, and cathepsin were inhibited by the boron analogs. These compounds did not demonstrate high antitumor activity at the doses employed, but blockage of methyl transfer from S-adenosylmethionine was established as a feasible method for controlling cell proliferation.

Animals↗

PubMed1979

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.

Acrosin↗

PubMed1979

Antitumor agents: structure--activity relationships in tenulin series.

Systematic structural modifications were performed on the natural sesquiterpene lactone tenulin to define those groupings essential to, or significant in, its in vivo antitumor activity. Accordingly, the following tenulin analogs were prepared: dihydrotenulin, 2,3-epoxytenulin, isotenulin, dihydroisotenulin, 2,3-epoxyisotenulin, and tetrahydrodeacetylisotenulin. Both the cyclopentenone and the hemiketal units in tenulin were necessary for high in vivo activity.

Animals↗

PubMed1979

Antitumor agents. XXXIV: Mechanism of action of bruceoside A and brusatol on nucleic acid metabolism of P-388 lymphocytic leukemia cells.

The quassinoids bruceantin, brucein D, brucein E, bruceoside A, and brusatol significantly inhibited P-388 lymphocytic leukemic cell RNA and protein synthesis in tissue culture. However, DNA synthesis inhibition seemed to correlate more directly with the anti-neoplastic activity of these compounds in the in vivo P-338 survival system. In vitro, brusatol and bruceoside A marginally inhibited 10-day P-388 lymphocytic leukemia DNA polymerase, RNA polymerase, thymidylate synthetase, dihydrofolate reductase, phosphoribosyl pyrophosphate aminotransferase, and cathepsin protease activities. In vivo studies demonstrated similar inhibition and elevated cyclic AMP levels, correlating positively with the antineoplastic activity of individual compounds. Purine synthesis was inhibited drastically by brusatol in vivo, and one key inhibition site in purine synthesis was at phosphoribosyl pyrophosphate aminotransferase, the regulatory enzyme. Histone phosphorylation and ribonucleotide reductase activity also were inhibited marginally by brusatol.

Animals↗

PubMed1979

Antitumor agents. XXXV: Effects of brusatol, bruceoside A, and bruceantin on P-388 lymphocytic leukemia cell respiration.

Brusatol, a quassinoid with potent antineoplastic activity against P-388 lymphocytic leukemia cell proliferation, significantly inhibited P-388 cell hexokinase, phosphofructokinase, malic dehydrogenase, and succinic dehydrogenase. Mitochondrial oxidative phosphorylation, basal, and adenosine diphosphate-stimulated respiration, utilizing succinate and alpha-ketoglutarate as the substrate, was suppressed significantly by in vivo treatment with brusatol. However, brusatol treatment had no effect on liver oxidative phosphorylation. Brusatol greatly increased P-388 cyclic AMP levels but had no effect on liver cyclic nucleotides. Similar inhibitory effects on P-388 cell oxidative phosphorylation were found in vitro with brusatol, bruceoside A, and bruceantin. Brusatol had no effect on adenosine triphosphatase activity or on uncoupling of oxidative phosphorylation. Rather, brusatol appeared to increase the concentration of reduced mitochondrial electron-transport cofactors, thereby blocking aerobic respiration. A proposed mechanism of action is discussed.

Aerobiosis↗

PubMed1979

Hypolipidemic activity of phthalimide derivatives. 1. N-Substituted phthalimide derivatives.

The general lipid-lowering action of the N-substituted phthalimide derivatives reported herein, as well as the activity of potassium phthalimide, implicates the phthalimide moiety as possessing hypolipidemic activity in rodents. Compounds containing substituents with chain lengths of four carbon or oxygen atoms showed the best hypolipidemic activity in the series tested. Tests involving 1-N-phthalimidobutan-3-one demonstrated a dose-dependent hypolipidemic action free of estrogenic side effects, with no apparent deposition of cholesterol in body organs, and with a high therapeutic index. Further work on the hypolipidemic activity of phthalimido, as well as other imido compounds, is underway.

Animals↗

PubMed1979

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.

Acetonitriles↗