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Biomedical subjects

I H Hall

Publications and source records attributed to I H Hall.

At least 217 records · Page 12Linked to original sources
PubMed1978

Antitumor agents XXVII: Effects of helenalin on anaerobic and aerobic metabolism of Ehrlich ascites cells.

Evidence is presented that the antitumor agent helenalin, a sesquiterpene lactone, suppresses anaerobic glycolytic enzymes of tumor cells at a number of sites and not exclusively at glycogen synthetase and phosphofructokinase, previously proposed sites for inhibition by alpha-methylene-gamma-lactones. Of the enzymes tested, the sulfhydryl-containing enzyme hexokinase was inhibited the maximum, i.e., 83%, by helenalin treatment, whereas phosphofructokinase and glycogen synthetase were suppressed approximately 45%. Another sulfhydryl-bearing enzyme, aldolase, was decreased approximately 43%. Phosphorylase a was inhibited 65%, glucose-6-phosphatase was inhibited 46%, and succinic dehydrogenase was inhibited 59% by helenalin treatment. Mitochondrial oxidative phosphorylation processes were also significantly depressed in the presence of helenalin in vitro with either succinate or alpha-ketoglutarate as substrates. Thus, a number of enzymes of anaerobic and aerobic carbohydrate metabolism of Ehrlich ascites cells appear to be inhibited by helenalin, which supposedly can alkylate functional groups, e.g., sulfhydryl groups of these enzymes, by a rapid Michael-type addition.

Aerobiosis↗
PubMed1978

Antitumor agents XXX: Evaluation of alpha-methylene-gamma-lactone-containing agents for inhibition of tumor growth, respiration, and nucleic acid synthesis.

Evidence is presented that a number of sesquiterpene lactones isolated from plants and synthesized pyrimidines containing the alpha-methylene-gamma-lactone moiety are potent inhibitors of Walker 256 carcinosarcoma and Ehrlich ascites tumor growth and marginal inhibitors of P-388 lymphocytic leukemia and Lewis lung tumor growth. In vitro aerobic basal respiration and oxidative phosphorylation processes of Ehrlich ascites cells were inhibited by these agents as well as deoxyribonucleic acid polymerase and thymidylate synthetase enzymatic activities. These studies indicate that the alpha-methylene-gamma-lactone moiety, the beta-unsubstituted cyclopentenone ring, and the alpha-epoxycyclopentanone system are the essential moieties for inhibition of these biochemical parameters.

Animals↗
PubMed1978

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.

Animals↗
PubMed1978

Antitumor agents 32. Synthesis and antitumor activity of cyclopentenone derivatives related to helenalin.

Several new cyclopentenones related to helenalin have been synthesized as potential alkylating antitumor agents. The procedure involved the transformation of 2-methyl-2-carbethoxycyclopentanone (2) to an ethylene ketal 3, bromination of 3 followed by dehydrobromination to yield a ketal olefin 5, reduction of 5 to the alcohol 6, conversion of 6 to the corresponding hydroxycyclopentenone 7, and estrification of 7 to afford the cyclopentenone esters 8--11. Biological assays indicated that only cyclopentenones possessing a conjugated ester side chain, such as 9 and 10, demonstrated significant in vitro cytotoxicity against the growth of tissue culture cells originating from human epidermoid carcinoma of the larynx (H.Ep.-2) as well as in vivo antitumor activity in Walker 256 carcinosarcoma in rats and P-388 lymphocytic leukemia in mice.

Animals↗
PubMed1977

Sesquiterpene antitumor agents: inhibitors of cellular metabolism.

Helenalin and tenulin injected into CF1 male mice bearing Ehrlich ascites tumors inhibit DNA synthesis and DNA polymerase enzymatic activity in the tumor cells. Helenalin inhibited protein synthesis. Both drugs increased the concentration of adenosine 3',5'-monophosphate, and interfered with glycolytic and mitochondrial energy processes. Cholesterol synthesis was also inhibited, resulting in lower serum cholesterol levels in tumor-bearing animals. Data obtained in vitro indicate that the cyclopentenone-bearing sesquiterpene lactone and related compounds do not alkylate puring bases of nucleic acids but rather undergo a Michael-type addition reaction with the sulfhydryl groups of reduced glutathione and l-cysteine. Thus, the inhibition of cellular enzyme activities and metabolism that has been observed with these drugs might be explained by the occurrence of a Michael-type teaction.

Alkylation↗
PubMed1977

Antitumor agents. 21. A proposed mechanism for inhibition of cancer growth by tenulin and helenalin and related cyclopentenones.

Evidence is presented that sesquiterpene lactones or ketones containing the O=CC=CH2 moiety, e.g., tenulin and helenalin, alkylate the thiol group of reduced glutathione and L-cysteine in vitro. A proposal is offered that this mechanism of action is responsible for the observed potent in vivo antitumor activity of these agents in the Ehrlich ascites and Walker 256 carcinosarcoma and to a lesser extent in the P388 leukemic screen. Inhibition of tumor growth is thought to occur due to the O=CC=CH2 system alkylating by rapid Michael addition the SH biological nucleophiles of key regulatory enzymes of nucleic acid and chromatin metabolism. This proposition is in accord with the ability of these agents to inhibit DNA synthesis and gene activity of Ehrlich ascites cells.

Animals↗
PubMed1977

Antitumor agents. 25. Synthesis and antitumor activity of uracil and thymine alpha-methylene-gamma-lactones and related derivatives.

Uracil and thymine alpha-methylene-gamma-lactones and related derivatives have been synthesized as novel potential alkylating antitumor agents. The synthesis of these compounds involved the convenient Reformatsky-type reaction between ethyl-alpha-(bromomethyl)acrylate and the proper pyrimidinyl ketones. Preliminary in vivo tumor assay indicated that these compounds were active against the Walker 256 carcinosarcoma in rats and the P-388 lymphocytic leukemia as well as the B-16 melanotic melanoma in mice at 2.5-25 mg/kg.

Animals↗
PubMed1977

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.

Acetonitriles↗
PubMed1977

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.

Acetonitriles↗
PubMed1976

Cycloalkanones. 8. Hypocholesterolemic activity of long-chain ketones related to pentadecanone.

Aliphatic analogs of 2,8-dibenzylcyclooctanone which includes C15-C18 ketones have been investigated for hypocholesterolemic activity in rats. The position of the carbonyl group in the chain for maximum activity appears to be the 2 position. 2-Hexadecanone reduced serum cholesterol levels significantly without altering serum triglyceride levels. This drug was not estrogenic at effective doses which is in contrast to the cyclooctanones which possess this activity.

Animals↗
PubMed1976

Hypocholesterolemic activity of 1,3-bis(substituted phenoxy)-2-propanones.

A series of 1,3-bis(substituted phenoxy)-2-propanones was found to be active hypocholesterolemic agents at 10 mg/kg/day. The p-chloro- and p-methyl-substituted phenoxy compounds possess the highest activity. These compounds did not possess the estrogenic and antifertility activities of the related previously reported derivatives of the bis(beta-phenylethyl) ketone series. The 1,3-bis(p-methylphenoxy)-2-propanone (7) also lowered serum triglycerides and glycerol which appeared to be due to increased levels of serum lipase and reduced activity of liver lipase. There was reduced incorporation of free fatty acids into complex lipids by the liver. Cholesterol was excreted faster in the treated animals.

Animals↗
PubMed1976

Cycloalkanones. 9. Comparison of analogues which inhibit cholesterol and fatty acid synthesis.

A number of 2,8-dibenzylcyclooctanone analogues inhibited the HMG-CoA reductases activity of Holtzman male rat liver, whereas only 2-octanone, 2-hexadecanone, 2,8-dibenzylcyclooctanone derivatives, and 2-bis(4-chlorophenyl)-3,5-dimethyltetrahydro-4-pyrone inhibited fatty acid synthetase activity. 2-Octanone significantly lowered serum cholesterol, triglycerides, and glycerol levels in Holtzman male rats and serlm cholesterol in male CF1 mice. Serum lipase activity was significantly elevated in rats administered 20 mg/kg/day of 2-octanone for 16 days. The activity of liver HMG-CoA reductase was inhibited in mice administered 10 mg/kg/day of 2-octanone for 10 days and in mouse and rat liver in vitro by 10 mg of 2-octanone. In mice, fecal excretion of [14C]cholesterol and tripalmitin was accelerated whereas palmitic acid and cholesteryl oleate were not affected by 10 mg/kg/day of 2-octanone. The LD50 in male mice for 2-octanone was 1.6g/kg.

Acetate-CoA Ligase↗
PubMed1976

Trichothecene analogues. 1. 1,5-Dioxaspiro(2.5)octanes.

Seven 1,5-dioxaspiro[2.5]octanes were synthesized and tested in the mouse P388 lymphocytic leukemia screen and the mouse Ehrlich ascites screen. These compounds possess the "epoxypyran" structure which has been believed to be the active portion of the trichothecene class of sesquiterpene tumor inhibitors. Three of the compounds were found to have marginal to moderate activity in the Ehrlich ascites screen (inhibition 74.1-86.3%) and low activity in the P388 screen (T/C = 126-131). A carbocyclic analogue, 1-oxaspiro[2.5]octane (9), was moderately active in both screens (inhibition 78.8%, T/C = 140). In the Ehrlich ascites screen, T-2 toxin (2) was about 25 times more potent than 9. None of the spirooctanes studied caused any skin irritation in 10-mg doses on the skin of rabbits, whereas 2 caused extensive necrosis at 0.1-mg doses.

Animals↗
PubMed1975

Cycloalkanones V: synthesis, distribution, and effects on triglyceride metabolism.

The 14-C-labeled 2,8-dibenzylcyclooctanone was synthesized to study its absorption, distribution, and excretion in rats. Maximum drug absorption from the GI tract occurred between 12 and 14 hr after administration. The major organs possessed maximum amounts of the drug in 1 hr, with the liver concentrating the most with 6.56% 14-C and the muscle mass reaching a maximum of 41% 14-C after 14 hr. The drug remained in the GI tract over the first 6 hr and was associated with the lipid and glycogen fractions. Eighty-seven percent was eliminated in the feces after 72 hr. 2,8-Dibenzylcyclooctanone caused a significant reduction in vitro of dihydroxyacetone phosphatase acyltransferase and sn-glycerol-3-phosphate acyltransferase, which is the proposed mechanism for the observed in vivo reduction of hepatic, intestinal, and serum triglycerides and total glycerolipids. In vivo administration of the drug resulted in a depression of liver acid phosphatidyl phosphatase, acid phosphatase and lipase, and adipose lipase. The drug increased the rates of excretion of exogenous cholesterol, palmitic acid, and progesterone.

Acid Phosphatase↗