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I H Hall

Publications and source records attributed to I H Hall.

At least 163 records · Page 9Linked to original sources
PubMed1984

Hypolipidemic activity of 4-pyrimidinecarboxylic acids in CF1 mice.

A series of 4-pyrimidinecarboxylic acids were evaluated for hypolipidemic activity in mice at 20-30 mg/kg/d ip. A number of these derivatives were observed to be active at this dose. Substitution of the hydroxyl group in position 2 and 6 of the 4-pyrimidinecarboxylic acid with a sulfhydryl and an amino group, respectively, led to a compound which produced a greater than 40% reduction of serum cholesterol and triglyceride levels in mice. Similarly, a compound which was substituted with an amino group in position 2 and an isobutyl group in position 5 led to equally potent activity as a hypolipidemic agent.

Animals↗
PubMed1984

Hypolipidemic activity of phthalimide derivatives. 7. Structure-activity studies of indazolone analogues.

The apparent benefit of limiting serum cholesterol and triglyceride levels either by dietary restriction or drug therapy has prompted work in our laboratories toward development of a suitable antihyperlipidemic agent. We have demonstrated the antihyperlipidemic activity of a series of phthalimide derivatives in rodents to be significantly greater than that of clofibrate at a dose of 20 mg/(kg day), intraperitoneally. Here we report the synthesis and biological evaluation of a series of indazolone derivatives, which are heterocycles that are structurally related to the phthalimides . In general, structure-activity relationships within the phthalimide series may be extended to the indazolones . While indazolone itself is only moderately active, N1-carbethoxy substitution produced a more active compound. Substitution of the N2 position with an n-butyl group afforded the most active compound, as also seen in the phthalimide series. Aromatic substitution with electron-releasing and -withdrawing groups lessened the antihyperlipidemic activity.

Animals↗
PubMed1983

Heteronomous DNA.

A fibrous form of poly d(A):poly d(T) has a heteronomous secondary structure which is the first to be confirmed for a polynucleotide duplex: although both chains are 10(1) helices, mutually hydrogen-bonded in the standard (Watson-Crick) fashion, each has a quite different conformation. One chain -- probably poly d(A) -- has C3'-endo-puckered furanose rings characteristic of the A family of polynucleotide secondary structures while the other -- probably poly d(T) -- has the C2'-endo-puckered rings of the B family. Since analogous heteronomous structures could be assumed by DNA-DNA or DNA-RNA duplexes containing more general base sequences the polymorphic range of polynucleotide double-helices may be even greater than we have come to suppose.

Crystallization↗
PubMed1983

Selective inactivation of rabbit reticulocyte initiation factor eIF-3 by helenalin.

Helenalin, a sesquiterpene lactone which reacts primarily with exposed sulfhydryl groups, was shown to be an effective inhibitor of protein synthesis in rabbit reticulocyte lysates. Optimal inhibition required a 30 min preincubation in the absence of any added thiol compound. Beta-Mercaptoethanol was more effective than reduced glutathione in protecting enzyme sulfhydryl groups from inactivation by helenalin. Using partially fractionated systems, it was possible to show that helenalin had no effect on the elongation reactions or on the formation of the ternary initiation complex. However, the conversion of the ternary complex to the 48 S initiation complex was strongly inhibited. In this assay, only the initiation factor(s) were sensitive to helenalin. Using an assay system which requires all the initiation factors for optimal activity it was possible to show that the 0-40% ammonium sulfate cut of initiation factors (containing eIF-3 and eIF-4B) was sensitive to helenalin, while the 40-50% ammonium sulfate cut (containing eIF-2 and eIF-5) was not. Both ammonium sulfate cuts were equally sensitive to inhibition by the sulfhydryl reagent N-ethylmaleimide. Three purified rabbit reticulocyte initiation factors were then tested in the same assay system. Only eIF-3 showed appreciable sensitivity to helenalin, while eIF-2, eIF-3 and eIF-4B were all sensitive to inactivation by N-ethylmaleimide. These data suggest that helenalin may possess a relatively high degree of specificity as a sulfhydryl reagent.

Animals↗
PubMed1983

Wrinkled DNA.

The B form of poly d(GC):poly d(GC) in orthorhombic microcrystallites in oriented fibers has a secondary structure in which a dinucleotide is the repeated motif rather than a mononucleotide as in standard, smooth B DNA. One set of nucleotides (probably GpC) has the same conformations as the smooth form but the alternate (CpG) nucleotides have a different conformation at C3'-O3'. This leads to a distinctive change in the orientation of the phosphate groups. Similar perturbations can be detected in other poly d(PuPy):poly d(PuPy) DNAs such as poly d(IC):poly d(IC) and poly d(AT):poly d(AT) in their D forms which have tetragonal crystal environments. This suggests that such perturbations are intrinsic to all stretches of duplex DNA where purines and pyrimidines alternate and may play a role in the detection and exploitation of such sequences by regulatory proteins.

DNA↗
PubMed1983

Investigation of sesquiterpene lactones as protein synthesis inhibitors of P-388 lymphocytic leukemia cells.

The mode of action of helenalin and bis(helenalinyl) malonate as protein synthesis inhibitors of P-388 lymphocytic leukemia cells was investigated. The initial characterizations were carried out in crude lysates of the P-388 cells. In the lysate, there was a 4 min lag after the addition of drug before inhibition of protein synthesis occurred. Both drugs allowed run-off of preformed polysomes, but did significantly inhibit the formation of the 80 S initiation complex suggesting a preferential inhibition of one or more initiation reactions. The effect of these drugs on inhibition of both elongation and initiation reactions was further investigated using more fractionated systems prepared from P-388 cells. Poly(U)-directed polyphenylalanine synthesis was marginally inhibited by both drugs, but the degree of inhibition was not sufficient to explain the inhibition observed in either the lysate or in whole cell preparations of P-388. The formation of the ternary initiation complex was not significantly inhibited by either drug, but the conversion of this complex to the 48 and 80 S initiation complexes was inhibited. The inhibition of 48 S initiation complex formation by both drugs was sufficient to explain their inhibition of protein synthesis in whole cells.

Animals↗
PubMed1983

Antitumor agents LIX: effects of quassinoids on protein synthesis of a number of murine tumors and normal cells.

The quassinoids (brusatol, bruceantin, bisbrusatolyl esters, and bisbruceantinyl esters of succinic and malonic acids) were observed not to be universal protein synthesis inhibitors. Rather, they were selective for both the types of cancers, e.g., P-388 lymphocytic leukemia, Ehrlich and hepatoma carcinoma and L-1210 lymphoid leukemia, as well as types of normal tissues (e.g., lymphocytes), in which they demonstrated protein synthesis inhibition. The data suggest that the observed difference in the magnitude of protein synthesis inhibition of two P-388 lymphocytic leukemia cell lines by the quassinoids was at the ribosomal levels, whereas the observed difference in normal livers from various strains of mice involve differences in cell membrane transport of the quassinoids into the various tissues. Detailed studies indicated that the mode of action of the quassinoids as protein synthesis inhibitors was identical in all of the cells where inhibition was observed; i.e., the elongation step of protein synthesis was blocked by the quassinoids. The data derived from assays for polyuridine-directed polyphenylalanine synthesis of isolated ribosomes demonstrated that the ID50 values obtained were consistent with the observed inhibition of whole cell protein synthesis inhibition for P-388 cells, as well as for BDF1 and DBA/2 liver cells. The ID50 values obtained from various cells, e.g., P-388 cells and normal liver, were all in the microM range and are consistent with previously published values for the quassinoids in the rabbit reticulocyte and yeast systems.

Animals↗
PubMed1983

Hypolipidemic activity of substituted 2-pyrrolidinones in rodents.

A series of substituted 2-pyrrolidinones was evaluated for hypolipidemic activity at 20 and 30 mg/kg/day in CF1 male mice. 4-Phenyl-5,5-dicarbethoxy-2-pyrrolidinone was the most potent compound at 30 mg/kg/day, reducing serum triglyceride levels 52% after 14 days of dosing and serum cholesterol levels 48% after 16 days of dosing. 4-Phenyl-5-carbethoxy-2-pyrrolidinone and 4-phenyl-3,5,5-tricarbethoxy-2-pyrrolidinone also demonstrated significant activity. Those compounds which contained a phenyl substituent were more potent than either the unsubstituted, the alkyl, or the dicarbethoxy 2-pyrrolidinone analogues.

Animals↗
PubMed1983

Antihyperlipidemic activity of phthalimide analogues in rodents.

Phthalimide analogues have been shown to effectively lower serum cholesterol and triglyceride levels in rats and mice. The mode of action of these agents was not to suppress the appetite of animals, but rather to reduce the activities of key enzymes in the early synthesis of liver cholesterol and fatty acids in the triglyceride pathway. Phthalimide analogues were effective in accelerating biliary excretion of cholesterol and blocking its absorption from the gut. After 16 days dosing, it was evident that higher levels of lipids were being excreted than in control mice. The major serum lipoprotein fractions were reduced in cholesterol, triglyceride, and neutral lipid content, but not phospholipid content in rats after 14 days of administration.

Animals↗
PubMed1983

Antitumor agents LXIII: the effects of microlenin on nucleic acid and protein syntheses of Ehrlich ascites cells.

Microlenin, a novel dimeric sesquiterpene lactone isolated from Texas Helenium microcephalum, was shown to inhibit Ehrlich ascites carcinoma growth. Metabolic studies demonstrated that DNA synthesis and protein synthesis were significantly inhibited by two doses of microlenin at 5 mg/kg/day. DNA synthesis appeared to be blocked at several sites including DNA polymerase, purine synthesis, and dihydrofolate reductase. Thymidine nucleotide pools were significantly reduced by microlenin. Protein synthesis inhibition by microlenin appeared to occur during the initiation step of polypeptide synthesis. The metabolic effects of microlenin were similar to other sesquiterpene lactones in the Ehrlich ascites carcinoma cells. However, a lower dose of microlenin was required to bring about these metabolic effects when compared with other sesquiterpene lactones. Thus, microlenin may be a more likely therapeutic agent than helenalin which has demonstrated cellular toxicity.

Animals↗
PubMed1983

Antitumor agents LXII: synthesis and biological evaluation of podophyllotoxin esters and related derivatives.

Synthetic esters of the C-4 hydroxyl group of podophyllotoxin (I) were prepared. In addition, esters were synthesized using the diol system of tetrahydropyranyl podophyllol (XV), produced by reducing the lactone ring of tetrahydropyranyl podophyllotoxin with lithium aluminum hydride. Six compounds, the acrylate (IV), 3,3-dimethyl acrylate (V), phenoxyacetate (IX), and ethyl adipate (XI) of I as well as podophyllol (XIV) and tetrahydropyranyl podophyllol dimesylate (XVIII), showed significant activity when tested using the P-388 lymphocytic leukemia screen at 3 mg/kg/day. None of the esters showed higher activity than that shown by the parent molecule I when tested at the same dosage level.

Animals↗
PubMed1983

Antihyperlipidemic activity of saccharin analogues in rodents.

Saccharin analogues were observed to be potent antihyperlipidemic agents at 20 mg/kg/day in rodents, significantly reducing both serum cholesterol and triglyceride levels in both normal and atherogenic mice. The saccharin analogues suppressed in vitro and in vivo liver enzymatic activity of acetyl-CoA synthetase, citrate lyase, and mitochondrial citrate exchange leading to a reduction of available cytoplasmic acetyl-CoA, which is required for the synthesis of cholesterol and fatty acids. Liver acetyl-CoA carboxylase, phosphatidate phosphohydralase, and glycerol-3-phosphate acyl transferase activities were markedly reduced by the saccharin analogues. Suppression of these enzymes would lead to a reduction of triglyceride synthesis. The saccharin analogues accelerated bile excretion of cholesterol metabolites and increased the fecal excretion of the cholesterol, triglycerides, neutral lipids, and phospholipids. The liver and plasma lipoprotein lipid content (including cholesterol, triglycerides, and neutral lipids) was markedly reduced by the saccharin analogues, whereas phospholipid content was elevated. The reduction of lipid content of serum chylomicron, very low-density, low-density, and high-density lipoprotein fractions by the saccharin analogues indicates that these agents may be useful in controlling hyperlipidemic diseases where specific lipoprotein fractions are elevated.

Animals↗
PubMed1983

Anti-inflammatory agents III: Structure-activity relationships of brusatol and related quassinoids.

A series of quassinoids were observed to be potent inhibitors of induced inflammation and arthritis in rodents. Brusatol afforded the most potent activity followed by brucein-D. A 3-hydroxy-delta 3-2-oxo moiety in brusatol or a 1-hydroxy-delta 3-2-oxo moiety in brucein-D, as well as a C-15 ester-bearing delta-lactone ring in brusatol and C-11 and C-12 free hydroxyl groups are required in both quassinoids for potent anti-inflammatory activity. Preliminary studies indicate that one of the modes of action of quassinoids as anti-inflammatory agents is to stabilize lysosomal membranes, reducing the release of hydrolytic enzymes that cause damage to surrounding tissues.

Animals↗
PubMed1983

Hypolipidemic activity of phthalimide derivatives IV: Further chemical modification and investigation of the hypolipidemic activity of N-substituted imides.

A further investigation of N-substituted derivatives of phthalimide for hypolipidemic activity has revealed that the chain length, as well as the type of substitution on the N-alkyl chain of phthalimide is critical for biological activity. In these studies the hypolipidemic activity was not improved by extending the chain length beyond five carbon atoms in the alkyl and alkanoic acid series. Imido nitrogen substituents, other than alkanoic acids, methyl ketones, and alkyl groups, caused a reduction in hypolipidemic activity, e.g., hydroxy, amino, hydroxymethyl, or carbethoxy. Reduction of the keto group in the side chain to an alcohol, as well as forming derivatives of the keto group, did not improve the hypolipidemic activity with the exception of 1-N-phthalimidobutan-3-one semicarbazone. This compound demonstrated improved hypocholesterolemic activity over phthalimide and 1-N-phthalimidobutan-3-one. Substitution of the 3-position of the aromatic moiety of phthalimide with an amino or nitro group, as well as substituting a pyridine or cyclohexyl ring for the phenyl ring, led to the loss of hypolipidemic activity.

Animals↗
PubMed1983

Hypolipidemic activity of phthalimide derivatives. 2. N-phenylphthalimide and derivatives.

A series of substituted N-phenylphthalimide derivatives was synthesized and examined for their ability to lower serum cholesterol and triglyceride levels in mice at 20 (mg/kg)/day, ip. Of the newly synthesized compounds, the most potent compound, o-(N-phthalimido)acetophenone, lowered serum cholesterol 57% after 16 days and lowered serum triglyceride levels 44% after 14 days. o-(N-Phthalimido)acetophenone was observed to be active in both normogenic (normal blood lipids levels) and hyperlipidemic mice and normogenic rats. In the latter, the reduction of serum lipids was reversible. The mode of this compound appeared to be multiple, including blockage of the de novo synthesis of lipids and acceleration of the excretion of lipids. The lipoprotein fractions of rat blood were reduced significantly in cholesterol, triglyceride, and neutral lipid content after 14 days treatment with o-(N-phthalimido)acetophenone.

Acetate-CoA Ligase↗
PubMed1983

Hypolipidemic activity of phthalimide derivatives. 3. A comparison of phthalimide and 1,2-benzisothiazolin-3-one 1,1-dioxide derivatives to phthalimidine and 1,2-benzisothiazoline 1,1-dioxide congeners.

Previously it has been observed that N-substituted phthalimide derivatives with chain lengths of four carbon or oxygen atoms showed potent hypolipidemic activity in rodents at 20 (mg/kg)/day ip. The 1,2-benzisothiazolin-3-one 1,1-dioxide (saccharin) nucleus, itself, had also been observed to be active at the same dose. An investigation was undertaken to examine a series of 1,2-benzisothiazolin-3-one 1,1-dioxide analogues for their hypolipidemic activity in mice and to compare them to their respective phthalimide congeners. In addition, a series of 1,2-benzisothiazoline 1,1-dioxide and phthalimidine analogues was prepared, and their hypolipidemic activity was compared to the phthalimide analogues. These studies show that the respective congeners of 1,2-benzisothiazolin-3-one 1,1-dioxide compared favorably to phthalimide congeners in reducing serum triglyceride and cholesterol levels in male CF1 mice at 20 (mg/kg)/day ip. Of the saccharin derivatives, 3-oxo-1,2-benzisothiazoline-2-propionic acid 1,1-dioxide was the most effective in lowering serum cholesterol levels by 53% after 16 days dosing and 3-oxo-1,2-benzisothiazoline-2-valeric acid 1,1-dioxide lowered serum triglycerides 56% after 14 days dosing. The 1,2-benzisothiazoline 1,1-dioxide and phthalimidine compounds were less active as hypolipidemic agents than their 1,2-benzisothiazolin-3-one 1,1-dioxide and phthalimide analogues, respectively.

Animals↗