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Biomedical subjects

I H Hall

Publications and source records attributed to I H Hall.

At least 37 records · Page 2Linked to original sources
PubMed1999

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

4-Hydroxyproline di- and tri-peptides and N-cbz-hydroxypropyl- glycinamides were observed to be potent cytotoxic agents against the growth of suspended single cells, L-1210, Tmolt3, and HeLa-S3. The agents were not as potent against the growth of cultured solid tumor cells. Selected derivatives were investigated for their mode of action in Tmolt3 leukemia cells. The compounds selectively inhibited DNA synthesis at 50 and 100 microM. The target site of action of the agents appeared to be the purine de novo pathway with marked inhibition of the activities of the two regulatory enzymes of the pathway, i.e. PRPP amido-transferase and IMP dehydrogenase. d[NTP] pools were reduced by the agents consistent with their overall reduction of DNA synthesis. Other marginally inhibited targets of the agents were r-RNA polymerase and TMP-kinase activities. The DNA molecule itself did not appear to be a target of these agents.

Animals↗
PubMed1999

The cytotoxicity and mode of action of 2,3,4-trisubstituted pyrroles and related derivatives in human Tmolt4 leukemia cells.

4-Carbethoxy-1-methyl-2-phenacyl-3-phenylpyrrole (9), 4-carbethoxy-2-(4-methoxybenzoyl)-3-(4-methoxyphenyl)pyrrole (10) and 2-(4-methoxybenzoyl)-3,4-bis-(4-methoxyphenyl)pyrrole (11) proved to be potent cytotoxic agents against the growth of murine and human leukemias and lymphomas. Selective toxicity was demonstrated against the growth of solid tumors, e.g., human adenocarcinoma of the colon SW480 and ileum HCT-8, glioma U-87-MG, and rat UMR-106 osteosarcoma. A mode of action study in Tmolt4 leukemia cells demonstrated that the agents inhibited de novo purine synthesis at the regulatory sites PRPP-amido transferase, IMP dehydrogenase as well as dihydrofolate reductase resulting in significant inhibition of DNA synthesis in 60 min. Other biochemical sites which were affected significantly were thymidylate synthetase, DNA polymerase alpha, RNA polymerases, nucleoside kinase and ribonucleoside reductase.

Animals↗
PubMed1998

The cytotoxicity of 2-formyl and 2-acetyl-(6-picolyl)-4N-substituted thiosemicarbazones and their copper(II) complexes.

2-Acetyl-(6-picolyl)-4N-substituted thiosemicarbazones and their copper(II) complexes were shown to be potent antineoplastic and cytotoxic agents against murine and human cultured cells. Numerous derivatives were as active against solid tumor growth as clinically useful agents. The agents inhibited L1210 DNA and RNA syntheses with inhibition of key regulatory enzyme activities of the purine pathway as well as nucleoside kinase activities. d[NTP] pools were reduced and DNA strand scission occurred. These agents were DNA topoisomerase II inhibitors with lower IC50 values than that of VP-16. However, they did not cause L1210 DNA protein linked breaks and actually protected against those breaks afforded by VP-16. The agents were not synergistic with VP-16 in reducing cell growth or DNA synthesis although they did reduce growth of L1210 cells in agar suspended media.

Animals↗
PubMed1998

Effects of alkyl amine carboxyboranes on L1210 DNA fragmentation and nucleic acid metabolism.

Amine-carboxyboranes with varying alkyl chain lengths were observed to be potent cytotoxic agents inhibiting the growth of a number of histological types of murine, rat, and human tumors. These agents preferentially reduced L1210 DNA synthesis with marked inhibition of the activities of regulatory enzymes of the purine pathway. Other enzyme activities which were marginally reduced were DNA polymerase alpha, ribonucleoside reductase, dihydrofolate reductase, t-RNA polymerase, and nucleoside kinases. Pyrimidine nucleotide pools were not reduced but DNA strand scission occurred after 24 h incubation with the agents. The amine-carboxyboranes were not DNA topoisomerase II inhibitors at 100 microM. The agents did not cause DNA protein linked breaks themselves; nevertheless, VP-16 [etoposide] induced DNA protein linked breaks were increased two fold in the presence of the agents suggesting synergistic effects. The amine-carboxyboranes decreased protein kinase C mediated phosphorylation of L1210 topoisomerase II protein, potentially decreasing its enzymatic catalytic activity. Thus, the amine-carboxyboranes did not function like VP-16 in affording cleavable products but were synergistic with VP-16 in causing DNA fragmentation. The agents were also additive with VP-16 in reducing tumor cell number, soft-agar colony growth and DNA synthesis and in producing DNA strand scission.

Animals↗
PubMed1998

Cytotoxicity of substituted alkyl-3,4-bis(4-methoxyphenyl)pyrrole-2-carboxylates in L1210 lymphoid leukemia cells.

Two alkyl-3,4-bis(4-methoxyphenyl)pyrrole-2-carboxylates proved to be potent cytotoxic agents in the murine L1210 lymphoid leukemia screen. DNA synthesis was preferentially inhibited with the major target of the agents being de novo purine biosynthesis at the regulatory enzyme sites of PRPP-amido transferase and IMP dehydrogenase. Other enzymatic activities which were suppressed by the drugs were DNA polymerase alpha, RNA polymerases, ribonucleoside reductase and dihydrofolate reductase. The d[NTP] pools, nucleoside kinase and the pyrimidine pathway were not affected by the presence of drugs. The DNA molecule itself was not the target of the agents, i.e. no alkylation of nucleotide bases, intercalation between bases or cross-linking of DNA strands occurred. The agents did cause L1210 DNA fragmentation after 24 h incubation at 100 microM.

Animals↗
PubMed1998

Relationship between amine-carboxyboranes and TNF alpha for the regulation of cell growth in different tumor cell lines.

The amine-carboxyboranes were shown to be synergistic with tumor necrosis factor alpha (TNF alpha) in cytotoxicity and inhibition of DNA synthesis in select types of cancer cells depending on the presence of a TNF alpha high affinity receptor on the membrane of the cell. Initially both TNF alpha and the amine-carboxyboranes reduce the influx of calcium but later cause a significant increase intracellularly. This influx is not linked with the amine-carboxyborane activating the calcitonin receptor in the tumor cells. Neither the agents nor TNF alpha directly inhibits DNA topoisomerase II activity but both did cause decreased phosphorylation of the enzyme by protein kinase C (PKC). The two agents caused synergistic inhibition. This event correlated with increased DNA protein linked breaks, DNA fragmentation and cell death. These protein linked breaks are additive with etoposide's effects but the latter agent's mechanism is different than phosphorylation of topoisomerase II. There was no evidence that the DNA fragmentation was caused by a calcium induced endonuclease enzyme in these cancer cells. The low-molecular weight amine-carboxyboranes appear to play an identical function as TNF alpha in its role to cause DNA breaks and fragmentation to cause apoptosis.

Animals↗
PubMed1998

Antineoplastic and cytotoxic activity of beta-alkylamino-(para-substituted)propiophenone and beta-alkylamino-(6-methyl)-naphthone derivatives in murine and human tissue culture cells.

The beta-alkylamino(para-substituted)propiophenone and beta-alkylamino-(6-methyl)naphthone derivatives were evaluated for their antineoplastic effects in vitro in CF1 mice at 8 mg/kg/day intraperitoneal for 9 days. A number of these agents showed over 70% inhibition of Ehrlich ascites carcinoma growth. In in vitro cytotoxicity assays, these agents significantly inhibited the growth of a number of cancer cell lines from both human and murine origins. Some agents showed more activity than several standard anticancer drugs against certain cell lines. Three analogs, beta-(4-methyl)piperidino-(para-methyl)propiophenone (4), beta-piperidino-(para-ethoxy)propiophenone (13), and beta-hexamethyleneimino-(para-ethoxy)-propiophenone (14), were selected for mode of action studies and all showed significant inhibition of DNA and RNA syntheses at 100 microM after 60 min incubation. However, the most significant site of action was the inhibition of the activity of dihydrofolate reductase.

Animals↗
PubMed1998

The cytotoxic action of 1,3,5-triazabicyclo[3.1.0]hexane-2,4-diones and 1,3,5-triazine-4,6-(1 H,5 H)-diones in murine and human tumor cells.

1,3,5-Triazabicyclo[3.1.0]hexane-2,4-diones proved to be potent antineoplastic and cytotoxic agents in murine and human cancer cells. In L1210 lymphoid leukemia cells DNA synthesis was significantly suppressed over 60 min by the agents from 25 to 100 microM. DNA synthesis was blocked at multiple sites including DNA polymerase alpha, ribonucleoside reductase, dihydrofolate reductase, PRPP-amido transferase, and nucleoside kinases which would be additive overall in suppressing DNA synthesis. The DNA molecule itself did not appear to be at target of the agents since no alkylation of nucleotide bases, intercalation between base-pairs or cross-linking of strands occurred after 24 h incubation at 100 microM. Nevertheless, L1210 DNA fragmentation did occur after 24 h incubation at 100 microM which is usually associated with tumor cell apoptosis.

Animals↗
PubMed1997

Synthesis and cytotoxic action of 3,5-isoxazolidinediones and 2-isoxazolin-5-ones in murine and human tumors.

The 3,5-isoxazolidinediones and 2-isoxazolin-5-ones demonstrated potent cytotoxicity against the growth of human Tmolt3 T cell leukemia, murine P388 and L1210 leukemias, as well as human HeLa-S3 uterine carcinoma and glioma tumor cell growth. The specificity of the 3,5-isoxazolidinedione and 2-isoxazoline-5-one derivatives as cytotoxic agents varied with the histological type of tumor cell. Selected compounds were active against solid HeLa uterine. KB nasopharynx, skin A431, SW-480 adenocarcinoma, osteosarcoma and glioma growth. Selected compounds demonstrated in vivo antineoplastic activity against Ehrlich ascites carcinoma growth. In L-1210 leukemia cells, the agents blocked DNA and protein synthesis at 25, 50 and 100 microM over 60 min. The agents were effective in reducing rate limiting enzymes in the de novo purine and pyrimidine pathways. In addition they suppressed dihydrofolate reductase and ribonucleoside reductase activities with moderate inhibition of DNA and RNA polymerase activities. DNA itself was not a target of the agents.

Animals↗
PubMed1996

The anti-inflammatory activity of N-substituted indazolones in mice.

N-Substituted indazolones were shown to be potent anti-inflammatory and analgesic agents in mice at 8 mg/kg. In addition, the agents were able to protect against death caused by endotoxins similar to those found in chronic infections. In part, the ability of these agents to suppress the inflammatory process is due to their blockage of cytokine release, e.g.TNF alpha and IL-1, as well as their inhibition of high affinity binding to receptors on target cells of inflammation. Suppressing these receptors can be linked to the inhibition by the agents of lysosomal hydrolytic enzymes, prostaglandin cyclooxygenase and 5'-lipoxygenase activities. Free radical generation involved in inflammation was also stabilized in the presence of most of these agents.

Animals↗
PubMed1996

Synthesis and pharmacological studies of 3-amino-2-methyl-1-phenyl-propanones as hypolipidemic agents in rodents.

A series of 3-amino-2-methyl-1-phenylpropanones were synthesized and proven to have potent hypolipidemic activity in rodents by lowering both serum cholesterol and triglyceride levels at 8 mg/kg/day, i.p. and orally. Many of these analogs showed significantly higher activity than standard drugs, lovastatin and clofibrate at their therapeutic doses. 2-Methyl-3 (perhydroazepin-1-yl)-1-phenylpropanone (4), 3-(4-methylpiperazin-1-yl)-1-phenylpropanone (5), and 2-methyl-3-(4-pyrrolidinocarbonyl-methylpiperazin-1-yl)-1-(4 -fluorophenyl) propanone (17) showed the best overall activities in lowering both serum cholesterol and triglyceride levels in CF1 mice at 8 mg/kg/day after 16 days of treatment. Compounds 4, 5, and 17 lowered serum cholesterol levels 63%, 58%, and 42%, respectively, after 16 days at 8 mg/kg/day i.p. These agents reduced the serum triglyceride levels by 33%, 37%, and 54%, respectively. In Sprague-Dawley rats these compounds also demonstrated significant serum lipid lowering effects by decreasing both serum cholesterol and triglyceride levels after 14 days of oral drug administration at 8 mg/kg/day. Compound 17 reduced the rat aorta cholesterol levels by 37%, triglyceride levels by 50%, and neutral lipid levels by 34% after 14 days of oral administration. These compounds lowered the chylomicron, VLDL, and LDL cholesterol and triglyceride levels while elevating the HDL cholesterol levels significantly. In hyperlipidemic rodents, these analogs also demonstrated significant serum lipid lowering effects but were, less active-than in normalipidemic rodents. The activities of some enzymes, such as mouse hepatic acetyl CoA synthetase, HMG GoA reductase, phosphatidylate phosphohydrolase, and hepatic lipoprotein lipase, were significantly reduced by these compounds.

Animals↗
PubMed1996

Hypolipidemic activity of 3-amino-1-(2,3,4-mononitro-, mono-, or dihalophenyl)propan-1-ones in rodents.

A series of 3-amino-1-(2,3,4-mononitro-, mono-, or dihalo-phenyl)propan-1-ones were synthesized and shown to be effective in lowering both serum cholesterol and triglyceride levels significantly in CF1 mice and Sprague-Dawley rats. All analogs showed better activity than the standard drugs, lovastatin and clofibrate, in reducing the serum cholesterol and triglyceride levels in mice at 8 mg/kg/day intraperitoneally. The best active analogs, 3-morpholino-1(3-nitrophenyl)propan-1-one (4) and 3-piperidino-1-(3-nitrophenyl)propan-1-one (5), exhibited 58% and 67% reduction of serum cholesterol levels, respectively, and 42% and 46% reduction of serum triglyceride levels, respectively, after 16 days of administration at 8 mg/kg/day intraperitoneally in CF1 mice. In Sprague-Dawley rats at 8 mg/kg/day oral administration, both compounds (4 and 5) significantly decreased the serum cholesterol and triglyceride levels. Rat tissue lipid levels were reduced significantly by compound 4, while less effects resulted from compound 5. The cholesterol and triglyceride levels in chylomicrons, VLDL, and LDL fractions were reduced by both analogs while the HDL cholesterol levels were significantly increased. Compound 5 was also effective in lowering serum cholesterol and triglyceride levels in hyperlipidemic mice, at 8 mg/kg/day intraperitoneally, but not effective in hyperlipidemic rats at 8 mg/kg/day orally. Cholesterol and triglyceride lowering effects of the agents were correlated with inhibition of the activities of liver acetyl CoA synthetase, HMG CoA reductase, phosphatidylate phosphohydrolase, and lipoprotein lipase, and with elevation of the activity of cholesterol ester hydrolase.

Animals↗
PubMed1996

Anti-inflammatory and analgesic activities of 3-imino-1-oxoisoindolines in CF1 mice.

A series of 3-imino-1-oxoisoindolines were shown to be potent anti-inflammatory and analgesic agents at 8 mg/kg, intraperitoneally in mice. The compounds were also able to protect against lipopolysaccharide induced endotoxic shock and death better than the current clinical agents. These agents appear to function by blocking the release of TNF alpha and IL-1 from macrophages as well as competition with their respective high affinity receptors on target tissue, eg. fibroblasts, and macrophages. In addition lysosomal hydrolytic enzymes were inhibited as well as leukotriene synthesis in macrophages by the agents.

Animals↗
PubMed1996

Cytoxicity of [(5,6-dichloro-9a-n-propyl-2,3,9,9a-tetrahydro-3-oxo-1H fluoren-7-yl)oxy]acetic acid, an agent known to reduce brain edema.

A known agent, [(5,6-dichloro-9a-n-propyl-2,3,9,9a-tetrahydro-3-oxo-1H fluoren-7-yl)oxy]acetic acid, which blocks brain edema, was also shown to be a potent cytotoxic agent in leukemia cells. The major site of action of the agents appears to be in the de novo purine synthetic pathway in L1210 leukemic cells. Both PRPP amido transferase and IMP dehydrogenase activities were suppressed by the agent. The inhibition of both regulatory enzymes of the pathway along with the reduction of dihydrofolate reductase activity would account for the observed suppression of DNA and RNA syntheses and subsequent cancer cell death.

Acetates↗
PubMed1996

Antineoplastic activities of 2,3,4-chloro-substituted beta-alkylaminopropiophenone derivatives in CF1 mice and in murine and human tumor cells.

A series of beta-alkylaminopropiophenone derivatives were demonstrated to be potent antineoplastic agents. Several compounds showed activity against Ehrlich ascites carcinoma growth in CF1 mice by demonstrating over 70% inhibition. Most of these agents proved to be potent cytotoxic agents in inhibiting the growth of a number of murine and human cancer cell lines grown in tissue culture. Their ED50 values were comparable to those of the selected standard anticancer drugs, such as 6-MP, ara-C, hydroxyurea, 5-FU, 6-aza-UMP, etoposide, antimycin A, actinomycin D and cycloheximide. In the mode of action studies in Tmolt3 cells, beta-(3",5"-dimethyl)piperidinopropiophenone was observed to reduce DNA and RNA synthesis significantly at 25 microM within 60 min incubation. The site of action of this agent appears to involve the reduction of the activities of Tmolt3 DNA polymerase alpha 1 dihydrofolate reductase, PRPP-amido transferase and ribonucleoside reductase.

Animals↗
PubMed1996

Synthesis and hypolipidemic evaluation of beta-alkylaminopropiophenone and beta-alkylaminopropio-2'-naphthone derivatives in rodents.

A series of beta-alkylamino-(4'-alkyl)-propiophenone or beta-alkylamino(7'-methyl)-propio-2'-naphthone derivatives were prepared and found to have hypolipidemic activity by lowering both serum cholesterol and triglyceride levels in rodents. The electron donating substituent at the para position of the phenyl ring seems to decrease the hypolipidemic activity when compared to non-substituted or electron withdrawing group substituted analogs as investigated previously in this laboratory. In comparison with lovastatin or clofibrate, most of these analogs showed similar or higher activity in lowering both serum cholesterol or triglyceride levels. beta-Pyrrolidino-(4'-methyl)-propiophenone (1) demonstrated the best activity after 16 d, i.p. administration in mice at 8 mg/kg/d. Further detailed studies in rats indicated that beta-pyrrolidino-(4'-methyl)-propiophenone also showed decreased serum cholesterol and triglyceride levels with increased HDL-cholesterol and triglyceride levels after 14 d. In hyperlipidemic mice and rats, this compound was observed to be effective in lowering serum lipid levels as well as tissue lipid levels. The activities of hepatic acetyl CoA synthetase, phosphatidylate phosphohydrolase, and hepatic lipoprotein lipase were moderately inhibited by beta-pyrrolidino-(4'-methyl)-propiophenone.

Animals↗
PubMed1996

Effect of trimethylamine-carbomethoxyborane on growth traits and lipid metabolism in lines of mice selected for high and low fat content.

The purpose of this study was to determine the effects of the amine carboxyborane, trimethylamine-carbomethoxyborane (B), on growth, body composition and lipid metabolism in lines of mice differing in fat content as a result of directional selection: high fat content (HF); low fat content (LF); and random control (RC). Mice were injected i.p. daily with either 20 mg/kg of B dissolved in 1% (w/v) carbomethoxycellulose as the vehicle or just vehicle (C) from 26 to 42 days of age. Growth rate, feed intake, feed efficiency, epididymal fat pad weight/BW and percentage body water were not affected by B treatment, but liver weight/BW was increased (P < 0.001). HF mice had larger epididymal fat pad weight/BW and less percentage body water when compared to LF mice (P < 0.001). Treatment with B lowered (P < 0.01) serum triglyceride and cholesterol levels, and selection for divergence in fat content led to positive divergence (P < 0.01, (HF-LF) > 0) in serum triglyceride and serum cholesterol levels; divergence x treatment interactions (P < 0.01) were due to administration of B eliminating the line differences present when C was administered. Treatment with B elevated (P < 0.001) HDL cholesterol level and lowered (P < 0.001) chylomicron, LDL and VLDL cholesterol levels, while positive divergence was found for all four fractions. Fecal triglyceride and cholesterol levels were increased (P < 0.01) by administering B, but were not affected by selection. Hepatic enzyme activity of cholesterol-7 alpha-hydroxylase was elevated (P < 0.001) by treatment with B while activities of other hepatic enzymes were depressed, e.g., acyl-CoA cholesterol acyltransferase. Line differences in activity of several hepatic enzymes also were found. These results indicate that B acts as a hypolipidemic agent in both high-fat and low-fat mouse genotypes, lowering serum cholesterol and triglyceride levels. However, at the administered dose, B had no affect on growth rate, feed intake, feed efficiency or body fat content.

Adipose Tissue↗