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Biomedical subjects

I H Hall

Publications and source records attributed to I H Hall.

At least 181 records · Page 10Linked to original sources
PubMed1983

Synthesis and antitumor evaluation of selected 5,6-disubstituted 1(2)H-indazole-4,7-diones.

A series of novel aziridinyl-substituted 1(2)H-indazole-4,7-diones and related 1(2)H-indazole-4,7-diones was synthesized and tested against Ehrlich ascites carcinoma growth in male CF1 mice. Ten of the test compounds, including two aziridinyl-substituted 1(2)H-indazole-4,7-diones, were found to be significantly active (inhibition of tumor growth greater than 80%) in the Ehrlich ascites carcinoma screen. Several structure-activity relationships were indicated for antitumor activity in this screen. An aziridinyl-substituted derivative, 5-aziridinyl-6-chloro-1H-indazole-4,7-dione (8a), also exhibited significant activity against the growth of P-388 lymphocytic leukemia cells in male BDF1 mice (% T/C = 145; % T/C greater than 125 is considered significant).

Animals↗
PubMed1982

Antitumor agents XLVII: The effects of bisbrusatolyl malonate on P-388 lymphocytic leukemia cell metabolism.

Bisbrusatolyl malonate, which was shown previously to be active against P-388 lymphocytic leukemia cell growth, was investigated for inhibitory effects on nucleic acid and protein synthesis. DNA and RNA synthesis as well as protein synthesis were markedly inhibited at 10,25, and 50 mu mole final concentrations in vitro. The major sites of inhibition of nucleic acid synthesis appeared to be DNA polymerase, messenger and transfer RNA polymerases, orotidine-5'-monophosphate decarboxylase, phosphoribosyl pyrophosphate amino transferase, and dihydrofolate reductase. Moderate inhibition of nucleotide kinase activities and oxidative phosphorylation processes occurred after drug treatment. Cyclic adenosine monophosphate levels were reduced. Protein synthesis was inhibited during the elongation step of peptide synthesis. The data suggested that bisbrusatolyl malonate interfered with the peptide bond formation. However, the ongoing polypeptide synthesis must be completed before the drug can bind to the ribosome effectively.

Amino Acids↗
PubMed1982

Antitumor agents XLV: Bisbrusatolyl and brusatolyl esters and related compounds as novel potent antileukemic agents.

A series of new bisbrusatolyl and brusatolyl esters and related compounds were synthesized and tested for in vivo antileukemia activity against a quassinoid sensitive strain of P-388 lymphocytic leukemia in BDF1 mice. The bisbrusatolyl malonate, succinate, glutarate, adipate, and sebacate were as active or more active than brusatol. The C-3 esters of brusatol and bruceantin were also found to be as active or more active than brusatol or bruceantin in general. The free hydroxyl groups at C-11 and C-12 as well as the enone double bond in ring A of both bisbrusatolyl and brusatolyl esters are required for antileukemic activity. The presence of a double bond in the ester side chain contributes to the enhanced activity of these esters.

Animals↗
PubMed1982

Antitumor agents XLVI: In vitro effects of esters of brusatol, bisbrusatol, and related compounds on nucleic acid and protein synthesis of P-388 lymphocytic leukemia cells.

A series of esters of brusatol, bisbrusatol, and bruceantin were shown to have potent antileukemic activity. Antineoplastic activity was correlated with the ability of the compounds to suppress DNA and protein synthesis in P-388 lymphocytic leukemia cells. Compounds with high T/C% values successfully inhibited DNA polymerase activity and purine synthesis. The ability to inhibit protein synthesis during the elongation process also correlated positively with high antileukemic activity in this series of quassinoids. Dihydrofolate reductase activity and basal and adenosine diphosphate stimulated respiration of P-388 cells were also inhibited.

Animals↗
PubMed1982

Antitumor agents XLVIII: Structure-activity relationships of quassinoids as in vitro protein synthesis inhibitors of P-388 lymphocytic leukemia tumor cell metabolism.

A series of brusatol, bisbrusatol, and bruceantin esters were examined for their ability to inhibit protein synthesis in P-388 lymphocytic leukemia cells. Compounds which produced high T/C % values (170-272) resulted in ID50 of 5.4-15.5 microM for inhibition of whole cell protein synthesis, ID50 of 1.3-13 microM for inhibition of endogenous protein synthesis in cell homogenates, and ID50 of 1.9-6 microM for inhibition of polyuridine directed polyphenylalanine synthesis using "runoff" ribosomes and a "pH 5" enzyme preparation. The polyuridine directed polyphenylalanine synthesis requires neither initiation nor termination factors, suggesting that quassinoids are exclusively elongation inhibitors. Bruceantin, brusatol, and bisbrusatolyl malonate allowed a runoff of the polyribosomes to 80S free ribosomes. However, formation of the ternary complex and 80S initiation complex were not inhibited by the quassinoids. Thus, these agents do not affect the individual steps leading to the formation of a stable 80S initiation complex in P-388 cells. Brusatol, bruceantin, and bisbrusatolyl malonate inhibited the formation of the first peptide bond between puromycin and [3H]methionyl-transfer RNA bound to the initiation complex, indicating peptidyl transferase activity is inhibited by the quassinoids in P-388 cells. These studies also suggest that the free 80S ribosome is the site of binding by the quassinoid. Ribosomes actively conducting protein synthesis will continue protein synthesis and terminate before the quassinoids bind. This proves quassinoids are elongation inhibitors of tumor cells. A strong correlation was observed between potent antileukemic activity and the ability to inhibit protein synthesis in P-388 lymphocytic leukemia cells.

Amino Acyl-tRNA Synthetases↗
PubMed1982

Antitumor agents LII: The effects of molephantinin on nucleic acid and protein synthesis of Ehrlich ascites cells.

Molephantinin, a germacranolide, has previously been shown to possess antineoplastic activity in rodents. The principle effect of molephantinin on Ehrlich ascites carcinoma cells was to depress DNA and protein synthesis both in vivo and in vitro. DNA synthesis was inhibited at the following sites: DNA polymerase, purine synthesis specifically at inosinic acid dehydrogenase and to a lesser degree at dihydrofolate reductase, pyrimidine synthesis at orotidine monophosphate decarboxylase, thymidine kinase, histone phosphorylation, and oxidative phosphorylation processes. The protein synthesis inhibition pattern resembled more an initiation inhibitor as opposed to an elongation inhibitor.

Animals↗
PubMed1982

Effects of 3-chloromethylthiochromone-1,1-dioxide on nucleic acid, protein, and aerobic and anaerobic metabolism of Ehrlich ascites tumor cells.

3-Chloromethylthiochromone-1,1-dioxide was observed to be a potent inhibitor of Ehrlich ascites carcinoma growth and a moderate inhibitor of P-388 lymphocytic leukemia growth at 10 mg/kg/day. Preliminary in vitro studies showed that the agents significantly inhibited RNA and DNA synthesis in Ehrlich ascites cells. In vivo studies after dosing on Days 6, 7, and 8 demonstrated the same reductions in nucleic acid synthesis and a moderate reduction in protein synthesis. The primary site of nucleic acid synthesis, which was blocked by 3-chloromethylthiochromone, was at orotidine monophosphate decarboxylase in the primidine pathway. Other enzymes, in anaerobic and aerobic glycolysis, which were blocked include hexokinase, phosphofructokinase, succinic and alpha-ketoglutarate dehydrogenases, as well as States 3 and 4 of oxidative phosphorylation.

Aerobiosis↗
PubMed1982

Antitumor agents LV: Effects of genkwadaphnin and yuanhuacine on nucleic acid synthesis of P-388 lymphocytic leukemia cells.

The diterpene esters, genkwadaphnin and yuanhuacine, have been shown to possess significant antileukemic activity in the P-388 screen. The major metabolic effects of the diterpene esters were on DNA and protein synthesis. The effects on DNA synthesis in vitro were evoked at a lower concentration than that required for protein synthesis inhibition. The sites in DNA synthesis which were inhibited were DNA polymerase and purine synthesis. In the latter pathway the enzyme activities inhibited were phosphoribosyl aminotransferase, inosinic acid dehydrogenase, and dihydrofolate reductase. In vivo administration of the diterpene esters at 0.8 mg/kg afforded identical types of effects on purine and DNA synthesis and in addition suppressed histone phosphorylation and reduced the number of surviving tumor cells. The in vivo effects on purine and DNA synthesis were evident as early as 6 and 24 hr after administration of a single dose of the diterpene esters.

Animals↗
PubMed1982

Antitumor agents LVI: the protein synthesis inhibition by genkwadaphnin and yuanhuacine of P-388 lymphocytic leukemia cells.

Two natural products isolated from the plant Daphne genkwa have been shown to possess antileukemic activity in mice. Genkwadaphnin and yuanhuacine were observed to inhibit DNA and protein synthesis in P-388 leukemic cells. A detailed study of the effects of these two diterpene esters on protein synthesis of leukemic cells was undertaken. The major effects of genkwadaphnin and yuanhuacine on protein synthesis were blockage of the elongation process and interference with the peptidyl transferase reaction. The latter reaction was suppressed at concentrations of the diterpene esters which were commensurate with concentrations that inhibited whole cell in vitro protein synthesis in P-388 cells.

Animals↗
PubMed1981

Mechanism of eukaryotic protein synthesis inhibition by brusatol.

The mechanism by which brusatol inhibits protein synthesis in rabbit reticulocytes has been investigated. When added to reticulocyte lysates, brusatol inhibits endogenous protein synthesis only after a lag of 2-4 min at 30 degrees C. During this period 80 S ribosomes accumulate. Brusatol is equally effective in inhibiting endogenous protein synthesis in lysates and poly(U)-directed polyphenylalanine synthesis with runoff ribosomes. In fractionated reticulocyte systems, brusatol does not inhibit formation of the ternary, 40 S, and 80 S initiation complexes, but does inhibit the reaction of puromycin with initiation complexes containing [35S]Met-tRNAf. These data suggest that brusatol inhibits the peptidyl transferase elongation reaction of protein synthesis, but can do so only after one round of protein synthesis has been completed. Thus, the mechanism of action of brusatol in the rabbit reticulocyte system is very similar to the effects previously reported for bruceantin in a yeast system.

Animals↗
PubMed1981

Antifertility activity of N-protected glycine activated esters.

A series of N-protected glycine activated esters was found to have antifertility activity in mice when administered intravaginally. The N-carbobenzoxyglycine vinyl ester and N-carbobenzoxyglycine 1,2-dibromoethyl ester analogs possessed the best activity in inhibiting pregnancy but were much less active when administered intraperitoneally. The acrosin enzymatic activity of sperm also was inhibited by these N-protected glycine activated esters, as measured by N-alpha-benzoyl-L-arginine ethyl ester and azocasein hydrolysis. The ability to inhibit N-alpha-benzoyl-L-arginine ethyl ester hydrolysis, a trypsin-like activity, appeared to have a positive correlation with antifertility activity when the agents were administered intravaginally.

Acrosin↗
PubMed1981

Effects of imide analogs on enzymes required for cholesterol and fatty acid synthesis.

Twelve imide analogs were examined for their ability to lower serum cholesterol and triglyceride levels in mice. Potent activity was observed for compounds containing a phthalimide or saccharin ring structure. The ability to lower serum cholesterol appears to be related to the ability to suppress acetyl-CoA synthetase activity. The availability of acetyl-CoA in the cytoplasm is a key regulatory component for cholesterol and fatty acid synthesis. The capacity to reduce serum triglycerides was related directly to the ability of the compound to inhibit acetyl-CoA carboxylase activity, the regulatory enzyme of fatty acid synthesis.

Acetate-CoA Ligase↗
PubMed1981

Antihyperlipidemic activity of amine cyanoboranes, amine carboxyboranes, and related compounds.

A series of amine cyanoboranes and amine carboxyboranes were observed to be antihyperlipidemic agents in mice; i.e., they lowered serum cholesterol and triglyceride levels significantly. These compounds appeared to inhibit lipid synthesis in the early stages. The ability to lower serum cholesterol levels appeared to correlate with the suppression of the regulatory enzyme of cholesterol synthesis, beta-hydroxy-beta-methylglutaryl-CoA reductase activity. The reduction of serum triglycerides correlated with ability of the borane compound to suppress liver fatty acid synthetase activity.

Acetate-CoA Ligase↗
PubMed1981

Antitumor agents XLII: Comparison of antileukemic activity of helenalin, brusatol, and bruceantin and their esters on different strains of P-388 lymphocytic leukemic cells.

Based on the fact that some known antineoplastic agents possess an ester moiety within their structure, the esters of helenalin, a sesquiterpene lactone, and of brusatol and bruceantin, quassinoids, were synthesized and tested for antileukemic activity in the P-388 screen. These agents gave different T/C% values dependent on the P-388 lymphocytic leukemia strain and the host strain of mice used. Later studies demonstrated that the agents caused different degrees of inhibition of nucleic acid and protein synthesis in the various P-388 strains. The higher the degree of inhibition of precursor incorporation into the nucleic acid or protein, the higher was the T/C% value obtained in a given P-388 strain. The study demonstrates the lack of consistency of P-388 lymphocytic leukemia cell lines used in various laboratories and indicates that the inbred strain of mice is a critical factor in the tolerance of drug toxicity and, thus, T/C% obtained.

Animals↗
PubMed1981

Synthesis and antitumor activity of a series of sulfone analogues of 1,4-naphthoquinone.

A series of novel substituted thiochromones and thiochroman-4-ones was synthesized. Compounds were designed as analogues of naphthoquinone and as potential "bioreductive alkylating agents" and were tested for antitumor activity. The lead compound, 3-(chloromethyl)thiochromone 1,1-dioxide (4), inhibited Ehrlich ascites tumor growth by 100% in CF1 male mice at 10 (mg/kg)/day ip. Similarly, 18 of the 29 related compounds demonstrated good activity in this tumor screen. Few definitive structure-activity correlations were evident regarding the nature of the 3-substituent. However, the 2,3 double bond and a sulfone or sulfoxide were required for activity. Four of the compounds synthesized showed marginal but significant activity against P-388 lymphocytic leukemia.

Animals↗