The cytotoxic principles of Prunella vulgaris, Psychotria serpens, and Hyptis capitata: ursolic acid and related derivatives.
Explore the source record for details and available documents.
Antineoplastic Agents, Phytogenic↗
Biomedical subjects
I H Hall
Publications and source records attributed to I H Hall.
Effects of 2,3-dihydrophthalazine-1,4-dione on Sprague Dawley rats lipid metabolism and serum lipoproteins.
2,3-Dihydrophthalazine-1,4-dione effectively lowers serum levels of cholesterol and triglycerides in Sprague Dawley rats after two weeks, after which the cholesterol levels continued to decline. The maximum serum lipid lowering effect on cholesterol or triglyceride levels was during the seventh and eighth week of drug administration. Similar magnitudes of reduction in lipids were observed in hyperlipidemic diet induced mice after four weeks of drug administration of 20 mg/kg.day. Lipid levels in liver, small intestines and aorta wall tissue were significantly reduced after eight weeks of drug administration, but no significant increase in fecal lipids was noted. The cholesterol content in the chylomicrons and in the VLDL and LDL-fractions was significantly reduced whereas HDL cholesterol was elevated by 112%. Neutral lipids and the triglyceride content were not altered in the chylomicron, VLDL and LDL; however, reductions of both levels were observed in the HDL fraction. The phospholipid content was reduced in the LDL and elevated in the other three fractions. Incorporation studies into lipoprotein fractions showed a decrease in cholesterol incorporation in chylomicrons, VLDL and LDL with an increase in HDL cholesterol incorporation. Palmitic acid incorporation was reduced in the chylomicron, VLDL and HDL fractions. 32P-Incorporation was reduced in the HDL fraction. Leucine incorporation into the apoproteins of all four fractions was elevated. Rate limiting enzymes involved in de novo cholesterol, fatty acid and triglyceride synthesis were inhibited by 2,3-dihydrophthalazine-1,4-dione after eight weeks of administration. There was no evidence that the drug caused an increase in peroxisome formation as measured by liver catalase activity nor the release of lysosomal hydrolytic enzymes as measured by acid phosphatase and cathepsin activities. The drug afforded no deleterious effects on clinical chemistry parameters after eight weeks administration.
Animals↗
Acute toxicity of helenalin in BDF1 mice.
The acute toxicity of helenalin, a sesquiterpene lactone isolated from Helenium microcephalum, was examined in male BDF1 mice. The 14-day LD50 for a single ip dose of helenalin in male mice was 43 mg/kg. A single ip injection of 25 mg helenalin/kg increased serum alanine aminotransferase (ALT), lactate dehydrogenase (LDH), urea nitrogen (BUN), and sorbitol dehydrogenase within 6 hr of treatment. Multiple helenalin exposures, ip injection of 25 mg helenalin/kg for 3 days, increased differential polymorphonuclear leukocyte counts and decreased lymphocyte counts. Serum ALT, BUN, and cholesterol levels were also increased by multiple helenalin exposures at 25 mg helenalin/kg/day. Helenalin significantly reduced liver, thymus, and spleen relative weights and histologic evaluation revealed substantial effects of multiple helenalin exposures on lymphocytes of the thymus, spleen, and mesenteric lymph nodes. No helenalin-induced histologic changes were observed in the liver or kidney. Multiple helenalin exposures (25 mg/kg/day) significantly inhibited hepatic microsomal enzyme activities (aminopyrine demethylase and aniline hydroxylase) and decreased microsomal cytochromes P-450 and b5 contents. Three concurrent days of diethyl maleate (DEM) pretreatment (3.7 mmol DEM/kg, 0.5 hr before helenalin treatment) significantly increased the toxicity of helenalin exposure. The present studies indicate that the hepatic microsomal drug metabolizing system and lymphoid organs are particularly vulnerable to the effects of helenalin. In addition, helenalin toxicity is increased by DEM pretreatments which have been shown to decrease glutathione concentrations.
Animals↗
Inhibition of inosine monophosphate dehydrogenase by sesquiterpene lactones.
Inosine monophosphate (IMP) dehydrogenase had previously been determined to be a likely target enzyme for the sesquiterpene lactones, a class of potential anti-neoplastic drugs. IMP dehydrogenase was purified approx. 770-fold from the P-388 lymphocytic leukemia tumor cell line. The Km values for the substrates, IMP and NAD, were determined to be 12 microM and 25 microM, respectively. Xanthine monophosphate (XMP) was shown to be a competitive inhibitor with a Ki of 67 microM. Mycophenolic acid gave mixed-type inhibition with a Ki of 8 nM for the noncompetitive component and a Ki of 2 nM for the competitive component. Dissociation constants (Kd) and rate constants for inhibition of IMP dehydrogenase by nine different sesquiterpene lactones were determined. The highest Kd was seen with 2,3-dihydrohelenalin while the lowest Kd was observed with bis-helenalinyl malonate. Binding of the drugs by IMP dehydrogenase increased as the size of the drug increased. Also, changes in structure at position 6 had a relatively large effect on the Kd. There was no correlation with hydrophobicity, as determined by octanol/water partition. The first-order rate constants for the reaction of the sesquiterpene lactones with IMP dehydrogenase (k1) and the second-order rate constants for the reaction of the sesquiterpene lactones with glutathione (k2) were also determined. The rate constants for most of the sesquiterpene lactones with the alpha-methylene-gamma-lactone moiety were similar and were approximately twice as great as the rate constants for those sesquiterpene lactones with only the alpha, beta-unsaturated cyclopentenone ring. Microlenin had approximately 5-times the reactivity of the other sesquiterpene lactones towards IMP dehydrogenase, but had approximately the same reactivity towards glutathione, suggesting that it was bound to the enzyme in a way which facilitated its reaction with one or more essential sulfhydryls. The same procedure was used for a series of N-substituted maleimide compounds with the N-substituent ranging in size from a methyl group to a benzyl group. The binding of the maleimide compounds was generally tighter than for the sesquiterpene lactones and there was an increase in binding with size.
Animals↗
Hypolipidemic activity of trimethylamine-carbomethoxyborane and related derivatives in rodents.
A number of substituted amine-carboxyborane esters were examined for their hypolipidemic activity in rodents. Trimethylamine-carbomethoxyborane, Me3NBH2C(O)OMe, was observed to be the most effective hypolipidemic agent in the rodent at the low dose of 8 mg/kg/d. This agent effectively increased the high density lipoprotein (HDL) cholesterol content and lowered the low density lipoprotein (LDL) cholesterol and triglyceride contents of rat lipoproteins. Furthermore, the agent accelerated cholesterol excretion from the body of the rat and reduced the activity of the rate-limiting enzyme involved in the de novo synthesis of lipids in the liver. The agent has a safe therapeutic index, and appeared to have more promise as a therapeutic agent than other borane esters.
Animals↗
A preliminary study on the anti-emphysema drug, 2-trifluoro-acetamidobenzenesulfonyl fluoride in CF1 mice.
2-Trifluoroacetamidobenzenesulfonyl fluoride was shown to be a potent inhibitor of porcine pancreatic elastase activity with an ID50-30.3 microM. When this enzyme was infused I.V. in mice inducing higher elastase activity in the blood, the agent at 20 mg/kg for 5 days suppressed elastase activity significantly below the value observed in normal mice. The drug was absorbed better by the I.P. route than the P.O. route. A more consistent and higher blood level of the drug was achieved by the I.P. route as opposed to the I.V. or oral routes. The drug distributed rapidly to all tissues concentrating in the skin and carcass. Approximately 56% of the drug was eliminated within 48 hr. The majority of the eliminated drug and its metabolites was via the urine. Whereas the LD50 value was greater than 350 mg/kg I.P. there was elevation in serum alkaline phosphotase activity; cholesterol and triglyceride levels were reduced, and the organ weight of the reproductive organs was markedly reduced. Further evaluation of this drug is necessary to determine if the observed acute toxicity findings are restrictive for the use of this agent in the treatment of emphysema.
Animals↗
The hypolipidemic activity of N(4-methyl-phenyl)diphenimide in rodents.
N(4-Methyl-phenyl)diphenimide afforded potent hypolipidemic activity in rodents. Serum cholesterol levels were reduced 67% and serum triglyceride were lowered 66% in rats by the drug after two weeks administration orally at 20 mg/kg/day. Rate limiting enzymes in the de novo synthesis of lipids in the liver were suppressed by the drug. Cholesterol was also removed from the body due to the drug accelerating bile excretion. Lipids removed from the blood compartment were not deposited in the organs of the body. VLDL and LDL cholesterol content was significantly reduced in rats treated with the drug with marked increase in HDL cholesterol after two weeks of administration. These data suggest that the drug may be useful in hyperlipidemic states and atherosclerosis in man, thus, further investigation of this class of chemicals is warranted.
Animals↗
Antitumor agents. 86. Synthesis and cytotoxicity of alpha-methylene-gamma-lactone-bearing purines.
alpha-Methylene-gamma-lactones covalently linked to adenine, hypoxanthine, and guanine were synthesized by using the convenient Reformatsky-type reaction between ethyl alpha-(bromomethyl)acrylate and the proper purine ketones. In vitro cytotoxicity data demonstrated that these compounds were active against L-1210 tissue culture cells with 3 being most potent (ED50 = 0.3 microgram/mL).
Adenine↗
Effect of helenalin and bis(helenalinyl)malonate on nucleic acid and protein synthesis in human KB carcinoma cells.
Helenalin and bis(helenalinyl)malonate were shown to be cytotoxic against the growth of human KB carcinoma cells. DNA synthesis was inhibited significantly. This inhibition was afforded because of the drugs' effects on a number of enzyme activities. The inhibition of IMP dehydrogenase and ribonucleotide reductase complex activities correlated positively with the inhibition of DNA synthesis of the KB cells. DNA polymerase activity was inhibited by the drugs to a lesser degree. The deoxyribonucleotide pools were markedly reduced in the presence of the drug, which would be consistent with a blockage of the enzyme ribonucleotide reductase as well as suppression of DNA synthesis. XMP levels were also reduced, which is consistent with suppression of IMP dehydrogenase activity by the drugs. Ribonucleoside phosphate pools, particularly CDP and GDP, were elevated after drug treatment, which would be expected with a blockage at ribonucleotide reductase. Thus DNA alkylation is not the mechanism of action of the antineoplastic sesquiterpene lactones; rather, the cell-killing effect is related to DNA synthesis inhibition by the drug.
Antineoplastic Agents, Phytogenic↗
Synthesis and hypolipidemic activity of 3-imino-1-oxoisoindolines in rodents.
A series of substituted 3-imino-1-oxoisoindolines derivatives demonstrated significant hypolipidemic activity, lowering both serum cholesterol and triglycerides levels after 16 days of dosing at 20 mg/kg/day ip in CF1 mice. 2-Butyl-3-butylimino-1-oxoisoindoline lowered serum cholesterol levels 52% and serum triglyceride 42%. 2-Pentyl-3-imino-1-oxoisoindoline lowered serum cholesterol levels 42% and serum triglyceride 61%. These derivatives resulted in better activity than the parent compound, 3-imino-1-oxoisoindoline. These studies showed that compounds with N-alkyl substitution of nitrogen atoms in the ring and outside the ring possessed potent hypolipidemic activity at the low dose of 20 mg/kg/day ip in normolipidemic CF1 mice. Studies with 2-butyl-3-butylimino-1-oxoisoinodine in rats showed that serum cholesterol was reduced 60% and serum triglyceride 43% after 14 days of dosing at 20 mg/kg/day, orally. Treatment with this agent lowered lipid levels in the liver and aorta tissue, with increases in lipid levels in the small intestine tissue. Higher levels of cholesterol and phospholipids were excreted in the feces of treated animals compared to the control. Cholesterol levels of the very low-density lipoprotein (VLDL) and high-density lipoprotein (HDL) fractions were reduced, whereas the HDL cholesterol levels were elevated significantly. This ratio of low-density lipoprotein (LDL) cholesterol:HDL cholesterol levels suggests that the agent may be effective in treating hyperlipidemic states in humans.
Animals↗
Hypolipidemic activity of o-(N-phthalimido)acetophenone in Sprague Dawley rats.
o-(N-Phthalimido)acetophenone has proven to be an effective hypolipidemic agent in rats at 20 mg/kg/day orally. The agent suppressed the activity of the rate-limiting enzyme of the liver involved in de novo synthesis of triglycerides. The synthetic rate-limiting enzyme for cholesterol esters was also inhibited by the drug in vivo. o-(N-Phthalimido)acetophenone lowered cholesterol in the liver and the aorta wall and generally caused an increase in phospholipids in body tissues. Serum lipoproteins were modulated by the drug with a decrease in cholesterol and triglycerides in the chylomicron, very low-density lipoproteins (VLDL), and low-density lipoproteins (LDL) and an increase in high-density lipoprotein (HDL) cholesterol. The phospholipid content was increased in the chylomicron, VLDL, and LDL fractions. In hyperlipidemic rats, o-(N-phthalimido)acetophenone lowered elevated blood lipid levels at 20 mg/kg/day orally after 3 weeks of administration. The hypolipidemic rat after drug treatment had a lower LDL cholesterol and a higher HDL cholesterol content, which is therapeutically desirable to protect against cardiovascular disease.
Acetophenones↗
Anti-inflammatory agents; IV. Structure activity relationships of sesquiterpene lactone esters derived from helenalin.
Explore the source record for details and available documents.
Animals↗
Antimalarial agents. III. Mechanism of action of artesunate against Plasmodium berghei infection.
Explore the source record for details and available documents.
Animals↗
A comparison of the S(+) and R(-) enantiomers of 5-ethyl-5-phenylhydantoin as hypolipidemic agents in rodents.
An investigation of the effects of the S-(+) and R-(-) enantiomers of 5-ethyl-5-phenylhydantoin as hypolipidemic agents was undertaken. The serum cholesterol and triglyceride levels were reduced approximately 40% by either oral or i.p. administration at 20 mg/kg.day of either enantiomer. Both agents blocked activities of enzymes involved in the de novo synthetic pathway of lipids. Lipids removed from the blood compartment were not deposited into tissue, but appeared to be cleared from the body at a more rapid rate. Serum lipoproteins showed a reduction in cholesterol and triglyceride content of very low density (VLDL) and low density (LDL) fractions after two-week administration at 20 mg/kg.day and HDL cholesterol content was elevated particularly with the R-(-) enantiomer. The LD50 values of the enantiomers were 500 mg/kg i.p. or greater.
Administration, Oral↗
Hypolipidemic activity of 6-substituted 6,7-dihydro-5H-dibenz[c,e]azepine and the effects of 6,7-dihydro-5H-dibenz[c,e]azepine on lipid metabolism of rodents.
A series of 6-substituted derivatives of 6,7-dihydro-5H-dibenz[c,e]azepine was found to be active hypolipidemic agents in rodents at doses of mg/kg per day. The parent drug was found to suppress the enzyme activity of ATP-dependent citrate lyase, sn-glycerol-3-phosphate acyl transferase, and phosphatidate phosphohydrolase. Treatment with 6,7-dihydro-5H-dibenz[c,e]azepine resulted in a reduction of cholesterol, neutral lipid, and triglyceride content in mouse and rat liver. The agent also afforded a reduction in cholesterol, triglycerides and neutral lipids in the chylomicron and very low density lipoprotein (VLDL) fractions. In the high density lipoprotein (HDL) fraction, the triglyceride, neutral lipids, and phospholipids were lowered but the cholesterol content was not. [H3]Cholesterol distribution studies showed that the 3H-content was lowered in the major organs but was elevated in the chyme and stomach, suggesting that the drug accelerated bile secretion of cholesterol or its metabolites.
Animals↗
Hypolipidemic activity of N,N-dimethyl-n-octadecylamine borane in rodents.
N,N-Dimethyl-n-octadecylamine borane proved to be an effective hypolipidemic agent in rodents, lowering both serum cholesterol and triglyceride levels by greater than 40% after 16 d of administration. The agent lowered serum lipid levels by inhibiting the enzymatic activity of rate-limiting enzymes of both de novo cholesterol and triglyceride pathways in the liver. The reduction led to lower levels of lipids in the liver and small intestine tissues, with a reduction of the cholesterol and triglyceride levels of the serum low density lipoprotein (LDL) fraction. Concurrently, the cholesterol level of high density lipoproteins (HDL) was significantly elevated in rats after 14 d of treatment. The drug caused an increased rate of cholesterol clearance from the body, essentially via the feces. The ability of the agent to modulate the cholesterol levels of LDL and HDL fractions suggests that the agent should be an effective agent for the treatment of hyperlipidemic states in humans.
Animals↗
Hypolipidemic activity of 3- and 4-phenyl-piperidine-2,6-diones and selected N-substituted derivatives.
Three- and 4-phenyl-piperidine-2,6-dione derivatives were investigated for hypolipidemic activity at 20 mg/kg/day intraperitoneally in rodents. The 3-phenyl compound afforded the best activity and effectiveness in both normal and hyperlipidemia-induced mice. The agent lowered lipids by blocking the de novo hepatic synthesis of cholesterol and triglycerides, specifically at the sites of ATP-dependent citrate lyase, acetyl CoA synthetase, sn-glycerol-3-phosphate acyl transferase and phosphatidylate phosphohydrolase. The agent caused a more rapid clearance of cholesterol by the fecal route. Cholesterol levels of the chylomicrons, very low density lipoprotein and low density lipoprotein (LDL) were reduced, whereas high density lipoprotein cholesterol was significantly elevated after drug administration. Triglyceride content was lowered in the chylomicron and LDL fractions. These modulations of lipid content of serum lipoproteins by the drug suggest a favorable situation for treatment of hyperlipidemic states.
Animals↗
The effects of genkwadaphnin and gnidilatidin on the growth of P-388, L-1210 leukemia and KB carcinoma cells in vitro.
Daphnane diterpene esters have previously been shown to have antineoplastic activity in vivo against the growth of P-388 lymphocytic leukemia cells. These studies demonstrate cytotoxic activity of genkwadaphnin and gnidilatidin against P-388 lymphocytic leukemia, L-1210 lymphoid leukemia and human KB carcinoma cell growth in vitro. At the ED50 values in the respective tumor lines DNA synthesis was preferentially suppressed in all three cell lines. RNA synthesis was essentially unaffected by the agents. Protein synthesis inhibition by the two agents demonstrated selectivity, e.g. in P-388 cells significant inhibition, in L-1210 cells marginal inhibition and in KB cells no inhibition was observed at these concentrations. Multiple sites in DNA synthesis were found to be inhibited by the daphnane diterpene esters. Two to three times the ED50 concentration in the respective tumor lines was required to observe suppression of DNA synthesis. Purine de novo synthesis appeared to be the major site of inhibition, with inosine monophosphate dehydrogenase and phosphoribosyl pyrophosphate amido transferase activities being inhibited in all three tissue lines. Dihydrofolate reductase activity was inhibited, significant only in the P-388 and KB cells. The magnitude of the enzyme suppression by the agents varied with the tumor line. However, the degree of enzyme suppression was of sufficient magnitude to account for the observed purine and DNA synthesis inhibition by the daphnane diterpene esters.
Animals↗