€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ *****AMERICAN JOURNAL OF VETERINARY RESEARCH***** Witzel DA Ivie W Dollahite JW Mammalian toxicity of helenalin, the toxic principle of Helenium microcephalum CD (smallhead sneezeweed). In: Am J Vet Res (1976 Jul) 37(7):859-61 ISSN: 0002-9645 Studies with smallhead sneezeweed (Helenium microcephalum DC) indicated that a sesquiterpene lactone, helenalin, is the only significant toxic constituent present. The oral median lethal dose of helenalin for 5 mammalian species was between 85 and 105 mg/kg. €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ *****CANCER CHEMOTHERAPY AND PHARMACOLOGY***** Powis G Gallegos A Abraham RT Ashendel CL Zalkow LH Grindey GB Bonjouklian R Increased intracellular Ca2+ signaling caused by the antitumor agent helenalin and its analogues. In: Cancer Chemother Pharmacol (1994) 34(4):344-50 ISSN: 0344-5704 The antitumor sesquiterpene lactone helenalin, which is found in species of the plant genus Helenium, caused a marked potentiation of the increases in intracellular free Ca2+ concentration ([Ca2+]i) produced by mitogens such as vasopressin, bradykinin, and platelet- derived growth factor in Swiss mouse 3T3 fibroblasts. Removing external Ca2+ partly attenuated the increased [Ca2+]i responses caused by helenalin. The increased [Ca2+]i responses occurred at concentrations of helenalin that inhibited cell proliferation. At higher concentrations, helenalin inhibited the [Ca2+]i responses. No change in resting [Ca2+]i was caused by helenalin even at high concentrations. Other helenalin analogues also increased the [Ca2+]i response. Helenalin did not inhibit protein kinase C (PKC) and PKC appeared to play a minor role in the effects of helenalin on [Ca2+]i responses in intact cells. Studies with saponin-permeabilized HT-29 human colon carcinosarcoma cells indicated that helenalin caused an increased accumulation of Ca2+ into nonmitochondrial stores and that the potentiating effect of helenalin on mitogen-stimulated [Ca2+]i responses was due in part to an increase in the inositol-(1,4,5)- trisphosphate-mediated release of Ca2+ from these stores. Registry Numbers: EC 2.7.1.- (Protein Kinase C) 6754-13-8 (helenalin) 7440-70-2 (Calcium) €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ *****CHEMICAL AND PHARMACEUTICAL BULLETIN***** Kozuka M Lee KH McPhail AT Onan KD STRUCTURE AND ABSOLUTE STEREOCHEMISTRY OF DIHYDROFLORILENALIN, A NEW SESQUITERPENE LACTONE FROM FLORIDA HELENIUM AUTUMNALE L In: Chem Pharm Bull (Tokyo) (1975) 23(8):1895-1897 ISSN: 0009-2363 The structure and absolute stereochemistry of dihydroflorilenalin (15H22O4) isolated from Helenium autumnale is presented. The sesquiterpene lactone represents a structural varient in the lactone ring which separates it from florilenalin. The conclusions were reached on the basis of physicochemical data, chemical transformation experiments, and x-ray crystallographic analysis. (7 refs) €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ *****FUNDAMENTAL AND APPLIED TOXICOLOGY***** Chapman DE Roberts GB Reynolds DJ Grippo AA Holbrook DJ Hall IH Chaney SG Chang J Lee KH Acute toxicity of helenalin in BDF1 mice. In: Fundam Appl Toxicol (1988 Feb) 10(2):302-12 ISSN: 0272-0590 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. Registry Numbers: 141-05-9 (diethyl maleate) 6754-13-8 (helenalin) €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ *****GENERAL PHARMACOLOGY***** Narasimham TR Kim HL Safe SH Effects of sesquiterpene lactones on mitochondrial oxidative phosphorylation. In: Gen Pharmacol (1989) 20(5):681-7 ISSN: 0306-3623 1. The toxic plant sesquiterpene lactones, helenalin, hymenoxon, mexicanin-E, tenulin, dihydrogriesenin, and psilotropin which were isolated from Helenium, Hymenoxys, and Geigeria spp markedly inhibited "state 3" respiration in mouse hepatic mitochondria. With the exception of dihydrogriesenin and psilotropin, all the other sesquiterpene lactones stimulated "state 4" respiration. 2. The sesquiterpene lactones also stimulated ATPase activity in the presence of Mg2+ ions and caused mitochondrial swelling in buffer solutions containing magnesium, sodium, ammonium and potassium chloride salts. 3. The number of alkylating sites present in a sesquiterpene lactone appears to be related to the inhibitory activity on mitochondrial oxidative phosphorylation, however, the structure-activity relationship of these lactones is not clear at present. 4. Mitochondria prepared from the liver of ethoxyquin hydrochloride-fed mice were less susceptible to sesquiterpene lactone- mediated inhibition of mitochondrial oxidative phosphorylation. Registry Numbers: EC 3.6.1.3 (Adenosinetriphosphatase) €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ *****JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY***** Hill DW Kim HL Martin CL Camp BJ Identification of Hymenoxon in Baileya multiradiata and Helenium hoopsii. In: J Agric Food Chem (1977 Nov-Dec) 25(6):1304-7 ISSN: 0021-8561 [No Abstract Available] €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ *****JOURNAL OF CARDIOVASCULAR PHARMACOLOGY***** Itoigawa M Takeya K Furukawa H Ito K Mode of cardiotonic action of helenalin, a sesquiterpene lactone, on guinea pig ventricular myocardium. In: J Cardiovasc Pharmacol (1987 Feb) 9(2):193-201 ISSN: 0160-2446 We investigated the mechanisms of the direct positive inotropic effect (PIE) of helenalin, a sesquiterpene lactone isolated from the plant genus Helenium of the family Compositae in guinea pig ventricular myocardium. Helenalin (3 X 10(-4) M) produced biphasic PIEs (first and second PIE phases) on normal nonreserpinized papillary muscles, driven at 1 Hz in Krebs-Henseleit solution at 30 degrees C. The first PIE phase was abolished by reserpine treatment. Helenalin increased the force of "rested-state contraction" in a manner similar to that of other cyclic AMP-elevating substances, such as norepinephrine and IBMX (3-isobutyl-1-methylxanthine). In isometric contraction curves of the papillary muscle stimulated at 0.2 Hz, helenalin showed two clear peaks of an early and a late component. Carbachol preferentially suppressed the late component of contraction, a component that is clearly apparent in the presence of intracellular cyclic AMP-increasing substances. Helenalin potentiated the PIEs of isoproterenol and histamine but not that of dihydroouabain. In the presence of a phosphodiesterase (PDE) inhibitor (IBMX 10(-3) M), helenalin did not produce any PIE. In electrophysiological studies, helenalin prolonged the duration of transmembrane action potentials of papillary muscle. In partially depolarized muscles (external K+ = 30 mM), helenalin increased the overshoot and the duration of the slow action potential. These results led to the conclusion that helenalin produces an elevation of cyclic AMP through PDE inhibition, thereby increasing Ca2+ influx which enhances the contractility of the myocardium by increasing Ca2+ release from the SR. Registry Numbers: 60-92-4 (Cyclic AMP) 6754-13-8 (helenalin) €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ *****JOURNAL OF MEDICINAL CHEMISTRY***** Pettit GR Budzinski JC Cragg GM Brown P Johnson LD ANTINEOPLASTIC AGENTS. 34. HELENIUM AUTUMNALE L In: J Med Chem (1974) 17(9):1013-1016 ISSN: 0022-2623 Separation of extracts from the common sneezeweed, Helenium autumnale L, was carried out making extensive use of sephadex column chromatography. Fractionation was followed and directed by bioassay (KB and PS cultures). Three pseudoguaianolide type sesquiterpene lactones, helenalin, autumnolide and mexicanin I, were isolated from the active fraction and their structures determined. Helenalin was previously shown to be active in vivo against P-388 leukemia; autumnolide (6.25-25 mg/kg) was not effective against this tumor. KB cytotoxicity was shown for helenalin (ED(50), 0.19 mg/kg) and autumnolide (ED(50), 3.1 mg/kg), and helenalin also inhibited growth of Walker 256 tumor and B-16 melanoma in vivo. Helenalin esters were prepared after large scale extraction, but none were more effective than the parent compound in PS and KB screening systems. (12 refs) €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ *****JOURNAL OF NATURAL PRODUCTS***** Kasai R Shingu T Wu RY Hall IH Lee KH Antitumor agents 57. The isolation and structural elucidation of microhelenin-E, a new antileukemic nor-pseudoguaianolide, and microhelenin-F from Helenium microcephalum. In: J Nat Prod (1982 May-Jun) 45(3):317-20 ISSN: 0163-3864 Two new nor-pseudoguaianolides, microhelenin-E (1) and -F (2), were isolated from Texas Helenium microcephalum and their structures elucidated on the basis of physicochemical data and spectral evidence. Microhelenin-E demonstrated significant in vitro and in vivo cytotoxic and antileukemic activities against KB tissue cell culture (ED50 = 1.38 microgram/ml) P-388 lymphocytic leukemia growth in BDF1 male mice (T/C-166% at 8 mg/kg/day), respectively. Registry Numbers: 61490-63-9 (microhelenins) €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ Sims D Lee KH Wu RY Antitumor agents 37. The isolation and structural elucidation of isohelenol, a new antileukemic sesquiterpene lactone, and isohelenalin from Helenium microcephalum. In: J Nat Prod (1979 May-Jun) 42(3):282-6 ISSN: 0163-3864 The known compound isohelenalin (1) was isolated from Helenium microcephalum and the previously reported structure confirmed on the basis of physicochemical data and chemical transformation. In addition, a new antileukemic sesquiterpene lactone, isohelenol (2), was isolated and its structure elucidated. €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ Arnason JT Isman MB Philogene BJ Waddell TG Mode of action of the sesquiterpene lactone, tenulin, from Helenium amarum against herbivorous insects. In: J Nat Prod (1987 Jul-Aug) 50(4):690-5 ISSN: 0163-3864 Tenulin [1], a sesquiterpene lactone from Helenuim amarum, is a potent antifeedant to the European corn borer Ostrinia nubilalis. At 3 mumol/g in artificial diets, 1 reduced growth and delayed larval development of O. nubilalis and the variegated cutworm Peridroma saucia larvae. An especially pronouned carry-over effect in O. nubilis was substantial reduction in fecundity of adult moths resulting from treated larvae. The LD50 (lethal dose for 50% mortality) of 1 by injection in the migratory grasshopper Melanoplus sanguinipes was 0.88 mumol/insect. Toxicity in M. sanguinipes was antagonized by co-administration of cysteine, suggesting that the cyclopentenone group of tenulin undergoes Michael addition of biological nucleophiles in vivo. This mechanism was partially confirmed by the finding that only tenulin analogues capable of acting as electrophic acceptors had significant antifeedant activity. Registry Numbers: 19202-92-7 (tenulin) 4371-52-2 (Cysteine) €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ *****JOURNAL OF ORGANIC CHEMISTRY***** Furukawa H Lee KH Shingu T Meck R Piantadosi C Carolenin and carolenalin, two new guaianolides in Helenium autumnale L. from North Carolina. In: J Org Chem (1973 May 4) 38(9):1722-5 ISSN: 0022-3263 [No Abstract Available] €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ *****JOURNAL OF PHARMACEUTICAL SCIENCES***** Imakura Y Lee KH Sims D Wu RY Hall IH Furukawa H Itoigawa M Yonaha K Antitumor agents XXXVI: Structural elucidation of sesquiterpene lactones microhelenins-A, B, and C, microlenin acetate, and plenolin from Helenium microcephalum. In: J Pharm Sci (1980 Sep) 69(9):1044-9 ISSN: 0022-3549 The antitumor sesquiterpene lactones microhelenins-A, B, and C, microlenin acetate, and plenolin were isolated from Helenium microcephalum. The structures and stereochemistry of these lactones were determined by physical methods as well as by chemical transformations and correlations. Microlenin acetate appears to be the first novel dimeric sesquiterpene lactone demonstrated to have significant antileukemic activity. Registry Numbers: 34257-95-9 (plenolin) 60622-41-5 (microlenin) 61490-63-9 (microhelenins) €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ Imakura Y Lee KH Sims D Wu RY Hall IH Furukawa H Itoigawa M Yonaha K ANTITUMOR AGENTS XXXVI: STRUCTURAL ELUCIDATION OF SESQUITERPENE LACTONES MICROHELENINS-A, B, AND C, MICROLENIN ACETATE, AND PLENOLIN FROM HELENIUM MICROCEPHALUM In: J Pharm Sci (1980) 69(9):1044-1049 ISSN: 0022-3549 The antitumor sesquiterpene lactones microhelenins-A, B, and C, microlenin acetate, and plenolin were isolated from Helenium microcephalum. The structures and stereochemistry of these lactones were determined by physical methods as well as by chemical transformations and correlations. Microlenin acetate appears to be the first novel dimeric sesquiterpene lactone demonstrated to have significant antileukemic activity. (Author abstract) (17 Refs) €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ Imakura Y Lee KH Sims D Hall IH ANTITUMOR AGENTS XXVIII: STRUCTURAL ELUCIDATION OF THE NOVEL ANTITUMOR SESQUITERPENE LACTONE, MICROLENIN, FROM HELENIUM MICROCEPHALUM In: J Pharm Sci (1978) 67(9):1228-1232 ISSN: 0022-3549 After removal of helenalin from whole-plant extracts of Helenium microcephalin, the mother liquor contained constituents with significant activity against Walker 256 carcinosarcoma in Sprague- Dawley rats. Further analysis of the chloroform extract resulted in the isolation and structural determination of microlenin, a novel dimeric sesquiterpene lactone with significant antitumor activity (treated/control survival time ratio, 172% at 2.5 mg/kg/day; no further details), as well as mexicanin-E and microhelenins-A, -B, and -C. Nuclear magnetic resonance and mass spectral data showing the structure and stereochemistry of microlenin are presented. (14 Refs) €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ Lee KH Imakura Y Sims D ANTITUMOR AGENTS XVII: STRUCTURE AND STEREOCHEMISTRY OF MICROHELENIN- A, A NEW ANTITUMOR SESQUITERPENE LACTONE FROM HELENIUM MICROCEPHALUM (LETTER). In: J Pharm Sci (1976) 65(9):1410-1412 ISSN: 0022-3549 Studies relating to the structure and stereochemistry of microhelenin- A are described. This sesquiterpene lactone from Helenium microcephalum has demonstrated significant inhibitory activity (T/Cb125%) against Walker 256 carcinosarcoma in rats at dosages of 2.5 mg/kg. (11 refs) €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€ *****JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH***** Merrill JC Kim HL Safe S Murray CA Hayes MA Role of glutathione in the toxicity of the sesquiterpene lactones hymenoxon and helenalin. In: J Toxicol Environ Health (1988) 23(2):159-69 ISSN: 0098-4108 Hymenoxon and helenalin are toxic sesquiterpene lactones present in the toxic range plants Hymenoxys odorata and Helenium microcephalum. Helenalin (25 mg/kg) or hymenoxon (30 mg/kg) administered to immature male ICR mice caused a rapid decrease in hepatic glutathione levels and were lethally toxic to greater than 60% of the animals within 6 d. L-2-Oxothiazolidine 4-carboxylate (OTC), a compound that elevates cellular glutathione levels, administered to mice 6 or 12 h before either helenalin or hymenoxon protected against hepatic glutathione depletion and the lethal toxicity of these toxins. OTC administered at the same time as the sesquiterpene lactones was not protective, suggesting that the critical events against which glutathione is protective occur within the first 6 h. In primary rat hepatocyte cultures, hymenoxon and helenalin (4-16 microM) caused a rapid lethal injury as determined by the release of lactate dehydrogenase. Cotreatment of cultures with N-acetylcysteine at high concentrations (4 mM) afforded significant protection against lethal injury by both toxins. In contrast, BCNU, which inhibits glutathione reductase, or diethylmaleate, which depletes hepatocellular glutathione, potentiated the hepatotoxicity of helenalin and hymenoxon in monolayer rat hepatocytes. These studies suggest that the in vivo and in vitro toxicity of hymenoxon and helenalin is strongly dependent on hepatic glutathione levels, which hymenoxon and helenalin rapidly deplete at very low concentrations. Registry Numbers: 19750-45-9 (2-oxothiazolidine-4-carboxylic acid) 57074-51-8 (hymenovin) 616-91-1 (Acetylcysteine) 6754-13-8 (helenalin) 70-18-8 (Glutathione) €€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€€