DOCSLIB.ORG

(12) United States Patent (10) Patent No.: US 8,389,522 B2 Mochly-Rosen Et Al

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
(12) United States Patent (10) Patent No.: US 8,389,522 B2 Mochly-Rosen Et Al US008389522B2 (12) United States Patent (10) Patent No.: US 8,389,522 B2 Mochly-Rosen et al. (45) Date of Patent: Mar. 5, 2013 (54) MODULATORS OF ALDEHYDE (56) References Cited DEHYDROGENASE AND METHODS OF USE THEREOF U.S. PATENT DOCUMENTS 6,900.338 B1* 5/2005 Haj-Yehia ....................... 549/20 Inventors: Daria Mochly-Rosen, Menlo Park, CA 2002fOO34783 A1 3/2002 Meyers et al. (75) 2005, 0171043 A1 8/2005 Mochly-Rosen et al. (US); Che-Hong Chen, Fremont, CA 2008. O153926 A1 6/2008 Mochly-Rosen et al. (US); Wenjin Yang, Foster City, CA 2008, 0200461 A1 8/2008 Anderson et al. (US) 2009/0082431 A1* 3/2009 Mochly-Rosen et al. ... 514/466 2009,0163545 A1* 6, 2009 Goldfarb ....................... 514/312 (73) Assignee: The Board of Trustees of the Leland FOREIGN PATENT DOCUMENTS Stanford Junior University, Stanford, WO WO 2008112164 A2 9, 2008 CA (US) OTHER PUBLICATIONS (*) Notice: Subject to any disclaimer, the term of this Chen et al. CAS: 149:548594, 2008.* patent is extended or adjusted under 35 Goldfarb's CAS: 151:92837, 2009.* U.S.C. 154(b) by 576 days. STN: 1 1/16, 1984.* Fernholz et al. CAS:37:40468, 1943.* (21) Appl. No.: 12/581,704 Tracey et al. CAS: 145:488790, 2006.* Nicoll-Griffith's CAS: 107: 141210, 1987.* (22) Filed: Oct. 19, 2009 Gilman et al. CAS: 40:2074, 1946.* Chen etal. Activation of aldehyde dehydrogenase-2 reduces ischemic Prior Publication Data damage to the heart. Science. Sep. 12, 2008:321 (5895): 1493-5. (65) Davis et al. Requirement for Pax6 in corneal morphogenesis: a role in US 2010/O113423 A1 May 6, 2010 adhesion. J Cell Sci. Jun. 1, 2003; 116(Pt 11):2157-67. * cited by examiner Related U.S. Application Data Primary Examiner — Rei-tsang Shiao (60) Provisional application No. 61/109,081, filed on Oct. (74) Attorney, Agent, or Firm — Paula A. Borden; Rudy J. 28, 2008, provisional application No. 61/225,827, Ng; Bozicevic, Field & Francis LLP. filed on Jul. 15, 2009. (57) ABSTRACT (51) Int. C. The present disclosure provides compounds that function as A6 IK3I/495 (2006.01) modulators of aldehyde dehydrogenase (ALDH) enzymatic CO7D 22.3/00 (2006.01) activity, as well as compositions and formulations comprising the compounds. The present disclosure provides therapeutic (52) U.S. C. ......... 514/248: 514/218: 540/484; 544/233 methods involving administering a Subject compound, or a (58) Field of Classification Search .................. 514/248, 514/218: 540/484; 544/233 Subject pharmaceutical composition. See application file for complete search history. 10 Claims, 25 Drawing Sheets U.S. Patent Mar. 5, 2013 Sheet 1 of 25 US 8,389,522 B2 upCS C CC upCO O ups C e upcy va s d CD - up C aC cts e O O O C c C O O s N c c O r cN 3. 3 2 woe wers s (OJuoo 9%) AAW euAzu U.S. Patent Mar. 5, 2013 Sheet 2 of 25 US 8,389,522 B2 02|| 09 09 0:2 (Ouluoo 9.) AAOW euAzu U.S. Patent Mar. 5, 2013 Sheet 3 of 25 US 8,389,522 B2 s c O c O O 3 N se eue (osuoo 9.) AmoW euAzu U.S. Patent US 8,389,522 B2 ZHGpIVp????und 4.OV/N U.S. Patent Mar. 5, 2013 Sheet 5 Of 25 US 8,389,522 B2 U.S. Patent Mar. 5, 2013 Sheet 6 of 25 US 8,389,522 B2 U.S. Patent Mar. 5, 2013 Sheet 8 of 25 US 8,389,522 B2 r : ait s Ces co 2 OP cis C CC isas ve o a OO t; a s < 9 CD8s: 2 L as: ve o s SS < its ers g of CC is s w 8 e d e s 3 s CD C C O C c c CN N trol ve (oluoo 9%) AA}ow eu Azu U.S. Patent US 8,389,522 B2 (ouguoo 96) AAW euAZu U.S. Patent Mar. 5, 2013 Sheet 10 of 25 US 8,389,522 B2 (ouoo 9.) AAW eulu Azu U.S. Patent Mar. 5, 2013 Sheet 11 of 25 US 8,389,522 B2 3g2 ?s S. %3- a 8 %W3 . 2 CD * (N N 2% %2.% % - 2 & s 3%%2. % 2. % % % - c. a É. %2 % * 2 2. % 2 . 3.S O O O O O O O C w w O C w N 3 3 vo true *u. (ouog 9.) AA3W euAzu U.S. Patent Mar. 5, 2013 Sheet 13 Of 25 US 8,389,522 B2 cr) wo c -e- 92P CDs C-S2 88s: O - are sP O of Ol OC 2 C 4, Yose8 - -- : O O O O O O O O O O cy cy N (N reas xas (%) AApoe oeu Mizue HOTW U.S. Patent Mar. 5, 2013 Sheet 14 of 25 US 8,389,522 B2 d O 2 r vo as 2P CD: C-S2 88: 2 - : i s s (%) AAoe oeu Mizue HOTW U.S. Patent Mar. 5, 2013 Sheet 15 Of 25 US 8,389,522 B2 s a *.*.*.*.*.*.* r * * * * * * 'lear O * **** * * * * * : * * * * a. * * *es* . x . * . x ."8 e . .. i.e.. e.. * * 2 . O v 8 .8 .8' . .x 8. - . - - . - . x88 * * : " : . " ' " - CD . .. .. .. .. .. x ...s. ". a . .2 . .. .. O O O O O c CO s (C s r 3. 8 (%) AA be oeu Azue SHOW U.S. Patent Mar. 5, 2013 Sheet 17 Of 25 US 8,389,522 B2 O s D. O S ve CD is t . D. S s D. s (%) AAOe oeu Azue ZHOTW i U.S. Patent Mar. 5, 2013 Sheet 18 of 25 US 8,389,522 B2 (68-epiv)ajou?es (Wn000L)?IOugeS 0 0"| (uu Ove O'O) AA3e ahov U.S. Patent Mar. 5, 2013 Sheet 19 Of 25 US 8,389,522 B2 Untreated + ALDA-1 6 Gy Radiation F.G. 19 U.S. Patent Mar. 5, 2013 Sheet 20 of 25 US 8,389,522 B2 {}{}{} {}{}Z {}{}} SS3.xt euliapi U.S. Patent US 8,389,522 B2 (sÁed)uo?eunpquæuu?eau1 eunioA Ioun emee. U.S. Patent US 8,389,522 B2 U.S. Patent Mar. 5, 2013 Sheet 23 Of 25 US 8,389,522 B2 OOO · (uu usuno eouen) AAOW 6uee U.S. Patent US 8,389,522 B2 eloose oAeueg U.S. Patent Mar. 5, 2013 Sheet 25 Of 25 US 8,389,522 B2 AOO 350 300 | 250 2OO vehicle Control Alda-1 + Aid-89 FIG. 25 US 8,389,522 B2 1. 2 MODULATORS OF ALDEHYDE FIG. 4 schematically depicts an exemplary fluorescent DEHYDROGENASE AND METHODS OF USE aldehyde dehydrogenase enzymatic assay. THEREOF FIG. 5A and FIG. 5B provide the amino acid sequence of human ALDH2 (SEQID NO: 1) and the amino acid sequence CROSS-REFERENCE of an E487K variant of human ALDH2 (SEQ ID NO:2), respectively. This application claims the benefit of U.S. Provisional FIGS. 6A and 6B provide exemplary ALDH1 amino acid Patent Application No. 61/109,081, filed Oct. 28, 2008, and Sequences. U.S. Provisional Patent Application No. 61/225,827, filed Jul. FIG. 7 provides an exemplary ALDH3 amino acid 15, 2009, which applications are incorporated herein by ref 10 Sequence. erence in their entirety. FIG. 8 depicts the effect of four exemplary activator com pounds, Alda-52, Alda-81, Alda-83 and Alda-84, on ALDH1 STATEMENT REGARDING FEDERALLY enzymatic activity using octylaldehyde as a Substrate. SPONSORED RESEARCH FIG.9 depicts the effect of four exemplary activator com 15 pounds—Alda-52, Alda-81, Alda-83, and Alda-84—on ALDH1 enzymatic activity using phenylacetaldehyde as a This invention was made with Government support under substrate. contract AAO 11147 awarded by the National Institutes of FIG. 10 depicts the effect offive exemplary activator com Health. The Government has certain rights in this invention. pounds—Alda-52, Alda-81, Alda-83, Alda-84, and Alda-1— BACKGROUND on ALDH2 enzymatic activity using acetaldehyde as a Sub Strate. FIG. 11 depicts the effect of four exemplary activator com Aldehyde dehydrogenases (ALDH) constitute a family of pounds—Alda-52, Alda-81, Alda-83, Alda-84, and Alda-1— enzymes that play a critical role in detoxification of various on ALDH2 enzymatic activity using phenylacetaldehyde as a cytotoxic Xenogenic and biogenic aldehydes. There are at 25 substrate. least 19 members/isozymes of the ALDH family, where the FIG. 12 provides an exemplary ALDH5 amino acid various isozymes may exhibit different substrate specificity Sequence. and/or cellular location relative to other members of the fam FIG. 13 depicts activation of ALDH3 by various com ily. pounds using acetaldehyde as Substrate. Cytotoxic aldehydes derive from a variety of sources. For 30 FIG. 14 depicts activation of ALDH3 by various com example, environmental (external) sources of aldehydes pounds using phenylacetaldehyde as Substrate. include those that result from ethanol consumption, from FIG. 15 depicts dosate effect of safrole on ALDH3 enzy consumption of food sources, from ingestion of hazardous matic activity using acetaldehyde as Substrate. materials such as vinyl chloride, pesticides, herbicides, etc., FIG. 16 depicts the effect of various compounds, desig or from inhalation of hazardous materials such as those found 35 nated Alda-101 to Alda-112, on ALDH3 enzymatic activity in cigarette Smoke, industrial pollution, etc. Aldehydes that acetaldehyde as Substrate. may be cytotoxic can also be produced biologically (e.g., FIG. 17 depicts the inhibitory effect of high concentration endogenously), e.g., as a result of oxidative stress Such as of safrole on ALDH2 enzymatic activity using acetaldehyde occurs in ischemia, irradiation, or metabolism or bioconver as Substrate.
Load more

Recommended publications
  • Kava Kava Extract Is Available from Ashland Chemical Co., Mini Star International, Inc., and QBI (Quality Botanical Ingredients, Inc.)
    SUMMARY OF DATA FOR CHEMICAL SELECTION Kava Kava 9000-38-8; 84696-40-2 November 1998 TABLE OF CONTENTS Basis for Nomination Chemical Identification Production Information Use Pattern Human Exposure Regulatory Status Evidence for Possible Carcinogenic Activity Human Data Animal Data Metabolism Other Biological Effects Structure-Activity Relationships References BASIS OF NOMINATION TO THE CSWG Kava kava is brought to the attention of the CSWG because it is a rapidly growing, highly used dietary supplement introduced into the mainstream U.S. market relatively recently. Through this use, millions of consumers using antianxiety preparations are potentially exposed to kava kava. A traditional beverage of various Pacific Basin countries, kava clearly has psychoactive properties. The effects of its long-term consumption have not been documented adequately; preliminary studies suggest possibly serious organ system effects. The potential carcinogenicity of kava and its principal constituents are unknown. INPUT FROM GOVERNMENT AGENCIES/INDUSTRY The U.S. Pharmacopeia is in the process of reviewing kava kava. No decision on preparation of a monograph has been made. SELECTION STATUS ACTION BY CSWG: 12/14/98 Studies requested: - Toxicological evaluation, to include studies of reproductive toxicity and neurotoxicity - Genotoxicity Priority: High Rationale/Remarks: - Significant human exposure - Leading dietary supplement with rapidly growing use - Concern that kava has been promoted as a substitute for ritilin in children - Test extract standardized to 30 percent kavalactones - NCI is conducting studies in Salmonella typhimurium CHEMICAL IDENTIFICATION CAS Registry Number: 9000-38-8 Kava-kava resin (8CI) Chemical Abstract Service Name: 84696-40-2 CAS Registry Number: Pepper (Piper), P. methysticum, ext. Chemical Abstract Service Name: Extract of kava; kava extract; Piper Synonyms and Trade Names: methisticum extract Description: The tropical shrub Piper methysticum is widely cultivated in the South Pacific.
    [Show full text]
  • Article – – = = = = C7-C8 – – – – Is Known to = = C5-C6
    J. Braz. Chem. Soc., Vol. 20, No. 9, 1687-1697, 2009. Printed in Brazil - ©2009 Sociedade Brasileira de Química 0103 - 5053 $6.00+0.00 Article Synthesis of Novel Kavain-like Derivatives and Evaluation of their Cytotoxic Activity Patricia de A. Amaral,a,b Julien Petrignet,c Nicolas Gouault,b Taciane Agustini,a Françoise Lohézic-Ledévéhat,b Alexandre Cariou,b René Grée,c Vera L. Eifler-Lima*,a and Michèle Davidb aLaboratório de Síntese Orgânica Medicinal, Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul, 90610-000 Porto Alegre-RS, Brazil bLaboratoire de Chimie Therapeutique, UPRES 4090, Université de Rennes 1, Rennes, France cLaboratoire de Chimie et Photonique Moléculaires, CNRS UMR 6510, Université de Rennes 1, Rennes, France Reações de acoplamento do tipo Heck, Sonogashira-Hagihara, Suzuki-Miyaura e reação de aldolisação catalizadas por metal foram utilizadas para a obtenção de três séries de d-valerolactonas substituídas em posições 3, 4, 5 e 6 do anel lactônico. As 26 d-valerolactonas sintetizadas foram testadas contra três linhagens celulares e cinco delas exibiram uma moderada atividade citotóxica. Palladium-catalyzed cross coupling reactions (Sonogashira-Hagihara, Suzuki-Miyaura, and Heck) coupling and nickel hydride-mediated tandem isomerization aldolisation have been used for the synthesis of three series of d-valerolactones substituted in positions 3, 4, 5 and 6 of the lactone ring. The 26 kavaïn-like derivatives were tested against three cell lines and five of them exhibited a weak cytotoxic activity. Keywords:
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 6,746,695 B1 Martin Et Al
    USOO6746695B1 (12) United States Patent (10) Patent No.: US 6,746,695 B1 Martin et al. (45) Date of Patent: Jun. 8, 2004 (54) PHARMACEUTICAL PREPARATIONS OF Abad, MJ et al., Anti-inflammatory activity of some medici BOACTIVE SUBSTANCES EXTRACTED nal plant extracts from Venezuela. J. Ethnopharmacol1996 FROM NATURAL SOURCES Dec;55(1):63–8. Alarcon-Aguilara, FJ, et al., Study of the anti-hyperglyce (75) Inventors: Michael Z. Martin, Laupahoehoe, HI mic effect of plants used as antidiabetics. J. Ethnopharmacol (US); Mehdi Ashraf-Khorassani, Blacksburg, VA (US); Larry Taylor, 612:101-110 (1998). Blacksburg, VA (US) Almeida CE et al., Analysis of anti-diarrheic effect of plants used in popular medicine. Rev Saude Publica 1995 (73) Assignees: Armadillo Pharmaceuticals, Inc., Dec;29(6):428-33. Armocas, CA (US); Virginia Tech. Alves KB, et al., Inhibition of aminopeptidase activity by Intellectual Properties, Inc., aromatic and other cyclic compounds. Braz, J Med Biol Res. Blackburg, VA (US) 1992:25(11):1103–6. (*) Notice: Subject to any disclaimer, the term of this Anesini C, et al., Screening of plants used in Argentine folk patent is extended or adjusted under 35 medicine for anti-microbial activity. J Ethnopharmacol. U.S.C. 154(b) by 0 days. 1993 Jun;39(2):119–28. Arletti, R, et al., Stimulating property of Turnera diffusa and Pfafia paniculata eXtracts on the Sexual behavior of male (21) Appl. No.: 09/578,849 rats, Psychopharmacology (Berl). 1999 Mar;143(1): 15-9. (22) Filed: May 26, 2000 Auterhoff, Het al., Constituents of the drug Damiana. Arch Related U.S.
    [Show full text]
  • Microbial Metabolism of Yangonin, a Styryl Lactone from Piper Methysticum(Kava)
    Natural Product Sciences 16(3) : 148-152 (2010) Microbial Metabolism of Yangonin, a Styryl Lactone from Piper methysticum (Kava) Ji Hye Kim1, Hyun Jung Kim2, and Ik-Soo Lee* College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, Republic of Korea 1Marine Natural Products Chemistry Laboratory, Korea Ocean Research & Development Institute, Ansan 426-744, Republic of Korea 2Medical Research Center for Gene Regulation and the Brain Korea 21 Project, Chonnam National University Medical School, Gwangju 501-746, Republic of Korea Abstract − Microbial metabolism studies of yangonin (1), a major styryl lactone from Piper methysticum, have resulted in the production of three hydroxylated metabolites (2-4). The chemical structures of these compounds were elucidated to be 4-methoxy-6-(12-hydroxystyryl)-2-pyrone (2), 4-methoxy-6-(11,12-dihydroxystyryl)-2-pyrone (3), and 4,12-dimethoxy-6-(7,8-dihydroxy-7,8-dihydrostyryl)-2-pyrone (4) on the basis of the chemical and spectroscopic analyses. The compounds 3 and 4 are reported herein as microbial metabolites of yangonin for the first time. Keywords − Microbial metabolism, Yangonin, Styryl lactone, Piper methysticum, Kava Introduction et al., 2003) studies provided several derivatives or metabolites including glucuronylated, hydroxylated, deme- The roots of the kava shrub (Piper methysticum G. thylated, and dehydrated metabolites. Microbial metabolism Forst, Piperaceae) have been used to prepare an intoxicating studies on kavalactones have been reported for kawain, beverage for South Pacific Islanders’ social occasions methysticin (Abourashed and Khan, 2000), and dihydro- (Whitton, et al., 2003). In Western countries, kava extracts kawain (Herath, et al., 2004).
    [Show full text]
  • Plant Powers, Poisons, and Herb Craft
    PLANT POWERS, POISONS, AND HERB CRAFT BY DALE PENDELL Foreword by Gary Snyde, $21.95 US In 'Pharmako/Poeia, Dale Pendell offers a mesmerizing guide to psychoactive Alternative plants, from their pharmacological roots to the literary offshoots. "This is a Health/ book," writes Gary Snyder, "about danger: dangerous knowledge, even more Literature dangerous ignorance." Against the greater danger, ignorance, Pendell strikes a formidable blow, as he proves himself a wise and witty guide to our plant teach- ers, their powers and their poisons. "Dale Pendell reactivates the ancient connection between the bardic poet and the shaman. His Pharmako/Poeia is a litany to the secret plant allies that have always accompanied us along the alchemical trajectory that leads to a new and yet authentically archaic future." — Terence McKenna, author of True Hallucinations "Much of our life-force calls upon the plant world for support, in medicines and in foods, as both allies and teachers. Pendell provides a beautifully crafted bridge between these two worlds. The magic he shares is that the voices are spoken and heard both ways; we communicate with plants and they with us. This book is a moving and poetic presentation of this dialogue." — Dr. Alexander T. Shulgin, University of California at Berkeley, Department of Public Health "Pharmako/Poeia is an epic poem on plant humours, an abstruse alchemic treatise, an experiential narrative jigsaw puzzle, a hip and learned wild-nature reference text, a comic paean to cosmic consciousness, an ecological handbook, a dried-herb pastiche, a countercultural encyclopedia of ancient fact and lore that cuts through the present 'conservative' war-on-drugs psychobabble." - Allen Ginsberg, poet Cover design "Dale PendelFs remarkable book will make it impossible to and color work ever again underestimate the most unprepossessing plant.
    [Show full text]
  • Analytical Reference Standards
    Cerilliant Quality ISO GUIDE 34 ISO/IEC 17025 ISO 90 01:2 00 8 GM P/ GL P Analytical Reference Standards 2 011 Analytical Reference Standards 20 811 PALOMA DRIVE, SUITE A, ROUND ROCK, TEXAS 78665, USA 11 PHONE 800/848-7837 | 512/238-9974 | FAX 800/654-1458 | 512/238-9129 | www.cerilliant.com company overview about cerilliant Cerilliant is an ISO Guide 34 and ISO 17025 accredited company dedicated to producing and providing high quality Certified Reference Standards and Certified Spiking SolutionsTM. We serve a diverse group of customers including private and public laboratories, research institutes, instrument manufacturers and pharmaceutical concerns – organizations that require materials of the highest quality, whether they’re conducing clinical or forensic testing, environmental analysis, pharmaceutical research, or developing new testing equipment. But we do more than just conduct science on their behalf. We make science smarter. Our team of experts includes numerous PhDs and advance-degreed specialists in science, manufacturing, and quality control, all of whom have a passion for the work they do, thrive in our collaborative atmosphere which values innovative thinking, and approach each day committed to delivering products and service second to none. At Cerilliant, we believe good chemistry is more than just a process in the lab. It’s also about creating partnerships that anticipate the needs of our clients and provide the catalyst for their success. to place an order or for customer service WEBSITE: www.cerilliant.com E-MAIL: [email protected] PHONE (8 A.M.–5 P.M. CT): 800/848-7837 | 512/238-9974 FAX: 800/654-1458 | 512/238-9129 ADDRESS: 811 PALOMA DRIVE, SUITE A ROUND ROCK, TEXAS 78665, USA © 2010 Cerilliant Corporation.
    [Show full text]
  • Versatile Asymmetric Synthesis of the Kavalactones
    ORGANIC LETTERS 2004 Versatile Asymmetric Synthesis of the Vol. 6, No. 14 Kavalactones: First Synthesis of 2317-2320 (+)-Kavain Thomas E. Smith,* Mabel Djang, Alan J. Velander, C. Wade Downey,† Kathleen A. Carroll, and Sophie van Alphen Department of Chemistry, Williams College, Williamstown, Massachusetts 01267 [email protected] Received April 1, 2004 ABSTRACT Three asymmetric pathways to the kavalactones have been developed. The first method is chiral auxiliary-based and utilizes aldol reactions of N-acetyl thiazolidinethiones followed by a malonate displacement/decarboxylation reaction. The second approach uses the asymmetric catalytic Mukaiyama additions of dienolate nucleophile equivalents developed by Carreira and Sato. Finally, tin-substituted intermediates, prepared by either of these routes, can serve as advanced general precursors of kavalactone derivatives via Pd(0)-catalyzed Stille couplings with aryl halides. The Kava plant (Piper methysticum) has a long and colorful ported.1 The psychoactive principals are a family of 15 history spanning several thousand years.1 Kava has been used R-pyrone derivatives known as the kavalactones that com- by Pacific Island societies to prepare an intoxicating cer- prise roughly 15% of the dried rootstock. The more prevalent emonial beverage renowned for its relaxing effects and ability of these include kavain (1, Figure 1), dihydrokavain (2), and to promote sociability. Modern use of Kava root, commonly methysticin (3). Structurally, the kavalactones differ chiefly available in dietary supplements labeled “Kava Kava”, is also with respect to their arene substitution patterns and the for its purported anxiolytic2 and soporific qualities. Anal- presence or absence of double bonds along their carbon gesic,3 anesthetic, antifungal, antithrombotic,4 anticonvul- backbones.
    [Show full text]
  • From Alpinia Zerumbet: Its Isolation, Synthesis, and Characterization
    Molecules 2015, 20, 16306-16319; doi:10.3390/molecules200916306 OPEN ACCESS molecules ISSN 1420-3049 www.mdpi.com/journal/molecules Review Dihydro-5,6-dehydrokavain (DDK) from Alpinia zerumbet: Its Isolation, Synthesis, and Characterization Tran Dang Xuan 1 and Rolf Teschke 2,* 1 Division of Development Technology, Graduate School for International Development and Cooperation (IDEC), Hiroshima University, Higashi Hiroshima 739-8529, Japan; E-Mail: [email protected] 2 Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, Academic Teaching Hospital of the Medical Faculty of the Goethe University, Frankfurt/Main, 63450 Hanau, Germany * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +49-6181-218-59; Fax: +49-6181-296-4211. Academic Editor: Derek J. McPhee Received: 9 June 2015 / Accepted: 20 August 2015 / Published: 9 September 2015 Abstract: Dihydro-5,6-dehydrokavain (DDK) is the major and most promising component of the tropical plant Alpinia zerumbet (shell ginger), a species of the ginger family Zingiberaceae. Alpinia zerumbet is known for its human use as a traditional herbal medicine, food, and dietary supplement. With its α-lactone ring, DDK belongs to the large chemical group of kavalactones, which are also found in kava (Piper methysticum), another herbal medicine; DDK is characterized by a double-bond linkage at positions 5,6 and the absence of a double-bond linkage at positions 7,8. This dissociates DDK from other kavalactones with their linkages at positions 7,8 and 5,6 that are both either completely saturated or unsaturated, or may have an unsaturated bond at the position 7,8 as well as a saturated bond at the position 5,6.
    [Show full text]
  • Applications Index
    HPLC: 4 8 1 - 5 1 3 I C : 5 1 4 - 5 2 1 GC: 5 2 2 - 5 5 6 Applications Index Androsterone 528 α-BHC 529 A Anesthetics 484 β-BHC 529 Acebutolol 487 Angiotensin I 501 δ-BHC 529 Acemetacin 482 Angiotensin II 501, 502, 505 γ-BHC 529 Acenaphthene 509 Angiotensin III 505 BHT (Butylated Hydroxytoluene) 538 Acenaphthylene 509, 555 Anthracene 509 Bicarbonate 517 Acetaldehyde (Ethanal) 524, 547 Anti-Asthmatics 484 Bilobalide 492 Acetaminophen 482 Antibacterials 490 Biotin (Vitamin B7) 495 Acetate (Acetic Acid) 497, 498, 516, 518, 535, Antibiotics 490 Biphenyl (Diphenyl) 507 537, 541, 542 Anticonvulsants 486, 528 2,2’-Bipyridine (2,2-Dipyridyl) 513 Acetazolamide 489 Anti-Depressants 483 Bis(2-ethylhexyl)phthalate (Diocytl Phthalate) Acetic Acid (Acetate) 497, 498, 516, 518, 535, Antihistimines 485 531 537, 541, 542 Anti-Hypertensives 487 β-Bisabolene 539 Acetone 524, 548, 554, 555 Anti-Inflammatories 482 Bisphenol-A 510 Acetonitrile 525 Antioxidants 538 Black Cohosh 492 Acetophenone (Phenyl Methyl Ketone) 507, 538 Antiseptics 491 Blood Alcohols 524 6-Acetylcodeine 524 Apigenin 493 Boldenone (Dehydrotestosterone) 522 Acetylene (Ethyne) 545, 546, 547 Aprobarbital 484, 528 Bombesin 501 Acetylsalicylic Acid (Aspirin) 482, 483 Arachidic Acid (Eicosanoic Acid) 498 Borate 518 Acrylonitrile (2-Propenenitrile) 556 Arg8-vassopressin 501 Bovine Insulin 500 Active Amyl Alcohol (2-Methyl-1-butanol) 537 Arginine (Arg) 505 Bovine Insulin Impurity 500 Actein 492 Argon 551 Bovine Serum Albumin (BSA) 500 Additives 497, 516 Aromatic Acids 507 Bradykinin 500 Adenine
    [Show full text]
  • Kavain Analogues As Potential Analgesic Agents
    Pharmacological Reports Copyright © 2012 2012, 64, 14191426 by Institute of Pharmacology ISSN 1734-1140 Polish Academy of Sciences Kavainanaloguesaspotentialanalgesicagents ElaineC.Kormann1,PatriciadeAguiarAmaral2,MicheleDavid3, VeraL.Eifler-Lima4,ValdirCechinelFilho1,FátimadeCamposBuzzi1 1 Chemical-PharmaceuticalInvestigationsCenter(NIQFAR)/CCS,UniversityofItajaíValey(UNIVALI),Itajaí/SC, Brazil 2 LaboratoryofMedicinalPlants(LaPlaM),UniversityoftheExtremeSouthofSantaCatarina(UNESC), Criciúma/SC,Brazil 3 LaboratoryofChemistryTherapeutic(UPRES4090),UniversityofRennes1,Rennes,France 4 LaboratoryofMedicinalOrganicSynthesis(LaSOM),FacultyofPharmacy,FederalUniversityofRioGrande doSul(UFRGS),PortoAlegre/RS,Brazil Correspondence: FátimadeCamposBuzzi,e-mail: [email protected]; VeraL.Eifler-Lima, e-mail: [email protected] Abstract: Background: Kavalactones are pharmacologically active compounds present in preparations of the root trunk of Piper methysticum Forst, known as kava. This work describes the analgesic activity of some synthesized analogues of synthetic kavain, which is the maincomponentofkava. Methods: The essays were initially performed against the writhing test in mice, and the most promising compound was analyzed us- ing other classical models of nociception, including formalin-, capsaicin-, glutamate-induced nociception, the hot plate test, and measurementofmotorperformance. Results: The results indicated that compound 6-(4-fluorophenyl)-4-methoxy-5,6-dihydropyran-2-one (2d) exerts potent and dose- dependent analgesic activity, inhibiting abdominal constrictions caused by acetic acid in mice, and being more active than some ref- erence drugs. It also presented activity in the other models of pain, with the exception of the hot plate test and the measurement of motorperformance. Conclusions: Although compound 2d exerts antinociceptive activity, the mechanism of action remains uncertain, but it does not in- volve the opioid system and does not appear to be associated with non-specific effects such as changes in locomotor activity or motor coordination.
    [Show full text]
  • Dr. Duke's Phytochemical and Ethnobotanical Databases List of Chemicals for Tinnitus
    Dr. Duke's Phytochemical and Ethnobotanical Databases List of Chemicals for Tinnitus Chemical Activity Count (+)-ALPHA-VINIFERIN 1 (+)-AROMOLINE 1 (+)-BORNYL-ISOVALERATE 1 (+)-CATECHIN 1 (+)-EUDESMA-4(14),7(11)-DIENE-3-ONE 1 (+)-HERNANDEZINE 2 (+)-ISOLARICIRESINOL 1 (+)-NORTRACHELOGENIN 1 (+)-PSEUDOEPHEDRINE 1 (+)-SYRINGARESINOL-DI-O-BETA-D-GLUCOSIDE 1 (+)-T-CADINOL 1 (-)-16,17-DIHYDROXY-16BETA-KAURAN-19-OIC 1 (-)-ALPHA-BISABOLOL 1 (-)-ANABASINE 1 (-)-APOGLAZIOVINE 1 (-)-BETONICINE 1 (-)-BORNYL-CAFFEATE 1 (-)-BORNYL-FERULATE 1 (-)-BORNYL-P-COUMARATE 1 (-)-CANADINE 1 (-)-DICENTRINE 1 (-)-EPICATECHIN 2 (-)-EPIGALLOCATECHIN-GALLATE 1 (1'S)-1'-ACETOXYCHAVICOL-ACETATE 1 (E)-4-(3',4'-DIMETHOXYPHENYL)-BUT-3-EN-OL 1 1,7-BIS-(4-HYDROXYPHENYL)-1,4,6-HEPTATRIEN-3-ONE 1 1,8-CINEOLE 4 Chemical Activity Count 1-ETHYL-BETA-CARBOLINE 2 10-ACETOXY-8-HYDROXY-9-ISOBUTYLOXY-6-METHOXYTHYMOL 1 10-DEHYDROGINGERDIONE 1 10-GINGERDIONE 1 12-(4'-METHOXYPHENYL)-DAURICINE 1 12-METHOXYDIHYDROCOSTULONIDE 1 13',II8-BIAPIGENIN 1 13-HYDROXYLUPANINE 1 13-OXYINGENOL-ESTER 1 16,17-DIHYDROXY-16BETA-KAURAN-19-OIC 1 16-HYDROXY-4,4,10,13-TETRAMETHYL-17-(4-METHYL-PENTYL)-HEXADECAHYDRO- 1 CYCLOPENTA[A]PHENANTHREN-3-ONE 16-HYDROXYINGENOL-ESTER 1 2'-O-GLYCOSYLVITEXIN 1 2-BETA,3BETA-27-TRIHYDROXYOLEAN-12-ENE-23,28-DICARBOXYLIC-ACID 1 2-METHYLBUT-3-ENE-2-OL 2 2-VINYL-4H-1,3-DITHIIN 1 20-DEOXYINGENOL-ESTER 1 22BETA-ESCIN 1 24-METHYLENE-CYCLOARTANOL 2 3,3'-DIMETHYLELLAGIC-ACID 1 3,4-DIMETHOXYTOLUENE 2 3,4-METHYLENE-DIOXYCINNAMIC-ACID-BORNYL-ESTER 1 3,4-SECOTRITERPENE-ACID-20-EPI-KOETJAPIC-ACID
    [Show full text]
  • Dr. Duke's Phytochemical and Ethnobotanical Databases List of Chemicals for Breached Birth
    Dr. Duke's Phytochemical and Ethnobotanical Databases List of Chemicals for Breached Birth Chemical Activity Count (+)-ALLOMATRINE 1 (+)-ALPHA-VINIFERIN 2 (+)-AROMOLINE 1 (+)-BORNYL-ISOVALERATE 1 (+)-CASSYTHICINE 1 (+)-CATECHIN 2 (+)-CATECHOL 1 (+)-EUDESMA-4(14),7(11)-DIENE-3-ONE 1 (+)-HERNANDEZINE 1 (+)-ISOCORYDINE 2 (+)-PSEUDOEPHEDRINE 1 (+)-SYRINGARESINOL-DI-O-BETA-D-GLUCOSIDE 1 (-)-16,17-DIHYDROXY-16BETA-KAURAN-19-OIC 1 (-)-ALPHA-BISABOLOL 3 (-)-ALPHA-HYDRASTINE 2 (-)-APOGLAZIOVINE 1 (-)-ARGEMONINE 1 (-)-BETONICINE 2 (-)-BORNYL-CAFFEATE 1 (-)-BORNYL-FERULATE 1 (-)-BORNYL-P-COUMARATE 1 (-)-CENTROLOBINE 1 (-)-DICENTRINE 3 (-)-EPICATECHIN 1 (-)-KAUR-16-EN-19-OIC-ACID 1 (-)-SPARTEINE 2 (1'S)-1'-ACETOXYCHAVICOL-ACETATE 1 Chemical Activity Count (15:1)-CARDANOL 1 (2Z,8Z)-10-ANGELOYLOXY-MATRICARIA-ESTER 1 (E)-2-HEXENAL 1 (E)-4-(3',4'-DIMETHOXYPHENYL)-BUT-3-EN-OL 1 1,2,11,13,2,3'-HEXAHYDROVERNODALIN 1 1,7-BIS-(4-HYDROXYPHENYL)-1,4,6-HEPTATRIEN-3-ONE 1 1,8-CINEOLE 5 1-MAACKIAIN 1 10-ACETOXY-8-HYDROXY-9-ISOBUTYLOXY-6-METHOXYTHYMOL 1 10-DEHYDROGINGERDIONE 1 10-GINGERDIONE 1 11-DIHYDRO-CANTHINE-6-ONE 1 11-HYDROXY-DELTA-8-THC 2 11-HYDROXY-DELTA-9-THC 2 12-ACETYLDEHYDROLUCICULINE 1 13',II8-BIAPIGENIN 1 13-OXYINGENOL-ESTER 1 16,17-DIHYDROXY-16BETA-KAURAN-19-OIC 1 16-EPIMETHUENINE 1 16-HYDROXYINGENOL-ESTER 1 2'-HYDROXY-FLAVONE 1 2'-O-GLYCOSYLVITEXIN 1 2-BETA,3BETA-27-TRIHYDROXYOLEAN-12-ENE-23,28-DICARBOXYLIC-ACID 1 2-HEXEN-1-OL 1 2-METHOXYPHASEOLLINISOFLAVON 1 2-METHYLBUT-3-ENE-2-OL 2 2-NAPTHOL 1 2 Chemical Activity Count 2-NONANONE 1 2-PROPENE-1-SULFINOTHIOCIC-ACIDS-2-PROPENYL-ESTER
    [Show full text]