DOCSLIB.ORG

THE BIOSYNTHESIS of SOME PHENOLIC ALKALOIDS a Thesis Submitted by GEOFFREY MELVILLE THOMAS for the Degree of DOCTOR of PHILOSOPH

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
THE BIOSYNTHESIS of SOME PHENOLIC ALKALOIDS a Thesis Submitted by GEOFFREY MELVILLE THOMAS for the Degree of DOCTOR of PHILOSOPH /1 THE BIOSYNTHESIS OF SOME PHENOLIC ALKALOIDS a thesis submitted by GEOFFREY MELVILLE THOMAS for the degree of DOCTOR OF PHILOSOPHY of THE UNIVERSITY OF LONDON Imperial College, June 1963. London, S. W.7. ABSTRACT A brief review of the biosynthesis of alkaloids, other than those of the Amaryllidaceae and morphine groups, is given. The biosynthesis of these two groups is discussed more fully with particular reference to the evidence for the Barton and Cohen concept of phenol oxidation as a biogenetic mechanism. The incorporation of labelled phenolic precursors, derivatives of norbelladine, has been shown and by means of multiple labelled experiments incorporation as a whole, without degradation, has been proved. Other experiments described have thrown light on the earlier stages of biogenesis. The norlaudanosine derivative, (±) reticuline, has been shown to be incorporated into morphine, and an in vitro synthesis of thebaine from (±) reticuline using a radiochemical dilution method is de-scribed. I am deeply grateful to Professor D. H. R. Barton and Dr. G. W. Kirby for the privilege and pleasure of working under their supervision and for their great help in matters chemical and non-chemical. To the Salters Company I would like to express my sincere thanks for the award of a scholarship and for their interest during the tenure of it. My thanks are also due to Dr. D. W. Turner for advice on counting techniques, Mr. D. Aldrich and his staff for valuable technical assistance, Miss J. Cuckney for microanalyses, Mr. R.H. Young who grew the daffodils and poppies and to my many friends and co-workers at Imperial College. REVIEW Alkaloid Biogenesis 1 THE AMARYLLIDACEAE ALKALOIDS Introduction 12 Early tracer experiments 16 Synthesis of precursors 21 Feeding experiments 23 Nature of the C - C unit .....34 6 1 THE MORPHINE ALKALOIDS Introduction 40 Feeding experiments 43 The configuration of morphine 52 EXPERIMENTAL Amaryllidaceae alkaloids 58 Morphine alkaloids 74 REFERENCES 83 REVIEW 31.,.r,•••• ALKALOID BIOSYNTHESIS There has been much thought and discussion about the way in which the wide variety of plant alkaloids are produced. With the advent of tracer methods in which compounds with a radioactive label have been fed to living plants, a rapidly growing amount of information on this subject is now available. 1, 2, 3 Recent authoritative reviews of this subject are now available and, for this reason, only a brief survey will be given here. One of the alkaloids from each of seven main groups has been taken, and the way in which tracer experiments have been used to investigate the mode of biogenesis, is described. Pyridine and piperidine alkaloids Nicotine Nicotine (I) the main alkaloid of many Nicotiana species, has been [2.1 extensively studied by tracer methods. 4C] Ornithine (II) was fed4' 5 to N.tabacum and N. rustica plants and found to be a good precursor for the 4 5 alkaloid. Oxidative degradation with nitric acid to nicotinic acid ' (III) 6 and the nitropyrazole (IV) showed that the label was equally divided between positions 2' and 5', NO2 CO2 H 5' 2 Me 2, These results indicated the formation of a symmetrical intermediate 7 which has been suggested by Leete to be putrescine (V) or the mesomeric anion (VI), dliO )* r* ".- H N *%••CO H 2 2 1/47" o2}1 (II) ••••••••,..3, nicotine (I) Support for this scheme came from the incorporation, albeit less efficiently than ornithine, of putrescine (V), proline and glutamic acid into the 7 pyrrolidine ring of nicotine . Experiments to investigate the derivation of the aromatic system have 14 been carried out. Although it was shown that [2 - C] lysine (VII) can serve as a precursor for the piperidine ring in the closely related alkaloid anabasine (VIII), it was found that it did not provide the aromatic system in either 3. 8 anabasine or nicotine . Nr "Z‘` H 2 z (VII) (VIII) Nicotine labelled in the pyridine ring was, however, isolated from plants fed with ring labelled nicotinic acid (III) whereas the carboxyl labelled 9 acid was not incorporated . Information about the derivation of the aromatic ring has come from 14 feeding experiments with labelled acetate. [2 - C] Acetate and 14 10 11 [2 - C] propionate have been shown to be incorporated into the pyridine 14 ring of the alkaloid whereas [1 - C] acetate provided only the pyrrolidine 14 ring, and [1 - C] propionate was not incorporated. [1, 3 - 14C] Glycerol provided nicotine with 57% of its activity in the ll aromatic nucleus . Tracer experiments have also shown that the N-methyl group of 12 13 nicotine can arise from choline or methionine and in the latter case that 14 14 a true transmethylation occurs . [Methyl- C] Nicotine has also been shown 14 to give rise to [methyl- C] choline in the plants so that methyl transfer from the alkaloid to acceptors can also occur. In the light of these results the biogenesis of nicotine may be summarised as follows. 4. CO2H Cozx Ornithine .160••••100,00 Proline Me Glutamic acid Choline Me . .,filethlonme Tropane alkaloids Hyoscyamine (IX) One relationship between the tropane alkaloids, based on the skeleton (X), and the pyrrolidine bases is shown by the incorporation into 14 15 hyoscyamine of [2 - CI ornithine , the precursor for the pyrrolidine portion of nicotine, Degradation proved the incorporation to be specific with the label inpositions 1 or 516'17 . The other three carbon atoms of the tropane system were shown, by the appropriate tracer experiments, to be 18 derivable from acetate . The biosynthesis of the tropic acid (XI) residue of the alkaloid was studied in three separate experiments in which phenylalanine (XII) labelled 19 in the 1-, 2- and 3-positions was fed to Datura stramoniurn . Hydrolysis of the alkaloids to tropic acid and subsequent simple degradations proved that phenylalanine is a direct precursor. The respective positions of the labels 5. were those indicated. H °2 C + HO 2C Ph CH 0H z 0 (XI) (IX) 14 *, o and + indicate [ C] labels from different experiments) Isoquinoline and phenethylamine alkaloids As early as 191020 before the advent of tracer experiments, it was 21 suggested that the main precursors of this large group of alkaloids are the aromatic amino acids phenylalanine (XII), tyrosine (XIII) and dihydroxy- phenylalanine, Hordenine (XV) Decarboxylation, oxidation and methylation, all well known in living systems, are all that are required to convert these amino acids into hordenine. Phenylalanine (XII), tyrosine (XIII) and tyramine (XIV)22 have all been shown to be incorporated into the alkaloid in sprouting barley. The 6, positions of the labels were as expected and the quantitative results suggest that hordenine is formed from tyramine in a stepwise methylation process. 23 24 This is supported by experiments in which methionine (XVI) and betaine (XVII) were shown to be sources of the methyl groups in the alkaloid. The biosynthesis may then be summarised thus: CO H 2 ed•-\\,,C0aH NH NH HO 2 HO 2 (XIV) (XIII) (XII) NH 2 Me CO H (XVI) z NMe HO Me V. + - (XV) 'Me N .0" CO (XVII) 3 2 CH 2 Papaverine (XVIII) 20 In 1910 it was suggested that norlaudanosoline (XIX) is formed from two moles of dihydroxyphenylalanine and it is apparent that papaverine could be derived from this by dehydrogenation of the heterocyclic system, 25 possibly by way of the N-oxide . 7. HO HO OH OMe OH OMe \OMe (XIX) (XVIII) (XX) Papaverine and laudanosine (XX) occur together in the opium poppy. 26 Battersby and Harper established the biosynthesis of papaverine from two molecules of tyrosine by feeding Papaver somniferum with 14 [2- C] tyrosine and showing equal activity in the expected positions of the alkaloid (XVIII). 27 14 In further work the same group showed that [1- C] norlaudanosoline provided papaverine specifically labelled at position 1. The relationship between the benzylisoquinoline and morphine alkaloids will be discussed in detail later. Berberine (XXI) An examination of the structure of berberine (XXI) suggests that it might also be derived from norlaudanosoline (XIX) and evidence of this came 28 from the specific incorporation of two molecules of [2-14C] tyrosine . In recent experiments in this laboratory, Mr. R. H. Hesse has isolated active berberine from Hydrastis canadensis fed with the norlaudanosoline derivative 3 (±) reticuline (XXII), labelled as shown. This also adds weight to the suggestion that the berberine bridge carbon atom (arrowed) arises from the N-methyl group but the degradation to prove this has not yet been carried out. 8. MeO /•?. - Me HO OH NO Me OMe (XXI) (XXII) Colchicine (XXIII) A complete picture of the mode of biogenesis of this alkaloid, found in the autumn crocus is not yet available. 14 [3 - C] Phenylalanine (XII) was specifically incorporated into 29 colchicine in Colchicum izirantium the label being at position 5. Me Me 0 Me0 0 (XXIII) (XII) Independently30 [2 - 14C] tyrosine was found to be incorporated into Colchicum autumnale but position 6 was virtually inactive. Half of the alkaloid activity was, however, found in the N-acetyl group. This suggests 9. that degradation of the amino acids to a C - C fragment takes place prior 6 1 to incorporation. 14 30 31 L-[methyl- C] Methionine was also found to be incorporated ' but provided only the methyl groups of the alkaloid. The origin of the tropolone part of the molecule is still unknown 14 30 31 since, although [1- C] acetate gave active colchicine, all the activity was found in the N-acetyl group. Indole alkaloids Ajmaline (XXIV) Although [2-14C] tryptophane has been shown to be the precursor of 32 the f3-carboline moiety of ajmaline , the origin of the remainder of the molecule is still not clear and has been the subject of much discussion, 33 34 Woodward and Robinson suggested derivation from dihydroxyphenyl- 35 alanine with subsequent 'Woodward' fission, Wenkert suggested derivation 36 from prephenic acid (XXV) and Thomas from a monoterpene skeleton (XXVI, numbered as would be expected in ajmaline).
Load more

Recommended publications
  • Neurotransmitter Resource Guide
    NEUROTRANSMITTER RESOURCE GUIDE Science + Insight doctorsdata.com Doctor’s Data, Inc. Neurotransmitter RESOURCE GUIDE Table of Contents Sample Report Sample Report ........................................................................................................................................................................... 1 Analyte Considerations Phenylethylamine (B-phenylethylamine or PEA) ................................................................................................. 1 Tyrosine .......................................................................................................................................................................................... 3 Tyramine ........................................................................................................................................................................................4 Dopamine .....................................................................................................................................................................................6 3, 4-Dihydroxyphenylacetic Acid (DOPAC) ............................................................................................................... 7 3-Methoxytyramine (3-MT) ............................................................................................................................................... 9 Norepinephrine ........................................................................................................................................................................
    [Show full text]
  • Mrx CLINICAL ALERT
    MRx AUGUST 2018 CLINICAL ALERT YOUR MONTHLY SOURCE FOR DRUG INFORMATION HIGHLIGHTS HOT TOPIC: potential to placebo in non-dependent FIRST DRUG COMPRISED adult recreational drug users. EDITORIAL OF ACTIVE MARIJUANA DERIVATIVE APPROVED Cannabidiol oral solution was studied STAFF in 3 randomized, double-blind, placebo- Under Priority review, the United States controlled clinical trials including 516 (US) Food and Drug Administration (FDA) patients with either LGS or Dravet EDITOR IN CHIEF approved cannabidiol oral solution syndrome. Cannabidiol taken with ® Maryam Tabatabai (Epidiolex ) for the treatment of the patient’s current anticonvulsant PharmD seizures associated with Lennox-Gastaut regimen was shown to be effective syndrome (LGS) or Dravet syndrome in in reducing the frequency of seizures patients ≥ 2 years of age. It is the only when compared with placebo. Over EXECUTIVE EDITOR drug approved to treat Dravet syndrome the 12-week treatment period, the Carole Kerzic and the FDA designated it as an Orphan reduction in median number of LGS RPh drug and Rare pediatric disease drug seizures ranged from 37% to 44% with to treat both serious, difficult-to-treat CBD and 17% to 22% with placebo. DEPUTY EDITORS childhood seizure disorders. Dravet For Dravet syndrome, seizure reductions Stephanie Christofferson syndrome is diagnosed in approximately were 39% and 13% with CBD and PharmD 1 in 15,700 individuals in the US and placebo, respectively. Common side is characterized by frequent prolonged effects (≥ 10%) reported with CBD Jessica Czechowski seizures and developmental delays. LGS were increased liver transaminases PharmD involves frequent drop seizures and (particularly with concurrent use of impaired intellectual development.
    [Show full text]
  • The Activation of Α1-Adrenoceptors Is Implicated in the Antidepressant-Like Effect of Creatine in the Tail Suspension Test
    CORE Metadata, citation and similar papers at core.ac.uk Provided by Elsevier - Publisher Connector Progress in Neuro-Psychopharmacology & Biological Psychiatry 44 (2013) 39–50 Contents lists available at SciVerse ScienceDirect Progress in Neuro-Psychopharmacology & Biological Psychiatry journal homepage: www.elsevier.com/locate/pnp The activation of α1-adrenoceptors is implicated in the antidepressant-like effect of creatine in the tail suspension test Mauricio P. Cunha, Francis L. Pazini, Ágatha Oliveira, Luis E.B. Bettio, Julia M. Rosa, Daniele G. Machado, Ana Lúcia S. Rodrigues ⁎ Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, 88040-900, Florianópolis, SC, Brazil article info abstract Article history: The antidepressant-like activity of creatine in the tail suspension test (TST) was demonstrated previously by Received 5 September 2012 our group. In this study we investigated the involvement of the noradrenergic system in the Received in revised form 8 January 2013 antidepressant-like effect of creatine in the mouse TST. In the first set of experiments, creatine administered Accepted 18 January 2013 by i.c.v. route (1 μg/site) decreased the immobility time in the TST, suggesting the central effect of this com- Available online 26 January 2013 pound. The anti-immobility effect of peripheral administration of creatine (1 mg/kg, p.o.) was prevented by the pretreatment of mice with α-methyl-p-tyrosine (100 mg/kg, i.p., inhibitor of tyrosine hydroxylase), Keywords: α α Antidepressant prazosin
    [Show full text]
  • Today's Topic
    May 7, 2021 Vol. 1, No. 8 Palliative Care Pharmacy Team: TODAY’S TOPIC: Antidepressant Adverse Drug Reactions: Focus on QT Prolongation Clinical Pharmacy Specialist: Background: Antidepressants have been used for many years to treat mental health conditions such as Maria Felton Lowry, depression and anxiety (not an all-inclusive list). Their mechanisms are somewhat unique to the PharmD, BCPS, BCGP class of antidepressant, for instance, tricyclic antidepressants are thought to delay the inward Assistant Professor sodium current into cardiomyocytes, slowing cardiac depolarization. In contrast, SSRIs directly block potassium channels and disrupt hERG protein expression, both reducing potassium ion flow. University of Pittsburgh Palliative care clinicians use these medications commonly in clinical practice for symptom School of Pharmacy, management and should be aware of their potential side effects. Department of Pharmacy and Therapeutics Importance: Palliative Antidepressants can cause QTc prolongation. As stated in previous weeks, clinically significant QTc Care Clinical Pharmacy prolongation is an absolute QTc > 500 msec, QTc > 25% from baseline, or change of QTc > 60 Specialist msec.1 The degree of QTc prolongation is a modest predictor of the risk of Torsades de Pointes UPMC Palliative and (TdP) and sudden cardiac death.2 Still, it is important for palliative care clinicians be aware of this Supportive Institute risk of commonly prescribed medications in our practice. Cell: 412-627-8473 Known QTc prolongation risk factors: Office: 412-864-2899
    [Show full text]
  • Assessment Report
    19 September 2013 EMA/737723/2013 Committee for Medicinal Products for Human Use (CHMP) Assessment report ABILIFY MAINTENA International non-proprietary name: ARIPIPRAZOLE Procedure No. EMEA/H/C/002755/0000 Note Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted. 7 Westferry Circus ● Canary Wharf ● London E14 4HB ● United Kingdom Telephone +44 (0)20 7418 8400 Facsimile +44 (0)20 7418 8613 E -mail [email protected] Website www.ema.europa.eu An agency of the European Union © European Medicines Agency, 2013. Reproduction is authorised provided the source is acknowledged. Table of contents 1.1. Submission of the dossier .................................................................................... 6 1.2. Manufacturers ................................................................................................... 6 1.3. Steps taken for the assessment of the product ....................................................... 7 2. Scientific discussion ................................................................................ 7 2.1. Introduction ...................................................................................................... 7 2.2. Quality aspects .................................................................................................. 9 2.2.1. Introduction ................................................................................................... 9 2.2.2. Active Substance ..........................................................................................
    [Show full text]
  • Binding Energies of Tyrosine Kinase Inhibitors: Error Assessment of Computational Methods for Imatinib and Nilotinib Binding Clifford Fong
    Binding Energies of Tyrosine Kinase Inhibitors: error assessment of computational methods for imatinib and nilotinib binding Clifford Fong To cite this version: Clifford Fong. Binding Energies of Tyrosine Kinase Inhibitors: error assessment of computational methods for imatinib and nilotinib binding. Computational Biology and Chemistry, Elsevier, 2015, 58, pp.40-54. 10.1016/j.compbiolchem.2015.05.002. hal-01344991 HAL Id: hal-01344991 https://hal.archives-ouvertes.fr/hal-01344991 Submitted on 13 Jul 2016 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Computational Biology and Chemistry, 18 May 2015, doi:10.1016/j.compbiolchem.2015.05.002 Computational Biology and Chemistry 58 (2015) 40–54 Binding Energies of Tyrosine Kinase Inhibitors: error assessment of computational methods for imatinib and nilotinib binding Clifford W. Fong* Eigenenergy, Adelaide, South Australia, Australia * Author to whom correspondence should be addressed; E-Mail: [email protected] The binding energies of imatinib and nilotinib to tyrosine kinase have been determined by quantum mechanical (QM) computations, and compared with literature binding energy studies using molecular mechanics (MM). The potential errors in the computational methods include these critical factors: Errors in X-ray structures such as structural distortions and steric clashes give unrealistically high van der Waals energies, and erroneous binding energies.
    [Show full text]
  • Wednesday, June 12, 2019 4:00Pm
    Wednesday, June 12, 2019 4:00pm Oklahoma Health Care Authority 4345 N. Lincoln Blvd. Oklahoma City, OK 73105 The University of Oklahoma Health Sciences Center COLLEGE OF PHARMACY PHARMACY MANAGEMENT CONSULTANTS MEMORANDUM TO: Drug Utilization Review (DUR) Board Members FROM: Melissa Abbott, Pharm.D. SUBJECT: Packet Contents for DUR Board Meeting – June 12, 2019 DATE: June 5, 2019 Note: The DUR Board will meet at 4:00pm. The meeting will be held at 4345 N. Lincoln Blvd. Enclosed are the following items related to the June meeting. Material is arranged in order of the agenda. Call to Order Public Comment Forum Action Item – Approval of DUR Board Meeting Minutes – Appendix A Update on Medication Coverage Authorization Unit/Use of Angiotensin Converting Enzyme Inhibitor (ACEI)/ Angiotensin Receptor Blocker (ARB) Therapy in Patients with Diabetes and Hypertension (HTN) Mailing Update – Appendix B Action Item – Vote to Prior Authorize Aldurazyme® (Laronidase) and Naglazyme® (Galsulfase) – Appendix C Action Item – Vote to Prior Authorize Plenvu® [Polyethylene Glycol (PEG)-3350/Sodium Ascorbate/Sodium Sulfate/Ascorbic Acid/Sodium Chloride/Potassium Chloride] – Appendix D Action Item – Vote to Prior Authorize Consensi® (Amlodipine/Celecoxib) and Kapspargo™ Sprinkle [Metoprolol Succinate Extended-Release (ER)] – Appendix E Action Item – Vote to Update the Prior Authorization Criteria For H.P. Acthar® Gel (Repository Corticotropin Injection) – Appendix F Action Item – Vote to Prior Authorize Fulphila® (Pegfilgrastim-jmdb), Nivestym™ (Filgrastim-aafi),
    [Show full text]
  • Psychopharmacology '! by Springer-Verlag 1978
    m : t Aoq Psychopharmacolos5y9, tl 3- 116(1978) Psychopharmacology _'! by Springer-Verlag 1978 Effects of LSD and BOL on the Catecholamine Synthesis and Turnover in Various Brain Regions Sven-Ake Persson Departmentof Pharmacology,Universityof Ume_, S-90I87 Ume_, Sweden Abstract. In the rat, lysergic acid diethylamide (LSD) cerebral dopamine (DA) levels (Diaz et al., 1968). 0.5 mg/kg and 2-bromo lysergic acid diethylamide However, increased cerebral DA levels after LSD have - (BOL) 0.5 mg/kg increased the rate of the striatal in also been reported (Smith et al., (1975), Relatively few vivo tyrosine hydroxylation as measured by the DOPA studies on the cerebral catecholamine turnover have accumulation after decarboxylase inhibition. Neither been reported. High doses of LSD increased the LSD nor BOL significantly changed the DOPA accu- disappearance of NA in the rat brain after treatment mulation in the olfactory tubercle, a dopamine-rich with a-methyl-p-tyrosine methylester (a-MT) (And6n part of the limbic system. LSD but not BOL increased et ai., 1968). LSD did not affect the disappearance of the DOPA accumulation in the cerebral cortex and in DA. Da Prada et al. (1975) found that LSD decreased the brain stem. LSD and BOL appeared not to alter the the disappearance of DA in the rat teldiencephalon rate ofa-MT-induced disappearance of DA or of NA in after _t-MT and that LSD also decreased the homova- the whole brain, nor did they change the rate of the a- nillic acid (HVA) level in the striatum and in the eyes, MT-induced disappearance of DA in the striatum.
    [Show full text]
  • Indications for Use Form
    DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service ____________________________________________________________________________________________________________________________ Food and Drug Administration 10903 New Hampshire Avenue Document Control Center – WO66-G609 Silver Spring, MD 20993-0002 W.H.P.M., INC. February 26, 2015 JOHN WAN 5358 IRWINDALE AVENUE IRWINDALE CA 91706 Re: K150162 Trade/Device Name: First Sign® Drug Of Abuse Cup Test First Sign® Drug Of Abuse Dip Card Test Regulation Number: 21 CFR 862.3610 Regulation Name: Methamphetamine test system Regulatory Class: II Product Code: LAF, JXM, DJG Dated: January 19, 2015 Received: January 26, 2015 Dear Mr. John Wan: We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading. If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls.
    [Show full text]
  • Visible Light Photoredox Catalysis with Transition Metal Complexes: Applications in Organic Synthesis Christopher K
    Review pubs.acs.org/CR Visible Light Photoredox Catalysis with Transition Metal Complexes: Applications in Organic Synthesis Christopher K. Prier, Danica A. Rankic, and David W. C. MacMillan* Merck Center for Catalysis at Princeton University, Princeton, New Jersey 08544, United States References 5360 1. INTRODUCTION CONTENTS A fundamental aim in the field of catalysis is the development 1. Introduction 5322 of new modes of small molecule activation. One approach 2+ toward the catalytic activation of organic molecules that has 2. Photochemistry of Ru(bpy)3 5323 3. Net Reductive Reactions 5324 received much attention recently is visible light photoredox 3.1. Reduction of Electron-Poor Olefins 5324 catalysis. In a general sense, this approach relies on the ability of 3.2. Reductive Dehalogenation 5326 metal complexes and organic dyes to engage in single-electron- 3.3. Reductive Cleavage of Sulfonium and transfer (SET) processes with organic substrates upon Sulfonyl Groups 5328 photoexcitation with visible light. 3.4. Nitrogen Functional Group Reductions 5329 Many of the most commonly employed visible light 3.5. Radical Cyclizations 5330 photocatalysts are polypyridyl complexes of ruthenium and iridium, and are typified by the complex tris(2,2′-bipyridine) 3.6. Reductive Epoxide and Aziridine Opening 5331 2+ 3.7. Reduction-Labile Protecting Groups 5331 ruthenium(II), or Ru(bpy)3 (Figure 1). These complexes 4. Net Oxidative Reactions 5332 4.1. Functional Group Oxidations 5332 4.2. Oxidative Removal of the PMB Group 5334 4.3. Oxidative Biaryl Coupling 5335 4.4. Oxidative Generation of Iminium Ions 5335 4.5. Azomethine Ylide [3 + 2] Cycloadditions 5338 4.6.
    [Show full text]
  • Doxepin > Printer-Friendly PDF
    Published on British Columbia Drug and Poison Information Centre (BC DPIC) ( http://www.dpic.org) Home > Drug Product Listings > Doxepin > Printer-friendly PDF Doxepin Trade Name: Silenor Manufacturer/Distributor: Paladin Labs www.paladin-labs.com 1-888-376-7830 Classification: Hypnotic ATC Class: N06AA - doxepin Status: active Notice of Compliance (yyyy/mm/dd): 2012/21/13 Date Marketed in Canada (yyyy/mm/dd): 2012/01/08 Presentation: Tablet: 3 mg. DIN: 02398257 Tablet: 6 mg. DIN: 02398265 Comments: Silenor is indicated for the treatment and symptomatic relief of insomnia characterized by frequent nocturnal awakening, and/or early morning awakenings. Keywords: doxepin sleep disorders hypnotics & sedatives Access: public Back to: Please note - this is not a complete list of products available in Canada. For a complete list of drug products marketed in Canada, visit the Health Canada Drug Product Database Status: <Any> ? Search Terms: Apply A (37) | B (20) | C (24) | D (37) | E (40) | F (12) | G (11) | H (9) | I (24) | K (1) | L (26) | M (12) | N (7) | O (12) | P (28) | R (14) | S (27) | T (33) | U (4) | V (13) | W (2) | Z (4) Common Date Marketed in Generic Name Trade Classification Canada Name(s) (yyyy/mm/dd) Co-stimulation modulator Abatacept Orencia 2006/09 for rheumatoid arthritis Abemaciclib Verzenio Protein kinase inhibitor 2019/07/03 Androgen biosynthesis Abiraterone Zytiga 2011/08/08 inhibitor Acamprosate Campral Alcohol abstinence aid 2007/03 Bronchodilator Duaklir Aclidinium + formoterol combination - LAMA plus 2015/07/09 Genuair
    [Show full text]
  • Adasuve, INN-Loxapine
    13 December 2012 EMA/91055/2013 Committee for Medicinal Products for Human Use (CHMP) Assessment report Adasuve International non-proprietary name: loxapine Procedure No. EMEA/H/C/002400 Note Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted. 7 Westferry Circus ● Canary Wharf ● London E14 4HB ● United Kingdom Telephone +44 (0)20 7418 8400 Facsimile +44 (0)20 7523 7455 E -mail [email protected] Website www.ema.europa.eu An agency of the European Union © European Medicines Agency, 2013. Reproduction is authorised provided the source is acknowledged. Contents 1. Background information on the procedure .............................................. 8 1.1. Submission of the dossier .................................................................................... 8 Information on Paediatric requirements ....................................................................... 8 Information relating to orphan market exclusivity .......................................................... 8 Scientific Advice ....................................................................................................... 8 Licensing status ....................................................................................................... 8 1.2. Steps taken for the assessment of the product ....................................................... 9 2. Scientific discussion .............................................................................. 10 2.1. Introduction ...................................................................................................
    [Show full text]