DOCSLIB.ORG

(12) United States Patent (10) Patent No.: US 6,660,832 B1 Jefferson 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 6,660,832 B1 Jefferson Et Al USOO6660832B1 (12) United States Patent (10) Patent No.: US 6,660,832 B1 Jefferson et al. (45) Date of Patent: Dec. 9, 2003 (54) MACROCYCLIC COMPOUNDS AND Bilodeau, M.T., et al., “Solid-Supported Synthesis of Imi PREPARATION METHODS THEREOF dazoles: A Stragegy for Direct Resin-Attachment to the Imidazole Core", J. Org. Chem., 1998, 63, 2800–2801. (75) Inventors: Elizabeth Jefferson, La Jolla, CA (US); Block, L., “Medicated Applications”, Remington's Pharma Eric Edward Swayze, Carlsbad, CA ceutical Sciences, 18th Ed., Gennaro (ed.), Mack Publishing (US) Co., Easton, PA, 1990, Ch. 87, 1596–1614. Bodanszky, M., et al., “Side Reactions in Peptide Synthesis. (73) Assignee: ISIS Pharmaceuticals, Inc., Carlsbad, 11. Possible Removal of the 9-Fluorenylmethyoxycarbonyl CA (US) Group by the Amino Components during Coupling, J. Org. Chem., 1979, 44, 1622–1625. (*) Notice: Subject to any disclaimer, the term of this Bomann, et al., “A Mild, Pyridine-Borane-Based Reductive patent is extended or adjusted under 35 Amination Protocol”, J. Org. Chem., 1995, 60,5995-5996. U.S.C. 154(b) by 0 days. Cheung, S.T., et al., “N-Methylamino acids in peptides Synthesis. VI. A method for determining the enantiomeric (21) Appl. No.: 09/378,529 purity of N-methylamino acids and their derivatives by ion-exchange chromatography as their C-terminal lysyl (22) Filed: Aug. 20, 1999 dipeptides”, Can. J. Chem., 1977, 55,911–915. (51) Int. Cl." .................................................. C07K 7/50 Chow, C.S., et al., “A Structural Basis for RNA-Ligand (52) U.S. Cl. ........................... 530/317; 514/11; 514/19; Interactions”, Chem. Rev., 1997, 97, 1489–1514. 514/159 Coste, J., et al., “Oxybenzotriazole Free Peptide Coupling (58) Field of Search ................................. 530/454, 474, Reagents for N-Methylated Amino Acids”, Tetrahedron Lett., 1991, 32, 1967-1970. 530/450, 317; 514/183, 11, 19 Coste, J., et al., “BROP: A New Reagent for Coupling (56) References Cited N-Methylated Amino Acids”, Tetrahedron Lett., 1990, 31, 669-672. U.S. PATENT DOCUMENTS Egorov, M.P., et al., “Some Aspects of Anionic O Com 3.687,808 A 8/1972 Merigan et al. ........... 435/91.3 plexes”, Chem. Rev., 1982, 82, 427–459. 5,741,462 A 4/1998 Nova et al. ................ 422/68.1 Enantioselective Synthesis of Beta-Amino Acids, Juarish, 5,751,629 A 5/1998 Nova et al. ................. 365/151 E., John Wiley & Sons, New York, N.Y. 1997. 5,770,455 A 6/1998 Cargill et al. ..... ... 436/518 Englisch, U., “Chemically Modified Oligonucleotides as 5,874.214 A 2/1999 Nova et al. .................... 435/6 Probes and Inhibitors', Angew. Chem. Int. Ed. Eng., 1991, 5,925,562 A 7/1999 Nova et al. .............. 435/287.1 30, 613-629. Feng, Y., et al., SNAr Cyclizations To Form Cyclic Pepti OTHER PUBLICATIONS domimetics of B-Turns, J. Am. Chem. Soc., 1998, 120, Corriveau Infectious Agents and Disease 2, 44-52, 1993.* 10768-10769. Gavini, Archiv der Pharmazie 333 (10) 341 6, 2000.* (List continued on next page.) Fudou, Journal of Antibiotics 54 (2) 149–52, 2001.* Juvvadi Journal of Peptide Research 53 (3) 244-51, 1999.* Primary Examiner-Christopher S. F. Low Avrahami, Biochemistry 40 (42) 12591-603, 2001.* ASSistant Examiner David Lukton Otvos, Protein Science 9 (4) 742–9, 2000.* (74) Attorney, Agent, or Firm Woodcock Washburn LLP Jefferson et al., Beta-Amino Acid Facilitates Macrocyclic (57) ABSTRACT Ring Closure in a Combinatorial Library, Tetrahedron Let ters, 40, pp. 7757-7760, 1999.* The present invention is directed to macrocyclic compounds Boggetto et al., Cyclic Peptides as Selective Substrates and of the formula (I) Suicide Substrate Precursors of Trypsin-like proteinases, Bull. Chim. Fr., 36(11), pp. 152–166, 1994.* (I) Feng et al., SNAr Cyclization to Form Cyclic Peptidomi metics of Beta-turns., J. Am. Chem. Soc., 120(41), pp. 10768-10769, 1998.* HN Kiselyov et al., Tetrahedron, 54 pp. 10635-10640, 1998.* Rama Rao et al., Chem. Rev., 95, pp. 2135-2167, 1995.* Marsh et al., J. Org. Chem., 62, pp. 6199-6202, 1997.* Angell, Y.M., et al., “Comparative Studies of the Coupling of N-Methylated, Sterically Hindered Amino Acids During Solid-Phase Peptide Synthesis”, Tetrahedron Lett., 1994, 35,5981-5984. Balasubramanian, S., et al., “Solid Phase Reductive Alky wherein Q, X, R and Rs are as defined herein. Compounds lation of Secondary Amines”, Tetrahedron Lett., 1996, 37, of the invention are useful for therapeutic and prophylactic 4819-4822. treatment of bacterial infection in mammals. Solid phase Beugelmans, R., et al., “The First Examples of Snar-based Synthetic procedures are provided effecting Synthesis of the Macrocyclisation: Synthesis of Model Carboxylate-Binding macrocyclic rings attached to a Solid Support. Pockets of Vancomycin, J. Chem. Soc., Chem. Commun., 1994,439. 31 Claims, 7 Drawing Sheets US 6,660,832 B1 Page 2 OTHER PUBLICATIONS Pearson, N.D. and Prescott, C.D., “RNA as a drug target', Fivush, A.M., et al., “AMEBA: An Acid Sensitive Aldehyde Chem. Biol., 1997, 97(4), 409–414. Resin for Solid Phase Synthesis”, Tetrahedron Lett., 1997, Pelter, A., et al., “Reductive Aminations of Ketones and 38, 7151-7154. Aldehydes using Borane-Pyridine”, J. Chem. Soc., Perkins Greene, T.W. and Wuts, P.G.M., Protective Groups in Trans I, 1984, 717–720. Organic Synthesis, 2" Ed., John Wiley & Sons, New York, Rama Rao, A.V., et al., “S.Ar Macrycyclisation: A New N.Y. 1991. Approach Towards the Synthesis of D-O-E Segment of Guichard, G., et al., “Preparation of N-Fmoc-Protected vancomycin, Tetrahedron lett., 1997, 38(42), 7433–7436. B°-and B-Amino Acids and Their Use as Building Blocks for the Solid-Phase Synthesis of B-Peptides”, Hell: Chem. Rama Rao, A.V., et al., “Studies Directed toward the Syn Acta., 1998, 81, 187-206. thesis of Vancomycin and Related Cyclin Peptides”, Chem. Hermann, T., “RNA as a drug target: chemical, modelling, Rev., 1995, 95, 2135-2167. and evolutionary tools”, Curr. Opin. Biotech., 1998, 9, Rich, D.H., “Bis(2-oxo-3-oxazolidinyl)phosphinic Chlo 66-73. ride (1) as a Coupling Reagent for N-Alkyl Amino Acids, Kearney, P.C., et al., “Solid-Phase Synthesis of 2-Ami J. Am. Chem. Soc., 1985, 107, 4342–4343. nothiazoles”, J. Org. Chem., 1998, 63, 196-200. Kiselyov, et al., “Solid Support Synthesis of 14-Membered Rudnic, E. et al., “Oral Solid Dosage Forms”, Remington's Macrocyles Containing the Thioether Bridge via SNAr Pharmaceutical Sciences, 18th Ed., Gennaro (ed.), Mack Methodology”, Tetrahedon, 1998, 54, 10635-10640. Publishing Co., Easton, PA, 1990, Ch. 89, 1633–1665. Kroschwitz, J.I., “Polynucleotides”, Concise Encyclopedia Sarantakis, et al., “Solid Phase Synthesis of Sec-Amides of Polymer Science and Engineering, 1990, John Wiley & and Removal from the Polymeric Support Under Mild Sons, New York, 858-859. Conditions”, Tetrahedron Lett., 1997, 38, 7325-7328. Longer, M. A. et al., “Sustained-Release Drug Delivery Swayze, E., “Secondary Amide-based Linkers for Solid Systems”, Remington's Pharmaceitucal Sciences, 18th Ed., Phase Organic Synthesis”, Tetrahedron Letters, 1997, Gennaro (ed.), Mack Publishing Co., Easton, PA, 1990, Ch. 38(49), 8465–8468. 91, 1676–1693. Marsh, I.R., et al., “Solid-Phase Total Synthesis of Oscil Wallis, M.G., et al., “The Binding of Antibiotics to RNA", lamide Y and Analogues”, J. Org. Chem., 1997, 62, Prog. Biophys. Molec. Biol., 1997, 67, 141–154. 61.99-62O3. Wei, G.P., et al., “Solid Phase Synthesis of Benzimidazolo McClinton, M.A., “Triethylamine Tris(hydrogen fluoride): nes”, Tetrahedron Letts., 1998, 39, 179-182. Applications in Synthesis”, Aldrichimica Acta, 1995, 28, Wenger, R.M., “270. Synthesis of Cyclosporine', Hell: 31-35. Meire, “The Woff Rearrangement of C-Diazo Carbonyl Chem. Acta., 1983, 66, 2672-2702. Compounds”, Angew. Chem. Int. Ed. Engl. 1975, 14, 32-43. Yoon, N.M., et al., “Selective Reductions. XIX. The Rapid Michael, K., “Designing Novel RNA Binders”, Chem. Eur: Reaction of Carboxylic Acids with Borane-Tetrahydrofu J., 1998, 4, 2091-2098. ran. A Remarkably Convenient Procedure for the Selective Moormann, A.E., “Reductive Amination of Piperidines with Conversion of Carboxylic Acids to the Corresponding Alco Aldehydes Using Borane-Pyridine', Synth. Commun., 1993, hols in the Presence of Other Functional Groups', J. Org. 23, 789-795. Chem., 1973, 38, 2786-2792. Nairn, et al., “Solutions, Emulsions, Suspensions and Boggetto, et al., “Cyclic peptides as Selective Substrates and Extracts”, Remington's Pharmaceutical Sciences, 18th Ed., Suicide Substrate precursors of trypsin-like proteinases,” Gennaro (ed.), Mack Publishing Co., Easton, PA, 1990, Ch. Bull. Soc. Chim. Fr., 1994, 131, 152–166. 83, 1519–1544. Nurgatin, et al., “Investigations in the 2,4,6-Trinitrothiophe Chemical Abstracts, 119(13), 1993, Columbus, OH, USA), nol Series. ... ", J. Org. Chem. USSR, 1983, 19, 343–346. 944; col. 1, the abstract No. 139765x, Wakselman, M., “New Ouyang, et al., “Solid Support Synthesis of 2-Substituted mechanism-based inactivators of trypsin-like proteinases,” Dibenzb,floxazepin-11(10H)-ones via S.Ar Methodology J. Med. Chem., 1993, 36(11), 1539–1547. on AMEBA Resin', Tetrahedron, 1999, 55, 2827–2834. Jefferson, E.A., et al., “B-amino acid facilitates macrocyclic Paradisi, C., “Arene Substitution via Nucleophilic Addition ring closure in a combinatorial library,” Tetra. Letts., 1999, to Electron Deficient Arenes”, Comprehensive Organic Syn 40, 7757-7760. thesis, Trost, B.M., et al., eds., Pergamon Press: Oxford, 1991, vol. 4, pp. 423–450. * cited by examiner U.S. Patent Dec. 9, 2003 Sheet 1 of 7 US 6,660,832 B1 R R b, C R d R ef ornoTBDMS Y---OH - - - loTBDMS -----OTBDMS - y - - R-M2 N ON ONo. O NH la-h 2a-h R- R 3 a Y: Emoc moC xNHFmoc ---- I - 3a-h 4-a-h ON R OTBDMS R R O h R2 O NS k R2 ŠO N-1S 9 R R4 HNOO,--Rs - - - HNO o, 1Rs O= F r NH NH y \ .
Load more

Recommended publications
  • Aldrich FT-IR Collection Edition I Library
    Aldrich FT-IR Collection Edition I Library Library Listing – 10,505 spectra This library is the original FT-IR spectral collection from Aldrich. It includes a wide variety of pure chemical compounds found in the Aldrich Handbook of Fine Chemicals. The Aldrich Collection of FT-IR Spectra Edition I library contains spectra of 10,505 pure compounds and is a subset of the Aldrich Collection of FT-IR Spectra Edition II library. All spectra were acquired by Sigma-Aldrich Co. and were processed by Thermo Fisher Scientific. Eight smaller Aldrich Material Specific Sub-Libraries are also available. Aldrich FT-IR Collection Edition I Index Compound Name Index Compound Name 3515 ((1R)-(ENDO,ANTI))-(+)-3- 928 (+)-LIMONENE OXIDE, 97%, BROMOCAMPHOR-8- SULFONIC MIXTURE OF CIS AND TRANS ACID, AMMONIUM SALT 209 (+)-LONGIFOLENE, 98+% 1708 ((1R)-ENDO)-(+)-3- 2283 (+)-MURAMIC ACID HYDRATE, BROMOCAMPHOR, 98% 98% 3516 ((1S)-(ENDO,ANTI))-(-)-3- 2966 (+)-N,N'- BROMOCAMPHOR-8- SULFONIC DIALLYLTARTARDIAMIDE, 99+% ACID, AMMONIUM SALT 2976 (+)-N-ACETYLMURAMIC ACID, 644 ((1S)-ENDO)-(-)-BORNEOL, 99% 97% 9587 (+)-11ALPHA-HYDROXY-17ALPHA- 965 (+)-NOE-LACTOL DIMER, 99+% METHYLTESTOSTERONE 5127 (+)-P-BROMOTETRAMISOLE 9590 (+)-11ALPHA- OXALATE, 99% HYDROXYPROGESTERONE, 95% 661 (+)-P-MENTH-1-EN-9-OL, 97%, 9588 (+)-17-METHYLTESTOSTERONE, MIXTURE OF ISOMERS 99% 730 (+)-PERSEITOL 8681 (+)-2'-DEOXYURIDINE, 99+% 7913 (+)-PILOCARPINE 7591 (+)-2,3-O-ISOPROPYLIDENE-2,3- HYDROCHLORIDE, 99% DIHYDROXY- 1,4- 5844 (+)-RUTIN HYDRATE, 95% BIS(DIPHENYLPHOSPHINO)BUT 9571 (+)-STIGMASTANOL
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2009/0156618 A1 Tollefson (43) Pub
    US 20090156618A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0156618 A1 Tollefson (43) Pub. Date: Jun. 18, 2009 (54) 1-(1-(2-ETHOXYETHYL)-3-ETHYL-7- Related U.S. Application Data (4-METHYLPYRIDIN-2-YLAMINO) - 1H-PYRAZOLO 4.3-D PYRIMIDIN-5-YL) (60) Provisional application No. 60/735,320, filed on Nov. PPERDINE-4-CARBOXYLIC ACID AND 10, 2005. SALTS THEREOF Publication Classification (51) Int. Cl. (75) Inventor: Michael B. Tollefson, Dardenne A 6LX 3/59 (2006.01) Prairie, MO (US) C07D 487/04 (2006.01) A6IP 9/12 (2006.01) A6IP 25/00 (2006.01) Correspondence Address: A6IP 9/00 (2006.01) PFZER INC. PATENT DEPARTMENT, Bld 114 M/S 114, (52) U.S. Cl. ...................................... 514/262.1; 54.4/262 EASTERN PONT ROAD (57) ABSTRACT GROTON, CT 06340 (US) The present invention comprises 1-(1-(2-ethoxyethyl)-3- ethyl-7-(4-methylpyridin-2-ylamino)-1H-pyrazolo 4.3-d (73) Assignee: Pfizer Inc pyrimidin-5-yl)piperidine-4-carboxylic acid and its salts. The invention further comprises pharmaceutical composi tions, methods of treatment, and synthetic methods relating to (21) Appl. No.: 111558,306 1-(1-(2-ethoxyethyl)-3-ethyl-7-(4-methylpyridin-2- ylamino)-1H-pyrazolo 4.3-dipyrimidin-5-yl)piperidine-4- (22) Filed: Nov. 9, 2006 carboxylic acid and its salts. Patent Application Publication Jun. 18, 2009 Sheet 2 of 2 US 2009/0156618 A1 "SOIHZ US 2009/0156618 A1 Jun. 18, 2009 1-(1-(2-ETHOXYETHYL)-3-ETHYL-7- 1H-pyrazolo 4,3-dipyrimidin-5-yl)piperidine-4-carboxylic (4-METHYLPYRIDIN-2-YLAMINO) - acid and its pharmaceutically acceptable salts.
    [Show full text]
  • Campro Catalog Stable Isotope
    Introduction & Welcome Dear Valued Customer, We are pleased to present to you our Stable Isotopes Catalog which contains more than three thousand (3000) high quality labeled compounds. You will find new additions that are beneficial for your research. Campro Scientific is proud to work together with Isotec, Inc. for the distribution and marketing of their stable isotopes. We have been working with Isotec for more than twenty years and know that their products meet the highest standard. Campro Scientific was founded in 1981 and we provide services to some of the most prestigious universities, research institutes and laboratories throughout Europe. We are a research-oriented company specialized in supporting the requirements of the scientific community. We are the exclusive distributor of some of the world’s leading producers of research chemicals, radioisotopes, stable isotopes and environmental standards. We understand the requirements of our customers, and work every day to fulfill them. In working with us you are guaranteed to receive: - Excellent customer service - High quality products - Dependable service - Efficient distribution The highly educated staff at Campro’s headquarters and sales office is ready to assist you with your questions and product requirements. Feel free to call us at any time. Sincerely, Dr. Ahmad Rajabi General Manager 180/280 = unlabeled 185/285 = 15N labeled 181/281 = double labeled (13C+15N, 13C+D, 15N+18O etc.) 186/286 = 12C labeled 182/282 = d labeled 187/287 = 17O labeled 183/283 = 13C labeleld 188/288 = 18O labeled 184/284 = 16O labeled, 14N labeled 189/289 = Noble Gases Table of Contents Ordering Information.................................................................................................. page 4 - 5 Packaging Information ..............................................................................................
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2007/0254920 A1 Delong Et Al
    US 20070254920A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/0254920 A1 deLong et al. (43) Pub. Date: Nov. 1, 2007 (54) PRODRUG DERIVATIVES OF ACIDS USING (52) U.S. Cl. ......................... 514/319; 514/323: 514/573; ALCOHOLS WITH HOMOTOPIC HYDROXY 514/415: 514/443; 514/469; GROUPS AND METHODS FOR THEIR 546/196; 546/201: 546/206; PREPARATION AND USE 548/495; 549/49; 549/462 (75) Inventors: Mitchell A. deLong, Raleigh, NC (US); (57) ABSTRACT Jill M. McFadden, Chapel Hill, NC This invention relates to novel homotopic prodrugs and (US); Susan M. Royalty, Cary, NC medicaments and methods for their preparation, testing and (US); Eric J. Toone, Durham, NC use. In one embodiment, the homotopic prodrug has the (US); Jeffrey D. Yingling, Apex, NC general formula (US) Correspondence Address: O MICHAEL BEST & FRIEDRCH LLP 100 E WISCONSNAVENUE Rb, Suite 3300 --- MILWAUKEE, WI 53202 (US) wherein (73) Assignee: Aerie Pharmaceuticals, Inc., Research Triangle Park, NC (21) Appl. No.: 11/412,207 (22) Filed: Apr. 26, 2006 -- Publication Classification is a biologically-active moiety comprising a carboxylic acid functional group, and R is a homotopically-symmetrical (51) Int. Cl. alcohol bonded to the biologically-active moiety through the A6 IK 3/558 (2006.01) carboxylic acid functional group to form an ester linkage, as CO7D 409/02 (2006.01) well as optical isomers, enantiomers, pharmaceutically CO7D 405/02 (2006.01) acceptable salts, biohydrolyzable amides, esters, and imides CO7D 403/02 (2006.01) thereof and combinations thereof. US 2007/0254920 A1 Nov. 1, 2007 PRODRUG DERVATIVES OF ACDS USING WO 99/12896, and WO 99/12898.) However, such modifi ALCOHOLS WITH HOMOTOPIC HYDROXY cations have either resulted in only modest increases in GROUPS AND METHODS FOR THEIR half-life or resulted in compounds with diminished potency.
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 7,304,086 B2 Schilling Et Al
    USOO7304086B2 (12) United States Patent (10) Patent No.: US 7,304,086 B2 Schilling et al. (45) Date of Patent: *Dec. 4, 2007 (54) INHIBITORS OF GLUTAMINYL CYCLASE WO WOOO,53596 9, 2000 WO WO O1/34594 A1 5, 2001 (75) Inventors: Stephan Schilling, Halle/Saale (DE); WO WO O2, 13821 2, 2002 WO WO O2, 16318 A1 2, 2002 Mirko Buchholz, Halle/Saale (DE): WO WO O2O16318 A1 * 2/2002 Andre Johannes Niestroj, Sennewitz WO WO O2/O66459 A1 8, 2002 (DE); Ulrich Heiser, Halle/Saale (DE): WO WO O2/O92103 A1 11 2002 Hans-Ulrich Demuth, Halle/Saale (DE) WO WO O2O94813 A1 * 11/2002 WO WO 03/04.0174 A2 5, 2003 (73) Assignee: Probiodrug AG, Halle/Saale (DE) WO WO O3,O70732 8, 2003 WO WO O3068738 8, 2003 (*) Notice: Subject to any disclaimer, the term of this WO WO O30954.21 A1 * 11/2003 patent is extended or adjusted under 35 WO WO 2004O26815 A2 * 4, 2004 U.S.C. 154(b) by 20 days. WO WO 2004/089366 10, 2004 WO WO 2004/098591 A2 11 2004 This patent is Subject to a terminal dis WO WO 2004/098.625 A2 11 2004 claimer. OTHER PUBLICATIONS (21) Appl. No.: 11/051,760 Haley et al. Giorn. Ital. Chemioterap. (1962) 6-9 (No. 3), 213-24. Abstract from CAS attached. (22) Filed: Feb. 4, 2005 Hough et al. Pharmacology, Biochemistry and Behavior 1999, 65(1), 61-66. * Abstract from CAS attached.* (65) Prior Publication Data Morissette et al. Advanced Drug Delivery Reviews 2004, 56. US 2005/0215573 A1 Sep.
    [Show full text]
  • Subject Index
    Cambridge University Press 0521462924 - Amino Acids and Peptides G. C. Barrett and D. T. Elmore Index More information Subject index acetamidomalonate synthesis 123–4 in fossil dating 15 S-adenosyl--methionine 11, 12, 174, 181 in geological samples 15 alanine, N-acetyl 9 in Nature 1 structure 4 IR spectrometry 36 alkaloids, biosynthesis from amino acids 16–17 isolation from proteins 121 alloisoleucine 6 mass spectra 61 allosteric change 178 metabolism, products of 187 allothreonine 6 metal-binding properties 34 Alzheimer’s disease 14 NMR 41 amidation at peptide C-terminus 57, 94, 181 physicochemical properties 32 amides, cis–trans isomerism 20 protein 3 N-acylation 72 PTC derivatives 87 N-alkylation 72 quaternary ammonium salts 50 hydrolysis 57 reactions of amino group 49, 51 O-trimethylsilylation 72 reactions of carboxy group 49, 53 reduction to ␤-aminoalkanols 72 racemisation 56 amidocarbonylation in amino acid synthesis 125 routine spectrometry 35 amino acids, abbreviated names 7 Schöllkopf synthesis 127–8 acid–base properties 32 Schiff base formation 49 antimetabolites 200 sequence determination 97 et seq. as food additives 14 following selective chemical degradation 107 as neurotransmitters 17 following selective enzymic degradation 109 asymmetric synthesis 127 general strategy for 92 ␤- 17–18 identification of C-terminus 106–7 biosynthesis 121 identification of N-terminus 94, 97 biosynthesis from, of creatinine 183 by solid-phase methodology 100 of nitric oxide 186 by stepwise chemical degradation 97 of porphyrins 185 by use of dipeptidyl
    [Show full text]
  • A Few Experimental Suggestions Using Minerals to Obtain Peptides with a High Concentration of L-Amino Acids and Protein Amino Acids
    S S symmetry Hypothesis A Few Experimental Suggestions Using Minerals to Obtain Peptides with a High Concentration of L-Amino Acids and Protein Amino Acids Dimas A. M. Zaia 1,* and Cássia Thaïs B. V. Zaia 2 1 Laboratório de Química Prebiótica-LQP, Departamento de Química, Universidade Estadual de Londrina, CEP 86 057-970 Londrina, Brazil 2 Laboratório de Fisiologia Neuroendocrina e Metabolismo–LaFiNeM, Departamento de Ciências Fisiológicas, Universidade Estadual de Londrina, CEP 86 057-970 Londrina, Brazil; [email protected] * Correspondence: [email protected] Received: 9 October 2020; Accepted: 25 November 2020; Published: 10 December 2020 Abstract: The peptides/proteins of all living beings on our planet are mostly made up of 19 L-amino acids and glycine, an achiral amino acid. Arising from endogenous and exogenous sources, the seas of the prebiotic Earth could have contained a huge diversity of biomolecules (including amino acids), and precursors of biomolecules. Thus, how were these amino acids selected from the huge number of available amino acids and other molecules? What were the peptides of prebiotic Earth made up of? How were these peptides synthesized? Minerals have been considered for this task, since they can preconcentrate amino acids from dilute solutions, catalyze their polymerization, and even make the chiral selection of them. However, until now, this problem has only been studied in compartmentalized experiments. There are separate experiments showing that minerals preconcentrate amino acids by adsorption or catalyze their polymerization, or separate L-amino acids from D-amino acids. Based on the [GADV]-protein world hypothesis, as well as the relative abundance of amino acids on prebiotic Earth obtained by Zaia, several experiments are suggested.
    [Show full text]
  • Ratio of Phosphate to Amino Acids
    National Institute for Health and Care Excellence Final Neonatal parenteral nutrition [D10] Ratio of phosphate to amino acids NICE guideline NG154 Evidence reviews February 2020 Final These evidence reviews were developed by the National Guideline Alliance which is part of the Royal College of Obstetricians and Gynaecologists FINAL Error! No text of specified style in document. Disclaimer The recommendations in this guideline represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, professionals are expected to take this guideline fully into account, alongside the individual needs, preferences and values of their patients or service users. The recommendations in this guideline are not mandatory and the guideline does not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or their carer or guardian. Local commissioners and/or providers have a responsibility to enable the guideline to be applied when individual health professionals and their patients or service users wish to use it. They should do so in the context of local and national priorities for funding and developing services, and in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Nothing in this guideline should be interpreted in a way that would be inconsistent with compliance with those duties. NICE guidelines cover health and care in England. Decisions on how they apply in other UK countries are made by ministers in the Welsh Government, Scottish Government, and Northern Ireland Executive.
    [Show full text]
  • Ion Channels
    UC Davis UC Davis Previously Published Works Title THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: Ion channels. Permalink https://escholarship.org/uc/item/1442g5hg Journal British journal of pharmacology, 176 Suppl 1(S1) ISSN 0007-1188 Authors Alexander, Stephen PH Mathie, Alistair Peters, John A et al. Publication Date 2019-12-01 DOI 10.1111/bph.14749 License https://creativecommons.org/licenses/by/4.0/ 4.0 Peer reviewed eScholarship.org Powered by the California Digital Library University of California S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2019/20: Ion channels. British Journal of Pharmacology (2019) 176, S142–S228 THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: Ion channels Stephen PH Alexander1 , Alistair Mathie2 ,JohnAPeters3 , Emma L Veale2 , Jörg Striessnig4 , Eamonn Kelly5, Jane F Armstrong6 , Elena Faccenda6 ,SimonDHarding6 ,AdamJPawson6 , Joanna L Sharman6 , Christopher Southan6 , Jamie A Davies6 and CGTP Collaborators 1School of Life Sciences, University of Nottingham Medical School, Nottingham, NG7 2UH, UK 2Medway School of Pharmacy, The Universities of Greenwich and Kent at Medway, Anson Building, Central Avenue, Chatham Maritime, Chatham, Kent, ME4 4TB, UK 3Neuroscience Division, Medical Education Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK 4Pharmacology and Toxicology, Institute of Pharmacy, University of Innsbruck, A-6020 Innsbruck, Austria 5School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, BS8 1TD, UK 6Centre for Discovery Brain Science, University of Edinburgh, Edinburgh, EH8 9XD, UK Abstract The Concise Guide to PHARMACOLOGY 2019/20 is the fourth in this series of biennial publications. The Concise Guide provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties.
    [Show full text]
  • Proteins, Peptides, and Amino Acids
    Proteins, Peptides, and Amino Acids Chandra Mohan, Ph.D. Calbiochem-Novabiochem Corp., San Diego, CA The Chemical Nature of Amino Acids Peptides and polypeptides are polymers of α-amino acids. There are 20 α-amino acids that make-up all proteins of biological interest. The α-amino acids in peptides and proteins α consist of a carboxylic acid (-COOH) and an amino (-NH2) functional group attached to the same tetrahedral carbon atom. This carbon is known as the -carbon. The type of R- group attached to this carbon distinguishes one amino acid from another. Several other amino acids, also found in the body, may not be associated with peptides or proteins. These non-protein-associated amino acids perform specialized functions. Some of the α-amino acids found in proteins are also involved in other functions in the body. For example, tyrosine is involved in the formation of thyroid hormones, and glutamate and aspartate act as neurotransmitters at fast junctions. R Amino acids exist in either D- or L- enantiomorphs or stereoisomers. The D- and L-refer to the absolute confirmation of optically active compounds. With the exception of glycine, all other amino acids are mirror images that can not be superimposed. Most of the amino acids found in nature are of the L-type. Hence, eukaryotic proteins are always composed of L-amino acids although D-amino acids are found in bacterial cell walls and in some peptide antibiotics. All biological reactions occur in an aqueous phase. Hence, it is important to know how the R-group of any given amino acid dictates the structure-function relationships of peptides and proteins in solution.
    [Show full text]
  • Vitamin K Dependent Modifications of Glutamic Acid Residues In
    Proc. Nat. Acad. Sci. USA Vol. 71, No. 7, pp. 2730-2733, July 1974 Vitamin K Dependent Modifications of Glutamic Acid Residues in Prothrombin (proton magnetic resonance spectroscopy/mass spectrometry) JOHAN STENFLO*, PER FERNLUND*, WILLIAM EGANt, AND PETER ROEPSTORFFt * Department of Clinical Chemistry, University of Lund, Malm6 General Hospital, 8-214 01 Malm6, Sweden; t Department of Physical Chemistry II, Lund Institute of Technology, Chemical Center, S-220 07 Lund, Sweden; and t The Danish Institute of Protein Chemistry, DK-2970 Horsholm, Denmark Communicated by Sune Bergstrom, May 9, 1974 ABSTRACT A tetrapeptide, residues 6 to 9 in normal hydrogen on the -y carbon atom by a carboxyl group. This prothrombin, was isolated from the NH2-terminal, Ca2+- work will be described in greater detail elsewhere. binding part of normal prothrombin. The electrophoretic mobility of the peptide was too high to be explained en- tirely by its amino-acid composition. According to 1H MATERIALS AND METHODS nuclear magnetic resonance spectroscopy and mass Isolation of Tetrapeptide. The heptapeptide from normal spectrometry, the peptide contained two residues of modi- fied glutamic acid, -y-carboxyglutamic acid (3-amino-1,1,3- prothrombin (residues 4 to 10) (ref. 13) was first thoroughly propanetricarboxylic acid), a hitherto unidentified amino digested with aminopeptidase M (Sigma) and afterwards with acid. This amino acid gives normal prothrombin the Ca2 +_ carboxypeptidase B (Sigma). A tetrapeptide was isolated binding ability that is necessary for its activation. Obser- from the digest by gel chromatography on Sephadex G-25 vations indicate that abnormal prothrombin, induced by the vitamin K antagonist, dicoumarol, lacks these modi- superfine and obtained in pure form as judged by high voltage fied glutamic acid residues and that this is the reason why electrophoresis at pH 6.5 (electrophoretic mobility relative to abnormal prothrombin does not bind Ca2+ and is non- that of aspartic acid 1.09) and amino-acid analysis (14), which functioning in blood coagulation.
    [Show full text]
  • Dissociation Constants of Organic Acids and Bases
    DISSOCIATION CONSTANTS OF ORGANIC ACIDS AND BASES This table lists the dissociation (ionization) constants of over pKa + pKb = pKwater = 14.00 (at 25°C) 1070 organic acids, bases, and amphoteric compounds. All data apply to dilute aqueous solutions and are presented as values of Compounds are listed by molecular formula in Hill order. pKa, which is defined as the negative of the logarithm of the equi- librium constant K for the reaction a References HA H+ + A- 1. Perrin, D. D., Dissociation Constants of Organic Bases in Aqueous i.e., Solution, Butterworths, London, 1965; Supplement, 1972. 2. Serjeant, E. P., and Dempsey, B., Ionization Constants of Organic Acids + - Ka = [H ][A ]/[HA] in Aqueous Solution, Pergamon, Oxford, 1979. 3. Albert, A., “Ionization Constants of Heterocyclic Substances”, in where [H+], etc. represent the concentrations of the respective Katritzky, A. R., Ed., Physical Methods in Heterocyclic Chemistry, - species in mol/L. It follows that pKa = pH + log[HA] – log[A ], so Academic Press, New York, 1963. 4. Sober, H.A., Ed., CRC Handbook of Biochemistry, CRC Press, Boca that a solution with 50% dissociation has pH equal to the pKa of the acid. Raton, FL, 1968. 5. Perrin, D. D., Dempsey, B., and Serjeant, E. P., pK Prediction for Data for bases are presented as pK values for the conjugate acid, a a Organic Acids and Bases, Chapman and Hall, London, 1981. i.e., for the reaction 6. Albert, A., and Serjeant, E. P., The Determination of Ionization + + Constants, Third Edition, Chapman and Hall, London, 1984. BH H + B 7. Budavari, S., Ed., The Merck Index, Twelth Edition, Merck & Co., Whitehouse Station, NJ, 1996.
    [Show full text]