DOCSLIB.ORG

<&Beta>-Dehydroamino Acids to the Proteolytic

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
<&Beta>-Dehydroamino Acids to the Proteolytic Brigham Young University BYU ScholarsArchive Theses and Dissertations 2018-03-01 Contribution of Bulky <&alpha>,<&beta>-Dehydroamino Acids to the Proteolytic Stability andEnhanced Folding of <&beta>-Hairpins and Progress Towards the Total Synthesis of Yaku<'>amide A Ankur Jalan Brigham Young University Follow this and additional works at: https://scholarsarchive.byu.edu/etd BYU ScholarsArchive Citation Jalan, Ankur, "Contribution of Bulky <&alpha>,<&beta>-Dehydroamino Acids to the Proteolytic Stability andEnhanced Folding of <&beta>-Hairpins and Progress Towards the Total Synthesis of Yaku<'>amide A" (2018). Theses and Dissertations. 7307. https://scholarsarchive.byu.edu/etd/7307 This Dissertation is brought to you for free and open access by BYU ScholarsArchive. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of BYU ScholarsArchive. For more information, please contact [email protected], [email protected]. Contribution of Bulky α,β-Dehydroamino Acids to the Proteolytic Stability and Enhanced Folding of β-Hairpins and Progress Towards the Total Synthesis of Yaku’amide A Ankur Jalan A dissertation submitted to the faculty of Brigham Young University in partial fulfillment of the requirements for the degree of Doctor of Philosophy Steven L. Castle, Chair Merritt B. Andrus Joshua L. Price David J. Michaelis Matthew R. Linford Department of Chemistry and Biochemistry Brigham Young University Copyright © 2018 Ankur Jalan All Rights Reserved ABSTRACT Contribution of Bulky α,β-Dehydroamino Acids to the Proteolytic Stability and Enhanced Folding of β-Hairpins and Progress Towards the Total Synthesis of Yaku’amide A Ankur Jalan Department of Chemistry and Biochemistry, BYU Doctor of Philosophy This dissertation primarily covers the impact of bulky α,β-dehydroamino acids on the proteolytic stability and enhanced folding of β-hairpins. It partly describes the progress towards the total synthesis of yaku’amide A, a potent anticancer peptide with an IC50 value of 14 ng/mL against leukemia cells. Proteins and peptides are a very attractive source of potential medicinal agents as they can target various protein–protein interactions that are implicated in several diseases and disorders. The global sales of peptide drugs in 2013 were estimated to be about $28 billion and are constantly rising at an appreciable rate. However, peptide drugs have a short plasma half-life because of their susceptibility to proteolysis. Multiple approaches have been discovered to overcome this shortcoming, but there is still an urgent need for better peptidomimetics to increase the stream of peptides entering the pharmaceutical market. Here, it has been demonstrated that the incorporation of a bulky α,β-dehydroamino acid in the turn regions of β-hairpins can substantially increase their proteolytic stability and folding. Insertion of a dehydrovaline (ΔVal) residue at the i+1 position imparted ca. 7-fold increase in proteolytic resistance and ca. 15% increase in folding when compared to the parent peptide. Since the insertion of a bulky α,β-dehydroamino acid into the turn regions of β-hairpins can promote proteolytic stability without perturbing the secondary structures, it is believed that this novel approach is very promising in stabilizing bioactive turn- containing peptides for therapeutic use. Yaku’amide A is a medium-sized peptide that contains several bulky dehydroamino acids, β- hydroxyamino acids and unique N- and C-termini. It has an unprecedented anticancer profile, and potent bioactivity, hence it was imperative to accomplish its total synthesis to elicit its unique mode of action and biological target. More efficient methods were developed to synthesize bulky dehydroamino acids and β-hydroxyamino acids. A regioselective base-free aminohydroxylation was developed for the synthesis of β-hydroxyamino acids. The major focus was the three-step synthesis of the N-terminal acyl group from a known compound by a one-pot indium-catalyzed cross-Claisen condensation/reduction and the synthesis of (2S,3R)-β-hydroxyisoleucine, and racemic β-hydroxyisoleucine, which are the precursors of E- and Z-dehydroisoleucine. Keywords: bulky α,β-dehydroamino acids, β-hairpins, proteolytic stability, increased folding, aminohydroxylation, β-hydroxyamino acids, N-terminal acyl group ACKNOWLEDGEMENTS At the very outset, I extend my gratitude to the Department of Chemistry and Biochemistry at Brigham Young University for providing me with an opportunity to pursue doctoral study, constant support and encouragement throughout the graduate program. I also want to thank them for granting access to the wonderful research facility and a very conducive research atmosphere. My gratitude is also due to the Simmons Center for Cancer Research Fellowship and the Woolley family for Telford & Frank Woolley Memorial Research Award. I would like to express my sincere gratitude to my mentor Professor Steven L. Castle for his constant motivation, guidance, research insights, patience and kindness. It was my privilege to work under his mentorship on diverse research projects and learn immensely from his scientific acumen. I attribute the development of my research and writing skills to him. He has been an ideal source of inspiration and I tried my best to emulate his perseverance, punctuality and professionalism. I am also grateful to him for supporting my career goals and his valuable guidance regarding the same. I always looked forward to the yearly group picnic with him and his amazing family. I am grateful to each of my graduate committee members: Professor Merritt B. Andrus, Professor Paul B. Savage, Assistant Professors Joshua L. Price, Dr. David J. Michaelis and Professor Matthew R. Linford. I am extremely indebted to Dr. Price for his valuable insights on the synthesis and analysis of peptides, materials and access to the HPLC instrument. He has been very supportive and helpful throughout. I was always encouraged by Dr. Andrus and Dr. David J. Michaelis and they were always forthcoming for fruitful discussions on several challenging synthetic problems. I would like to thank Dr. Andrus and Dr. Price for their recommendation letters for fellowship and post-doctoral applications. Dr. Linford, Dr. Savage, Dr. Daniel H. Ess and Dr. Matt A. Peterson have been great sources of inspiration. I will like to profusely thank my colleagues especially Dr. Zhiwei Ma, Dr. Yu Cai, Dr. Brad M. Loertscher and Seyed Hadi Nazari for their willingness to help and guide me both professionally and personally. They provided a wonderful work environment and motivated me always to excel. I published my first scientific paper with Dr. Yu Cai and I thank him for his diligent work on iminyl radical cyclization and yaku’amide A. I would like to thank the best undergraduate students I worked with and trained. David W. Kastner and Kei G. I. Webber were instrumental in the successful and timely completion of the project “Contribution of bulky α,β- dehydroamino acids to the proteolytic stability and enhanced folding of β-hairpins.” I also would like to offer my gratitude to very helpful colleagues Concordia Lo, Sia Im, Seth R. Bohman, Aaron R. Kubosumi, Shi Luo, and Blake Christensen. I would like to thank Mason S. Smith for his guidance on peptide synthesis, purification and analysis. I am also grateful to Sara Mata and Dr. Shenglou Deng for several discussions on synthetic roadblocks I came across during my Ph.D. program. Thanks to Associate Professor Scott R. Burt and Mr. Bruce J. Jackson for providing well maintained NMR and MS facilities. Dr. Burt had been very generous and allotted sufficient time for conducting 1D and 2D 1H NMR experiments on β-hairpin peptides. I am also grateful to Janet Fonoimoana and Susan Mortensen for their constant support during the graduate program. Last but not least, I would like to especially thank my parents Shiv Kr. Jalan and Maina Devi Jalan, and my siblings Abhishek Jalan, Abhilasha Aggarwal and Amit Jalan for their unwavering love and support. I am extremely grateful to my fiancée Gunjan Sharma for her unconditional support and taking care of me when I needed it the most. She was very kind to cook and bring delicious meals for me to the lab while I was engrossed in work. I am grateful to my uncle Suresh Jalan for motivating and helping me to pursue doctoral studies in the United States. I would also like to thank the friends I made at BYU: Dr. Mukul Sonker, Dr. Bhupinder Singh, Dr. Pankaj Aggarwal, Dr. Anupriya Fartiyal, Dr. Anubhav Diwan, Dr. Abhijit Ghosh and Ying Zhang. TABLE OF CONTENTS ABSTRACT.............................................................................................................................. ii ACKNOWLEDGEMENTS .................................................................................................... iii TABLE OF CONTENTS ........................................................................................................ vi LIST OF FIGURES ................................................................................................................ ix LIST OF SCHEMES ............................................................................................................. xiii LIST OF TABLES .................................................................................................................. xv DEHYDROAMINO ACIDS ..............................................................................................1 1.1 Introduction .....................................................................................................................1
Load more

Recommended publications
  • Dehydropeptide Supramolecular Hydrogels and Nanostructures As Potential Peptidomimetic Biomedical Materials
    International Journal of Molecular Sciences Review Dehydropeptide Supramolecular Hydrogels and Nanostructures as Potential Peptidomimetic Biomedical Materials Peter J. Jervis * , Carolina Amorim, Teresa Pereira, José A. Martins and Paula M. T. Ferreira Centre of Chemistry, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal; [email protected] (C.A.); [email protected] (T.P.); [email protected] (J.A.M.); [email protected] (P.M.T.F.) * Correspondence: [email protected] Abstract: Supramolecular peptide hydrogels are gaining increased attention, owing to their potential in a variety of biomedical applications. Their physical properties are similar to those of the extracel- lular matrix (ECM), which is key to their applications in the cell culture of specialized cells, tissue engineering, skin regeneration, and wound healing. The structure of these hydrogels usually consists of a di- or tripeptide capped on the N-terminus with a hydrophobic aromatic group, such as Fmoc or naphthalene. Although these peptide conjugates can offer advantages over other types of gelators such as cross-linked polymers, they usually possess the limitation of being particularly sensitive to proteolysis by endogenous proteases. One of the strategies reported that can overcome this barrier is to use a peptidomimetic strategy, in which natural amino acids are switched for non-proteinogenic analogues, such as D-amino acids, β-amino acids, or dehydroamino acids. Such peptides usually possess much greater resistance to enzymatic hydrolysis. Peptides containing dehydroamino acids, Citation: Jervis, P.J.; Amorim, C.; i.e., dehydropeptides, are particularly interesting, as the presence of the double bond also intro- Pereira, T.; Martins, J.A.; Ferreira, duces a conformational restraint to the peptide backbone, resulting in (often predictable) changes P.M.T.
    [Show full text]
  • Highly Stereoselective and Efficient Synthesis of the Dopa Analogue In
    Turk J Chem 34 (2010) , 181 – 186. c TUB¨ ITAK˙ doi:10.3906/kim-0904-14 Highly stereoselective and efficient synthesis of the dopa analogue in pepticinnamin E via enantioselective hydrogenation of dehydroamino acids Dequn SUN Marine College, Shandong University at Weihai, Weihai 264209, P. R. CHINA e-mail: [email protected] Received 13.04.2009 An efficient and new method was developed to prepare the dopa analogue 11 in natural pepticinnamin via catalytic hydrogenation of dehydroamino acids (DDAA) with a good yield and ee. Product 11 is a key intermediate towards the total synthesis of pepticinnamin E and its analogues. Key Words: Synthesis; dopa analogue; enantioselective hydrogenation; dehydroamino acid. Introduction Pepticinnamin E1 (Figure) is a major product of the pepticinnamins, which are isolated from the culture of Streptomyces sp. OH-4652. It was identified as a depsipeptide having an O − Z -pentenylcinnamin acid and a novel dopa analogue, whose configuration has been determined as S by the Waldmann group using the Sch¨ollkopf method. 2 Pepticinnamin E shows rather potent inhibitory activity against farnesyl protein transferase (FPTase) with an IC 50 of 0.3 μM and is the first competitive inhibitor derived from a natural product. Our interest in the exploitation of a new methodology to synthesise naturally bioactive peptides containing non-ribosomal amino acids led us to initiate the synthesis of pepticinnamin E (1). Emphasis was placed on preparing both dopa analogue 2 and O − Z -pentenylcinnamin acid. 3 This study reports the enantioselective synthesis of the precursor of the dopa analogue 2, which would be suitable for the total synthesis of pepticinnamin E and its analogues.
    [Show full text]
  • Phosphorus-Containing Amino Acids with a P–C Bond in the Side Chain Or a P–O, P–Sorp–N Bond: Cite This: RSC Adv., 2020, 10, 6678 from Synthesis to Applications
    RSC Advances View Article Online REVIEW View Journal | View Issue Phosphorus-containing amino acids with a P–C bond in the side chain or a P–O, P–SorP–N bond: Cite this: RSC Adv., 2020, 10, 6678 from synthesis to applications a b b Mathieu Arribat, Florine Cavelier * and Emmanuelle Remond´ * Since the discovery of (L)-phosphinothricin in the year 1970, the development of a-amino acids bearing a phosphorus group has been of renewed interest due to their diverse applications, including their use in [18F]-fluorolabeling, as fluorescent probes, as protecting groups and in the reversible immobilization of amino acids or peptide derivatives on carbon nanomaterials. Considerable progress has also been achieved in the field of antiviral agents, through the development of phosphoramidate prodrugs, which increase significantly the intracellular delivery of nucleoside monophosphate and monophosphonate analogues. This review aims to summarize the strategies reported in the literature for the synthesis of P(III), P(IV) and P(V) phosphorus-containing amino acids with P–C, P–O, P–SorP–N bonds in the side Received 2nd December 2019 Creative Commons Attribution-NonCommercial 3.0 Unported Licence. chains and their related applications, including their use in natural products, ligands for asymmetric Accepted 22nd January 2020 catalysis, peptidomimetics, therapeutic agents, chemical reagents, markers and nanomaterials. The DOI: 10.1039/c9ra10917j discussion is organized according to the position of the phosphorus atom linkage to the amino acid side rsc.li/rsc-advances chain, either in an a-, b-, g-ord-position or to a hydroxyl, thiol or amino group. 1. Introduction phosphinothricin has engendered the development of numerous drugs for neurodegenerative disease treatment.
    [Show full text]
  • Sandra Cristina Gomes Oliveira Aminoácidos Não-Proteinogénicos
    Universidade do Minho Escola de Ciências Sandra Cristina Gomes Oliveira Aminoácidos não-proteinogénicos como antioxidantes Aminoácidos não-proteinogénicos como antioxidantes Aminoácidos não-proteinogénicos como antioxidantes Sandra Cristina Gomes Oliveira Cristina Gomes Oliveira Sandra Minho | 2016 U Outubro de 2016 Universidade do Minho Escola de Ciências Sandra Cristina Gomes Oliveira Aminoácidos não-proteinogénicos como antioxidantes Tese de Mestrado Mestrado em Química Medicinal Trabalho efetuado sob a orientação de Doutor Luís Miguel Oliveira Sieuve Monteiro e de Doutora Maria de Fátima Azevedo Brandão Amaral Paiva Martins Outubro de 2016 Agradecimentos O projeto que desenvolvi ao longo do segundo ano de mestrado, só foi possível graças à colaboração de diversas pessoas que, ajudaram na sua realização, às quais aproveito desde já para agradecer. Em primeiro lugar, gostaria de agradecer ao Doutor Luís Monteiro e à Doutora Paula Ferreira, pelo enorme e incansável apoio, pelos seus ensinamentos, paciência e disponibilidade. À Doutora Fátima Paiva-Martins da Faculdade de Ciências da Universidade do Porto, agradeço por me ter proporcionado a oportunidade de desenvolver uma parte deste trabalho na Faculdade de Ciências da Universidade do Porto, pela sua orientação, ensinamento, disponibilidade e apoio. Gostaria também de agradecer aos meus amigos de mestrado pelo companheirismo e os momentos agradáveis. Aos meus colegas que estiveram comigo no laboratório da Faculdade de Ciências da Universidade do Porto por toda a ajuda que deram a integrar- me no laboratório nos primeiros tempos de trabalho. Agradeço também aos restantes amigos. Quero agradecer de uma forma muito especial à minha família que sempre se mostrou presente, disponível e compreensiva, principalmente aos meus pais por fazerem de mim aquilo que sou hoje.
    [Show full text]
  • Copyrighted Material
    353 Index a aromatic 1,2-diphosphines 84 absolute asymmetric synthesis 67, 88 aspergillomarasmine 10 acetaldehyde 48, 203, 223, 292, 321 asymmetric synthesis (ÀS) acetic acid moiety 207, 321 – absolute asymmetric synthesis 67 acetic anhydride 51, 93, 209 – classification 51, 67 acetoacetic ether 129 – diastereoselective asymmetric synthesis 67 acetonitrile 51, 100, 103, 227, 236, 360 –effectivenessof 67 acetoxy-ion elimination 58 – enantiomeric asymmetric synthesis 68 (R)-O-acetylserine complex 294 – partial asymmetric synthesis 67 (S)-O-acetylserine complex 204, 293 atropoisomer 296 acrylic acid 113, 120 azetidine-2-carboxylic acid 8 alanine alkylation 215, 220 alanopine 4, 7, 11 aldol condensation 111, 188, 222, 223 b aldol reaction 159, 224 Bacillus brevis 2 alkylhalides 115, 152, 216 Balz–Schiemann reaction 264 allyl chloride 218 benzaldehyde 147, 148–151, 162 aluminum nitrate 39 benzophenone moiety 96, 97 amino acid moiety 47, 110, 186 benzylamine 100, 102, 176 -amino aldehydes 173 benzylation reaction 82, 111 2-amino-2’-carboxyindan 95 benzylbromide 82, 111, 140, 143, 145, 184, 2-aminoacetophenone 190, 201, 285 218, 290, 318 2-aminoacrylic acid 99 benzylcinchonidine 75 aminobinaphthols 104, 106, 112, 114, 125 benzylcinchonine 81 3-aminobutanoic acid 179 (S)-2-N-(N’-benzylprolyl)aminobenzophenone -aminobutyric acid (GABA) 2 (BPB) 200 1-aminocyclopropanecarboxylic acid (ACC) (S)-BINOLAM 81 85 biomimetic chemical approach 25 1-amino-2,2-dideuterocyclopropanecarboxylicCOPYRIGHTEDbiomimetic enzymeMATERIAL systems 25 acid 85 Δ-bis[N-3-methylsalicylideneglycinate]sodium
    [Show full text]
  • Structure￢ﾀﾓactivity Relationship Study at C9 Position of Kaitocephalin
    Bioorganic & Medicinal Chemistry Letters 26 (2016) 3543–3546 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl Structure–activity relationship study at C9 position of kaitocephalin Yoko Yasuno a, Makoto Hamada a, Yuya Yoshida a, Keiko Shimamoto b, Yasushi Shigeri c, ⇑ Toshifumi Akizawa d, Motomi Konishi d, Yasufumi Ohfune a, Tetsuro Shinada a, a Graduate School of Science, Osaka City University, 3-3-138, Sugimoto, Sumiyoshi, Osaka 558-8585, Japan b Bioorganic Research Institute, Suntory Foundation for Life Sciences, 8-1-1, Seikadai, Seika-cho, Soraku-gun, Kyoto 619-0284, Japan c National Institute of Advanced Industrial Science and Technology, 1-8-31, Midorigaoka, Ikeda, Osaka 563-8577, Japan d Analytical Chemistry, Pharmaceutical Science, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan article info abstract Article history: Kaitocephalin (KCP) isolated from Eupenicillium shearii PF1191 is an unusual amino acid natural product Received 17 May 2016 in which serine, proline, and alanine moieties are liked with carbon–carbon bonds. KCP exhibits potent Revised 8 June 2016 and selective binding affinity for one of the ionotropic glutamate receptor subtypes, NMDA receptors Accepted 9 June 2016 (K = 7.8 nM). In this study, new structure–activity relationship studies at C9 of KCP were implemented. Available online 11 June 2016 i Eleven new KCP analogs with different substituents at C9 were prepared and employed for binding affin- ity tests using native ionotropic glutamate receptors. Replacement of the 3,5-dichloro-4-hydroxybenzoyl Keywords: group of KCP with a 3-phenylpropionyl group resulted in significant loss of binding affinity for NMDARs Ionotropic glutamate receptors (K = 1300 nM), indicating an indispensable role of the aromatic ring of KCP in the potent and selective Kaitocephalin i Natural product binding to NMDARs.
    [Show full text]
  • Comprehensive Review on the Interaction Between Natural Compounds and Brain Receptors: Benefits and Toxicity
    European Journal of Medicinal Chemistry 174 (2019) 87e115 Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech Review article Comprehensive review on the interaction between natural compounds and brain receptors: Benefits and toxicity * Ana R. Silva a, Clara Grosso b, , Cristina Delerue-Matos b,Joao~ M. Rocha a, c a Centre of Molecular and Environmental Biology (CBMA), Department of Biology (DB), University of Minho (UM), Campus Gualtar, P-4710-057, Braga, Portugal b REQUIMTE/LAQV, Instituto Superior de Engenharia do Instituto Politecnico do Porto, Rua Dr. Antonio Bernardino de Almeida, 431, P-4249-015, Porto, Portugal c REQUIMTE/LAQV, Grupo de investigaçao~ de Química Organica^ Aplicada (QUINOA), Laboratorio de polifenois alimentares, Departamento de Química e Bioquímica (DQB), Faculdade de Ci^encias da Universidade do Porto (FCUP), Rua do Campo Alegre, s/n, P-4169-007, Porto, Portugal article info abstract Article history: Given their therapeutic activity, natural products have been used in traditional medicines throughout the Received 6 December 2018 centuries. The growing interest of the scientific community in phytopharmaceuticals, and more recently Received in revised form in marine products, has resulted in a significant number of research efforts towards understanding their 10 April 2019 effect in the treatment of neurodegenerative diseases, such as Alzheimer's (AD), Parkinson (PD) and Accepted 11 April 2019 Huntington (HD). Several studies have shown that many of the primary and secondary metabolites of Available online 17 April 2019 plants, marine organisms and others, have high affinities for various brain receptors and may play a crucial role in the treatment of diseases affecting the central nervous system (CNS) in mammalians.
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2015/0202317 A1 Rau Et Al
    US 20150202317A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0202317 A1 Rau et al. (43) Pub. Date: Jul. 23, 2015 (54) DIPEPTDE-BASED PRODRUG LINKERS Publication Classification FOR ALPHATIC AMNE-CONTAINING DRUGS (51) Int. Cl. A647/48 (2006.01) (71) Applicant: Ascendis Pharma A/S, Hellerup (DK) A638/26 (2006.01) A6M5/9 (2006.01) (72) Inventors: Harald Rau, Heidelberg (DE); Torben A 6LX3/553 (2006.01) Le?mann, Neustadt an der Weinstrasse (52) U.S. Cl. (DE) CPC ......... A61K 47/48338 (2013.01); A61 K3I/553 (2013.01); A61 K38/26 (2013.01); A61 K (21) Appl. No.: 14/674,928 47/48215 (2013.01); A61M 5/19 (2013.01) (22) Filed: Mar. 31, 2015 (57) ABSTRACT The present invention relates to a prodrug or a pharmaceuti Related U.S. Application Data cally acceptable salt thereof, comprising a drug linker conju (63) Continuation of application No. 13/574,092, filed on gate D-L, wherein D being a biologically active moiety con Oct. 15, 2012, filed as application No. PCT/EP2011/ taining an aliphatic amine group is conjugated to one or more 050821 on Jan. 21, 2011. polymeric carriers via dipeptide-containing linkers L. Such carrier-linked prodrugs achieve drug releases with therapeu (30) Foreign Application Priority Data tically useful half-lives. The invention also relates to pharma ceutical compositions comprising said prodrugs and their use Jan. 22, 2010 (EP) ................................ 10 151564.1 as medicaments. US 2015/0202317 A1 Jul. 23, 2015 DIPEPTDE-BASED PRODRUG LINKERS 0007 Alternatively, the drugs may be conjugated to a car FOR ALPHATIC AMNE-CONTAINING rier through permanent covalent bonds.
    [Show full text]
  • Synthesis of Bis-Dehydroamino Acid Derivatives by Suzuki
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Universidade do Minho: RepositoriUM High yielding synthesis of N-ethyl dehydroamino acids Luís S. Monteiro* and Ana S. Suárez Chemistry Centre, University of Minho, Gualtar, 4710-057 Braga, Portugal Author’s address: L. S. Monteiro, Chemistry Centre, University of Minho, Gualtar, 4710-057 Braga, Portugal, Fax: +351 253604382, e-mail: [email protected]. Abstract. Recently we reported the use of a sequence of alkylation and dehydration methodologies to obtain N-ethyl-- dehydroamino acid derivatives. The application of this N-alkylation procedure to several methyl esters of -dibromo and - bromo, -substituted dehydroamino acids protected with standard amine protecting groups was subsequently reported. The corresponding N-ethyl, -bromo dehydroamino acid derivatives were obtained in fair to high yields and some were used as substrates in Suzuki cross coupling reactions to give N-ethyl, -disubstituted dehydroalanine derivatives. Herein, we further explore N-ethylation of -halo dehydroamino acid derivatives using triethyloxonium tetrafluoroborate as alkylating agent but substituting N,N-diisopropylethylamine for potassium tert-butoxide as auxiliary base. In these conditions, for all -halo dehydroamino acid derivatives, reactions were complete and the N-ethylated derivative could be isolated in high yield. This method was also applied for N-ethylation of non-halogenated dehydroamino acids. Again, with all compounds the reactions were complete and the N-ethyl dehydroamino acid derivatives could be isolated in high yields. Some of these N-ethyl dehydroamino acid methyl ester derivatives were converted in high yields to their corresponding acids and coupled to an amino acid methyl ester to give N-ethyl dehydrodipeptide derivatives in good yields.
    [Show full text]
  • N,N-Diprotected Dehydroamino Acid Derivatives: Versatile Substrates for the Synthesis of Novel Amino Acids
    N,N-DIPROTECTED DEHYDROAMINO ACID DERIVATIVES: VERSATILE SUBSTRATES FOR THE SYNTHESIS OF NOVEL AMINO ACIDS Paula M. T. Ferreira and Luís S. Monteiro Department of Chemistry, University of Minho, Gualtar, 4710-057 Braga, Portugal (e-mail: [email protected]) Abstract. Non-proteinogenic amino acids are an important class of organic compounds that can have intrinsic biological activity or can be found in peptides with antiviral, antitumor, anti-inflammatory or immunosuppressive activities. This type of compounds is also important in drug development, in the elucidation of biochemical pathways and in conformational studies. Therefore, research towards efficient methods that allow the synthesis of these compounds constitutes an important area of peptide chemistry. In our laboratories we have developed a new and high yielding method for the synthesis of N,N-diprotected dehydroamino acid derivatives using tert-butyl pyrocarbonate and 4-dimethylaminopyridine. These compounds were used as substrates in several types of reactions, allowing the synthesis of a variety of new amino acid derivatives. Some of these new compounds are heterocyclic systems or contain heterocyclic moieties such as pyrazole, indole, or imidazole. Thus, several nitrogen heterocycles were reacted with N,N-diprotected dehydroalanine to give new β-substituted alanines and dehydroalanines. Furanic amino acids were obtained treating the methyl ester of N-(4-toluenesulfonyl), N-(tert-butoxycarbonyl) dehydroalanine with carbon nucleophiles of the β-dicarbonyl type having at least one methyl group attached to one of the carbonyl groups. Treatment of these furanic amino acids with trifluoracetic acid afforded pyrrole derivatives in good to high yields. A N,N-diprotected 1,4-dihydropyrazine was obtained reacting the methyl ester of N-(4-toluenesulfonyl), N-(tert-butoxycarbonyl)dehydroalanine with 4-dimethylaminopyridine and an excess of potassium carbonate.
    [Show full text]
  • Natural Compounds and Neuroprotection: Mechanisms of Action and Novel Delivery Systems ELENI BAGLI 1,2 , ANNA GOUSSIA 3, MARILITA M
    in vivo 30 : 535-548 (2016) Review Natural Compounds and Neuroprotection: Mechanisms of Action and Novel Delivery Systems ELENI BAGLI 1,2 , ANNA GOUSSIA 3, MARILITA M. MOSCHOS 4, NIKI AGNANTIS 3 and GEORGIOS KITSOS 2 1Institute of Molecular Biology and Biotechnology - FORTH, Division of Biomedical Research, Ioannina, Greece; 2Department of Ophthalmology, University of Ioannina, Ioannina, Greece; 3Department of Pathology, University of Ioannina, Ioannina, Greece; 4Department of Ophthalmology, University of Athens, Athens, Greece Abstract. Neurodegeneration characterizes pathologic pathological events, including oxidative stress, mitochondrial conditions, ranging from Alzheimer’s disease to glaucoma, dysfunction, inflammation and protein aggregation (2, 3). with devastating social and economic effects. It is a The increasing knowledge of the cellular and molecular complex process implicating a series of molecular and events underlying the degenerative process has greatly cellular events, such as oxidative stress, mitochondrial stimulated research for identifying compounds capable of dysfunction, protein misfolding, excitotoxicity and stopping or, at least, slowing the progress of neural inflammation. Natural compounds, because of their broad deterioration. spectrum of pharmacological and biological activities, Natural compounds are complex chemical multiple-target could be possible candidates for the management of such molecules found mainly in plants and microorganisms (4). multifactorial morbidities. However, their therapeutic These agents
    [Show full text]
  • 1 the Historical Development of Asymmetric Hydrogenation
    1 1 The Historical Development of Asymmetric Hydrogenation John M. Brown Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK 1.1 Introduction How did chemists gain the current levels of knowledge and expertise for control- ling molecular chirality through hydrogenation or otherwise? The desirability of asymmetric synthesis was recognized in the 1880s by Emil Fischer and others, but practical solutions only arose more than 80 years later. The key reasons are explored here. This brief review has five main Sections 1.2–1.6, covering first the development of ideas underpinning our understanding of asymmetry, then the initial applications to asymmetric synthesis, and also the development of asymmetric heterogeneous hydrogenation of alkenes. The final sections on asymmetric homogeneous hydro- genation of alkenes are limited to work published in or before the early 1980s, in advance of extensive developments, and thus excluding the important inputs of irid- ium catalysts and more recently early transition metals. 1.2 Early Work on the Recognition of Molecular Asymmetry Chemistry was an emerging science by the beginning of the nineteenth century with many opportunities for fundamental discovery. At that time scientists crossed dis- ciplines easily; optics and mineralogy played important roles because of the ready accessibility and verifiable purity of solid substances. Malus had invented the first polarimeter in 1808, enabling measurement of both the sense and magnitude of rota- tion of plane-polarized light [4]. Following this, work by Arago and others on the interaction of polarized light with minerals intensified in the following decade [5]. Haüy had earlier concluded that each type of crystal has a fundamental primitive, nucleus or “integrant molecule” of a particular shape, that could not be broken fur- ther without destroying both the physical and chemical nature of the crystal.
    [Show full text]