DOCSLIB.ORG

A Selective Class of Inhibitors for the CLC-Ka Chloride Ion Channel

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
A Selective Class of Inhibitors for the CLC-Ka Chloride Ion Channel A selective class of inhibitors for the CLC-Ka chloride ion channel Anna K. Kostera,b,1, Chase A. P. Woodb,1, Rhiannon Thomas-Trana, Tanmay S. Chavanb, Jonas Almqvistc, Kee-Hyun Choid, J. Du Boisa,2, and Merritt Madukeb,2 aDepartment of Chemistry, Stanford University, Stanford, CA 94305; bDepartment of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305; cDepartment of Cell and Molecular Biology, Uppsala University, 751 24 Uppsala, Sweden; and dMaterials and Life Science Research Division, Korea Institute of Science and Technology, 02792 Seoul, Republic of Korea Edited by Richard W. Aldrich, The University of Texas at Austin, Austin, TX, and approved March 21, 2018 (received for review December 7, 2017) CLC proteins are a ubiquitously expressed family of chloride- without intervention, permanent neurological damage can occur (20, selective ion channels and transporters. A dearth of pharmacolog- 21). Selectivity between small molecule inhibitors of CLC-Ka and ical tools for modulating CLC gating and ion conduction limits CLC-Kb is critical for any clinical application, as these two channels investigations aimed at understanding CLC structure/function and are also expressed in the inner ear, where they play critical but re- physiology. Herein, we describe the design, synthesis, and evalu- dundant roles: disruption of both homologs results in deafness, while ation of a collection of N-arylated benzimidazole derivatives (BIMs), disruption of either individually has no effect on hearing (22). one of which (BIM1) shows unparalleled (>20-fold) selectivity for CLC- The development of selective small molecules that specifically Ka over CLC-Kb, the two most closely related human CLC homologs. target either CLC-Ka or CLC-Kb poses a formidable challenge in Computational docking to a CLC-Ka homology model has identified a ligand design due to the >90% sequence identity between the two BIM1 binding site on the extracellular face of the protein near the homologs. Prior reports of CLC inhibitors largely describe low- chloride permeation pathway in a region previously identified as a affinity (midmicromolar to millimolar IC50) compounds that lack binding site for other less selective inhibitors. Results from site- selectivity. The most potent CLC inhibitor known is a peptide directed mutagenesis experiments are consistent with predictions of toxin, GaTx2, which selectively inhibits CLC-2 with an IC50 of this docking model. The residue at position 68 is 1 of only ∼20 extra- ∼20 pM. However, despite its potency, GaTx2 inhibition saturates cellular residues that differ between CLC-Ka and CLC-Kb. Mutation of at ∼50% (23), thus limiting its use as a pharmacological probe. this residue in CLC-Ka and CLC-Kb (N68D and D68N, respectively) Accordingly, we have been motivated to identify small molecule reverses the preference of BIM1 for CLC-Ka over CLC-Kb, thus show- inhibitors of specific CLCs. Two classes of small molecule inhibi- ing the critical role of residue 68 in establishing BIM1 selectivity. Mo- tors have been reported to display moderate potency and selectivity lecular docking studies together with results from structure–activity forCLC-KaoverCLC-Kb.Thefirst, a collection of stilbene relationship studies with 19 BIM derivatives give insight into the in- disulfonates, is a promiscuous class of anion transport inhibitors creased selectivity of BIM1 compared with other inhibitors and iden- (24–26). One of these, 4,4′-diisothiocyano-2,2′-stilbenedisulfonic tify strategies for further developing this class of compounds. acid (DIDS), was used as a chemical tool to corroborate the dimeric architecture of the Torpedo CLC-0 channel (27). Sub- chloride channel | molecular probes | electrophysiology sequently, our laboratories showed that DIDS hydrolyzes in − LC proteins are a class of highly selective chloride (Cl ) ion Significance Cchannels and transporters that are essential for proper physiological function, including electrical signaling in muscles Chloride ion channels and transporters (CLCs) are critical to car- and neurons and regulation of ion homeostasis (1–4). CLCs diovascular, neurological, and musculoskeletal function. Small possess a unique homodimeric, double-barreled structure and molecules capable of selectively inhibiting CLCs would serve as operate through distinct gating (opening/closing) mechanisms valuable tools for investigating CLC function and would have po- (5–10), which differ markedly from those of sodium, potassium, tential applications for treating CLC-related disorders. The lack of and calcium channels. While researchers in the field have made such agents has impeded efforts to study this family of proteins. important progress toward understanding general CLC structural This work introduces a class of inhibitors with unprecedented se- dynamics and physiology, achieving a precise mechanistic un- lectivity for a single CLC homolog, CLC-Ka. Insights gained through derstanding of these processes has remained a challenge (11–13). experiments to validate a predicted ligand binding site and to Small molecules that bind and modulate specific CLC homologs evaluate structure–activity relationships rationalize inhibitor po- could serve as valuable tools for untangling the complex gating tency and CLC-Ka selectivity. Our findings provide tools for studies behaviors and diverse physiological functions within the CLC of CLC-Ka function and will assist subsequent efforts to advance family. Small molecule modulators of CLCs also hold promise as specific molecular probes for different CLC homologs. therapeutic leads (14, 15). For certain kidney-related disorders, two Author contributions: A.K.K., C.A.P.W., J.A., K.-H.C., J.D.B., and M.M. designed research; CLC homologs, CLC-Ka and CLC-Kb, are particularly compelling A.K.K., C.A.P.W., R.T.-T., T.S.C., J.A., and K.-H.C. performed research; A.K.K., C.A.P.W., targets due to their important roles in maintaining electrolyte R.T.-T., T.S.C., J.A., K.-H.C., J.D.B., and M.M. analyzed data; and A.K.K., J.D.B., and M.M. balance. In humans, CLC-Kb loss-of-function mutations result in wrote the paper with contributions from all authors. type III Bartter’s syndrome, a salt-wasting disorder characterized The authors declare no conflict of interest. by low blood pressure (16). This phenotype suggests CLC-Kb as This article is a PNAS Direct Submission. a potential target for antihypertensive therapeutics. Similarly, Published under the PNAS license. − mouse KO models show that CLC-Ka Cl transport is necessary See Commentary on page 5311. for concentration of urine (17, 18) and thus suggest that inhibitors 1A.K.K. and C.A.P.W. contributed equally to this work. could be used to treat hyponatremia (19), a condition in which 2To whom correspondence may be addressed. Email: [email protected] or maduke@ blood concentrations of sodium are low. Hyponatremia develops stanford.edu. when the kidneys fail to excrete water efficiently and can occur in This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. patients with heart failure, cirrhosis, renal failure, or other condi- 1073/pnas.1720584115/-/DCSupplemental. tions (19, 20). Treatment of hyponatremia can be challenging, and Published online April 18, 2018. E4900–E4909 | PNAS | vol. 115 | no. 21 www.pnas.org/cgi/doi/10.1073/pnas.1720584115 Downloaded by guest on September 23, 2021 NH buffer solution to form polythiourea oligomers, which are more NO2 NO2 2 t KO Bu Fe/FeCl3 SEE COMMENTARY potent antagonists of CLC-0, CLC-Ka, and CLC-ec1 than DIDS Cl F Cl NH Cl NH DMF, 0 °C HOAc itself (28). A DIDS pentamer (Fig. 1A) is the most potent and NH Cl Cl 2 EtOH, 70 °C selective nonpeptidic CLC inhibitor known, with an IC50 against Cl CLC-Ka of 0.5 μM and ∼100-fold increased IC50 against CLC- Kb (28). However, structure–activity relationship (SAR) studies NH and further development of DIDS-based inhibitors are severely 2 N N CS2, KOH 30% H2O2 hampered due to the low water solubility of these oligomeric SH SO3 K Cl NH N N Cl Cl Cl Cl molecules as well as the synthetic challenges of systematically Cl EtOH, H2O 1 M KOH modifying the DIDS scaffold. A second class of CLC inhibitors 70 °C MeOH isbasedonanaryl-substitutedbenzofurancarboxylicacid(29, 30). The most notable of these compounds, MT-189 and SRA- Scheme 1. Synthesis of BIMs. 36 (Fig. 1B), are ∼10-fold less potent than the DIDS pentamer but more amenable to synthetic manipulation. While SRA- 36 inhibits both CLC-Ka and CLC-Kb with equal potency, MT- BIM1 Exhibits Enhanced Homolog Selectivity. CLC-K channels were 189 has a nearly threefold greater apparent affinity for CLC-Ka expressed in Xenopus oocytes, and two-electrode voltage clamp (TEVC) recording was used to measure currents before and over CLC-Kb (IC50 = 7vs.20μM) (29). after perfusion of inhibitor solutions. At 100 μM, BIM1 is an Results and Discussion effective inhibitor of CLC-Ka but shows markedly reduced ac- Inhibitor Design and Synthesis. Our design of N-arylated benz- tivity toward CLC-Kb (Fig. 2 A and B and Table S1). The IC50 ± μ imidazole derivatives (BIMs) follows from previous reports by for BIM1 against CLC-Ka, 8.5 0.4 M, is similar to that ± μ Liantonio et al. (29, 30) that describe the inhibitory effects of reported for MT-189 (7.0 1.0 M) (29). In contrast, the po- benzofuran carboxylate compounds against CLC-Ka and CLC- tency of BIM1 against CLC-Kb is significantly diminished [IC50 = 200 ± 20 μM for BIM1 (Fig. 2C) vs. 20 ± 2 μM for MT- Kb (29, 30). In these studies, the most potent CLC-K biaryl in- > hibitors were found to be conformationally restricted molecules 189 (29)]. The identification of BIM1, which displays 20-fold selectivity for CLC-Ka over CLC-Kb, is notable given that these that favor a twisted, noncoplanar structure of the two aromatic ∼ rings (Fig.
Load more

Recommended publications
  • 68 3 1 5"! Patent Request: Standard Patent/Patent of Addition
    Λ _ ___ _ KWU/lXHJIMI AUSTRALIA Patents Act 1990 68 3 1 5"! PATENT REQUEST: STANDARD PATENT/PATENT OF ADDITION We, being the persons identified below as the Applicant, request the grant of a patent to the person identified below as the Nominated Person, for an invention described in the accompanying standard complete specification. ,· Full application details follow. [71] Applicant: ADIR ET COMPAGNIE Address: 1 RUE cXrLE HEBERT, F-92415 COURBEVOIE CEDEX, FRANCE [70] Nominated Person: ADIR ET COMPAGNIE Address: 1 RUE CARLE HEBERT, F-92415 COURBEVOIE CEDEX, FRANCE [54] Invent»·* Title: NOVEL N-PYRIDYL CARBOXAMIDES AND DERIVATIVES, PROCESSES FOR THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS WHICH CONTAIN THEM Name(s) of actual inventor(s): JEAN-MICHEL ROBERT, ODILE RIDEAU, SYLVIE ROBERT-PIESSARD, JACQUELINE COURANT, GUILLAUME LE BAUT, DANIEL-HENRI CAIGNARD, PIERRE RENARD and GERARD ADAM Address for service in Australia: c/o WATERMARK PATENT & TRADEMARK ATTORNEYS, of 290 Burwood Road, Hawthorn, Victoria 3122, Australia Attorney Code: WM :,.··. BASIC CONVENTION APPLICATION(S) DETAILS .... [31] Application Number [33] Country Country [32] Date of Application : Code 9406412 FRANCE FR 27 MAY 1994 Basic Applicants): ADIR ET COMPAGNIE • · · · • · · *· Di awing number recommended to accompany the abstract ............................... By our Patent Attorneys, WATERMARK PATENT & TRADEMARK ATTORNEYS ...CM&/.VV2...... ....... DATED this 25th day of May 1995,. Carolyn J, Harris Registered Patent Attorney i P/00/008b 12/11/91 Section 29 (η Regulation 3.1 (2) AUSTRALIA Patents Act 1990 NOTICE OF ENTITLEMENT We, ADIR ET COMPAGNIE of, 1 Rue Carle Hebert, F-92415 Courbevoie Cedex, France, being the applicant in respect of Application No.
    [Show full text]
  • Dibenzothiophene/Oxide and Quinoxaline/Pyrazine Derivatives Serving As Electron-Transport Materials**
    FULL PAPER DOI: 10.1002/adfm.200500823 Dibenzothiophene/Oxide and Quinoxaline/Pyrazine Derivatives Serving as Electron-Transport Materials** By Tai-Hsiang Huang, Wha-Tzong Whang,* Jiun Yi Shen, Yuh-Sheng Wen, Jiann T. Lin,* Tung-Huei Ke, Li-Yin Chen, and Chung-Chih Wu* A series of 2,8-disubstituted dibenzothiophene and 2,8-disubstituted dibenzothiophene-S,S-dioxide derivatives containing quinoxaline and pyrazine moieties are synthesized via three key steps: i) palladium-catalyzed Sonogashira coupling reaction to form dialkynes; ii) conversion of the dialkynes to diones; and iii) condensation of the diones with diamines. Single-crystal characterization of 2,8-di(6,7-dimethyl-3-phenyl-2-quinoxalinyl)-5H-5k6-dibenzo[b,d]thiophene-5,5-dione indicates a triclinic crystal structure with space group P1 and a non-coplanar structure. These new materials are amorphous, with glass-transition temperatures ranging from 132 to 194 °C. The compounds (Cpd) exhibit high electron mobilities and serve as effective elec- tron-transport materials for organic light-emitting devices. Double-layer devices are fabricated with the structure indium tin oxide (ITO)/Qn/Cpd/LiF/Al, where yellow-emitting 2,3-bis[4-(N-phenyl-9-ethyl-3-carbazolylamino)phenyl]quinoxaline (Qn) serves as the emitting layer. An external quantum efficiency of 1.41 %, a power efficiency of 4.94 lm W–1, and a current efficien- cy of 1.62 cd A–1 are achieved at a current density of 100 mA cm–2. 1. Introduction efficiency, brightness, and durability.[4] In contrast, reports of the use of small molecules as electron-transporting materials [5] Organic and polymer light-emitting diodes (OLEDs and are still rare in the literature.
    [Show full text]
  • Furans in the Reactions with Electrophiles
    Theoretical Study of Benzofused Thieno[3,2-b]furans in the reactions with electrophiles Ausra Vektariene1*, Gytis Vektaris1, Jiri Svoboda2 (1) Institute of Theoretical Physics and Astronomy of Vilnius University, A. Gostauto 12, LT- 01108 Vilnius, Lithuania (2) Department of Organic Chemistry, Prague Institute of Chemical Technology, Technicka 5, CZ-166 28 Prague 6, Czech Republic E-mail: [email protected] Keywords: Benzofused thieno[3,2-b]furans, electrophile, theoretical study, DFT. Abstract Calculations of traditional HF and DFT based reactivity descriptors are reported for the benzofused thieno[3,2-b]furans in order to get insight into the factors determining the exact nature of its interactions with electrophiles. Global descriptors such as chemical potential, molecular hardness, electrophilicity, frontier molecular orbital energies and shapes, the condensed Fukui functions were determined and used to identify the differences in the stability and reactivity of heterocycles. In general calculated values lead to the conclusion that heterocyclic system in thieno[3,2-b]benzofuran is more aromatic and stable than in isomeric benzothieno[3,2-b]furan. Theoretical results are in complete agreement with the experimental results showing exceptional reactivity of C(2) atom for both isomers. The bond order uniformity analysis, local ionization energy and electrostatic potential energy maps revealed structural and reactivity differences of isomeric thieno[3,2-b]furans. Benzothieno[3,2-b]furan structurally could be analogues with molecule of aromatic benzothiophene substituted with C(2)-C(3) vinylic moiety. Contrary, calculated values for the of thieno[3,2-b]benzofuran shows delocalized π–electron surface that reports stable aromatic system between benzene ring and thiene heterocycle.
    [Show full text]
  • Haloselectivity of Heterocycles Will Gutekunst
    Baran Group Meeting Haloselectivity of Heterocycles Will Gutekunst Background SN(ANRORC) Addition of Nuclophile, Ring Opening, Ring Closure Polysubstituted heterocycles represent some of the most important compounds in the realm of pharmaceutical and material sciences. New and more efficient ways to selectively produce these Br Br molecules are of great importance and one approach is though the use of polyhalo heterocycles. Br NaNH2 N N Consider: Ar N 3 Ar2 NH3(l), 90% NH2 3 Halogenations H NH2 H N CO2Me Ar H 3 Suzuki Couplings 1 N CO2Me - Br H Ar 3 Ar2 1 Triple Halogenation NH2 NH CO Me N N 2 Ar1 H 1 Triple Suzuki Coupling N CO2Me N NH H NH2 Ar H 3 Ar2 1 Triple C-H activation? CO Me N 2 Ar1 H N CO2Me Cross Coupling H Virtually all types of cross coupling have been utilized in regioselective cross coupling reactions: Nucleophilic Substitution Kumada, Negishi, Sonogashira, Stille, Suzuki, Hiyama, etc. SNAr or SN(AE) In all of these examples, the oxidative addition of the metal to the heterocycle is the selectivity determining steps and is frequently considered to be irreversible. This addition highly resembles a nucleophilic substitution and it frequently follows similar regioselectivities in traditional S Ar reactions. Nu N The regioselectivity of cross coupling reaction in polyhalo heterocycles do not always follow the BDE's Nu of the corresponding C-X bonds. N X N X N Nu 2nd 2nd Meisenheimer Complex 1st Br Br 88.9 83.2 S (EA) Br 88.9 N 87.3 Br O O via: st OMe 1 Br NaNH , t-BuONa 2 N N pyrrolidine + Merlic and Houk have determined that the oxidative addition in palladium catalyzed cross coupling N N THF, 40ºC N reactions is determined by the distortion energy of the C-X bond (related to BDE) and the interaction of N the LUMO of the heterocycle to the HOMO of the Pd species.
    [Show full text]
  • Modeling the Hydrodesulfurization Reaction at Nickel. Unusual Reactivity of Dibenzothiophenes Relative to Thiophene and Benzothiophene
    7606 J. Am. Chem. Soc. 1999, 121, 7606-7617 Modeling the Hydrodesulfurization Reaction at Nickel. Unusual Reactivity of Dibenzothiophenes Relative to Thiophene and Benzothiophene David A. Vicic and William D. Jones* Contribution from the Department of Chemistry, The UniVersity of Rochester, Rochester, New York 14627-0216 ReceiVed February 25, 1999 Abstract: The nickel hydride dimer [(dippe)NiH]2 (1) was found to react with a variety of organosulfur substrates under mild conditions leading to C-S bond insertion adducts. The transition-metal insertions into the C-S bonds of thiophene, benzothiophene, and dibenzothiophene are all reversible, and lead to new organometallic complexes when dissolved in hydrocarbon solvent. (dippe)Ni(η2-C,S-dibenzothiophene) (6) converts to four new organometallic species in a unique desulfurization reaction that is believed to proceed via the intermediacy of the late-metal terminal sulfido complex (dippe)NidS(23). Independent synthetic routes to the desulfurization products have also provided an entry into the preparation of a variety of nickel-sulfur complexes such as (dippe)Ni(SH)2, (dippe)2Ni2(µ-H)(µ-S), [(dippe)2Ni2(µ-H)(µ-S)][PF6], and [(dippe)Ni(µ-S)]2, all of which have been structurally characterized. The reactivity of 1 with 4-methyldibenzothiophene, 4,6-dimethyldiben- zothiophene, 1,9-dimethyldibenzothiophene, thioxanthene, and thianthrene is also presented. Introduction desulfurize the more stubborn organosulfur compounds such as dibenzothiophene upon acidic workup5 and in the presence Raney nickel has seen widespread use in the desulfurization of reducing agents.6 These results, along with recent successes of organic and organometallic compounds.1 Catalytic desulfu- in platinum HDS modeling studies,7 encouraged us to prepare rization with Raney nickel under mild laboratory conditions is a new nickel hydride complex and examine the reactivity of not feasible, however, because of the chemical inertness of the this reagent toward carbon-sulfur bond activation in thiophenic resulting nickel sulfide that is produced.
    [Show full text]
  • Heterocyclic Compounds
    Lecture note- 3 Organic Chemistry CHE 502 HETEROCYCLIC COMPOUNDS Co-Coordinator – Dr. Shalini Singh DEPARTMENT OF CHEMISTRY UTTARAKHAND OPEN UNIVERSITY UNIT 4: HETEROCYCLIC COMPOUNDS- I CONTENTS 4.1 Objectives 4.2 Introduction 4.3 Classification of heterocyclic compounds 4.4 Nomenclature of heterocyclic compounds 4.5 Molecular orbital picture 4.6 Structure and aromaticity of pyrrole, furan, thiophene and pyridine 4.7 Methods of synthesis properties and chemical reactions of Pyrrole, Furan, Thiophene and Pyridine 4.8 Comparison of basicity of Pyridine, Piperidine and Pyrrole 4.9 Summary 4.10 Terminal Question 4.1 OBJECTIVES In this unit learner will be able to • Know about the most important simple heterocyclic ring systems containing heteroatom and their systems of nomenclature and numbering. • Understand and discuss the reactivity and stability of hetero aromatic compounds. • Study the important synthetic routes and reactivity for five and six member hetero aromatic compounds. • Understand the important physical and chemical properties of five and six member hetero aromatic compounds. • Know about the applications of these hetero aromatic compounds in the synthesis of important industrial and pharmaceutical compounds 4.2 INTRODUCTION Heterocyclic compound is the class of cyclic organic compounds those having at least one hetero atom (i.e. atom other than carbon) in the cyclic ring system. The most common heteroatoms are nitrogen (N), oxygen (O) and sulphur (S). Heterocyclic compounds are frequently abundant in plants and animal products; and they are one of the important constituent of almost one half of the natural organic compounds known. Alkaloids, natural dyes, drugs, proteins, enzymes etc. are the some important class of natural heterocyclic compounds.
    [Show full text]
  • Essentials of Heterocyclic Chemistry-I Heterocyclic Chemistry
    Baran, Richter Essentials of Heterocyclic Chemistry-I Heterocyclic Chemistry 5 4 Deprotonation of N–H, Deprotonation of C–H, Deprotonation of Conjugate Acid 3 4 3 4 5 4 3 5 6 6 3 3 4 6 2 2 N 4 4 3 4 3 4 3 3 5 5 2 3 5 4 N HN 5 2 N N 7 2 7 N N 5 2 5 2 7 2 2 1 1 N NH H H 8 1 8 N 6 4 N 5 1 2 6 3 4 N 1 6 3 1 8 N 2-Pyrazoline Pyrazolidine H N 9 1 1 5 N 1 Quinazoline N 7 7 H Cinnoline 1 Pyrrolidine H 2 5 2 5 4 5 4 4 Isoindole 3H-Indole 6 Pyrazole N 3 4 Pyrimidine N pK : 11.3,44 Carbazole N 1 6 6 3 N 3 5 1 a N N 3 5 H 4 7 H pKa: 19.8, 35.9 N N pKa: 1.3 pKa: 19.9 8 3 Pyrrole 1 5 7 2 7 N 2 3 4 3 4 3 4 7 Indole 2 N 6 2 6 2 N N pK : 23.0, 39.5 2 8 1 8 1 N N a 6 pKa: 21.0, 38.1 1 1 2 5 2 5 2 5 6 N N 1 4 Pteridine 4 4 7 Phthalazine 1,2,4-Triazine 1,3,5-Triazine N 1 N 1 N 1 5 3 H N H H 3 5 pK : <0 pK : <0 3 5 Indoline H a a 3-Pyrroline 2H-Pyrrole 2-Pyrroline Indolizine 4 5 4 4 pKa: 4.9 2 6 N N 4 5 6 3 N 6 N 3 5 6 3 N 5 2 N 1 3 7 2 1 4 4 3 4 3 4 3 4 3 3 N 4 4 2 6 5 5 5 Pyrazine 7 2 6 Pyridazine 2 3 5 3 5 N 2 8 N 1 2 2 1 8 N 2 5 O 2 5 pKa: 0.6 H 1 1 N10 9 7 H pKa: 2.3 O 6 6 2 6 2 6 6 S Piperazine 1 O 1 O S 1 1 Quinoxaline 1H-Indazole 7 7 1 1 O1 7 Phenazine Furan Thiophene Benzofuran Isobenzofuran 2H-Pyran 4H-Pyran Benzo[b]thiophene Effects of Substitution on Pyridine Basicity: pKa: 35.6 pKa: 33.0 pKa: 33.2 pKa: 32.4 t 4 Me Bu NH2 NHAc OMe SMe Cl Ph vinyl CN NO2 CH(OH)2 4 8 5 4 9 1 3 2-position 6.0 5.8 6.9 4.1 3.3 3.6 0.7 4.5 4.8 –0.3 –2.6 3.8 6 3 3 5 7 4 8 2 3 5 2 3-position 5.7 5.9 6.1 4.5 4.9 4.4 2.8 4.8 4.8 1.4 0.6 3.8 4 2 6 7 7 3 N2 N 1 4-position
    [Show full text]
  • Pd and Cu-MEDIATED DOMINO REACTIONS for THE
    254 Pd AND Cu-MEDIATED DOMINO REACTIONS FOR THE SYNTHESIS OF SULFUR HETEROCYCLES DOI: http://dx.medra.org/10.17374/targets.2018.21.254 Morgan Donnard,* Thomas Castanheiro and Mihaela Gulea* CNRS, University of Strasbourg, LIT UMR 7200, 67000 Strasbourg, France (e-mail: [email protected]; [email protected]) Abstract. Pd and Cu-mediated domino reactions are powerful tools for the synthesis of heterocycles. In this chapter we have compiled the most relevant examples of such transformations for the synthesis of sulfur- containing heterocycles. These sequences have been organized by type of heterocycle formed and the nature of the substrates (with or without a sulfur atom). Contents 1. Introduction 2. Synthesis of heterocycles incorporating only sulfur heteroatom 2.1. From sulfur-containing starting material 2.2. From sulfur-free starting material 3. Synthesis of heterocycles incorporating one sulfur and at least another heteroatom 3.1. N,S-Heterocycles 3.1.1. From sulfur-containing starting material 3.1.2 From sulfur-free starting material 3.2 O,S-Heterocycles 3.2.1. From sulfur-containing starting material 3.2.2. From sulfur-free starting material 4. Conclusion Acknowledgements References 1. Introduction The impact of organosulfur compounds in pharmaceutical industry is significant, several sulfur- containing drugs being among the most prescribed and sold at present in the world.1 Some of them contain in their structure a sulfur heterocycle (Figure 1). Considering the continual need for the development of medicinal therapies, new S-heterocyclic compounds could lead to forthcoming pharmaceuticals. Figure 1. Structures of drugs containing a sulfur-heterocycle. 255 As a consequence, the search for new syntheses to provide original compounds of these types represents a topical subject.
    [Show full text]
  • UNITED STATE S PATENT OFFICE BENZOTHIOPHENE ANTHRAQUINONE DYESTUFFS - Fritz Max, Staten Island, N
    Patented Oct. 28, 1952 2,615,898 UNITED STATE s PATENT OFFICE BENZOTHIOPHENE ANTHRAQUINONE DYESTUFFS - Fritz Max, Staten Island, N. Y., and Wilhelm Schmidt-Nickels, Little York, N. J., assignors to General Aniline & Film Corporation, New York, N. Y., a corporation of Delaware No Drawing. Application October 14, 1948, Serial No. 54,582 . 12 Claims. (CI. 260-329.2) This invention relates to novel dyestuffs of the wherein the first compound has four unsubstis benzothiophene anthraquinone Series. tuted alpha-positions in the anthraquinone nu More specifically, the invention relates to novel cleus and the second compound has three unsub a-amino-benzothiophene anthraquinones which stituted alpha-positions. are valuable as dyestuffs for organic derivatives In preparing the novel dyestuffs suitable for of cellulose, particularly cellulose esters and coloring cellulose esters and ethers in accordance ethers such as cellulose acetate and ethyl cellu with this invention, the aforesaid benzothiophene lose and fibers or textile materials containing the anthraquinones are subjected to nitration by treat same, such dyestuffs being applied to the afore ment With a mixture of concentrated nitric and said materials in the form of an aqueous disper O Sulfuric acids. An d-dinitro benzothiophene an sion. Further, the invention relates to d-aroyl thraquinone is thereby formed wherein the a amino benzothiophene anthraquinones, corre nitro groups apparently occupy the 15- and 1.8- sponding to the aforesaid d-amino derivatives positions of the anthraquinone nucleus. The a and prepared therefrom by reaction with an aryl dinitro compounds are thereupon Subjected to re. carboxylating agent, which are valuable vat dye 5 duction, for example, by heating with an aqueous stuffs suitable for producing colorations on cellu alkali metal sulfide solution, yielding the corre losic fiber and textiles by conventional vat dyeing sponding diamino - benzothiophene anthraquin or printing procedures.
    [Show full text]
  • Thiophenes and Their Benzo Derivatives: Structure
    2.09 Thiophenes and their Benzo Derivatives: Structure MARIA SZAJDA Monroe, NY, USA JAMSHED N. LAM Monroe, NY, USA 2.09.1 INTRODUCTION 438 2.09.2 THEORETICAL METHODS 440 2.09.2.1 General 440 2.09.2.2 The Role of d-Orbitals on Sulfur 441 2.09.2.3 Total Energies 441 2.09.2.4 Charge Distribution 442 2.09.2.5 Dipole Moments 444 2.09.2.6 Orbital Energies-Ionization Potentials 445 2.09.2.7 Excitation Energy-UV Spectra 447 2.09.2.8 Vibrational Frequencies 448 2.09.2.9 Bond Lengths and Angles 449 2.09.2.10 Other Molecular Properties 452 2.09.2.11 Miscellaneous 452 2.09.3 EXPERIMENTAL STRUCTURAL METHODS 454 2.09.3.1 Molecular Structure 454 2.09.3.2 Molecular Spectroscopy 462 2.09.3.2.1 Proton NMR spectroscopy 462 2.09.3.2.2 Carbon-13 NMR spectroscopy 464 2.09.3.2.3 Sulfur-33 NMR spectroscopy 466 2.09.3.2.4 Mass spectroscopy 466 2.09.3.2.5 Ultraviolet spectroscopy 468 2.09.3.2.6 Infrared spectroscopy 469 2.09.3.2.7 Photoelectron spectroscopy 470 2.09.4 THERMODYNAMICS 471 2.09.4.1 Aromaticity 471 2.09.4.2 Conformational Analysis 480 2.09.4.3 Tautomerism 483 2.09.4.3.1 Compounds with a hydroxy group 483 2.09.4.3.2 Compounds with more than one hydroxy group 487 2.09.4.3.3 Compounds with a thiol group 488 2.09.4.3.4 Compounds with an amino group 489 438 Thiophenes and their Benzo Derivatives: Structure 2.09.1 INTRODUCTION Heterocyclic compounds are divided into heteroaromatic and heteroalicyclic derivatives.
    [Show full text]
  • Heterocyclic Anticancer Compounds: Recent Advances and the Paradigm Shift Towards the Use of Nanomedicine’S Tool Box
    Molecules 2015, 20, 16852-16891; doi:10.3390/molecules200916852 OPEN ACCESS molecules ISSN 1420-3049 www.mdpi.com/journal/molecules Review Heterocyclic Anticancer Compounds: Recent Advances and the Paradigm Shift towards the Use of Nanomedicine’s Tool Box Pedro Martins 1, João Jesus 1, Sofia Santos 1, Luis R. Raposo 1, Catarina Roma-Rodrigues 1, Pedro Viana Baptista 1,* and Alexandra R. Fernandes 1,2,* 1 UCIBIO, Departamento de Ciências da Vida, Faculdade de Ciências e Tecnologia da Universidade Nova de Lisboa, Campus de Caparica, 2829-516 Caparica, Portugal; E-Mails: [email protected] (P.M.); [email protected] (J.J.); [email protected] (S.S.); [email protected] (L.R.R.); [email protected] (C.R.-R.) 2 Centro de Química Estrutural, Complexo 1, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal * Authors to whom correspondence should be addressed; E-Mails: [email protected] (P.V.B.); [email protected] (A.R.F.); Tel./Fax: +351-21-2894-8530 (P.V.B. & A.R.F.). Academic Editor: Richard A. Bunce Received: 19 June 2015 / Accepted: 9 September 2015 / Published: 16 September 2015 Abstract: The majority of heterocycle compounds and typically common heterocycle fragments present in most pharmaceuticals currently marketed, alongside with their intrinsic versatility and unique physicochemical properties, have poised them as true cornerstones of medicinal chemistry. Apart from the already marketed drugs, there are many other being investigated for their promising activity against several malignancies. In particular, anticancer research has been capitalizing on the intrinsic versatility and dynamic core scaffold of these compounds.
    [Show full text]
  • Potential Chemical Contaminants in the Marine Environment
    Potential chemical contaminants in the marine environment An overview of main contaminant lists Victoria Tornero, Georg Hanke 2017 EUR 28925 EN This publication is a Technical report by the Joint Research Centre (JRC), the European Commission’s science and knowledge service. It aims to provide evidence-based scientific support to the European policymaking process. The scientific output expressed does not imply a policy position of the European Commission. Neither the European Commission nor any person acting on behalf of the Commission is responsible for the use that might be made of this publication. Contact information Name: Victoria Tornero Address: European Commission Joint Research Centre, Directorate D Sustainable Resources, Water and Marine Resources Unit, Via Enrico Fermi 2749, I-21027 Ispra (VA) Email: [email protected] Tel.: +39-0332-785984 JRC Science Hub https://ec.europa.eu/jrc JRC 108964 EUR 28925 EN PDF ISBN 978-92-79-77045-6 ISSN 1831-9424 doi:10.2760/337288 Luxembourg: Publications Office of the European Union, 2017 © European Union, 2017 The reuse of the document is authorised, provided the source is acknowledged and the original meaning or message of the texts are not distorted. The European Commission shall not be held liable for any consequences stemming from the reuse. How to cite this report: Tornero V, Hanke G. Potential chemical contaminants in the marine environment: An overview of main contaminant lists. ISBN 978-92-79-77045-6, EUR 28925, doi:10.2760/337288 All images © European Union 2017 Contents Acknowledgements ................................................................................................ 1 Abstract ............................................................................................................... 2 1 Introduction ...................................................................................................... 3 2 Compilation of substances of environmental concern .............................................
    [Show full text]