- Novel chiral stationary phases based on 3,5-dimethyl phenylcarbamoylated β-cyclodextrin combining cinchona alkaloid moiety
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Novel chiral selectors based on 3,5-dimethyl phenylcarbamoylated β-cyclodextrin connecting quinine (QN) or quinidine (QD) moiety were synthesized and immobilized on silica gel. Their chromatographic performances were investigated by comparing to the 3,5-dimethyl phenylcarbamoylated β-cyclodextrin (β-CD) chiral stationary phase (CSP) and 9-O-(tert-butylcarbamoyl)-QN-based CSP (QN-AX). Fmoc-protected amino acids, chiral drug cloprostenol (which has been successfully employed in veterinary medicine), and neutral chiral analytes were evaluated on CSPs, and the results showed that the novel CSPs characterized as both enantioseparation capabilities of CD-based CSP and QN/QD-based CSPs have broader application range than β-CD-based CSP or QN/QD-based CSPs. It was found that QN/QD moieties play a dominant role in the overall enantioseparation process of Fmoc-amino acids accompanied by the synergistic effect of β-CD moiety, which lead to the different enantioseparation of β-CD-QN-based CSP and β-CD-QD-based CSP. Furthermore, new CSPs retain extraordinary enantioseparation of cyclodextrin-based CSP for some neutral analytes on normal phase and even exhibit better enantioseparation than the corresponding β-CD-based CSP for certain samples.
- Zhu, Lunan,Zhu, Junchen,Sun, Xiaotong,Wu, Yaling,Wang, Huiying,Cheng, Lingping,Shen, Jiawei,Ke, Yanxiong
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p. 1080 - 1090
(2020/05/25)
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- AMINE-SUBSTITUTED HETEROCYCLIC COMPOUNDS AS EHMT2 INHIBITORS, SALTS THEREOF, AND METHODS OF SYNTHESIS THEREOF
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The present disclosure relates to amine-substituted heterocyclic compounds. The present disclosure also relates to pharmaceutical compositions containing these compounds and methods of treating a disorder (e.g., cancer) by administering an amine-substituted heterocyclic heterocyclic compound disclosed herein or a pharmaceutical composition thereof to subjects in need thereof. The present disclosure also relates to the use of such compounds for research or other non-therapeutic purposes.
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Paragraph 01608
(2019/05/10)
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- Probing the Existence of a Metastable Binding Site at the β2-Adrenergic Receptor with Homobivalent Bitopic Ligands
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Herein, we report the development of bitopic ligands aimed at targeting the orthosteric binding site (OBS) and a metastable binding site (MBS) within the same receptor unit. Previous molecular dynamics studies on ligand binding to the β2-adrenergic receptor (β2AR) suggested that ligands pause at transient, less-conserved MBSs. We envisioned that MBSs can be regarded as allosteric binding sites and targeted by homobivalent bitopic ligands linking two identical pharmacophores. Such ligands were designed based on docking of the antagonist (S)-alprenolol into the OBS and an MBS and synthesized. Pharmacological characterization revealed ligands with similar potency and affinity, slightly increased β2/β1AR-selectivity, and/or substantially slower β2AR off-rates compared to (S)-alprenolol. Truncated bitopic ligands suggested the major contribution of the metastable pharmacophore to be a hydrophobic interaction with the β2AR, while the linkers alone decreased the potency of the orthosteric fragment. Altogether, the study underlines the potential of targeting MBSs for improving the pharmacological profiles of ligands.
- Gaiser, Birgit I.,Danielsen, Mia,Marcher-R?rsted, Emil,R?pke J?rgensen, Kira,Wróbel, Tomasz M.,Frykman, Mikael,Johansson, Henrik,Br?uner-Osborne, Hans,Gloriam, David E.,Mathiesen, Jesper Mosolff,Sejer Pedersen, Daniel
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p. 7806 - 7839
(2019/09/07)
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- Synthesis and biological evaluation of new simple indolic non peptidic HIV Protease inhibitors: The effect of different substitution patterns Dedicated to CINMPIS on the occasion of its 20th anniversary.
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New structurally simple indolic non peptidic HIV Protease inhibitors were synthesized from (S)-glycidol by regioselective methods. Following the concept of targeting the protein backbone, different substitution patterns were introduced onto the common stereodefined isopropanolamine core modifying the type of functional group on the indole, the position of the functional group on the indole and the type of the nitrogen containing group (sulfonamides or perhydroisoquinoline), alternatively. The systematic study on in vitro inhibition activity of such compounds confirmed the general beneficial effect of the 5-indolyl substituents in presence of arylsulfonamide moieties, which furnished activities in the micromolar range. Preliminary docking analysis allowed to identify several key features of the binding mode of such compounds to the protease.
- Bonini,Chiummiento,Di Blasio,Funicello,Lupattelli,Tramutola,Berti,Ostric,Miertus,Frecer,Kong
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p. 4792 - 4802
(2014/10/15)
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- Synthesis of the calcilytic ligand NPS 2143
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(R)-3 (NPS 2143) is a negative allosteric modulator of the human calcium-sensing receptor (CaSR) and as such represents an important pharmacological tool compound for studying the CaSR. Herein, we disclose for the first time a complete experimental description, detailed characterisation and assessment of enantiomeric purity for (R)-3. An efficient, reproducible and scalable synthesis of (R)-3 that requires a minimum of chromatographic purification steps is presented. (R)-3 was obtained in excellent optical purity (er > 99:1) as demonstrated by chiral HPLC and the pharmacological profile for (R)-3 is in full accordance with that reported in the literature.
- Johansson, Henrik,Cailly, Thomas,Thomsen, Alex Rojas Bie,Braeuner-Osborne, Hans,Pedersen, Daniel Sejer
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supporting information
p. 1383 - 1387
(2013/08/23)
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- Synthesis and biological evaluation of novel small non-peptidic HIV-1 PIs: The benzothiophene ring as an effective moiety
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Synthesis and biological evaluation of a new series of potential HIV-1 protease inhibitors incorporating different heterocycles are described. The variation of heteroatom in such molecules has displayed totally different biological activities and a benzothiophene containing inhibitor has shown high potency against wild type HIV-1 protease with IC50 = 60 nM, thanks to the lower desolvation penalty to be payed by such hydrophobic moiety.
- Chiummiento, Lucia,Funicello, Maria,Lupattelli, Paolo,Tramutola, Francesco,Berti, Federico,Marino-Merlo, Francesca
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experimental part
p. 2948 - 2950
(2012/06/15)
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- Synthesis of 5-oxyquinoline derivatives for reversal of multidrug resistance
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The inhibition of ABC (ATP binding cassette) transporters is considered a powerful tool to reverse multidrug resistance. Zosuquidar featuring a difluorocyclopropyl-annulated dibenzosuberyl moiety has been found to be an inhibitor of the P-glycoprotein, one of the best-studied multidrug efflux pumps. Twelve 5-oxyisoquinoline derivatives, which are analogues of zosuquidar wherein the dibenzosuberyl-piperazine moiety is replaced by either a diarylaminopiperidine or a piperidone-derived acetal or thioacetal group, have been synthesized as pure enantiomers. Their inhibitory power has been evaluated for the bacterial multidrugresistance ABC transporter LmrCD and fungal Pdr5. Four of the newly synthesized compounds reduced the transport activity to a higher degree than zosuquidar, being up to fourfold more efficient than the lead compound in the case of LmrCD and about two times better for Pdr5.
- Dittrich, Torsten,Hanekop, Nils,Infed, Nacera,Schmitt, Lutz,Braun, Manfred
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p. 1700 - 1704
(2013/01/15)
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- NO-SSRIs: Nitric oxide chimera drugs incorporating a selective serotonin reuptake inhibitor
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Hybrid nitrate drugs have been reported to provide NO bioactivity to ameliorate side effects or to provide ancillary therapeutic activity. Hybrid nitrate selective serotonin reuptake inhibitors (NO-SSRIs) were prepared to improve the therapeutic profile of this drug class. A synthetic strategy for use of a thiocarbamate linker was developed, which in the case of NO-fluoxetine facilitated hydrolysis to fluoxetine at pH 7.4 within 7 h. In cell culture, NO-SSRIs were weak inhibitors of the serotonin transporter; however, in the forced swimming task (FST) in rats, NO-fluoxetine demonstrated classical antidepressant activity. Comparison of NO-fluoxetine, with fluoxetine, and an NO-chimera nitrate developed for Alzheimer's disease (GT-1061) were made in the step through passive avoidance (STPA) test of learning and memory in rats treated with scopolamine as an amnesic agent. Fluoxetine was inactive, whereas NO-fluoxetine and GT-1061 both restored long-term memory. GT-1061 also produced antidepressant behavior in FST. These data support the potential for NO-SSRIs to overcome the lag in onset of therapeutic action and provide cotherapy of neuropathologies concomitant with depression.
- Abdul-Hay, Samer,Schiefer, Isaac T.,Chandrasena, R. Esala P.,Li, Min,Abdelhamid, Ramy,Wang, Yue-Ting,Tavassoli, Ehsan,Michalsen, Bradley,Asghodom, Rezene T.,Luo, Jia,Thatcher, Gregory R. J.
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supporting information; experimental part
p. 656 - 661
(2011/11/07)
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- METHODS AND COMPOSITIONS INVOLVING (S)-BUCINDOLOL
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Disclosed is bucindolol substantially free of its R-stereoisomer. Also disclosed are pharmaceutical compositions that include bucindolol substantially free of its R-stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Also disclosed are methods of treating a patient that involve administering to the patient a therapeutically effective amount of a composition of the present invention. Formula (I).
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Page/Page column 54
(2010/04/03)
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- Chimeric Nitrate Esters and Use of the Same in a Treatment for Depression
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Chimeric nitrate esters and their use in the treatment of depression are disclosed. The chimeric nitrate esters also are useful in the treatment of depression and comorbidity associated with aging.
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Page/Page column 13
(2009/07/25)
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- New indolic non-peptidic HIV protease inhibitors from (S)-glycidol: synthesis and preliminary biological activity
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A series of non-peptidic HIV protease inhibitors were synthesized starting from the same optically active precursor, (S)-glycidol. The substrate was easily converted into different indolic sulfonamides or amines by regioselective reactions. The preliminary inhibitory activity was evaluated.
- Chiummiento, Lucia,Funicello, Maria,Lupattelli, Paolo,Tramutola, Francesco,Campaner, Pietro
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scheme or table
p. 5984 - 5989
(2011/03/17)
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- New propranolol analogues: Binding and chiral discrimination by cellobiohydrolase Cel7A
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Novel propranolol analogues have been designed and synthesised and their enantioselective binding to the cellulose degrading enzyme, Cel7A, has been evaluated. Affinity and enantioselectivity have been determined by capillary electrophoresis experiments. Ligands with significantly improved affinity and selectivity have been obtained and an analysis of the results has led to insights concerning the relation between the changes in ligand structure and selectivity as well as affinity to the protein. The Royal Society of Chemistry 2006.
- Fagerstroem, Alexandra,Nilsson, Mikael,Berg, Ulf,Isaksson, Roland
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p. 3067 - 3076
(2008/02/12)
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- Scavenger assisted combinatorial process for preparing libraries of tertiary amine compounds
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This invention relates to a novel solution phase process for the preparation of tertiary amine combinatorial libraries. These libraries have utility for drug discovery and are used to form wellplate components of novel assay kits.
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- Pyridazinones having cardiotonic and beta blocking activities
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Pyridazinones of the following formula (I): STR1 where R1 -R4 are a variety of substituents and L is a linking group, a pharmaceutical composition for treating congestive heart failure, novel intermediates, methods for such treatment and processes for preparing compounds of formula (I).
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- Arenesulfonate Derivatives of Homochiral Glycidol: Versatile Chiral Building Blocks for Organic Synthesis
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The preparation of a series of crystalline arenesulfonate derivatives of enantiomerically enriched glycidol is described.The enhancement of optical purity by recrystallization was particularly successful for two of these derivatives, glycidyl tosylate and glycidyl 3-nitrobenzenesulfonate, which were obtained in 97 percent ee and 99 percent ee, respectively.Very high regioselectivity was observed in the reactions of these compounds with a variety of nucleophiles, including aryl oxides, Et2AlCN, organometallic reagents, and BH3-NaBH4.The application of this methodology to the synthesis of homochiral β-adrenergic blocking agents and homochiral terminal epoxides is discussed.
- Klunder, Janice M.,Onami, Tetsuo,Sharpless, K. Barry
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p. 1295 - 1304
(2007/10/02)
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