- An efficient synthesis and bioactivity evaluation of oxazole-containing natural hinduchelins A-D and their derivatives
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Oxazoles are an important class of biologically active metabolites from nature, and exhibit broad biological activities as the lead for drug discovery. Hinduchelins are a class of unusual natural products with an oxazole unit, isolated from Streptoalloteichus hindustanus, and with a potential iron-chelating ability. These compounds are the first identified naturally occurring unusual oxazole derivatives to possess a catechol unit. However, some of these compounds are not abundant in nature, and thus, the efficient syntheses of these compounds are advantageous in exploring their potential applications. This paper reports the efficient synthesis and bio-evaluation of hinduchelins A-D and their derivatives with convenient procedures and high yields.
- Ke, Shaoyong,Zhang, Zhigang,Shi, Liqiao,Liu, Manli,Fang, Wei,Zhang, Yani,Wu, Zhaoyuan,Wan, Zhongyi,Long, Tong,Wang, Kaimei
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- Continued Exploration of Trifunctional Alkyl 4-Chloro-2-diazo-3-oxobutanoates: Streamlined Entry into [1,2,3]Triazolo[5,1- c ][1,4]benzoxazines and [1,2,3]Triazolo[5,1- c ][1,4]benzoxazepines
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Further exploration of the trifunctional character of previously introduced alkyl 4-chloro-2-diazo-3-oxobutanoates in reactions with N -protected substituted o -aminophenols followed by deprotection provided a convenient entry into [1,2,3]triazolo[5,1- c ][1,4]benzoxazines, which are of high medicinal importance, as documented in the literature. The same approach applied to N -protected substituted o -(aminomethyl)phenols afforded [1,2,3]triazolo[5,1- c ][1,4]benzoxazepines, which are practically unexplored compounds from a medicinal chemistry perspective. The syntheses start with S N 2-type alkylation of the phenol. Removal of the protecting group triggers imine formation followed by Wolff 1,2,3-triazole synthesis.
- Budeev, Anton V.,Kantin, Grigory,Dar'In, Dmitry,Krasavin, Mikhail
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p. 2155 - 2166
(2021/02/22)
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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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- Monoligated Pd(0)-catalyzed intramolecular ortho- and para-arylation of phenols for the synthesis of aporphine alkaloids. Synthesis of (-)-lirinine
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An intramolecular palladium(0)-mediated ortho-arylation of phenols applied to the synthesis of various substituted aporphines is reported. Most significantly, the efficiency of the transformation was enhanced by the use of monoligated Pd(0) complexes. This methodology was extended to para-arylation of phenols and employed in the synthesis of the aporphine alkaloid (-)-lirinine.
- Hellal, Malik,Singh, Shambhavi,Cuny, Gregory D.
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experimental part
p. 1674 - 1681
(2012/03/10)
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- Novel Pyrimidine- And Triazine-Hepcidine Antagonists
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The present invention relates to new hepcidin antagonists, pharmaceutical compositions containing them and the use thereof as a drug, in particular for the treatment of iron metabolism disorders such as, in particular, iron deficiency diseases and anaemia, in particular anaemia associated with chronic inflammatory disease (ACD: anaemia of chronic disease and AI: anaemia of inflammation).
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- Optimization of the potency and pharmacokinetic properties of a macrocyclic ghrelin receptor agonist (Part I): Development of ulimorelin (TZP-101) from Hit to Clinic
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High-throughput screening of Tranzyme Phar-ma's proprietary macrocycle library using the aequorin Ca2+-bioluminescence assay against the human ghrelin receptor (GRLN) led to the discovery of novel agonists against this G-protein coupled receptor. Early hits such as 1 (Ki = 86 nM, EC50 = 134 nM) though potent in vitro displayed poor pharmacokinetic properties that required optimization. While such macrocycles are not fully rule-of-five compliant, principally due to their molecular weight and clogP, optimization of their pharmacokinetic properties proved feasible largely through conformational rigidification. Extensive SAR led to the identification of 2 (Ki = 16 nM, EC50 = 29 nM), also known as ulimorelin or TZP-101, which has progressed to phase III human clinical trials for the treatment of postoperative ileus. X-ray structure and detailed NMR studies indicated a rigid peptidomimetic portion in 2 that is best defined as a nonideal type-I′ β-turn. Compound 2 is 24% orally bioavailable in both rats and monkeys. Despite its potency, in vitro and in gastric emptying studies, 2 did not induce growth hormone (GH) release in rats, thus demarcating the GH versus GI pharmacology of GRLN. (Figure presented)
- Hoveyda, Hamid R.,Marsault, Eric,Gagnon, René,Mathieu, Axel P.,Vézina, Martin,Landry, Annick,Wang, Zhigang,Benakli, Kamel,Beaubien, Sylvie,Saint-Louis, Carl,Brassard, Martin,Pinault, Jean-Fran?ois,Ouellet, Luc,Bhat, Shridhar,Ramaseshan, Mahesh,Peng, Xiaowen,Foucher, Laurence,Beauchemin, Sophie,Bhérer, Patrick,Veber, Daniel F.,Peterson, Mark L.,Fraser, Graeme L.
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p. 8305 - 8320
(2012/01/15)
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- Enantiomeric propanolamines as selective N-methyl-D-aspartate 2B receptor antagonists
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Enantiomeric propanolamines have been identified as a new class of NR2B-selective NMDA receptor antagonists. The most effective agents are biaryl structures, synthesized in six steps with overall yields ranging from 11-64%. The compounds are potent and selective inhibitors of NR2B-containing recombinant NMDA receptors with IC50 values between 30-100 nM. Potency is strongly controlled by substitution on both rings and the centrally located amine nitrogen. SAR analysis suggests that well-balanced polarity and chain-length factors provide the greatest inhibitory potency. Structural comparisons based on 3D shape analysis and electrostatic complementarity support this conclusion. The antagonists are neuroprotective in both in vitro and in vivo models of ischemic cell death. In addition, some compounds exhibit anticonvulsant properties. Unlike earlier generation NMDA receptor antagonists and some NR2B-selective antagonists, the present series of propanolamines does not cause increased locomotion in rodents. Thus, the NR2B-selective antagonists exhibit a range of therapeutically interesting properties.
- Tahirovic, Yesim A.,Geballe, Matthew,Gruszecka-Kowalik, Ewa,Myers, Scott J.,Lyuboslavsky, Polina,Le, Phuong,French, Adam,Irier, Hasan,Choi, Woo-Baeg,Easterling, Keith,Yuan, Hongjie,Wilson, Lawrence J.,Kotloski, Robert,McNamara, James O.,Dingledine, Raymond,Liotta, Dennis C.,Traynelis, Stephen F.,Snyder, James P.
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supporting information; experimental part
p. 5506 - 5521
(2009/08/07)
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- COMPOSITIONS AND METHODS INCLUDING CELL DEATH INDUCERS AND PROCASPASE ACTIVATION
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Compositions and methods are disclosed in embodiments relating to induction of cell death such as in cancer cells. Compounds and related methods for synthesis and use thereof, including the use of compounds in therapy for the treatment of cancer and selective induction of apoptosis in cells are disclosed. Compounds are disclosed in connection with modification of procaspases such as procaspase-3. In embodiments, compositions are capable of activation of procaspase-3.
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Page/Page column 73
(2008/12/08)
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- Structure-activity correlations for β-phenethylamines at human trace amine receptor 1
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A cell line in which RD-HGA16 cells were stably transfected with the hTAAR 1 receptor was created and utilized to carry out a systematic evaluation of a series of β-phenethylamines. Fair agreement was observed with data obtained for aryl and ethylene chain substituted analogs in an AV12-664 cell line in which hemagglutinin-tagged hTAAR 1 was stably co-expressed with rat Gαs. Analogs with multiple substituents as well as analogs with bulky groups were found to be partial agonists. Analogs in which the primary amino group was converted to a secondary or a tertiary amino group by N-methylation were also partial agonists. Comparative Molecular Field Analysis (CoMFA) using the potency data yielded a regression coefficient r2 of 0.824. The steric field contribution to the model was 61% with the balance (39%) contributed by the electrostatic field. The collective results suggest that increasing steric bulk both at the amino nitrogen, particularly by N-dimethylation, and at the 4-position of the aromatic ring leads to low efficacy ligands.
- Lewin, Anita H.,Navarro, Hernan A.,Wayne Mascarella
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p. 7415 - 7423
(2008/12/22)
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- Compounds and pharmaceutical use thereof
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PCT No. PCT/JP97/00291 Sec. 371 Date Aug. 6, 1998 Sec. 102(e) Date Aug. 6, 1998 PCT Filed Feb. 6, 1997 PCT Pub. No. WO97/29079 PCT Pub. Date Aug. 14, 1997The compounds of the formula (I) wherein each symbol is as defined in the specification, pharmaceutically acceptable salts thereof and pharmaceutical use thereof. The Compound (I) and pharmaceutically acceptable salts thereof of the present invention selectively act on cannabinoid receptors, particularly peripheral receptors, cause less side effects on the central system, and have superior immunoregulating action, antiinflammatory action, antiallergic action and therapeutic effect on nephritis. Therefore, they are useful as cannabinoid receptor, particularly peripheral cannabinoid receptor activators and antagonists, immunoregulators, therapeutic agents for autoimmune diseases, antiinflammatory agents, antiallergic agents and therapeutic agents for nephritis.
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- An intramolecular cyclization of phenol derivatives bearing aminoquinones using a hypervalent iodine reagent
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The hypervalent iodine oxidation of phenol derivatives bearing aminoquinones at the ortho (9) or meta positions (19) in 2,2,2-trifluoroethanol was investigated with the aim of preparing novel antitumor compounds. Azacarbocyclic spirodienone derivatives (13) or phenol derivatives containing the 2,3-dihydro-1H-azepine systems (17, 20) were selectively obtained by the reaction of these phenol derivatives and the hypervalent iodine reagent, phenyliodine(III) bis(trifluoroacetate). The application of this reaction to phenol derivatives bearing aminoquinones (10-12) is also described.
- Kita, Yasuyuki,Takada, Takeshi,Ibaraki, Megumi,Gyoten, Michiyo,Mihara, Sachiko,Fujita, Shigekazu,Tohma, Hirofumi
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p. 223 - 227
(2007/10/03)
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- Aromatic L-Amino Acid Decarboxylase from Micrococcus percitreus Purification, Crystallization and Properties
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An aromatic L-amino acid decarboxylase was crystallized from the cell free extract of Micrococcus percitreus.The purification procedure included protamine sulfate treatment, ammonium sulfate fractionation, DEAE-Sephadex column chromatography and Sephadex G-200 filtration.Crystals were obtained from a solution of the purified enzyme by addition of ammonium sulfate.The crystalline enzyme preparation was homogeneous as judged by ultracentrifugation and SDS-polyacrylamide gel electrophoresis.The molecular weight was determined to be approximately 101,000.The enzyme was evidently composed of two identical subunits of a molecular weight of 48,000.The enzyme catalyzed the stoichiometric conversion of L-tryptophan to tryptamine and CO2 in the presence of pyridoxal phosphate.The optimum pH was 9.0 for the conversion.The Km value and the maximum velocity of L-tryptophan decarboxylation were 2.4E-3 M and 44 μmol/min/mg of protein, respectively.This enzyme also catalyzed decarboxylation of 5-hydroxy-L-tryptophan, L-phenylalanine, L-tyrosine, 3,4-dihydroxy-L-phenylalanine, L-kynurenine and thier α-methyl amino acid derivatives.
- Nakazawa, Hidetsugu,Kumagai, Hidehiko,Yamada, Hideaki
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p. 2543 - 2552
(2007/10/02)
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- Biogenesis of Epidithiadiketopiperazines. Synthesis of Three Isomeric (β-Aminoethyl)benzene Oxides
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Three isomeric amine-substituted arene oxides have been synthesized to serve as models for the postulated involvement of amino acid derived arene oxides during the biosyntheses of various epidithiadiketopiperazines.No biogenetic-type reactivity was noted for the arene oxides.In all three cases aromatization rather than amine/epoxide cyclization was observed.The failure to duplicate the presumed in vivo reactivity of aminoarene oxides is discussed in terms of possible enzyme-mediated cyclizations in the natural systems.
- Rastetter, William H.,Nummy, Larry J.
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p. 3149 - 3155
(2007/10/02)
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