2016年10月31日月曜日

Quinoline Biochemistry 2016

Discovery and Pharmacological Characterization of Novel Quinazoline-Based PI3K Delta-Selective Inhibitors

^†Global Discovery Chemistry, ^‡Center for Proteomic Chemistry, ^§Metabolism and Pharmacokinetics, ^∥Autoimmunity, Transplantation and Inflammation, Novartis Institutes for BioMedical Research, Novartis Campus, CH-4002 Basel, Switzerland

^⊥ Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 5300 Chiron Way, Emeryville, California 94608, United States

ACS Med. Chem. Lett., 2016, 7 (8), pp 762–767

DOI: 10.1021/acsmedchemlett.6b00119

Publication Date (Web): June 2, 2016

*(K.H.) Tel: +41 79 6181814. E-mail: klemens.hoegenauer@novartis.com., *(N.S.) Tel: +41 79 8451506. E-mail: nicolas.soldermann@novartis.com.

Abstract

Inhibition of the lipid kinase PI3Kδ is a promising principle to treat B and T cell driven inflammatory diseases.

Using a scaffold deconstruction–reconstruction strategy, we identified 4-aryl quinazolines that were optimized into potent PI3Kδ isoform selective analogues with good pharmacokinetic properties.

With compound 11, we illustrate that biochemical PI3Kδ inhibition translates into modulation of isoform-dependent immune cell function (human, rat, and mouse).

After oral administration of compound 11 to rats, proximal PD markers are inhibited, and dose-dependent efficacy in a mechanistic plaque forming cell assay could be demonstrated.

Keywords:

B cell inhibition; lead optimization; Phosphoinositide-3-kinase delta inhibitor; PI3Kδ inhibitor; PK/PD studies; structure−activity relationship

Supporting Information

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsmedchemlett.6b00119.

Full descriptions of all biological assays and in vivo studies. Characterization of all compounds. Full experimental procedures for the sequence leading to compound 11. Crystallographic data collection and refinement statistics for crystal structures (PDF)

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Discovery of novel pyrrolidineoxy-substituted heteroaromatics as potent and selective PI3K delta inhibitors with improved physicochemical properties

Klemens Hoegenauer, Nicolas Soldermann, Christina Hebach, Gregory J. Hollingworth, Ian Lewis, Anette von Matt, Alexander B. Smith, Romain M. Wolf, Rainer Wilcken, Dorothea Haasen, Christoph Burkhart, Frédéric Zécri

Bioorganic & Medicinal Chemistry Letters 2016

Imidazole Biochemistry 2016

Mechanistic and Evolutionary Insights from Comparative Enzymology of Phosphomonoesterases and Phosphodiesterases across the Alkaline Phosphatase Superfamily

Fanny Sunden^†, Ishraq AlSadhan^†, Artem Y. Lyubimov, Susanne Ressl^§, Helen Wiersma-Koch^†^⊥, Jamar Borland^†, Clayton L. BrownJr.^†, Tory A. Johnson^†, Zorawar Singh^†, and Daniel Herschlag^*^†^∥

^† Department of Biochemistry, Beckman Center, Stanford University, Stanford, California 94305, United States

^‡ Departments of Molecular and Cellular Physiology, Neurology and Neurological Science, Structural Biology, and Photon Science, Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, United States

^§ Molecular and Cellular Biochemistry Department, Indiana University, Bloomington, Indiana 47405, United States

^⊥ Department of Biology, Indian River State College, Fort Pierce, Florida 34981, United States

^∥ Departments of Chemical Engineering and Chemistry, and Stanford ChEM-H (Chemistry, Engineering, and Medicine for Human Health), Stanford University, Stanford, California 94305, United States

J. Am. Chem. Soc., Article ASAP

DOI: 10.1021/jacs.6b06186

Publication Date (Web): September 26, 2016

*herschla@stanford.edu

Abstract

Naively one might have expected an early division between phosphate monoesterases and diesterases of the alkaline phosphatase (AP) superfamily. On the contrary, prior results and our structural and biochemical analyses of phosphate monoesterase PafA, from Chryseobacterium meningosepticum, indicate similarities to a superfamily phosphate diesterase [Xanthomonas citri nucleotide pyrophosphatase/phosphodiesterase (NPP)] and distinct differences from the three metal ion AP superfamily monoesterase, from Escherichia coli AP (EcAP). We carried out a series of experiments to map out and learn from the differences and similarities between these enzymes. First, we asked why there would be independent instances of monoesterases in the AP superfamily? PafA has a much weaker product inhibition and slightly higher activity relative to EcAP, suggesting that different metabolic evolutionary pressures favored distinct active-site architectures. Next, we addressed the preferential phosphate monoester and diester catalysis of PafA and NPP, respectively. We asked whether the >80% sequence differences throughout these scaffolds provide functional specialization for each enzyme’s cognate reaction. In contrast to expectations from this model, PafA and NPP mutants with the common subset of active-site groups embedded in each native scaffold had the same monoesterase:diesterase specificities; thus, the >10⁷-fold difference in native specificities appears to arise from distinct interactions at a single phosphoryl substituent. We also uncovered striking mechanistic similarities between the PafA and EcAP monoesterases, including evidence for ground-state destabilization and functional active-site networks that involve different active-site groups but may play analogous catalytic roles. Discovering common network functions may reveal active-site architectural connections that are critical for function, and identifying regions of functional modularity may facilitate the design of new enzymes from existing promiscuous templates. More generally, comparative enzymology and analysis of catalytic promiscuity can provide mechanistic and evolutionary insights.

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.6b06186.

S1, PafA gene sequence; S2, pH dependencies for PafA WT and mutants; S3, inhibition curves for PafA WT and mutants; S4, determination of Me-P kinetics at pH 8; S5–S9, sequence alignments and structural comparisons in the AP superfamily (PDF)
Crystallographic data for PafA_refine_reflections (CIF)
Crystallographic data for PafA_refine_99 (CIF)

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2016年10月28日金曜日

これを炭酸ガスでやりたいと思った日！！２０１６　Oct

環境負荷の少ない

シンプルなアシル化への途

Environmentally Benign Avenue to Pd-Catalyzed Acylation

Basuli Suchand and Gedu Satyanarayana^*

Department of Chemistry, Indian Institute of Technology Hyderabad, Kandi 502 285, Sangareddy, Telangana, India

J. Org. Chem., 2016, 81 (15), pp 6409–6423

gvsatya@iith.ac.in

Abstract

Recent trends in research have gained an orientation toward developing efficient strategies using innocuous reagents. The earlier reported transition-metal-catalyzed carbonylations involved either toxic carbon monoxide (CO) gas as carbonylating agent or functional-group-assisted ortho sp² C–H activation (i.e., ortho acylation) or carbonylation by activation of the carbonyl group (i.e., via the formation of enamines). Contradicting these methods, here we describe an environmentally benign process, [Pd]-catalyzed direct carbonylation starting from simple and commercially available iodo arenes and aldehydes, for the synthesis of a wide variety of ketones. Moreover, this method comprises direct coupling of iodoarenes with aldehydes without activation of the carbonyl and also without directing group assistance. Significantly, the strategy was successfully applied to the synthesis n-butylphthalide and pitofenone.

Supporting Information

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.6b01064.

¹H NMR and ¹³C NMR spectra of all compounds and CIF file for 3ah (PDF)
(PDF)
(XLS)

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Related Content

2016年10月26日水曜日

Imidazopyridines or Fused Imidazoles for Anti-TB 2016

Identification of N-(2-Phenoxyethyl)imidazo[1,2-a]pyridine-3-carboxamides as New Antituberculosis Agents

Zhaoyang Wu^†⊥, Yu Lu^‡⊥, Linhu Li^†, Rui Zhao^†, Bin Wang^‡, Kai Lv^†^§, Mingliang Liu^*^†, and Xuefu You^*^†

^† Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China

^‡ Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Department of Pharmacology, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing 101149, China

^§ Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, United States

ACS Med. Chem. Lett., Article ASAP

DOI: 10.1021/acsmedchemlett.6b00330

Publication Date (Web): October 11, 2016

*Tel: 010-63030965. Fax: 010-63036965. E-mail: lmllyx@126.com., *E-mail: xuefuyou116@yahoo.cn.

Abstract

A series of imidazo[1,2-a]pyridine carboxamides (IPAs) bearing an N-(2-phenoxyethyl) moiety

was designed and synthesized as new antitubercular agents. Seven 2,6-dimethyl IPAs demonstrated excellent in vitro activity (MIC: 0.025–0.054 μg/mL) against the drug susceptive H37Rv strain and two clinically isolated multidrug-resistant Mycobacterium tuberculosisstrains. Compound 10j displayed acceptable safety and pharmacokinetic properties, opening a new direction for further development.

Keywords:

Antitubercular agents; MTB H37Rv; multidrug resistant-MTB; N-(2-phenoxyethyl)imidazo[1,2-a]pyridine carboxamides; structure−activity relationship

Supporting Information

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsmedchemlett.6b00330.

Experimental procedures and analytical data for compounds 10a–m, 11a–n, and 14 (PDF)

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Quinolinyl Oxy Acettoamide Derivatives As Ant-TB Compounds 2016

2-(Quinolin-4-yloxy)acetamides Are Active against Drug-Susceptible and Drug-Resistant Mycobacterium tuberculosis Strains

Kenia Pissinate^†, Anne Drumond Villela^†^‡, Valnês Rodrigues-Junior^†^§, Bruno Couto Giacobbo^†^§, Estêvão Silveira Grams^†, Bruno Lopes Abbadi^†^§, Rogério Valim Trindade^†^§, Laura Roesler Nery^∥, Carla Denise Bonan^§^∥, Davi Fernando Back^⊥, Maria Martha Campos^†^‡^§, Luiz Augusto Basso^†^‡^§, Diógenes Santiago Santos^*^†^§, and Pablo Machado^*^†^§

^† Instituto Nacional de Ciência e Tecnologia em Tuberculose (INCT-TB), Centro de Pesquisas em Biologia Molecular e Funcional, Pontifícia Universidade Católica do Rio Grande do Sul, 90619-900 Porto Alegre, RS, Brazil

^‡ Programa de Pós-Graduação em Medicina e Ciências da Saúde, Pontifícia Universidade Católica do Rio Grande do Sul, 90619-900 Porto Alegre, RS, Brazil

^§ Programa de Pós-Graduação em Biologia Celular e Molecular, Pontifícia Universidade Católica do Rio Grande do Sul, 90619-900 Porto Alegre, RS, Brazil

^∥ Laboratório de Neuroquímica e Psicofarmacologia, Pontifícia Universidade Católica do Rio Grande do Sul, 90619-900 Porto Alegre, RS, Brazil

^⊥ Departamento de Química, Laboratório de Materiais Inorgânicos, Universidade Federal de Santa Maria, 97105-900 Santa Maria, RS, Brazil

ACS Med. Chem. Lett., 2016, 7 (3), pp 235–239

DOI: 10.1021/acsmedchemlett.5b00324

Publication Date (Web): January 11, 2016

*Phone/Fax: +55 51 3320 3629. E-mail: diogenes@pucrs.br., *Phone/Fax: +55 51 3320 3629. E-mail: pablo.machado@pucrs.br.

Abstract

2-(Quinolin-4-yloxy)acetamides have been described as potent in vitro inhibitors of Mycobacterium tuberculosis growth. Herein, additional chemical modifications of lead compounds were carried out, yielding highly potent antitubercular agents with minimum inhibitory concentration (MIC) values as low as 0.05 μM. Further, the synthesized compounds were active against drug-resistant strains and were devoid of apparent toxicity to Vero and HaCat cells (IC₅₀s ≥ 20 μM). In addition, the 2-(quinolin-4-yloxy)acetamides showed intracellular activity against the bacilli in infected macrophages with action similar to rifampin, low risk of drug–drug interactions, and no sign of cardiac toxicity in zebrafish (Danio rerio) at 1 and 5 μM. Therefore, these data indicate that this class of compounds may furnish candidates for future development to, hopefully, provide drug alternatives for tuberculosis treatment.

Keywords:

drug-resistant research; quinoline-based compounds; SAR; Tuberculosis

Supporting Information

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsmedchemlett.5b00324.

Synthetic procedures, analytical data, crystal data and details of the data collection, and bioassay protocols (PDF)

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Differential characterization using readily accessible NMR experiments of novel N- and O-alkylated quinolin-4-ol, 1,5-naphthyridin-4-ol and quinazolin-4-ol derivatives with antimycobacterial activity

Eleni Pitta, Olga Balabon, Maciej K. Rogacki, Jesús Gómez, Fraser Cunningham, Jurgen Joosens, Koen Augustyns, Pieter van der Veken, Robert Bates

European Journal of Medicinal Chemistry 2016 ,
SAR and identification of 2-(quinolin-4-yloxy)acetamides as Mycobacterium tuberculosis cytochrome bc 1 inhibitors

Narisa Phummarin, Helena I. Boshoff, Patricia S. Tsang, James Dalton, Siouxsie Wiles, Clifton E. Barry 3rd, Brent R. Copp

Med. Chem. Commun. 2016 ,
An efficient synthesis of 1,3-dimethyl-5-(2-phenyl-4H-chromen-4-ylidene) pyrimidine-2,4,6(1H,3H,5H)-triones and investigation of their interactions with β-lactoglobiulin

Nayim Sepay, Sumitava Mallik, Chayan Guha, Asok K. Mallik

RSC Adv. 2016 6 (98), 96016-96024

http://pubs.rsc.org/en/content/articlelanding/2016/md/c6md00236f#!divAbstract

Quinolinyl OxyAcetamide Dearivative for TB 2016

SAR and identification of 2-(quinolin-4-yloxy)acetamides as Mycobacterium tuberculosis cytochrome bc1 inhibitors

Narisa Phummarin,^a Helena I. Boshoff,^b Patricia S. Tsang,^b James Dalton,^c Siouxsie Wiles,^c^d Clifton E. Barry 3rd^b and Brent R. Copp*^a

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Corresponding authors

School of Chemical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
E-mail: b.copp@auckland.ac.nz
Fax: +64 9 3737422
Tel: +64 9 3737599

Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, USA

Bioluminescent Superbugs Lab, Department of Molecular Medicine and Pathology, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand

Te Pūnaha Matatini, c/o University of Auckland, Private Bag 92019, Auckland 1142, New Zealand

Med. Chem. Commun., 2016, Advance Article

DOI: 10.1039/C6MD00236F
Received 28 Apr 2016, Accepted 17 Aug 2016
First published online 22 Aug 2016

A previous phenotypic screen by GSK identified 2-(quinolin-4-yloxy)acetamides as potent growth inhibitors of Mycobacterium tuberculosis (Mtb). We report the results of a preliminary structure–activity relationship (SAR) study of the compound class which has yielded more potent inhibitors. An Mtb cytochrome bd oxidase deletion mutant (cydKO) was found to be hypersensitive to most members of the compound library,

while strains carrying single-nucleotide polymorphisms of the qcrB gene, which encodes a subunit of the menaquinol cytochrome c oxidoreductase (bc1) complex, were resistant to the library.

These results identify that the 2-(quinolin-4-yloxy)acetamide class of Mtb growth inhibitors can be added to the growing number of scaffolds that target the M. tuberculosis bc1 complex.

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2016年10月31日月曜日

Discovery and Pharmacological Characterization of Novel Quinazoline-Based PI3K Delta-Selective Inhibitors

Abstract

Keywords:

PDF

Mechanistic and Evolutionary Insights from Comparative Enzymology of Phosphomonoesterases and Phosphodiesterases across the Alkaline Phosphatase Superfamily

Abstract

2016年10月28日金曜日

環境負荷の少ない

シンプルなアシル化への途

Environmentally Benign Avenue to Pd-Catalyzed Acylation

Abstract

PDF

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2016年10月26日水曜日

Identification of N-(2-Phenoxyethyl)imidazo[1,2-a]pyridine-3-carboxamides as New Antituberculosis Agents

Abstract

A series of imidazo[1,2-a]pyridine carboxamides (IPAs) bearing an N-(2-phenoxyethyl) moiety

Keywords:

2-(Quinolin-4-yloxy)acetamides Are Active against Drug-Susceptible and Drug-Resistant Mycobacterium tuberculosis Strains

Abstract

Keywords:

PDF

SAR and identification of 2-(quinolin-4-yloxy)acetamides as Mycobacterium tuberculosis cytochrome bc1 inhibitors

while strains carrying single-nucleotide polymorphisms of the qcrB gene, which encodes a subunit of the menaquinol cytochrome c oxidoreductase (bc1) complex, were resistant to the library.

These results identify that the 2-(quinolin-4-yloxy)acetamide class of Mtb growth inhibitors can be added to the growing number of scaffolds that target the M. tuberculosis bc1 complex.