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Graphical Abstracts

Graphical Abstracts Designing Anticancer Drugs Via the Achilles Heel: Ceramide, Allylic Ketones, and Mitochondria Bioorg. Med. Chem. 11 (2003) 2123 ...

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Graphical Abstracts Designing Anticancer Drugs Via the Achilles Heel: Ceramide, Allylic Ketones, and Mitochondria

Bioorg. Med. Chem. 11 (2003) 2123

Norman S. Radin Mental Health Research Institute, University of Michigan, Ann Arbor, MI, USA This review hypothesizes that ceramide, the apoptosis-inducing sphingolipid, acts by undergoing oxidation to an allylic ketone in tumor mitochondria. The graphic suggests that the reaction occurs in complex III, with ubiquinone as the oxidant. The presence of an allylic alcohol or allylic ketone group in a drug seems to make it a good antineoplastic agent.

Bioorg. Med. Chem. 11 (2003) 2143 Synthesis and Cytotoxic Activity of N,N-bis-{3-[N-(4Chlorobenzo[g]-phthalazin-1-yl)]aminopropyl}-N-methylamine: A New Potential DNA Bisintercalator

Marinela Rodrı´guez-Ciria,a Ana M. Sanz,a Maria J. R. Yunta,a Fernando Gomez-Contreras,a,* Pilar Navarro,b Isabel Fernandez,c Mercedes Pardoa and Carmen Canoa a

Departamento de Quimica Organica I, Facultad de Quimica, Universidad Complutense, 28040 Madrid, Spain Instituto de Quimica Medica, C.S.I.C., Juan de la Cierva, 3, 28006 Madrid, Spain c Laboratorios Knoll, Avda. de Burgos 91, 28050 Madrid, Spain b

The design, synthesis and cytotoxic activities of some benzo[g]phthalazine derivatives are described, and the DNA bisintercalating mode of the most active ligand is discussed with the help of molecular modeling techniques.

Synthesis and Antimycobacterial Activity of New Quinoxaline-2carboxamide 1,4-di-N-Oxide Derivatives

Bioorg. Med. Chem. 11 (2003) 2149

Bele´n Zarranz, Andre´s Jaso, Ignacio Aldana* and Antonio Monge Unidad en Investigacio´n y Desarrollo de Medicamentos, Centro de Investigacio´n en Farmacobiologı´a Aplicada (CIFA), Universidad de Navarra, Pamplona, Spain As a continuation of our research and with the aim of obtaining new antituberculosis agents which can improve the current chemotherapeutic antituberculosis treatments, new series of quinoxaline-2-carboxamide 1,4-di-Noxide derivatives were synthesized and evaluated for in vitro antituberculosis activity against Mycobacterium tuberculosis strain H37Rv, using the radiometric BACTEC 460-TB methodology. Active compounds were also screened by serial dilution to assess toxicity to a VERO cell line. The results indicate that some compounds exhibited a good antituberculosis activity and the arylcarboxamide analogues 3, 8 and 9 were the most active compounds (EC90/MIC 1). Also, the cytotoxic effects indicate that these compounds have a good Selectivity Index (SI).

Bioorg. Med. Chem. 11 (2003) 2157 Formation of a Diimino-Imidazole Nucleoside from 20 -Deoxyguanosine by Singlet Oxygen Generated by Methylene Blue Photooxidation

Toshinori Suzuki, Marlin D. Friesen and Hiroshi Ohshima* International Agency for Research on Cancer, 150 Cours Albert Thomas, F 69372 Lyon Cedex 08, France

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Imidazole Derivatives as a Novel Class of Hybrid Compounds with Inhibitory Histamine N-Methyltransferase Potencies and Histamine hH3 Receptor Affinities

Bioorg. Med. Chem. 11 (2003) 2163

Sven Graßmann,a Joachim Apelt,a Wolfgang Sippl,b Xavier Ligneau,c Heinz H. Pertz,a Yuan Hui Zhao,d Jean-Michel Arrang,e C. Robin Ganellin,d Jean-Charles Schwartz,e Walter Schunacka and Holger Starkf,* a

Institut fu¨r Pharmazie, Freie Universita¨t Berlin, Ko¨nigin-Luise-Strasse 2+4, 14195 Berlin, Germany Institut fu¨r Pharmazeutische Chemie, Heinrich-Heine-Universita¨t Du¨sseldorf, Universita¨tsstrasse 1, 40225 Du¨sseldorf, Germany Laboratoire Bioprojet, 30 rue des Francs-Bourgeois, 75003 Paris, France d Department of Chemistry, Christopher Ingold Laboratories, University College London, 20 Gordon Street, London WC1H 0AJ, UK e Unite´ de Neurobiologie et Pharmacologie Mole´culaire (U. 573), Centre Paul Broca de l’INSERM, 2ter rue d’Ale´sia, 75014 Paris, France f Johann Wolfgang Goethe-Universita¨t, Biozentrum, Institut fu¨r Pharmazeutische Chemie, Marie-Curie-Strasse 9, 60439 Frankfurt am Main, Germany b c

Syntheses, inhibitory histamine N-methyltransferase activities, and histamine hH3 receptor binding affinities of novel highly active imidazole derivatives are described.

Synthesis and Antiprotozoal Activity of Naphthofuranquinones and Naphthothiophenequinones Containing a Fused Thiazole Ring

Bioorg. Med. Chem. 11 (2003) 2175

Ricardo A. Tapia,a,* Luz Alegria,a Carlos D. Pessoa,a Cristian Salas,a Manuel J. Corte´s,a Jaime A. Valderrama,a Marie-Elisabeth Sarciron,b Fe´lix Pautet,c Nadia Walchshoferc and Houda Fillionc,* a

Facultad de Quı´mica, Pontificia Universidad Cato´lica de Chile, Correo 22, Santiago, Chile Laboratoire de Parasitologie (EA 1887), Faculte´ de Pharmacie, Universite´ Claude Bernard Lyon 1, 8, Avenue Rockefeller, F-69373 Lyon Cedex 08, France c Laboratoire de Chimie Organique (EA 635), Faculte´ de Pharmacie, Universite´ Claude Bernard Lyon 1, 8, Avenue Rockefeller, F-69373 Lyon Cedex 08, France b

Tetracyclic quinones and their regiosomers were prepared and evaluated for their antiprotozoal properties.

2,8-Disubstituted Adenosine Derivatives as Partial Agonists for the Adenosine A2A Receptor

Bioorg. Med. Chem. 11 (2003) 2183

Erica W. van Tilburg,* Matty Gremmen, Jacobien von Frijtag Drabbe Ku¨nzel, Miriam de Groote and Ad P. IJzerman Leiden/Amsterdam Center for Drug Research, Division of Medicinal Chemistry, PO Box 9502, 2300 RA Leiden, The Netherlands

Bioorg. Med. Chem. 11 (2003) 2193 Synthesis of -(1!6)-Branched -(1!3) Glucohexaose and Its Analogues Containing an -(1!3) Linked Bond with Antitumor Activity

Jun Ning,a,* Wenhui Zhang,a Yuetao Yi,a Guangbin Yang,a Zhikui Wu,b Jie Yib and Fanzuo Konga,* a

Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, PO Box 2871, Beijing 100085, PR China Guang Anmen Hospitol, Chinese Academy of Traditional Chinese Medicine, PR China

b

2116

A Study on the Conversion of Indanones into Carbostyrils

Bioorg. Med. Chem. 11 (2003) 2205

Yasuhiro Torisawa,* Takao Nishi and Jun-ichi Minamikawa Process Research Laboratory, Second Tokushima Factory, Otsuka Pharmaceutical Co., Ltd., Kawauchi, Tokushima, 771-0182, Japan

Synthesis and Properties of 20 -O,40 -C-Ethylene-Bridged Nucleic Acids (ENA) as Effective Antisense Oligonucleotides

Bioorg. Med. Chem. 11 (2003) 2211

Koji Morita,a Miho Takagi,a Chikako Hasegawa,a Masakatsu Kaneko,a Shinya Tsutsumi,b Junko Sone,b Tomio Ishikawa,b Takeshi Imanishic and Makoto Koizumia,* a

Exploratory Chemistry Research Laboratories, Sankyo Co., Ltd., Tokyo 140-8710, Japan Biomedical Research Laboratories, Sankyo Co., Ltd., Tokyo 140-8710, Japan c Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan b

Novel bicyclo nucleosides, 20 -O,40 -C-ethylene nucleosides and 20 -O,40 -C-propylene nucleosides, were synthesized as building blocks for antisense oligonucleotides.

Protease Inhibitors: Synthesis of Bacterial Collagenase and Matrix Metalloproteinase Inhibitors Incorporating Arylsulfonylureido and 5-Dibenzo-suberenyl/suberyl Moieties

Bioorg. Med. Chem. 11 (2003) 2227

Monica Ilies,a,b Mircea D. Banciu,c Andrea Scozzafava,a Marc A. Ilies,b Miron T. Caproiud and Claudiu T. Supurana,* a Universita` degli Studi, Laboratorio di Chimica Inorganica e Bioinorganica, Via della Lastruccia 3, Rm 188, Polo Scientifico, 50019-Sesto Fiorentino, Firenze, Italy b University of Agricultural Sciences and Veterinary Medicine, Faculty of Biotechnologies, Department of Chemistry, B-dul Marasti 59, 71331-Bucharest, Romania c Polytechnic University, Department of Organic Chemistry, Splaiul Independentei 313, Bucharest, Romania d ‘C.D. Nenitzescu’ Institute of Organic Chemistry, Splaiul Independentei 202B, Bucharest, Romania

Bioorg. Med. Chem. 11 (2003) 2241

Hydroxyurea Is a Carbonic Anhydrase Inhibitor Andrea Scozzafava and Claudiu T. Supuran*

Universita` degli Studi di Firenze, Dipartimento di Chimica, Laboratorio di Chimica Bioinorganica, Via della Lastruccia 3, Rm. 188, I-50019 Sesto Fiorentino, Firenze, Italy

2117

Synthesis of Photoactivable Inhibitors of Osteoclast Vacuolar ATPase

Bioorg. Med. Chem. 11 (2003) 2247

Barbara Biasotti,a Sabrina Dallavalle,a Lucio Merlini,a,* Carlo Farina,b Stefania Gagliardi,b,* Carlo Parinib and Pietro Belfiorec a

Dipartimento di Scienze Molecolari Agroalimentari, Universita` di Milano, Via Celoria 2, 20133 Milan, Italy b NiKem Research Srl, Via Zambeletti 25, 20021 Baranzate di Bollate (Mi), Italy c GlaxoSmithKline, MuscoloSkeletal Disease, 709 Swedeland Road, King of Prussia, PA 19406, USA A series of inhibitors of vacuolar ATPase containing a photoactivable group were synthesized.

Quantitative Studies of the Binding of the Class II PapG Adhesin from Uropathogenic Escherichia coli to Oligosaccharides

Bioorg. Med. Chem. 11 (2003) 2255

Andreas Larsson,a Jo¨rgen Ohlsson,b Karen W. Dodson,c Scott J. Hultgren,c Ulf Nilssonb and Jan Kihlberga,* a

Organic Chemistry, Department of Chemistry, Umea˚ University, SE-901 87 Umea˚, Sweden Bioorganic Chemistry, Lund University, PO Box 124, SE-221 00 Lund, Sweden c Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA b

Surface plasmon resonance was used to determine dissociation constants for binding of the class II PapG adhesin to globoseries di-pentasaccharides, and to modified galabiose derivatives.

Bioorg. Med. Chem. 11 (2003) 2263 Synthesis and Muscarinic Activities of O-[(Benzyl- or Benzoylpyrazolyl)propynyl]-oximes of N-Methylpiperidinone, 3-Tropinone, and 3-Quinuclidinone

Marı´a Isabel Rodrı´guez-Franco,a,* Isabel Dorronsoro,a Ana Castro,a Ana Martı´nez,a Albert Badı´ab and Josep E. Ban˜osb a Instituto de Quı´mica Me´dica (C.S.I.C.), Juan de la Cierva 3, 28006 Madrid, Spain b Departamento de Farmacologı´a, Terape´utica, y Toxicologı´a, Facultad de Medicina, Universidad Auto´noma de Barcelona, 08913 Bellaterra, Spain

The synthesis of O-propynyloximes of N-methylpiperidinone, 3-tropinone, and 3-quinuclidinone, containing several pyrazole frameworks, is described, together with their muscarinic receptor affinities.

Isoxazole-Based Derivatives from Baylis–Hillman Chemistry: Assessment of Preliminary Hypolipidemic Activity

Bioorg. Med. Chem. 11 (2003) 2269

A. Patra,a S. Batra,a,* A. P. Bhaduri,a A. Khanna,b R. Chanderb and M. Dikshitc a Medicinal Chemistry Division, Central Drug Research Institute, PO Box, 173, Lucknow 226001, India b Biochemistry Division, Central Drug Research Institute, PO Box, 173, Lucknow 226001, India c Pharmacology Division, Central Drug Research Institute, PO Box, 173, Lucknow 226001, India

The synthesis of isoxazole-based derivatives utilizing Baylis–Hillman chemistry and results of their preliminary bioevaluation as hypolipidemic agents are described.

2118

Bioorg. Med. Chem. 11 (2003) 2277 Prodrug Mono Therapy: Synthesis and Biological Evaluation of an Etoposide Glucuronide-Prodrug

Fre´de´ric Schmidt* and Claude Monneret UMR 176 CNRS/Institut Curie, Section Recherche, 26, rue d’Ulm, 75248 Paris Cedex 05, France The synthesis and biological evaluation of a glucuronide-based prodrug are reported. This compound fulfils all the requirements for a Prodrug Mono Therapy strategy in cancer chemotherapy.

Bioorg. Med. Chem. 11 (2003) 2285

Synthesis and Antimycotic Activity of N-azolyl-2,4-dihydroxythiobenzamides Joanna Matysiak and Andrzej Niewiadomy*

Department of Chemistry, University of Agriculture, Akademicka 15, 20-950 Lublin, Poland A series of N-azolyl-2,4-dihydroxythiobenzamides have been synthesised and their fungistatic properties were described.

Bioorg. Med. Chem. 11 (2003) 2293 Structure-Based Approach to Falcipain-2 Inhibitors: Synthesis and Biological Evaluation of 1,6,7-Trisubstituted Dihydroisoquinolines and Isoquinolines

Sanjay Batra,a,* Yogesh A. Sabnis,b Philip J. Rosenthalc and Mitchell A. Averyb,d,* a

Medicinal Chemistry Division, Central Drug Research Institute, Lucknow 226001, India Department of Medicinal Chemistry, National Center for Natural Products Research, School of Pharmacy, University of Mississippi, University, MI 38677-1848, USA c Department of Medicine, University of California at San Francisco, San Francisco, CA, USA d Department of Chemistry, PO Box 1848, University of Mississippi, University, MI 38677-1848, USA b

Evaluation of the Effects of Several Zoanthamine-type Alkaloids on the Aggregation of Human Platelets

Bioorg. Med. Chem. 11 (2003) 2301

Rosa M. Villar,b Jose´ Gil-Longo,b Antonio H. Daranas,c Marı´a L. Souto,c Jose´ J. Ferna´ndez,c Solange Peixinho,d Miguel A. Barral,a Gilmar Santafe´,a Jaime Rodrı´gueza and Carlos Jime´neza,* a

Departamento de Quı´mica Fundamental, Facultade de Ciencias, Universidade de A Corun˜a, 15071 A Corun˜a, Spain Departamento de Farmacoloxı´a, Facultade de Farmacia, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain c Instituto Universitario de Bio-Orga´nica ‘Antonio Gonza´lez’, Universidad de La Laguna, 38206 La Laguna, Spain d Departamento de Zoologia, Instituto de Biologia, Universidade Federal de Bahı´a, 4071-290 Salvador da Bahı´a, Brazil b

Ten zoanthamine-type alkaloids from two marine zoanthids belonging to the Zoanthus genus (Z. nymphaeus and Zoanthus sp.) along with one semisynthetic derivative were evaluated for their antiplatelet activities on human platelet aggregation induced by several stimulating agents.

2119

A Comparative Molecular Similarity Indices (CoMSIA) Study of Peptide Binding to the HLA-A3 Superfamily

Bioorg. Med. Chem. 11 (2003) 2307

Pingping Guan, Irini A. Doytchinova and Darren R. Flower* Edward Jenner Institute for Vaccine Research, Compton, Berkshire RG20 7NN, UK The motif of the peptides binding to the HLA-A3 superfamily was produced.

Bioorg. Med. Chem. 11 (2003) 2313

Design, Synthesis and Biological Evaluation of Oxazolidinone–Quinolone Hybrids

Christian Hubschwerlen,* Jean-Luc Specklin, Christine Sigwalt, Susanne Schroeder and Hans H. Locher Morphochem AG, Schwarzwaldallee 215, CH-4058 Basel, Switzerland

Transcription Inhibition Using Modified Pentanucleotides

Bioorg. Med. Chem. 11 (2003) 2321

Jae-Taeg Hwang,a Francis E. Baltasar,b Daniel L. Cole,b David S. Sigman,,b Chi-hong B. Chenb,* and Marc M. Greenbergc,* a

Department of Chemistry, Colorado State University, Fort Collins, CO 80523, USA Department of Biological Chemistry, School of Medicine, Department of Chemistry and Biochemistry, Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095-1570, USA c Department of Chemistry, Johns Hopkins University, 3400 N. Charles St., Baltimore, MD 21218, USA b

Manganese-Based Complexes of Radical Scavengers as Neuroprotective Agents

Bioorg. Med. Chem. 11 (2003) 2329

Opa Vajragupta,a,* Preecha Boonchoong,a Yaowared Sumanont,a Hiroshi Watanabe,b Yuvadee Wongkrajanga and Naparat Kammasuda a Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Mahidol University, 447 Sri-Ayudhya Road, Bangkok 10400, Thailand b Department of Pharmacology, Institute of Natural Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan

Manganese complexes from ligands 1–5 showed potent SOD and action against lipid peroxidation in vitro. In vivo, Mn complexes of L1 and L3 significantly suppressed MAP-induced hypermotility but did not significantly decrease the locomotor activity in normal condition. Manganese complex 3 (12.5 mg/kg) protected the learning and memory impairment in transient cerebral ischemic mice.

2120

Bioorg. Med. Chem. 11 (2003) 2339 Structure–Activity Studies of Glucose Transfer: Determination of the Spontaneous Rates of Hydrolysis of Uridine 50 -Diphospho- -D-glucose (UDPG) and Uridine 50 -Diphospho- -D-glucuronic Acid (UDPGA)

Colin T. Bedford,a,b,* Alan D. Hickmanb and Christopher J. Loganb a

School of Biosciences, University of Westminster, 115 New Cavendish Street, London W1W 6UW, UK b Shell Research Ltd, Sittingbourne Research Centre, Sittingbourne, Kent ME9 8AG, UK From the measured pH-rate profiles for the hydrolysis of UDPG and UDPGA, the catalytic power (kcat/kuncat) of the glycosltransferases has been estimated for the first time to be in the order of 101113.

Assessment of the Sequence Dependency for the Binding of 2-Aminonaphthyridine to the Guanine Bulge

Bioorg. Med. Chem. 11 (2003) 2347

Kazuhiko Nakatani,a,b,* Souta Horie,a Takashi Murase,a Shinya Hagiharaa and Isao Saitoa,* a Department of Synthetic Chemistry and Biological Chemistry, Faculty of Engineering, Kyoto University, Kyoto 606-8501, Japan b PRESTO, Japan Science and Technology Corporation (JST), Kyoto 606-8501, Japan

The sequence dependency for the binding of naphthyridine derivative was investigated.

Synthesis and Evaluation of Peptidomimetics That Bind DNA Jeffrey A. Turk and David B. Smithrud* Department of Chemistry, University of Cincinnati, Cincinnati, OH 45221-0172, USA

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Bioorg. Med. Chem. 11 (2003) 2355