Highly enantioselective synthesis and cellular evaluation of spirooxindoles inspired by natural products

被引：515

作者：

Antonchick, Andrey P. ^{[1
,2
]}

Gerding-Reimers, Claas ^{[1
,2
]}

Catarinella, Mario ^{[4
]}

Schuermann, Markus ^{[2
]}

Preut, Hans ^{[2
]}

Ziegler, Slava ^{[1
]}

Rauh, Daniel ^{[3
]}

Waldmann, Herbert ^{[1
,2
]}

机构：

[1] Max Planck Inst Mol Physiol, Abt Chem Biol, D-44227 Dortmund, Germany

[2] Tech Univ Dortmund, Fak Chem, D-44221 Dortmund, Germany

[3] Max Planck Soc, Chem Genom Ctr, D-44227 Dortmund, Germany

[4] Univ Konstanz, Konstanz Res Sch Chem Biol, D-78457 Constance, Germany

来源：

NATURE CHEMISTRY | 2010年 / 2卷 / 09期

关键词：

STRUCTURE-BASED DESIGN; AZOMETHINE YLIDES; 1,3-DIPOLAR CYCLOADDITION; DRUG DISCOVERY; INHIBITORS; COMPLEXES; POTENT;

D O I：

10.1038/nchem.730

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

In biology-oriented synthesis the underlying scaffold classes of natural products selected in evolution are used to define biologically relevant starting points in chemical structure space for the synthesis of compound collections with focused structural diversity. Here we describe a highly enantioselective synthesis of natural-product-inspired 3,3'-pyrrolidinyl spirooxindoles-which contain an all-carbon quaternary centre and three tertiary stereocentres. This synthesis takes place by means of an asymmetric Lewis acid-catalysed 1,3-dipolar cycloaddition of an azomethine ylide to a substituted 3-methylene-2-oxindole using 1-3 mol% of a chiral catalyst formed from a N,P-ferrocenyl ligand and CuPF(6)(CH(3)CN)(4). Cellular evaluation has identified a molecule that arrests mitosis, induces multiple microtubule organizing centres and multipolar spindles, causes chromosome congression defects during mitosis and inhibits tubulin regrowth in cells. Our findings support the concept that compound collections based on natural-product-inspired scaffolds constructed with complex stereochemistry will be a rich source of compounds with diverse bioactivity.

引用

页码：735 / 740

页数：6

共 28 条

[11] Natural products in drug discovery [J].

Harvey, Alan L. .

DRUG DISCOVERY TODAY, 2008, 13 (19-20) :894-901

[12] Biology-inspired synthesis of compound libraries [J].

Kaiser, M. ;

Wetzel, S. ;

Kumar, K. ;

Waldmann, H. .

CELLULAR AND MOLECULAR LIFE SCIENCES, 2008, 65 (7-8) :1186-1201

[13] Charting biologically relevant chemical space: A structural classification of natural products (SCONP) [J].

Koch, MA ;

Schuffenhauer, A ;

Scheck, M ;

Wetzel, S ;

Casaulta, M ;

Odermatt, A ;

Ertl, P ;

Waldmann, H .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2005, 102 (48) :17272-17277

[14] Synthesis of Natural Product Inspired Compound Collections [J].

Kumar, Kamal ;

Waldmann, Herbert .

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, 2009, 48 (18) :3224-3242

[15] Drug Discovery and Natural Products: End of an Era or an Endless Frontier? [J].

Li, Jesse W. -H. ;

Vederas, John C. .

SCIENCE, 2009, 325 (5937) :161-165

[16] Bis-sulfonyl ethylene as masked acetylene equivalent in catalytic asymmetric [3+2] cycloaddition of azomethine ylides [J].

Lopez-Perez, Ana ;

Adrio, Javier ;

Carretero, Juan C. .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2008, 130 (31) :10084-+

[17] Construction of spiro[pyrrolidine-3,3′-oxindoles] -: Recent applications to the synthesis of oxindole alkaloids [J].

Marti, C ;

Carreira, EM .

EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, 2003, 2003 (12) :2209-2219

[18] Natural products as sources of new drugs over the last 25 years [J].

Newman, David J. ;

Cragg, Gordon M. .

JOURNAL OF NATURAL PRODUCTS, 2007, 70 (03) :461-477

[19] Discovery of protein phosphatase inhibitor classes by biology-oriented synthesis [J].

Noeren-Mueller, Andrea ;

Reis-Correa, Ivan, Jr. ;

Prinz, Heino ;

Rosenbaum, Claudia ;

Saxena, Krishna ;

Schwalbe, Harald J. ;

Vestweber, Dietmar ;

Cagna, Guiseppe ;

Schunk, Stefan ;

Schwarz, Oliver ;

Schiewe, Hajo ;

Waldmann, Herbert .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2006, 103 (28) :10606-10611

[20] Structure-activity-relationship studies of conformationally restricted analogs of combretastatin A-4 derived from SU5416 [J].

Pandit, Bulbul ;

Sun, Yanjun ;

Chen, Ping ;

Sackett, Dan L. ;

Hu, Zhigen ;

Rich, Wendy ;

Li, Chenglong ;

Lewis, Andrew ;

Schaefer, Kevin ;

Li, Pui-KaI .

BIOORGANIC & MEDICINAL CHEMISTRY, 2006, 14 (19) :6492-6501

← 1 2 3 →