Chemical biology--identification of small molecule modulators of cellular activity by natural product inspired synthesis.

The aim of this tutorial review is to introduce the reader to the concept, synthesis and application of natural product-inspired compound collections as an important field in chemical biology. This review will discuss how potentially interesting scaffolds can be identified (structural classification of natural products), synthesized in an appropriate manner (including stereoselective transformations for solid phase-bound compounds) and tested in biological assays (cell-based screening as well as biochemical in vitro assays). These approaches will provide the opportunity to identify new and interesting compounds as well as new targets for chemical biology and medicinal chemistry research.

[1]  B. Suter,et al.  Yeast-based functional genomics and proteomics technologies: the first 15 years and beyond. , 2006, BioTechniques.

[2]  S. Danishefsky,et al.  Small molecule natural products in the discovery of therapeutic agents: the synthesis connection. , 2006, The Journal of organic chemistry.

[3]  A Ganesan,et al.  Natural products as a hunting ground for combinatorial chemistry. , 2004, Current opinion in biotechnology.

[4]  H. Waldmann,et al.  Solid-Phase Synthesis and Biological Evaluation of a Teleocidin Library—Discovery of a Selective PKCδ Down Regulator , 2000 .

[5]  H. Waldmann,et al.  Stereocomplementary synthesis of a natural product-derived compound collection on a solid phase. , 2006, Chemical communications.

[6]  Â. de Fátima,et al.  (R)-Goniothalamin: total syntheses and cytotoxic activity against cancer cell lines. , 2005, Bioorganic & medicinal chemistry.

[7]  H. Osada,et al.  Photo-cross-linked small-molecule affinity matrix for facilitating forward and reverse chemical genetics. , 2005, Angewandte Chemie.

[8]  B. Stockwell Exploring biology with small organic molecules , 2004, Nature.

[9]  C. Forsyth,et al.  Phorboxazole analogues induce association of cdk4 with extranuclear cytokeratin intermediate filaments. , 2006, Journal of the American Chemical Society.

[10]  L. Meijer,et al.  Identification of intracellular targets of small molecular weight chemical compounds using affinity chromatography , 2007, Biotechnology journal.

[11]  P. Arya,et al.  Toward high-throughput synthesis of complex natural product-like compounds in the genomics and proteomics age. , 2002, Chemistry & biology.

[12]  G. G. Stokes "J." , 1890, The New Yale Book of Quotations.

[13]  Y. Feng,et al.  Use of biomimetic diversity-oriented synthesis to discover galanthamine-like molecules with biological properties beyond those of the natural product. , 2001, Journal of the American Chemical Society.

[14]  Kevin Barraclough,et al.  I and i , 2001, BMJ : British Medical Journal.

[15]  Gisbert Schneider,et al.  Properties and Architecture of Drugs and Natural Products Revisited , 2007 .

[16]  Miklos Feher,et al.  Property Distributions: Differences between Drugs, Natural Products, and Molecules from Combinatorial Chemistry , 2003, J. Chem. Inf. Comput. Sci..

[17]  David R Spring,et al.  Chemical genetics to chemical genomics: small molecules offer big insights. , 2005, Chemical Society reviews.

[18]  J. Wölcke,et al.  Miniaturized HTS technologies - uHTS. , 2001, Drug discovery today.

[19]  M Elofsson,et al.  The anti-inflammatory natural product parthenolide from the medicinal herb Feverfew directly binds to and inhibits IkappaB kinase. , 2001, Chemistry & biology.

[20]  Stefan Wetzel,et al.  The Scaffold Tree - Visualization of the Scaffold Universe by Hierarchical Scaffold Classification , 2007, J. Chem. Inf. Model..

[21]  Hendrik Luesch,et al.  Towards high-throughput characterization of small molecule mechanisms of action. , 2006, Molecular bioSystems.

[22]  Stefan Wetzel,et al.  Cheminformatic Analysis of Natural Products and their Chemical Space , 2007 .

[23]  H. Waldmann,et al.  Enantioselective synthesis on the solid phase. , 2006, Chemical Communications.

[24]  R. S. Shaw,et al.  α-Pyrones and their derivatives from two Cryptocarya species , 1995 .

[25]  Herbert Waldmann,et al.  From protein domains to drug candidates – natural products as guiding principles in , 2002 .

[26]  Herbert Waldmann,et al.  Compound library development guided by protein structure similarity clustering and natural product structure. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[27]  Dalia Cohen,et al.  Functional genomics to new drug targets , 2004, Nature Reviews Drug Discovery.

[28]  G. Terstappen,et al.  Target deconvolution strategies in drug discovery , 2007, Nature Reviews Drug Discovery.

[29]  Xiaofeng S Zheng,et al.  Genetic and genomic approaches to identify and study the targets of bioactive small molecules. , 2004, Chemistry & biology.

[30]  A. Schuffenhauer,et al.  Charting biologically relevant chemical space: a structural classification of natural products (SCONP). , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[31]  W Patrick Walters,et al.  Prediction of 'drug-likeness'. , 2002, Advanced drug delivery reviews.

[32]  Timothy J Mitchison,et al.  Small‐Molecule Screening and Profiling by Using Automated Microscopy , 2005, Chembiochem : a European journal of chemical biology.

[33]  D. Boger,et al.  Fostriecin: chemistry and biology. , 2002, Current medicinal chemistry.

[34]  F. Koehn,et al.  The evolving role of natural products in drug discovery , 2005, Nature Reviews Drug Discovery.

[35]  H. Waldmann,et al.  Natural products are biologically validated starting points in structural space for compound library development: solid-phase synthesis of dysidiolide-derived phosphatase inhibitors. , 2002, Angewandte Chemie.

[36]  K. Nishikawa,et al.  The Anticancer Natural Product Pironetin Selectively Targets Lys352 of α-Tubulin , 2004 .

[37]  N. Shimada,et al.  Pironetin, a novel plant growth regulator produced by Streptomyces sp. NK10958. I. Taxonomy, production, isolation and preliminary characterization. , 1994, The Journal of antibiotics.

[38]  Brian J Eastwood,et al.  A Comparison of Assay Performance Measures in Screening Assays: Signal Window, Z' Factor, and Assay Variability Ratio , 2006, Journal of biomolecular screening.

[39]  Paul A Wender,et al.  Function-oriented synthesis, step economy, and drug design. , 2008, Accounts of chemical research.

[40]  John B. Shoven,et al.  I , Edinburgh Medical and Surgical Journal.

[41]  Herbert Waldmann,et al.  Discovery of protein phosphatase inhibitor classes by biology-oriented synthesis. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[42]  B. Cravatt,et al.  Protein-reactive natural products. , 2005, Angewandte Chemie.

[43]  Christopher T. Walsh,et al.  Lessons from natural molecules , 2004, Nature.

[44]  L. Burdine,et al.  Target identification in chemical genetics: the (often) missing link. , 2004, Chemistry & biology.

[45]  Jun O. Liu,et al.  Simultaneous arming and structure/activity studies of natural products employing O-H insertions: an expedient and versatile strategy for natural products-based chemical genetics. , 2007, Journal of the American Chemical Society.

[46]  E J Licitra,et al.  A three-hybrid system for detecting small ligand-protein receptor interactions. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[47]  Stuart L Schreiber,et al.  A planning strategy for diversity-oriented synthesis. , 2004, Angewandte Chemie.

[48]  Introduction to Chemical Proteomics for Drug Discovery and Development , 2007, Archiv der Pharmazie.

[49]  R. Aebersold,et al.  Mass spectrometry-based proteomics , 2003, Nature.

[50]  H. Waldmann,et al.  An Enzyme-Labile Linker Group for Organic Syntheses on Solid Supports. , 1998, Angewandte Chemie.

[51]  G. Schneider,et al.  Scaffold architecture and pharmacophoric properties of natural products and trade drugs: application in the design of natural product-based combinatorial libraries. , 2001, Journal of combinatorial chemistry.

[52]  Derek S. Tan,et al.  Advancing chemistry and biology through diversity-oriented synthesis of natural product-like libraries. , 2005, Current opinion in chemical biology.

[53]  Paul A Clemons,et al.  The Connectivity Map: Using Gene-Expression Signatures to Connect Small Molecules, Genes, and Disease , 2006, Science.

[54]  Harald Schwalbe,et al.  Identification of inhibitors for mycobacterial protein tyrosine phosphatase B (MptpB) by biology-oriented synthesis (BIOS). , 2007, Chemistry, an Asian journal.

[55]  Anang A Shelat,et al.  Scaffold composition and biological relevance of screening libraries. , 2007, Nature chemical biology.

[56]  Christopher P Austin,et al.  High-throughput screening assays for the identification of chemical probes. , 2007, Nature chemical biology.

[57]  Herbert Waldmann,et al.  From protein domains to drug candidates-natural products as guiding principles in the design and synthesis of compound libraries. , 2002, Angewandte Chemie.

[58]  D. Pereira,et al.  Origin and evolution of high throughput screening , 2007, British journal of pharmacology.

[59]  D. Newman,et al.  Natural products as sources of new drugs over the last 25 years. , 2007, Journal of natural products.

[60]  Elizabeth A. Winzeler,et al.  Genomic profiling of drug sensitivities via induced haploinsufficiency , 1999, Nature Genetics.

[61]  Herbert Waldmann,et al.  Natural product-derived modulators of cell cycle progression and viral entry by enantioselective oxa Diels-Alder reactions on the solid phase. , 2007, Chemistry & biology.

[62]  E. Jacoby,et al.  Chemogenomics: an emerging strategy for rapid target and drug discovery , 2004, Nature Reviews Genetics.

[63]  H. Waldmann,et al.  Organic Synthesis and Biological Signal Transduction , 1998, Angewandte Chemie.

[64]  David J Newman,et al.  Natural products as sources of new drugs over the period 1981-2002. , 2003, Journal of natural products.

[65]  Steven V. Ley,et al.  New tools and concepts for modern organic synthesis , 2002, Nature Reviews Drug Discovery.

[66]  H. Waldmann,et al.  Synthesis and biological evaluation of an indomethacin library reveals a new class of angiogenesis-related kinase inhibitors. , 2004, Angewandte Chemie.

[67]  D G Hall,et al.  Solution- and solid-phase strategies for the design, synthesis, and screening of libraries based on natural product templates: a comprehensive survey. , 2001, Journal of combinatorial chemistry.

[68]  Waldmann,et al.  Natural Product Synthesis on Polymeric Supports-Synthesis and Biological Evaluation of an Indolactam Library. , 1999, Angewandte Chemie.