TOTAL SYNTHESIS AND BIOSYNTHESIS OF BIOACTIVE SUBSTANCES

Summary

Principal Investigator: Robert Michael Williams
Affiliation: Colorado State University
Country: USA
Abstract: DESCRIPTION (provided by applicant): This grant application is divided into three major sections to study the total synthesis and biosynthesis of three unrelated families of natural products: (1) taxol;(2) the paraherquamides, stephacidins, norgeamides, notoamides, malbrancheamides, asperparalines and congeners;and (3) the okaramines. I. Stephacidins, Paraherquamides, norgeamides, notoamides, malbrancheamides &Asperparalines. The goals of this program are to utilize the tools of total synthesis to fully elucidate the biosynthetic pathway from the primary amino acids (isoleucine, proline, and tryptophan) and mevalonate-derived isoprene moieties to the polycyclic indole alkaloids comprising the paraherquamides, stephacidins, avrainvillamide, notoamides, norgeamides, malbrancheamides and asperparalines. Provocative evidence has been elucidated in our laboratory indicating that this class of alkaloids, are constructed by a rare biosynthetic intramolecular [4+2] cycloaddition reaction. Through the use of total chemical synthesis of isotopically labeled intermediate metabolites, key features of the biosynthetic pathways to these complex secondary metabolites will be experimentally elucidated. In collaboration with Prof. David Sherman's laboratory (University of Michigan), we are actively engaged in the identification, isolation, cloning and functional expression of the biosynthetic gene clusters responsible for the biosynthesis of these agents. Stephacidins A, B and the norgeamides A-D represent new structural and mechanistic classes of anticancer agents. Their mechanism of action is unique which holds promise to develop more selective and less toxic chemotherapeutic agents for treating cancer. The recently discovered malbrancheamides display calmodulin inhibitory activity which is an entirely new biological activity for this family of natural products. Our broad synthetic platform has allowed the synthesis of numerous unnatural, structural analogs of these natural products and are continuously being evaluated for cytotoxic activity and calmodulin inhibitory acitivity. II. Taxol. The biosynthesis of taxol from the cyclization of geranylgeranyl pyrophosphate (ggPP) via taxa- 4(5),11(12)-diene, will be studied in collaboration with Prof. Rod Croteau's laboratory at Washington State University. The sequence of hydroxylation reactions from this simple diterpenoid comprising the core A/B/C ring system of taxol shall be elucidated. Taxol is the number one selling anti-cancer drug in the world. Determination of the biosynthetic pathway to taxol holds significant promise in assisting the expected growing demand for this drug because of limitations on its isolation and production which comes from the Yew tree. III. Okaramines. As a natural out-growth of our work on the paraherquamide family of prenylated indole alkaloids, we propose to initiate a new project to study the total synthesis and biosynthesis of the okaramines, which are complex, polycyclic prenylated indole alkaloids that possess insecticidal activity. PUBLIC HEALTH RELEVANCE: The purpose of this application is to utilize the tools of chemical synthesis to study the molecular details of how Nature biosynthesizes anti-cancer drugs. In one sub-project, involving the study of taxol biosynthesis, the goal is to improve the cell-culture yields of production of the drug, which is currently obtained from the Yew tree, the harvest of which, has created a severe supply-demand problem and important environmental consequences. In addition, the chemical technologies being developed, will be applied to the design and synthesis of new anti-cancer drugs.
Funding Period: -------------------- - --------------------
more information: NIH RePORT

Top Publications

  1. pmc Administering cultured Taxus cells with early precursors reveals bifurcations in the taxoid biosynthetic pathway
    Raymond E B Ketchum
    Institute of Biological Chemistry, Washington State University, 299 Clark Hall, P O Box 646340, Pullman, WA 99164 6340, USA
    Phytochemistry 68:335-41. 2007
  2. pmc Synthesis and bioconversions of notoamide T: a biosynthetic precursor to stephacidin A and notoamide B
    James D Sunderhaus
    Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, USA
    Org Lett 15:22-5. 2013
  3. pmc Enantiomeric natural products: occurrence and biogenesis
    Jennifer M Finefield
    Department of Chemistry, Colorado State University, Fort Collins, 80523, USA
    Angew Chem Int Ed Engl 51:4802-36. 2012
  4. pmc Fungal origins of the bicyclo[2.2.2]diazaoctane ring system of prenylated indole alkaloids
    Jennifer M Finefield
    Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, USA
    J Nat Prod 75:812-33. 2012
  5. pmc Natural products synthesis: enabling tools to penetrate Nature's secrets of biogenesis and biomechanism
    Robert M Williams
    Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, United States
    J Org Chem 76:4221-59. 2011
  6. pmc Calmodulin inhibitory activity of the malbrancheamides and various analogs
    Kenneth A Miller
    Department of Chemistry, Colorado State University, 1301 Center Avenue, Fort Collins, CO 80523 1872, USA
    Bioorg Med Chem Lett 18:6479-81. 2008
  7. pmc Premalbrancheamide: synthesis, isotopic labeling, biosynthetic incorporation, and detection in cultures of Malbranchea aurantiaca
    Yousong Ding
    Life Sciences Institute and Department of Medicinal Chemistry, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, Michigan 48109 2216, USA
    Org Lett 10:4863-6. 2008
  8. ncbi A concise total synthesis of the notoamides C and D
    Alan W Grubbs
    Department of Chemistry, Colorado State University, Fort Collins, CO 80523, USA
    Angew Chem Int Ed Engl 46:2257-61. 2007
  9. ncbi A concise, biomimetic total synthesis of stephacidin A and notoamide B
    Thomas J Greshock
    Department of Chemistry, Colorado State University, Fort Collins, CO 80523, USA
    Angew Chem Int Ed Engl 46:2262-5. 2007
  10. ncbi Notoamides A-D: prenylated indole alkaloids isolated from a marine-derived fungus, Aspergillus sp
    Hikaru Kato
    Graduate School of Natural Science and Technology, Kanazawa University, Kanazawa 920 1192, Japan
    Angew Chem Int Ed Engl 46:2254-6. 2007

Scientific Experts

  • Sachiko Tsukamoto
  • Robert Michael Williams
  • Jennifer M Finefield
  • David H Sherman
  • Kenneth A Miller
  • Thomas J Greshock
  • Yousong Ding
  • James D Sunderhaus
  • Shengying Li
  • Alan W Grubbs
  • Hikaru Kato
  • Timothy J McAfoos
  • Gerald D Artman
  • Jennifer Guerra-Bubb
  • Christopher M Rath
  • Raymond E B Ketchum
  • Jens C Frisvad
  • Rodney Croteau
  • Martin Kreitman
  • Meg Dahlgren
  • Garth D Ehrlich
  • Michael A Christiansen
  • Kristina Hakansson
  • Fen Z Hu
  • Luisa Hiller
  • Rachael Kreft
  • Hye Kyong Kweon
  • Azad Ahmed
  • Benjamin Janto
  • Jeremy J Wolff
  • Josh Earl
  • Fengan Yu
  • James Cavalcoli
  • Jeffrey R de Wet
  • Rachel Mata
  • Mario Figueroa
  • Donald T Wicklow
  • Ping Jiao
  • James B Gloer
  • Timothy R Welch
  • Sabine Gruschow
  • Meriah W N Valente
  • Deyou Qiu
  • Tomihisa Ohta
  • Hiroshi Hirota
  • Takanori Tokue
  • Yuka Nojiri
  • Takushi Yoshida
  • Tohru Horiguchi
  • Rodney B Croteau

Detail Information

Publications41

  1. pmc Administering cultured Taxus cells with early precursors reveals bifurcations in the taxoid biosynthetic pathway
    Raymond E B Ketchum
    Institute of Biological Chemistry, Washington State University, 299 Clark Hall, P O Box 646340, Pullman, WA 99164 6340, USA
    Phytochemistry 68:335-41. 2007
    ....
  2. pmc Synthesis and bioconversions of notoamide T: a biosynthetic precursor to stephacidin A and notoamide B
    James D Sunderhaus
    Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, USA
    Org Lett 15:22-5. 2013
    ..Furthermore, [(13)C](2)-notoamide T was synthesized and provided to Aspergillus versicolor and Aspergillus sp. MF297-2, in which significant incorporation was observed in the advanced metabolite, notoamide B...
  3. pmc Enantiomeric natural products: occurrence and biogenesis
    Jennifer M Finefield
    Department of Chemistry, Colorado State University, Fort Collins, 80523, USA
    Angew Chem Int Ed Engl 51:4802-36. 2012
    ..Extensive research has been carried out over the years in an attempt to understand the biogenesis of naturally occurring enantiomers; however, many fascinating puzzles and stereochemical anomalies still remain...
  4. pmc Fungal origins of the bicyclo[2.2.2]diazaoctane ring system of prenylated indole alkaloids
    Jennifer M Finefield
    Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, USA
    J Nat Prod 75:812-33. 2012
    ..2.2]diazaoctane ring system. Furthermore, the diverse fungal origin of these natural products is closely examined and, in many cases, updated to reflect the currently accepted fungal taxonomy...
  5. pmc Natural products synthesis: enabling tools to penetrate Nature's secrets of biogenesis and biomechanism
    Robert M Williams
    Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, United States
    J Org Chem 76:4221-59. 2011
    ..The examples demonstrate the often untapped richness of complex molecule synthesis to provide powerful tools to understand, manipulate and exploit Nature's vast and creative palette of secondary metabolites...
  6. pmc Calmodulin inhibitory activity of the malbrancheamides and various analogs
    Kenneth A Miller
    Department of Chemistry, Colorado State University, 1301 Center Avenue, Fort Collins, CO 80523 1872, USA
    Bioorg Med Chem Lett 18:6479-81. 2008
    ..2.2]diazaoctane core oxidation state on the ability of these analogs to inhibit calmodulin dependent phosphodiesterase (PDE1) was studied, and a number of potent compounds were identified...
  7. pmc Premalbrancheamide: synthesis, isotopic labeling, biosynthetic incorporation, and detection in cultures of Malbranchea aurantiaca
    Yousong Ding
    Life Sciences Institute and Department of Medicinal Chemistry, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, Michigan 48109 2216, USA
    Org Lett 10:4863-6. 2008
    ..In addition, premalbrancheamide has been detected as a natural metabolite in cultures of M. aurantiaca. The biosynthetic implications of these experiments are discussed...
  8. ncbi A concise total synthesis of the notoamides C and D
    Alan W Grubbs
    Department of Chemistry, Colorado State University, Fort Collins, CO 80523, USA
    Angew Chem Int Ed Engl 46:2257-61. 2007
  9. ncbi A concise, biomimetic total synthesis of stephacidin A and notoamide B
    Thomas J Greshock
    Department of Chemistry, Colorado State University, Fort Collins, CO 80523, USA
    Angew Chem Int Ed Engl 46:2262-5. 2007
  10. ncbi Notoamides A-D: prenylated indole alkaloids isolated from a marine-derived fungus, Aspergillus sp
    Hikaru Kato
    Graduate School of Natural Science and Technology, Kanazawa University, Kanazawa 920 1192, Japan
    Angew Chem Int Ed Engl 46:2254-6. 2007
  11. pmc Concise, asymmetric, stereocontrolled total synthesis of stephacidins A, B and notoamide B
    Gerald D Artman
    Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, USA
    J Am Chem Soc 129:6336-42. 2007
    ..2.2] bridged bicyclic ring system. Furthermore, our synthesis has taken advantage of microwave heating to shorten reaction times as well as increase yields for the preparation of vital intermediates...
  12. pmc Biomimetic total synthesis of malbrancheamide and malbrancheamide B
    Kenneth A Miller
    Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523 1872, USA
    J Org Chem 73:3116-9. 2008
    ..The syntheses each feature an intramolecular Diels-Alder reaction of a 5-hydroxypyrazin-2(1H)-one to construct the bicyclo[2.2.2]diazaoctane core, which has also been proposed as the biosynthetic route to these compounds...
  13. pmc Isolation, structure elucidation, and biomimetic total synthesis of versicolamide B, and the isolation of antipodal (-)-stephacidin A and (+)-notoamide B from Aspergillus versicolor NRRL 35600
    Thomas J Greshock
    Department of Chemistry, Colorado State University, Fort Collins, CO 80523, USA
    Angew Chem Int Ed Engl 47:3573-7. 2008
  14. pmc Molecular analysis of a 4-dimethylallyltryptophan synthase from Malbranchea aurantiaca
    Yousong Ding
    Life Sciences Institute and Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA
    J Biol Chem 283:16068-76. 2008
    ....
  15. pmc Detection of VM55599 and preparaherquamide from Aspergillus japonicus and Penicillium fellutanum: biosynthetic implications
    Yousong Ding
    Life Sciences Institute and Department of Medicinal Chemistry, The University of Michigan, 210 Washtenaw Avenue, Ann Arbor, Michigan 48109 2216, USA
    J Nat Prod 71:1574-8. 2008
    ..In accord with a previous proposal, the identification of both metabolites, which have a diastereomeric relationship, provides indirect support for a unified biosynthetic scheme...
  16. pmc Biochemical characterization of NotB as an FAD-dependent oxidase in the biosynthesis of notoamide indole alkaloids
    Shengying Li
    Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA
    J Am Chem Soc 134:788-91. 2012
    ....
  17. pmc The early stages of taxol biosynthesis: an interim report on the synthesis and identification of early pathway metabolites
    Jennifer Guerra-Bubb
    Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, USA
    Nat Prod Rep 29:683-96. 2012
    ..An overview of the current state of knowledge on the early-stages of taxol biosynthesis is presented...
  18. pmc Meta-omic characterization of the marine invertebrate microbial consortium that produces the chemotherapeutic natural product ET-743
    Christopher M Rath
    Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, United States
    ACS Chem Biol 6:1244-56. 2011
    ..We expect that the interdisciplinary approach described is applicable to diverse host-symbiont systems that generate valuable natural products for drug discovery and development...
  19. pmc Synthetic approaches to the bicyclo[2.2.2]diazaoctane ring system common to the paraherquamides, stephacidins and related prenylated indole alkaloids
    Kenneth A Miller
    Department of Chemistry, Colorado State University, Fort Collins, CO 80523 1872, USA
    Chem Soc Rev 38:3160-74. 2009
    ..Detailed herein are a number of synthetic disconnections including intramolecular S(N)2' cyclizations, biomimetic Diels-Alder reactions, radical cyclizations, and cationic cascade reactions...
  20. pmc Asymmetric total syntheses of (+)- and (-)-versicolamide B and biosynthetic implications
    Kenneth A Miller
    Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523 1872, USA
    Nat Chem 1:63-8. 2009
    ....
  21. pmc Isolation of notoamide E, a key precursor in the biosynthesis of prenylated indole alkaloids in a marine-derived fungus, Aspergillus sp
    Sachiko Tsukamoto
    Graduate School of Science, Chiba University, 1 33 Yayoi cho, Inage Ku, Chiba 263 8522, Japan
    J Am Chem Soc 131:3834-5. 2009
    ..In addition, the feeding experiment of the (13)C-labeled notoamide E afforded structurally novel metabolites...
  22. pmc Synthesis of notoamide J: a potentially pivotal intermediate in the biosynthesis of several prenylated indole alkaloids
    Jennifer M Finefield
    Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, USA
    J Org Chem 75:2785-9. 2010
    ..Starting from L-proline and a substituted tryptophan derivative, this synthesis also employs an oxidation and pinacol rearrangement for the formation of the oxindole in the final step...
  23. pmc Genome-based characterization of two prenylation steps in the assembly of the stephacidin and notoamide anticancer agents in a marine-derived Aspergillus sp
    Yousong Ding
    Life Sciences Institute and Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA
    J Am Chem Soc 132:12733-40. 2010
    ..The work provides the first genetic and biochemical insights for understanding the structural diversity of this important family of fungal alkaloids...
  24. pmc Studies on the biosynthesis of the notoamides: synthesis of an isotopomer of 6-hydroxydeoxybrevianamide E and biosynthetic incorporation into notoamide J
    Jennifer M Finefield
    Department of Chemistry, Colorado State University, 1301 Center Avenue, Fort Collins, Colorado 80523, USA
    J Org Chem 76:5954-8. 2011
    ..Analysis of the metabolites showed incorporation of the intermediate only into the natural product notoamide J...
  25. pmc Biosynthetic studies of the notoamides: isotopic synthesis of stephacidin A and incorporation into notoamide B and sclerotiamide
    Jennifer M Finefield
    Department of Chemistry, Colorado State University, 1301 Center Avenue, Fort Collins, Colorado 80523, USA
    Org Lett 13:3802-5. 2011
    ..MF297-2. (13)C-Labeled sclerotiamide was also isolated from both fungal cultures...
  26. pmc Isolation of antipodal (-)-versicolamide B and notoamides L-N from a marine-derived Aspergillus sp
    Sachiko Tsukamoto
    Graduate School of Science, Chiba University, 1 33 Yayoi cho, Inage Ku, Chiba 263 8522, Japan
    Org Lett 11:1297-300. 2009
    ..Notoamide M is potentially a precursor to the proposed azadiene species involved in the putative intramolecular Diels-Alder reaction in the biogenesis of the bicyclo[2.2.2]diazaoctane ring system...