CHIRAL APPROACHES TO NATURAL PRODUCT SYNTHESIS

Summary

Principal Investigator: Gary E Keck
Abstract: DESCRIPTION (provided by applicant): This renewal project seeks to continue and expand a program of synthesis, biology, and computational chemistry based on the exciting profile of biological activity displayed by the natural product bryostatin 1. This marine natural product has been shown to have anticancer activity, and has been in over 80 clinical trials in man. In addition, bryostatin 1 has demonstrated effects on memory, on stimulation of the immune system, and on Alzheimer's disease. Moreover, recent studies in rats have shown that bryostatin 1 offers promise in the treatment of stroke, in that rescue of damaged neural tissue can be effected for up to 24 hours following the ischemic event. The mode of action of bryostatin is only partially understood, but it is known to involve interaction with a family of signaling proteins containing C1 domains. Amongst the known ligands for this Protein Kinase C superfamily, bryostatin 1 is unique in being a functional antagonist to the tumor-promoting phorbol esters. The studies proposed are aimed at realizing the therapeutic potential of this agent. We propose to continue our studies of structure-function relationships in bryostatin 1, in an attempt to define the structural features responsible for the various biological activities already established for bryostatin 1. We also propose to prepare this agent on gram scale, to provide more material for further studies. We plan to continue to investigate the biology of analogues of bryostatin 1, both in the hope of identifying selective new agents with unique patterns of biological activity, and also in terms of using these agents as tools to study the underlying biology of the signaling mechanisms. We have already established, during the preceding grant period, proof of concept in each of these areas. New analogues of bryostatin 1 will be prepared to investigate various hypotheses regarding mechanisms of action and structure activity relationships, and evaluated in detail for their effects in living cells of various types. Detailed biological investigations will be pursued to establish the underlying mechanisms for the biological endpoints observed in the various systems. Computational methods will be employed both to help interpret the structural effects observed and to suggest promising new avenues for structural exploration. Ongoing collaborations with leading experts in the biology of bryostatin and PKC signaling, and in computational investigations of these same systems will be continued. PUBLIC HEALTH RELEVANCE: This project seeks to realize the potential of a very promising substance, bryostatin 1, which was originally isolated from a marine (ocean) source. This material has shown fascinating activity against a variety of diseases including cancer, Alzheimers'disease, and stroke, and has been in clinical trials in man. Our dual approach is to develop a laboratory synthesis of this agent (there is no supply from natural sources) as well as to use this compound as a lead structure. Thus we are developing other structures, similar to that of bryostatin, and studying their biology. The hopes are to identify new and more easily prepared structures for use in therapy, and also to use these structures as biological tools for study of the underlying disease.
Funding Period: 1981-06-01 - 2015-03-31
more information: NIH RePORT

Top Publications

  1. pmc Synthetic studies toward the bryostatins: a substrate-controlled approach to the A-ring
    Gary E Keck
    Department of Chemistry, University of Utah, 315 South 1400 East RM 2020, Salt Lake City, Utah 84112 0850, USA
    Org Lett 8:3667-70. 2006
  2. pmc Comparison of transcriptional response to phorbol ester, bryostatin 1, and bryostatin analogs in LNCaP and U937 cancer cell lines provides insight into their differential mechanism of action
    N Kedei
    Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
    Biochem Pharmacol 85:313-24. 2013
  3. pmc Role of the C8 gem-dimethyl group of bryostatin 1 on its unique pattern of biological activity
    Gary E Keck
    University of Utah, Department of Chemistry, 315 South 1400 East, RM 2020, Salt Lake City, UT 84112, USA
    Bioorg Med Chem Lett 22:4084-8. 2012
  4. pmc Some phorbol esters might partially resemble bryostatin 1 in their actions on LNCaP prostate cancer cells and U937 leukemia cells
    Noemi Kedei
    Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892 4255, USA
    Chembiochem 12:1242-51. 2011
  5. pmc The synthetic bryostatin analog Merle 23 dissects distinct mechanisms of bryostatin activity in the LNCaP human prostate cancer cell line
    Noemi Kedei
    Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
    Biochem Pharmacol 81:1296-308. 2011
  6. pmc Total synthesis of bryostatin 1
    Gary E Keck
    Department of Chemistry, University of Utah, 315 South 1400 East, Room 2020, Salt Lake City, Utah 84112, United States
    J Am Chem Soc 133:744-7. 2011
  7. pmc The bryostatin 1 A-ring acetate is not the critical determinant for antagonism of phorbol ester-induced biological responses
    Gary E Keck
    University of Utah, Department of Chemistry, Salt Lake City, Utah 84112, USA
    Org Lett 11:2277-80. 2009
  8. pmc Substitution on the A-ring confers to bryopyran analogues the unique biological activity characteristic of bryostatins and distinct from that of the phorbol esters
    Gary E Keck
    Department of Chemistry, University of Utah, 315 South 1400 East, RM 2020, Salt Lake City, Utah 84112, USA
    Org Lett 11:593-6. 2009
  9. pmc Total synthesis of epothilones B and D: stannane equivalents for beta-keto ester dianions
    Gary E Keck
    Department of Chemistry, University of Utah, 315 South 1400 East, RM 2020, Salt Lake City, Utah, 84112, USA
    J Org Chem 73:9675-91. 2008
  10. pmc Diastereoselective synthesis of cyclopentapyridazinones via radical cyclization: synthetic studies toward halichlorine
    Gary E Keck
    Department of Chemistry, University of Utah, 315 South 1400 East RM 2020, Salt Lake City, Utah 84112 0850, USA
    Org Lett 10:4783-6. 2008

Research Grants

Detail Information

Publications17

  1. pmc Synthetic studies toward the bryostatins: a substrate-controlled approach to the A-ring
    Gary E Keck
    Department of Chemistry, University of Utah, 315 South 1400 East RM 2020, Salt Lake City, Utah 84112 0850, USA
    Org Lett 8:3667-70. 2006
    ..The key features of the approach include the convergent fragment assembly with a highly stereoselective construction of the C7-C8 bond indicated above...
  2. pmc Comparison of transcriptional response to phorbol ester, bryostatin 1, and bryostatin analogs in LNCaP and U937 cancer cell lines provides insight into their differential mechanism of action
    N Kedei
    Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
    Biochem Pharmacol 85:313-24. 2013
    ....
  3. pmc Role of the C8 gem-dimethyl group of bryostatin 1 on its unique pattern of biological activity
    Gary E Keck
    University of Utah, Department of Chemistry, 315 South 1400 East, RM 2020, Salt Lake City, UT 84112, USA
    Bioorg Med Chem Lett 22:4084-8. 2012
    ....
  4. pmc Some phorbol esters might partially resemble bryostatin 1 in their actions on LNCaP prostate cancer cells and U937 leukemia cells
    Noemi Kedei
    Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892 4255, USA
    Chembiochem 12:1242-51. 2011
    ..Depending on the system, some might partially resemble bryostatin 1 in their behavior; this encourages the concept that bryostatin-like behavior may be obtained from other structural templates...
  5. pmc The synthetic bryostatin analog Merle 23 dissects distinct mechanisms of bryostatin activity in the LNCaP human prostate cancer cell line
    Noemi Kedei
    Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
    Biochem Pharmacol 81:1296-308. 2011
    ..The pattern of response, moreover, varied depending on the conditions. We conclude that the newly emerging bryostatin derivatives such as Merle 23 provide powerful tools to dissect subsets of bryostatin mechanism and response...
  6. pmc Total synthesis of bryostatin 1
    Gary E Keck
    Department of Chemistry, University of Utah, 315 South 1400 East, Room 2020, Salt Lake City, Utah 84112, United States
    J Am Chem Soc 133:744-7. 2011
    ..Further elaborations of the resulting very highly functionalized intermediate include macrolactonization and selective cleavage of just one of five ester linkages present...
  7. pmc The bryostatin 1 A-ring acetate is not the critical determinant for antagonism of phorbol ester-induced biological responses
    Gary E Keck
    University of Utah, Department of Chemistry, Salt Lake City, Utah 84112, USA
    Org Lett 11:2277-80. 2009
    ..Functional assays showed biological responses characteristic of those induced by the phorbol ester PMA and distinctly different from those observed with bryostatin 1...
  8. pmc Substitution on the A-ring confers to bryopyran analogues the unique biological activity characteristic of bryostatins and distinct from that of the phorbol esters
    Gary E Keck
    Department of Chemistry, University of Utah, 315 South 1400 East, RM 2020, Salt Lake City, Utah 84112, USA
    Org Lett 11:593-6. 2009
    ..Biological assays reveal a crucial role for substitution in the bryostatin 1 A-ring in conferring those responses which are characteristic of bryostatin 1 and distinct from those observed with PMA...
  9. pmc Total synthesis of epothilones B and D: stannane equivalents for beta-keto ester dianions
    Gary E Keck
    Department of Chemistry, University of Utah, 315 South 1400 East, RM 2020, Salt Lake City, Utah, 84112, USA
    J Org Chem 73:9675-91. 2008
    ..Other key reactions in the synthesis include a stereoselective SmI(2) reduction of a beta-hydroxy ketone and a critical opening of a valerolactone with aniline which required extensive investigation...
  10. pmc Diastereoselective synthesis of cyclopentapyridazinones via radical cyclization: synthetic studies toward halichlorine
    Gary E Keck
    Department of Chemistry, University of Utah, 315 South 1400 East RM 2020, Salt Lake City, Utah 84112 0850, USA
    Org Lett 10:4783-6. 2008
    ..This overall approach was successfully employed in the preparation of a functionalized aza-spirocycle...
  11. pmc A new method for the synthesis of H(4)-BINOL
    Lars V Heumann
    Department of Chemistry, University of Utah, Salt Lake City, UT 84112 0850, USA
    J Org Chem 73:4725-7. 2008
    ..The key step is the net partial hydrogenation of (R)-BINOL made possible by prior bis-etherification of the parent BINOL...
  12. pmc Convergent assembly of highly potent analogues of bryostatin 1 via pyran annulation: bryostatin look-alikes that mimic phorbol ester function
    Gary E Keck
    Department of Chemistry, University of Utah, 315 South 1400 East, RM 2020, Salt Lake City, Utah 84112, USA
    J Am Chem Soc 130:6660-1. 2008
    ..This tricyclic intermediate was elaborated to bryostatin analogues which displayed nanomolar to subnanomolar affinity for PKC, but displayed properties indistinguishable from a phorbol ester in a proliferation/attachment assay...
  13. pmc A catalytic asymmetric vinylogous Mukaiyama aldol reaction
    Lars V Heumann
    Department of Chemistry, University of Utah, 315 South 1400 East RM 2020, Salt Lake City, Utah 84112 0850, USA
    Org Lett 9:4275-8. 2007
    ..A vinylogous Mukaiyama aldol reaction, conducted using 10 mol % of a BITIP catalyst and B(OMe)3 as an additive, effects an enantioselective four-carbon chain extension to give versatile E-alpha,beta-unsaturated thiol esters...
  14. pmc A new construction of 2-alkoxypyrans by an acylation-reductive cyclization sequence
    Lars V Heumann
    Department of Chemistry, University of Utah, Salt Lake City, UT 84112 0850, USA
    Org Lett 9:1951-4. 2007
    ..In this approach, two fragments are joined by esterification, and a subsequent intramolecular reductive cyclization affords the 2-hydroxypyran...
  15. pmc Biological profile of the less lipophilic and synthetically more accessible bryostatin 7 closely resembles that of bryostatin 1
    Noemi Kedei
    Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
    ACS Chem Biol 8:767-77. 2013
    ..The results suggest that the more easily synthesized and less lipophilic bryostatin 7 may be an effective surrogate for bryostatin 1...

Research Grants30

  1. Capture the Inhibitor: Affinity Approaches to the Discovery of Secretase Leads
    Philip Williams; Fiscal Year: 2013
    ....
  2. Natural Products for Treatment of Emergent AIDS-Related Pathogens
    Tadeusz F Molinski; Fiscal Year: 2013
    ..grubbi, with potential of beneficial outcomes in quality of life for patients living with HIV/AIDS. ..
  3. MITOCHONDRIAL ENCEPHALOMYOPATHIES AND MENTAL RETARDATION
    Salvatore DiMauro; Fiscal Year: 2013
    ....
  4. Molecular and Cellular Therapies for Muscular Dystrophy
    Stanley C Froehner; Fiscal Year: 2013
    ..The mechanism of NPC1 phenotype amelioration and its applicability to LGMDs will be studied. Two core facilities will serve the participating laboratories. ..
  5. ROLE AND REGULATION OF PROTEIN KINASE C ISOENZYMES
    Yusuf Awni Hannun; Fiscal Year: 2013
    ..We are defining the significance and mechanisms by which this process occurs and is regulated. In particular we focus on a key signaling protein known as protein kinase C (PKC) and its activating lipids. ..
  6. Water Soluble Antimitotics That Circumvent Rumor Resistance
    Susan L Mooberry; Fiscal Year: 2013
    ....
  7. Discovery of Anticancer Drugs from Cyanophytes
    FREDERICK AUGUSTUS VALERIOTE; Fiscal Year: 2013
    ..Therapeutically active drugs will be pursued further in preclinical and clinical development outside of this application. ..