Arisugacin, a potent and selective inhibitor of acetylcholinesterase (AchE), has significant implications in the therapeutic treatment of Alzheimer's disease based on the cholinergic hypothesis. Given the biological relevance and the synthetic interest surrounding arisugacin, this research proposal illustrates 1) approaches to the total synthesis of arisugacin, 2) detailed plans for developing a formal [3+3] cycloaddition method, and 3) development of a proposed binding site model for arisugacin. These research ideas are presented in three distinct sections. In the first section, a total synthesis of arisugacin is proposed on the basis on a formal [3+3] cycloaddition reaction involving alpha,beta-unsaturated imuniums that we have developed recently. The synthetic sequence features the utility of the [3+3] cycloaddition strategy in constructing the pentacyclic core of arisugacin. An alternative approach to the same key pentacycle using condensation reactions of alpha,beta-unsaturated acids is also described. This total synthesis is convergent and should be practical for synthesis of structural analogs as well as studies involving a proposed binding-site model. In the second section, efforts are devoted to develop the formal [3+3] cycloaddition reaction involving alpha,beta-unsaturated iminiums and diketo equivalents. This formal cycloaddition reaction represents a unique approach to synthesis of heterocycles. Three specific areas of its synthetic application are proposed: 1) To examine various diketo equivalents and alpha,beta-unsaturated iminiums to widen the scope of this reaction, 2) to develop intramolecular formal [3+3] cycloaddition reactions, and 3) to explore stereoselective formal [3+3] cycloadditions for natural product synthesis. In the final section, a binding-site model for arisugacin is proposed based on structural comparison. Various tricyclic CDE- ring analogs are being evaluated to determine the structural significance of the DE-ring. Synthesis of tetracyclic and pentacyclic analogs are proposed to further examine the binding- site model. These studies should be significant because they can provide a variety of useful synthetic methodologies for natural product synthesis and important insight into the binding property of arisugacin to AChE, thereby leading to potential discovery of novel and effective therapeutics structurally modeled after arisugacin for Alzheimer's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS038049-04
Application #
6639545
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Murphy, Diane
Project Start
2000-07-01
Project End
2004-05-31
Budget Start
2003-06-01
Budget End
2004-05-31
Support Year
4
Fiscal Year
2003
Total Cost
$214,184
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Chemistry
Type
Other Domestic Higher Education
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Al-Rashid, Ziyad F; Hsung, Richard P (2015) A computational view on the significance of E-ring in binding of (+)-arisugacin A to acetylcholinesterase. Bioorg Med Chem Lett 25:4848-53
Gerasyuto, Aleksey I; Ma, Zhi-Xiong; Buchanan, Grant S et al. (2013) Establishing the concept of aza-[3 + 3] annulations using enones as a key expansion of this unified strategy in alkaloid synthesis. Beilstein J Org Chem 9:1170-8
Buchanan, Grant S; Cole, Kevin P; Li, Gang et al. (2011) Constructing the Architecturally Distinctive ABD-Tricycle of Phomactin A through an Intramolecular Oxa-[3 + 3] Annulation Strategy. Tetrahedron 67:10105-10118
Al-Rashid, Ziyad F; Hsung, Richard P (2011) (+)-Arisugacin A--computational evidence of a dual binding site covalent inhibitor of acetylcholinesterase. Bioorg Med Chem Lett 21:2687-91
Buchanan, Grant S; Cole, Kevin P; Tang, Yu et al. (2011) Total synthesis of (±)-phomactin A. Lessons learned from respecting a challenging structural topology. J Org Chem 76:7027-39
Buchanan, Grant S; Dai, Huifang; Hsung, Richard P et al. (2011) Asymmetric aza-[3+3] annulation in the synthesis of indolizidines: an unexpected reversal of regiochemistry. Org Lett 13:4402-5
Buchanan, Grant S; Feltenberger, John B; Hsung, Richard P (2010) Aza-[3 + 3] Annulations: A New Unified Strategy in Alkaloid Synthesis. Curr Org Synth 7:363-401
Li, Gang; Carlson, Lauren J; Sagamanova, Irina K et al. (2009) A Stereodivergent Approach for Accessing Both C2,8a-Syn and C2,8a-Anti Relative Stereochemical Manifolds in the Lepadin Family via a TiCL(4)-Promoted Aza-[3 + 3] Annulation. Synthesis (Stuttg) 2009:2905
Tang, Yu; Cole, Kevin P; Buchanan, Grant S et al. (2009) Total synthesis of phomactin A. Org Lett 11:1591-4
Li, Gang; Hsung, Richard P (2009) Assignment of the C5' relative stereochemistry in (+)-lepadin F and (+)-lepadin G and absolute configuration of (+)-lepadin G. Org Lett 11:4616-9

Showing the most recent 10 out of 30 publications