As the majority of small molecule drugs (and drug candidates) targeting the CNS are heterocycles, predominantly nitrogen and oxygen heterocycles, the focus of our NS program is the invention of new methods and synthesis strategies for preparing such molecules. The proposed research program has three components: total synthesis of structurally novel natural products, development of new chemical synthesis methods, and studies of the unique effect of oxygen heterocycles having the 6-acetoxy-2,7-dioxabicyclo[3.2.1]octan-3-one ring system on the organization and function of the Golgi. The natural products targeted for enantioselective total synthesis-daphnipaxinin, aspergillin PZ, macfarlandin E, aplyviolene, norrlandin, chromodorolide A-have not been previously prepared;as a result, our investigations will define synthetic strategies for assembling these uncommon, bioactive, structural motifs. Moreover, the proposed studies will define the chemical peculiarities of these target molecules, develop chemistry for manipulating their structures, and provide analog structures for biological evaluation. Daphniphyllum alkaloids are neurotoxic and target directly the central nervous system, resulting in depression of voluntary movement as well as respiratory function;daphnipaxinin was isolated form an evergreen tree whose leaves and stems are used as antiinflammation herbs in Chinese folk medicine. Aspergillin PZ, also isolated in China, is reported to be an antitumor agent. Macfarlandin E, norrlandin, and chromodorolide A are rearranged spongian diterpenes that contain the rare 4,6-diacetoxy-2,7-dioxabicyclo[3.2.1]octan-3-one ring system. In collaboaration with the laboratory of Christine Sutterlin, we have recently shown that macfarlandin E and synthetic analogs containing the 4,6-diacetoxy-2,7-dioxabicyclo[3.2.1]octan-3-one ring system induce a unique modification of the Golgi ribbon in which the ribbon is fragmented with localization of the fragments in the pericentriolar region with concurrent block of protein transport out of the Golgi. As natural macfarlandin E is no longer available, synthetic macfarlandin E and analogs will allow cell biology studies to dissect the individual contributions of Golgi organization and position to the regulation of protein trafficking, cell polarization, centrosome organization, and cell division. If the purported neurotrophic properties of nankakurines A and B are confirmed, we will prepare analogue structures to enhance these properties and determine what aspects of their structures are important for neurotrophic activity;these rare alkaloids were first prepared during this project period and are currently undergoing pharmacological evaluation. Exploratory chemical synthesis studies are proposed that will: (a) develop new ways to initiate Prins cyclizations and explore the synthetic utility of O-acyloxonium ions, (b) continue our development of a new enantioselective method for preparing angularly substituted 1-azabicyclic molecules and unusual ?-amino acids in which dynamic kinetic resolution is achieved by combining a rapid tautomeric equilibration of diastereomeric iminium cations with a diastereoselective rearrangement, and (c) develop new cascade sequences that exploit oxocarbenium ions produced in a first cascade reaction to initiate a second C-C bond-forming process. In addition exploratory chemical biology studies will be undertaken to evaluate the utility of 6-acyloxy-2,7-dioxabicyclo[3.2.1]octan-3-ones to selectively tag lysine side chains and potentially directly introduce a fluorphore to allow in situ analysis of the modified biomolecule.

Public Health Relevance

If the aims of this application are realized, biomedical researchers will have new tools for synthesizing and modifying the structure of complex nitrogen and oxygen heterocycles. The availability of the new organic synthesis methods that we are developing will facilitate discovery and production of improved chemical agents for treating neurological and other medical disorders. In addition, the proposed studies will enable collaborative studies of several cellular processes that are critical for cellular function.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM098601-35
Application #
8207244
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
Project Start
1978-06-01
Project End
2014-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
35
Fiscal Year
2012
Total Cost
$412,821
Indirect Cost
$132,816
Name
University of California Irvine
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Tao, Daniel J; Muuronen, Mikko; Slutskyy, Yuriy et al. (2016) Diastereoselective Coupling of Chiral Acetonide Trisubstituted Radicals with Alkenes. Chemistry 22:8786-90
Tao, Daniel J; Slutskyy, Yuriy; Overman, Larry E (2016) Total Synthesis of (-)-Chromodorolide B. J Am Chem Soc 138:2186-9
Büschleb, Martin; Dorich, Stéphane; Hanessian, Stephen et al. (2016) Synthetic Strategies toward Natural Products Containing Contiguous Stereogenic Quaternary Carbon Atoms. Angew Chem Int Ed Engl 55:4156-86
Nawrat, Christopher C; Jamison, Christopher R; Slutskyy, Yuriy et al. (2015) Oxalates as Activating Groups for Alcohols in Visible Light Photoredox Catalysis: Formation of Quaternary Centers by Redox-Neutral Fragment Coupling. J Am Chem Soc 137:11270-3
Pratsch, Gerald; Overman, Larry E (2015) Synthesis of 2,5-Diaryl-1,5-dienes from Allylic Bromides Using Visible-Light Photoredox Catalysis. J Org Chem 80:11388-97
Baumann, Marcus; Dieskau, André P; Loertscher, Brad M et al. (2015) Tricyclic Analogues of Epidithiodioxopiperazine Alkaloids with Promising In Vitro and In Vivo Antitumor Activity. Chem Sci 6:4451-4457
Pratsch, Gerald; Lackner, Gregory L; Overman, Larry E (2015) Constructing Quaternary Carbons from N-(Acyloxy)phthalimide Precursors of Tertiary Radicals Using Visible-Light Photocatalysis. J Org Chem 80:6025-36
Lackner, Gregory L; Quasdorf, Kyle W; Pratsch, Gerald et al. (2015) Fragment Coupling and the Construction of Quaternary Carbons Using Tertiary Radicals Generated From tert-Alkyl N-Phthalimidoyl Oxalates By Visible-Light Photocatalysis. J Org Chem 80:6012-24
Canham, Stephen M; Hafensteiner, Benjamin D; Lebsack, Alec D et al. (2015) Stereocontrolled enantioselective total synthesis of the [2+2] quadrigemine alkaloids. Tetrahedron 71:6424-6436
Quasdorf, Kyle W; Overman, Larry E (2014) Catalytic enantioselective synthesis of quaternary carbon stereocentres. Nature 516:181-91

Showing the most recent 10 out of 27 publications