Natural products are regaining their traditional importance as drug candidates, leads for drug candidates and biological probes. Complex natural products typically contain many stereocenters, but only one or at most a handful of stereoisomers are available for study. A new and general approach to making natural product stereoisomer libraries is being developed. The libraries are made as mixtures coded with fluorous (fluoroalkyl) tags, which allows for isolation of individual pure products at the final stage. The total synthesis of 16 isomers of murisolin in a single mixture library by using four fluorous tags and four members of a new class of tags will be accomplished. This new "double tagging" method will be considerably more efficient than the current single tagging method, which requires four separate mixtures to be made to prodice sixteen compounds. The stereoisomer library members will be tested for their anticancer activity, and this will provide the first detailed stereostructure/activity relationship for any acetogenin. The total synthesis of all 64 isomers of the protein phosphatase inhibitor cytostatin will be undertaken by using a combination-of double tagging and splitting. Once the sixty-four member library of individual cytostatin isomers is in hand, the stereostructure of cytostatin will be assigned, and the samples will be tested as potential selective phosphatase inhibitors. A new iterative, multi-tagging strategy for synthesis of natural products with repeating stereocenter units such as polyols will be reduced to practice. To prove the concept, first eight diastereomers and later all sixteen isomers of passifloricin A will be synthesized.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37GM033372-28
Application #
8300930
Study Section
Special Emphasis Panel (NSS)
Program Officer
Lees, Robert G
Project Start
1984-04-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
28
Fiscal Year
2012
Total Cost
$330,352
Indirect Cost
$104,929
Name
University of Pittsburgh
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Buter, Jeffrey; Yeh, Edmund A-H; Budavich, Owen W et al. (2013) Synthesis and analysis of the all-(S) side chain of phosphomycoketides: a test of NMR predictions for saturated oligoisoprenoid stereoisomers. J Org Chem 78:4913-8
Zhang, Hanmo; Hay, E Ben; Geib, Steven J et al. (2013) Radical cyclizations of cyclic ene sulfonamides occur with *-elimination of sulfonyl radicals to form polycyclic imines. J Am Chem Soc 135:16610-7
Yeh, Edmund A-H; Kumli, Eveline; Damodaran, Krishnan et al. (2013) Bare-minimum fluorous mixture synthesis of a stereoisomer library of 4,8,12-trimethylnonadecanols and predictions of NMR spectra of saturated oligoisoprenoid stereoisomers. J Am Chem Soc 135:1577-84
Dewanji, Abhishek; Murarka, Sandip; Curran, Dennis P et al. (2013) Phenyl hydrazine as initiator for direct arene C-H arylation via base promoted homolytic aromatic substitution. Org Lett 15:6102-5
Mandel, Jeremie; Pan, Xiaohong; Hay, E Ben et al. (2013) Rotational isomers of N-methyl-N-arylacetamides and their derived enolates: implications for asymmetric Hartwig oxindole cyclizations. J Org Chem 78:4083-9
Moretti, Jared D; Wang, Xiao; Curran, Dennis P (2012) Minimal fluorous tagging strategy that enables the synthesis of the complete stereoisomer library of SCH725674 macrolactones. J Am Chem Soc 134:7963-70
Gudipati, Venugopal; Curran, Dennis P (2011) Synthesis of C1-C20 and C21-C40 fragments of tetrafibricin. Tetrahedron Lett 52:2254-2257
Zhang, Kai; Curran, Dennis P (2010) Fluorous Mixture Synthesis of Four Stereoisomers of the C21-C40 Fragment of Tetrafibricin. Synlett 2010:667-674
Sui, Bin; Yeh, Edmund A-H; Curran, Dennis P (2010) Assignment of the structure of petrocortyne A by mixture syntheses of four candidate stereoisomers. J Org Chem 75:2942-54
Wang, Liang; Cai, Chun; Curran, Dennis P et al. (2010) Enantioselective alpha-Chlorination of Aldehydes with Recyclable Fluorous (S)-Pyrrolidine-Thiourea Bifunctional Organocatalyst. Synlett 3:433-436

Showing the most recent 10 out of 18 publications