Higuchi Biosciences Center - University of Kansas

Fall 2008 Science Talks
December 5, 2008

G1. Diverse Libraries based on the Stemona Alkaloid Skeleton
Kevin Frankowski and Jeffrey Aubé
University of Kansas Center for Chemical Methodologies and Library Development (KU CMLD), University of Kansas, Lawrence, KS 66047

The reported antitussive activity of two Stemona alkaloids, neostenine and neotuberostemonine have inspired the total synthesis of neostenine. The combination of a tandem endo selective Diels-Alder and azido Schmidt reactions provided access to the complex tricyclic skeleton of this class of alkaloids in an efficient and rapid manner. The successful total synthesis of neostenine was complemented by applying the above methodogy toward the construction of a series of unnatural Stemona alkaloid skeleta. These skeleta served as scaffolds for the parallel synthesis of highly unusual Stemona alkaloid analogues. Several demonstration libraries illustrate how the careful choice of reaction conditions allowed for the substrate-controlled diastereoselective diversification of these scaffolds.

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G2. High Throughput Screening Laboratory, a KUCC Shared Resource, Aids in Accelerating Drug Discovery Research Initiatives
Dr. Rathnam Chaguturu, High Throughput Screening, University of Kansas, Lawrence, Kansas

The primary goal of the High Throughput Screening Laboratory (HTSL) at the University of Kansas (KU) has been to make modern drug discovery tools available in the most cost-effective manner to biomedical researchers in Kansas, the Greater Kansas City area and beyond. The 4500 sq. ft HTSL research/office complex is fully equipped with state-of-the-art instrumentation, 100,000+ chemical library, and includes a separate cell culture lab as well as a high content screening microscopy laboratory. A modern chemical library management system will soon be housed for compound storage and retrieval. Personnel have extensive experience in executing cell-based, biochemical, siRNA as well as high content screening campaigns against a plethora of therapeutic target classes. KU-HTSL is innovative and flexible in providing superior service to the drug discovery research community, from assay development to screening to compound profiling and data mining. We screen about 100,000 compounds in two days for end point assays, or one week for kinetic assays. KU-HTSL further leverages the strengths of the KU Core facilities and the KU Medical Center’s Office of Therapeutics, Drug Discovery and Development to advance new lead discovery research endeavors.

Funded in part by NIH Grant (P20 RR015563, Timmermann, PI) (COBRE Program of the NCRR.KUMC Shared Resource)

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G3. ROMP Strategies in Library Development
Toby R. Long,¹ Dinesh Rayabarapu,¹ Maria Jimenez,¹ Josh Wewel,¹ Sarra Klimberg,² Paul R. Hanson,¹ and Daniel L. Flynn²
Department of Chemistry, University of Kansas, Lawrence, Kansas 66045

Methodologies incorporating ring-opening metathesis polymerization (ROMP) for use in library synthesis are reported. Utilization of a norbornenyl-tagged monochlorophosphate in Capture/ROMP/Cuprate-release protocols yields functionalized sultams and phosphonate scaffolds. Propargylated norbornenyl tags have also been developed for the incorporation of a Click-capture, diversify-release protocol to afford various triazoles. In addition, an atom-economical method has been developed whereby various reactions on an internally-armed bicyclic-norbornenyl sultam are coupled to ROM polymerization. This coupling allows for parallel processing of both sultam product as well as reclamation of excess sultam polymer which can be diversified and subjected to a vanishing support protocol.

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G4. Synthesis of cyclic peptidomimetics inspired by ?-turns and applications to library design
Erik Fenster, David Hill, Benjamin Neuenswander and Jeffrey Aubé
The Center for Chemical Methodology and Library Development at the University of Kansas, Structural Biology Center (SBC), 2121 Simons Drive, Lawrence KS 66047

A series of peptidomimetics based on a ?-turn motif were prepared, in which N-substituted piperidones were reacted with a selection of 2-hydroxyalkyl azides derived from common L-amino acids. A variety of nucleophiles were found to add at the distal ether carbon in the initially formed iminium ethers rather than the more electrophilic oxazolinium carbon. This consequence was exploited such that a series of diversely substituted 1,4-diazepinones were prepared. The applicability of this chemistry to the construction of 1,4-diazepinone libraries has also been investigated.

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G5. Vinyl Sulfonamides: Versatile Synthons for Library Production
Christopher A. Knudtson, Aihua Zhou, Nick Allen and Paul R. Hanson
Department of Chemistry, University of Kansas 1251 Wescoe Hall Dr, Lawrence, KS 66045-7582 and The Center for Chemical Methodologies and Library Development at the University of Kansas (KU-CMLD), Lawrence, KS 66045-7582

The development of new cyclization methods for the synthesis of an array of sultams is reported. The first method utilizes a domino deprotection/intramolecular oxa-Michael addition en route to a diverse library of 7- and 8-membered sultams. A second method involves an intramolecular Baylis-Hillman reaction affording a variety of functionalized 5- and 6-member sultams. These methods are utilized to synthesize libraries of chiral mono- and bicyclic sultams derived from commercially available non-racemic amino alcohols.

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Higuchi Biosciences Center
University of Kansas
2099 Constant Avenue
Lawrence, KS 66047-2535
785-864-5183
hbc@ku.edu