In response to RFA-RM-08-003, we plan to use solution-phase strategies to synthesize several pilot-scale libraries (totaling 1,900 compounds) to be submitted to the NIH Molecular Libraries Small-Molecule Repository (MLSMR) for subsequent distribution for various biological assays.
Our aims are to synthesize (1) 440 diverse lactams that emanate from multicomponent reactions and formal cycloadditions employing anhydrides, (2) 308 enantiomerically-pure 3-hydroxy-2-oxindoles and spirocyclic oxindole-oxazolines featuring stereochemical (the series of both R- and S-enantiomers), central (core/skeleton), and peripheral (appendage) diversity, (3) 384 diverse bis-heterocycle and pyrazole substructures featuring both central (core/skeleton) and peripheral (appendage) diversity, and (4) 288 hybrid molecules using a convergent coupling strategy employing heterocycle core scaffolds (sub-libraries) prepared in Aims 1-3. An additional 480 compounds will be obtained by coupling the heterocycle core scaffolds from Aims 1-3 with a common set of building blocks. As described here, our planned synthetic routes include features such as a new multicomponent reaction, a modular approach for the stereo-divergent preparation of spirocyclic lactams, a new spirocyclic oxindole-oxazoline scaffold, syntheses of novel bis-heterocycle and pyrazole structures, and a new convergent coupling strategy for heterocycle hybrid libraries. Libraries will have ~20-200 members each with >95% purity of non-commercial small-molecules for submission (10-20 mg quantities) to the MLSMR. Each compound will be analyzed by HPLC for purity and its identity confirmed by mass spectroscopy. Preparatory HPLC chromatography will be used for compound purification. The NIH's PubChem database, a component of the National Institute of Health Repository, will be used for management of our various pilot libraries. PubChem interfaces substance information, compound structures, and bioactivity data.
The NIH "Roadmap" seeks to contribute biomedical research by supporting initiatives that will draw from different scientific areas to speed up the discovery of new medicines. This proposal will provide new compounds for the collection of molecules (MLSMR) used in screening experiments to develop a better understanding of biological processes and may ultimately lead to new cures for human diseases.
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|Farber, Kelli M; Haddadin, Makhluf J; Kurth, Mark J (2014) Davis-Beirut reaction: route to thiazolo-, thiazino-, and thiazepino-2H-indazoles. J Org Chem 79:6939-45|
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|Martin, Kevin S; Di Maso, Michael J; Fettinger, James C et al. (2013) Synthesis of a Library of "Lead-Like" ýý-Lactams by a One Pot, Four-Component Reaction. ACS Comb Sci :|
|Pattawong, Ommidala; Tan, Darlene Q; Fettinger, James C et al. (2013) Stereocontrol in asymmetric ?-lactam syntheses from imines and cyanosuccinic anhydrides. Org Lett 15:5130-3|
|Shupe, Benjamin H; Allen, Emily E; MacDonald, Jacob P et al. (2013) Synthesis of spirocarbamate oxindoles via intramolecular trapping of a *-silyl carbocation by an N-Boc group. Org Lett 15:3218-21|
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