The grant proposal "Complex Chemo types: Discovery, Methodology, and Library Expansion" describes a renewal application for The Center for Chemical Methodology and Library Development at Boston University (CMLD-BU) which was initiated in 2002 with funding from the NIGMS. The three goals of Center have been to develop new reaction methodologies for the stereo controlled synthesis of complex libraries, to create a publicly accessible database of chemical protocols, and to provide chemical libraries to members of the biological community in collaborative efforts. The CMLD-BU has organized the Chemical Library Consortium (CLC) to provide members of the biology community with chemical libraries. The PI (Porco) and co-Pi's (Panek, Snyder, and Schaus) have demonstrated the ability to construct a number of complex chemical libraries in the first funding period with several members exhibiting unique bioactivities. The CMLD-BU currently maintains a collection of approximately 5000 novel compounds which have been made available to 23 collaborators in the U.S. for biological screening in a wide variety of assays. The proposed projects described in the renewal application are focused on development of new reaction processes to obtain novel molecular structures (chemo types) for biological screening. The CMLD-BU will also develop strategies, chemical methods, and micro fluidic technologies to accomplish the syntheses of small-molecule libraries. The first project, "Skeletal Diversity Employing Scaffold Rearrangements, Annulations, and Cycloadditions" will focus on the development of rearrangements, cycloadditions, and ring annulation processes for diversity-oriented synthesis. Project 2, "Discovery of Novel Transformations and Chemo types Using Reaction Screening" continues reaction screening and discovery approaches to access novel chemotypes.Project 3, "Development of Micro fluidic Technologies for Reaction Discovery, Methodology Development, and Library Synthesis" is a collaborative effort between the CMLD-BU and the laboratory of Professor Klavs Jensen of the Department of Chemical Engineering at MIT to develop enabling microfluidic technologies for multidimensional reaction screening, photochemical and microwave-mediated reactions, automated reaction optimization, and chemical synthesis of libraries. All chemical libraries and arrays will be submitted to the Molecular Libraries Small Molecular Repository and biological data uploaded to PubChem. Taken together, the proposed projects will create valuable tools to study biology and advance the role of chemistry in biomedical research.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Specialized Center (P50)
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Special Emphasis Panel (ZGM1-PPBC-3 (CL))
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Fabian, Miles
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Boston University
Schools of Arts and Sciences
United States
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Grenning, Alexander J; Snyder, John K; Porco Jr, John A (2014) Remodeling of fumagillol: discovery of an oxygen-directed oxidative Mannich reaction. Org Lett 16:792-5
Grenning, Alexander J; Boyce, Jonathan H; Porco Jr, John A (2014) Rapid synthesis of polyprenylated acylphloroglucinol analogs via dearomative conjunctive allylic annulation. J Am Chem Soc 136:11799-804
Wolfe, Andrew L; Singh, Kamini; Zhong, Yi et al. (2014) RNA G-quadruplexes cause eIF4A-dependent oncogene translation in cancer. Nature 513:65-70
Brawn, Ryan A; Zhu, Kaicheng; Panek, James S (2014) Rhodium(II)-catalyzed alkyne amination of homopropargylic sulfamate esters: stereoselective synthesis of functionalized norcaradienes by arene cyclopropanation. Org Lett 16:74-7
Zhu, Lijia; Qi, Ji; Chiao, Christine Ya-Chi et al. (2014) Identification of a novel polyprenylated acylphloroglucinol?derived SIRT1 inhibitor with cancer?specific anti-proliferative and invasion-suppressing activities. Int J Oncol 45:2128-36
Qin, Tian; Porco Jr, John A (2014) Total syntheses of secalonic acids?A and D. Angew Chem Int Ed Engl 53:3107-10
Yeung, Charles S; Ziegler, Robert E; Porco Jr, John A et al. (2014) Thiourea-catalyzed enantioselective addition of indoles to pyrones: alkaloid cores with quaternary carbons. J Am Chem Soc 136:13614-7
Martin, VĂ©ronique I; Goodell, John R; Ingham, Oscar J et al. (2014) Multidimensional reaction screening for photochemical transformations as a tool for discovering new chemotypes. J Org Chem 79:3838-46
Lee, Jihoon; Panek, James S (2014) Synthesis of isochromene-type scaffolds via single-flask Diels-Alder-[4 + 2]-annulation sequence of a silyl-substituted diene with menadione. Org Lett 16:3320-3
Xiong, Yuan; Schaus, Scott E; Porco Jr, John A (2013) Metal-catalyzed cascade rearrangements of 3-alkynyl flavone ethers. Org Lett 15:1962-5

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