Chemical Methodologies & Library Development Center
Program Summary
The KU Chemical Methodologies & Library Development (CMLD) Center worked to synthesized thousands of small molecules over the project period. Most of these were submitted to the Molecular Libraries Small Molecule Repository (MLSMR) for inclusion in the MLPCN screening collection. As part of the MLPCN, the compounds made via the KU CMLD were also published on PubChem with relevant bioactivity data. The KU CMLD goal was to make available cherry-picks or complete libraries to biologists looking for specific chemical moieties. The KU CMLD program initially established in 2003 and supported by a grant from the National Institute of General Medical Sciences at the National Institutes of Health, ended in July 2018.
Mission
The mission of KU Chemical Methodologies & Library Development (KU CMLD) Center of Excellence was to design and synthesize libraries that:
- Utilize new principles of scaffold design (and especially the incorporation of multiple scaffold cores into a single library)
- Are likely to have pharmacological activity based on sound drug design principles, and
- Are likely to have drug-like characteristics.
Novel synthetic technology is the primary product of our academic research. The KU CMLD accomplished its mission by combining this new knowledge with standing parallel synthesis capabilities, enabling the production of unique chemical libraries. The specialized expertise and hardware within the KU CMLD translated into cost effectiveness, high quality, timely turnaround and structural diversity. Dedicated staff coupled with versatility and adaptability meant the KU CMLD stood ready to adapt synthetic methodology to library production. This wide scope positioned the Center to be a source of new and exciting investigational tools for the Chemical Biology research community.
Cores and Projects
Core A: Administration
Core A was responsible for the organization, coordination, and administration of the activities of the KU CMLD Center. This included ensuring that the facilities were appropriately equipped, monitoring progress of individual projects, overseeing of the scientific cores, convening meetings for the researchers and the external advisory committee, administering the budget, and coordinating outreach.
Core B: Synthesis
Core B was responsible for the maintenance and operation of a centralized combinatorial and parallel synthesis facility, which housed much of the specialized equipment for library preparation, analysis, and storage.
Core C: Library Design, Analysis & Purification
Core C was responsible for the characterization of the libraries synthesized with respect to identity and purity. The LDAP Core also handles informatics issues and provides computational assistance to scientists designing libraries with an eye to downstream biological collaborations.
Project 1: Enhancement of Library Synthesis Using Microwave Flow Technology
Original Project Description:
Performing reactions using flow techniques instead of conventional static batch reactors enables in-process reaction optimization and in-line processing (analysis or purification) of the products. One potential drawback with flow is a shorter exposure time of the reactants to the appropriate conditions in comparison with a standard batch reactor. For slow reactions the benefits of flow can be offset by low conversion and purification problems due to unreacted starting materials. Microwave irradiation dramatically accelerates chemical transformations; using microwave with flow combines the benefits of both techniques. Recent work reveals that reactions flowed through small diameter tubes (capillaries) during irradiation are much faster than those using larger diameter tubes. We believe this offers the potential for wide acceptance of flow microwave synthesis. This project seeks further advances by performing flow microwave using capillaries containing new supported reagents, catalysts and scavengers through which the reactions flow to allow sequential multi-step synthesis and purification. This could lead to the creation of an automated, multi-step chemical synthesis device capable of running multiple reactions simultaneously through parallel capillaries.
Project Investigators:
- Paul R. Hanson, Ph.D., Professor of Chemistry, University of Kansas
- Michael G. Organ, Ph.D., Associate Professor of Chemistry, York University
Project 2: Libraries Based on Natural Products and Privileged Structures
Original Project Description:
This project develops methods for synthesis of chemical libraries that are related to biologically relevant natural products and heterocycles. These libraries are important because such products are often available only as single entities or as part of a complex mixture. Thus, the synthesis of natural product inspired libraries will expedite the identification of new bio-activity and facilitate both SAR and mechanistic studies. To this end we prepare medium ring compounds that resemble anti-cancer polyketides as well as polyphenolic compounds including coumarins and flavans. Significantly, available data validates the relevance of several of the libraries.
In addition to the utility of the described libraries, the development of new synthetic methods allows rapid parallel synthesis of new heterocyclic chemotypes. Examples of our methodology include palladium-catalyzed decarboxylative cycloadditions, iterative CH-functionalization of phenols, enyne metathesis/Diels-Alder sequences and Paterno-Büchi reactions. We develop not only new chemistry but also new reagents to facilitate parallel synthesis. For example the use of N-vinypyridinium salts as versatile coupling partners in Suzuki and Nozaki-Hiyama-Kishi reactions overcomes the difficulties of utilizing unstable ß-halocarbonyl compounds. We believe that using N-vinypyridinium reagents permits efficient construction of compounds that would be otherwise difficult to make.
Project Investigators:
- Jon A. Tunge, Ph.D., Associate Professor of Chemistry, University of Kansas
- Keith R. Buszek, Ph.D., Professor of Chemistry, University of Missouri–Kansas City
Project 3: Lactam and Sulfoxamide Libraries
Original Project Description:
This project seeks to discover and then generalize new ways of generating heterocyclic scaffolds that contain lactams and the related sulfoxamide linkage. In the first part of the project, Aubé and coworkers will seek to broadly address bottlenecks that hinder the application of alkyl azides in library construction. The first aim will be to develop a suite of reactions that involve tandem sequences in which a Lewis acid-promoted reaction of an alkyl azide with a ketone is partnered with another, similarly promoted reaction like (but not limited to) the Diels–Alder reaction. A second project will broadly address the use of flow chemistry to overcome well-known practical issues encountered with using alkyl azides on scale or with using highly energetic azide intermediates. The third project will utilize reaction screening as a reaction discovery tool. Although focusing on the reactions of azidoalkyl azide sublibraries with ketones and other potential reaction partners, the techniques developed in this reaction (carried out in collaboration with the Porco group at Boston University) will be brought to bear on other reactions as well, including a set of double conjugate addition reactions of quinone ketals developed recently in the Aubé lab. The last project in this section will concern the exploration of conformation control to establish regiochemistry in library-constructing reactions, ultimately with the goal of developing efficient means to shape-diverse libraries of piperidine privileged structures.
In the second part of this project, the Hanson group will target sulfonamide and sultam libraries, which show promising potential as bioactive agents yet still constitute a rare chemical class in Pubchem. We aim to develop a generalized strategic approach that first constructs a series of sulfonamide linchpins using an underdeveloped example of a “click” reaction. Once made, a single sulfonamide linchpin will be made to diverge to multiple scaffolds using a set of orthogonal cyclization pathways. Elements of this project will involve the integration of flow technology to facilitate sultam library production and the development of facilitated protocols for late-stage annotation using ROM polymerization technology developed by the Hanson group within the first granting period.
Project Investigators:
- Jeffrey Aubé, Ph.D., Professor of Medicinal Chemistry, University of Kansas
- Paul R. Hanson, Ph.D., Professor of Chemistry, University of Kansas
Project 4: Organometallic Reactions in Parallel Synthesis
Original Project Description:
In this project, metal-mediated routes to library synthesis will be developed using several thematically related approaches. In the first, chemoselective transition metal-catalyzed multi-component coupling reactions will be used to construct multifunctional scaffolds, such as α-N-substituted amides, α,β-unsaturated-δ-lactones, and lactams; up to three elements of diversity can be introduced simultaneously during this initial operation. A series of tactical reaction combinations (e.g., intramolecular Diels–Alder reactions or organometallic coupling processes like the Heck reaction) will then be carried out on these main structures. A series of applications of these methods to libraries inspired by the structural cores of bioactive natural products and synthetic heterocycles will follow. In a different project, a recently developed palladium-catalyzed three-component coupling of imines or aldehydes with allenes and boronic acids to afford functionalized lactones and lactams will be investigated. This chemistry will be applied to libraries containing substituted tetrahydropyrans and piperidines related to cytotoxic natural product calyxin L. A second theme involves the conjunction of aromatic/heteroaromatic building blocks with reactants featuring complementary reactive functionalities. These reactions can be viewed as facile annulations able to construct libraries featuring multiple distinct heterocyclic scaffolds in a single step. The application of Pd thin film capillaries to facilitate these reactions will also be explored.
Project Investigators:
- Helena C. Malinakova, Ph.D., Associate Professor of Chemistry, University of Kansas
- Richard C. Larock, Ph.D., Distinguished Professor of Chemistry, Iowa State University
Participants
Core A: Administration
- Jeffrey Aubé, Director from 2003 - 2015
- Thomas Prisinzano, Director of the Legacy Continuation CMLD Mission from 2015 - 2018
- Frank Schoenen, Associate Director from 2005 - 2009
- Shelley K. Sandberg, Program Assistant from 2009 - 2018
- Cady Bush, Program Assistant from 2005 - 2009
Core B: Synthesis
- Conrad Santini, Director from 2009-2015
- Frank J. Schoenen, Director from 2005-2009; Sr. Investigator from 2009-2015
- Chan Woo Huh, Research Associate
- David A. Hill, Lab Manager
- Prashi Jain, Postdoc
- Mike McLeod, Postdoc
- Digamber Rane, Postdoc
Core C: Library Design, Analysis & Purification
- Todd D. Williams, Sr. Investigator
- Justin T. Douglas, Sr. Investigator
- Benjamin Neuenswander, Assistant Director/Analytical Chemist
- Patrick Porubsky, Sr. Research Assistant
Project 1: Enhancement of Library Synthesis Using Microwave Flow Technology
- Paul R. Hanson, Co-Investigator, professor of chemistry, University of Kansas
- Michael G. Organ, Co-Investigator, professor of chemistry and biomolecular sciences, York University
- Farman Ullah, Postdoc
- Srinivas Achanta, Graduate Research Assistant
Project 2: Libraries Based on Natural Products and Privileged Structures
- Jon A. Tunge, Co-Investigator, professor of chemistry, University of Kansas.
- Keith R. Buszek, Co-Investigator, professor of chemistry, University of Missouri-Kansas City
- Ramakumar Kinthada, Postdoc
Project 3: Lactam and Sulfoxamide Libraries
- Jeffrey Aubé, Co-Investigator, professor of medicinal chemistry, University of Kansas
- Paul R. Hanson, Co-Investigator, professor of chemistry, University of Kansas
- Kyu Ok Jeon, Graduate Research Assistant, University of Kansas
- Moon Young Hur, Graduate Research Assistant
Project 4: Organometallic Reactions in Parallel Synthesis
- Helena C. Malinakova, Co-Investigator, associate professor of chemistry, University of Kansas
- Richard C. Larock, Co-Investigator, professor of chemistry, Iowa State University
- Anton Dubrovskiy, Graduate Research Assistant
- Thomas R. Beattie
- Scott R. Gilbertson
- Anna K. Mapp
- John M. Nuss
- James S. Panek
- Michael F. Rafferty
- Daryl R. Sauer