Karl A. Scheidt, Ph.D. - US grants

While great advances have been made in asymmetric C-C bond formation utilizing chiral Lewis acids, less attention has been focused on the construction of C-N bonds with high levels of selectivity. This research proposal describes the development of a catalytic enantioselective method to synthesize allylamines via a [3,3] sigmatropic rearrangement. This study aims to extend the scope of enantioselective reactions catalyzed by bis(oxazoline)- metal Lewis acid complexes. The knowledge about these systems from structural and mechanistic studies of these Lewis acids by Evans provides a foundation on which to test this hypothesis. The proposal first presents acyl isocyanates as bidentate substrates that will allow the utilization of organized cationic bis(oxazoline)-copper-substrate complexes for asymmetric induction. Addition of substituted allylic ethers or thioethers to the Lewis acid activated acyl isocyanate generates a reactive intermediate bound to the chiral ligand-metal complex. The subsequent [3,3] rearrangement proceeds in a chiral environment, thus providing a chiral allylamine doubly protected as an acylcarbamate. Use of the bidentate bis(oxazoline) ligand provides chiral allylamines with the opposite stereochemistry at the newly formed center compared to the use of the tridentate pyridyl-bis(oxazoline) ligands of the same absolute configuration. The successful realization of the experiments described within will evaluate the ability of this bis(oxazoline)-metal complexes to catalyze asymmetric sigmatropic rearrangements. Information gained from these experiments will be utilized to develop new catalytic enantioselective reactions.

Professor Scheidt is developing new methods for the synthesis of heterocyclic compounds utilizing catalytic, multi-component reactions in which a transition metal complex initiates a cascade involving a metallocarbenoid and Lewis base-containing molecules. The reactive intermediate generated will be trapped by a subsequent cycloaddition reaction. Use of chiral ligand-transition metal complexes as catalysts will allow enantiocontrolled heterocyclic synthesis, while intramolecular variants will permit the rapid construction of complex polycyclic products. Professor Scheidt will develop new broad-platform molecular visualization capabilities designed to enhance classroom and Web-based learning, and he will facilitate the transfer of this technology to the high school arena through establishment of a high school teacher outreach program.

With this CAREER award, the Organic and Macromolecular Chemistry Program is supporting the teaching and research efforts of Professor Karl A. Scheidt, of the Department of Chemistry at Northwestern University. Professor Scheidt is developing novel methods for the rapid construction of complex organic structures, exploiting the unusual reactivity and versatility of metal complexes. His methods hold promise for general utility in the synthesis of the complex molecular structures often displaying important chemical or biological properties. In order to facilitate student learning about the often confusing three-dimensional structures of organic molecules, Professor Scheidt is developing versatile and accessible methods for visualization of molecular structures. He is introducing these techniques throughout the organic chemistry curriculum and is facilitating their usage in the high school setting through establishment of a high school teacher outreach program.

[unreadable] DESCRIPTION (provided by applicant): New organic reactions that employ Lewis bases (nucleophiles) as catalysts have received much less attention than the corresponding areas of Lewis acid catalysis or transition metal catalysis. However, this Lewis base strategy can access innovative and different reactivity patterns unattainable with these established catalysis approaches. The long range goals of these studies are to develop new polarity reversal reactions (Umpolung) catalyzed by Lewis bases and to uncover the fundamental interactions/characteristics that guide them. Our approach focuses on fully developing our recently discovered nucleophile-catalyzed carbonyl anion addition reaction employing acylsilanes and a-keto acids. These processes rely on the insight that acylsilanes and a-keto acids are viable carbonyl anion precursors when exposed to the correct catalytic additions. The use of acylsilanes and a-keto acids as practical acyl anion precursors avoids the potential problem of benzoin formation incurred when using aldehydes as acyl anion precursors. Furthermore, the anions generated from these precursors using achiral and chiral Lewis bases will be added to prochiral electrophiles to produce high value compounds that are immensely important in the construction of health- improving materials such as Pharmaceuticals and compounds to be used as biological probes. Additional related focuses of this proposal include the discovery and development of two related Umpolung reactions: catalytic homoenolate additions and stereoselective vinylogous carbonyl anion additions. These novel, unconventional bond-forming strategies have significant potential to efficiently access target-oriented or diversity-oriented molecules of interest. The proposed research explores the general applicability our organocatalytic carbonyl anion strategies for rapidly synthesizing molecules that directly impact human health. Each of these processes has mechanistic aspects to explore that will provide general information regarding nucleophile-catalyzed processes. In addition, a strong emphasis has been placed on the development of new Lewis base catalysts (achiral and chiral) in order to render many of our current reactions stereoselective. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): The synthesis of molecular probes, imaging agents, biomaterials, and therapeutic lead compounds always involves iterative, multi-step chemical synthesis. Consequently, research institutions engaged in small molecule discovery prepare thousands to tens of thousands of compounds each year. The pace of compound purification almost always determines the overall pace at which target compounds are evaluated in biological contexts. To address this serious bottleneck at Northwestern University (NU), we request funds to purchase a state-of-the-art high throughput (HT) liquid chromatography (LC) system. With this unique instrument, we will provide a staff-supported open-access HT system broadly useful for organic, medicinal, bioorganic, and biomaterials purifications. The integrated system combines analytical-to-preparative (A2Prep) chromatography components with elastic light scattering, diode array ultraviolet-visible, and mass spectrometry detectors. Associated robotics provide for sample preparation/ reformatting, auto sampling, and fraction collection. Agilent Technologies will provide the overall system, with a significant hardware component for the robotics being supplied to them by LEAP Technologies. The Agilent-LEAP A2Prep system will be housed in the new Richard and Barbara Silverman Hall, in the Center for Synthesis and Molecular Medicine (CESAMM), in NU's Chemistry of Life Processes Institute (CLPI). The instrument will be available to users on both the Evanston and downtown Chicago medical campuses and will be overseen by a Internal Advisory Committee composed of the investigator and three major Co-Investigators, representatives of the biology faculty and of minor users, the Directors of the CLPI and of the NU Center for Drug Discovery and Chemical Biology. Also participating ex officio will be those responsible for the technical and daily oversight of the A2Prep system, the Directors of CESAMM, NU's developing HT chemistry center, and of NU's Integrated Molecular Structure Education and Research Center (IMSERC), where related analytical experiments, including extensive LC-MS, are performed. This instrument will fuel new directions with a wide array of major NU projects such as the drug discovery relating to epilepsy and stroke, the design of metal-based imaging contrast agents and therapeutics, the synthesis of complex new anticancer natural products based on novel chemical transformations, and new treatments for Alzheimer's disease and related neurodegenerative conditions. Progress is each of these and in other important research areas is seriously limited by the current pace of compound purification. Funding for the A2Prep instrument system will allow researchers to return their focus to the true goal of their biomedical research efforts: better concepts and designs for molecules, as we seek to prepare increasingly effective diagnostic and therapeutic agents in molecular medicine. PUBLIC HEALTH RELEVANCE: The preparation of molecules to test biologically driven hypotheses to diagnose and treat diseases involves multi-step routes of chemical synthesis. This process is much like an assembly line: each intermediate compound must be purified before moving on to the next operation, eventually producing the target molecule for testing. With the many thousands of intermediate compounds produced each year at Northwestern, this purification step is a critical and labor-intensive research task. The challenges posed by compound purifications include a substantial investment of research time, thus critically curtailing the pace at which new discoveries can be made. The acquisition of a specialized purification system for the Northwestern University biomedical research community will greatly enhance the impact of existing NIH-funded projects, and fuel new molecule-focused programs that require large numbers of purified compounds. Most importantly, it will allow researchers to focus less on tedious purification and more on the design of increasingly effective diagnostic and therapeutic agents.

Investigating the chemical reactivity and biological activity of anti-tumor natural products is vital to understanding their mechanism of action and developing new therapeutics for the treatment and/or prevention of cancer. This research program aims to develop efficient synthesis of biologically active natural products possessing six-membered oxygen heterocycles through the development and subsequent application of new tactics and methodologies for organic synthesis. Strategies that generate the targeted natural products structures while providing broad solutions to synthesizing related families of compounds will be pursued. The targets selected for these investigations possess interesting and novel molecular architecture, lack significant prior synthetic studies, and have promising biological activity in the context of cancer. The planned synthetic approaches are designed to feature catalytic stereoselective pyran-forming reactions, the enantioselective synthesis of flavanones, and incorporate multiple bond forming sequences. The specific goals of this research are: (1) Synthesis of the natural products chrolactomycin and okilactomycin. These antitumor antibiotics possess a unique and highly oxygenated tricyclic core. We will use a new butenolide macrocyclization/conjugate addition approach as the key strategic sequence. (2) Total synthesis of exiguolide (3) Syntheses of flavanone natural products abyssinone II and kurarinone. We will employ a new enantioselective flavanone synthesis catalyzed by chiral thioureas for the syntheses of these compounds. (4) Evaluate all compounds in these studies for their activity against various human tumor cell lines including breast, prostate, colon, and pancreatic cancer. This last aim will be accomplished in a collaboration combining our synthetic knowledge and capabilities acquired in Aims 1-3 with two expert cancer researchers at Northwestern's Robert H. Lurie Comprehensive Cancer Center and one expert bioorganic chemist at Yale University

The principal goal of this research program is the discovery of new, unconventional reagents and their development as tools for chemical synthesis. This plan outlines a comprehensive approach to the development of new catalytic reactions using organosilicon compounds. Acylsilanes are silicon-containing small molecules that have been investigated for over 30 years due to their unusual reactivity (e.g., acyl anions), yet there remains many opportunities to exploit and utilize these unique compounds in chemical synthesis.
Silyloxyallenes are versatile compounds with significant potential in cycloadditions, tandem bond-forming sequences and group transfer reactions. By integrating the reactivity of these unique enolsilanes with tandem or subsequent reactions, the PI will be able to access important compound classes with high efficiency and minimal waste. The complementary mechanistic and target-oriented approaches driving this work allows for studies that are unique among current investigations in organosilicon and catalysis research. The group is developing sophisticated and highly versatile methods for the convergent construction of new small molecules that have broad utility.

Broader Impact: The investigation of the research goals of this proposal will simultaneously provide the undergraduate students, graduate students, postdoctoral fellows and visiting scholars working on these projects with essential experience and scientific knowledge. They will learn synthesis techniques, instrumentation analysis, organometallic chemistry, purification science, and problem solving strategies. In addition to acquiring laboratory skills, the Scheidt team has regular weekly full group meetings and daily sub-group gatherings to discuss prior results and chart new research directions. Weekly meetings include research presentations, short discussions on recent high-impact publications, and chemical problems for pedagogical growth. Overall, the individual training in the laboratory combined with small, medium and large group formats for presenting and discussing chemical topics provides for a rich, vibrant and dynamic learning environment. Additionally, there is strong participation by underrepresented groups in the laboratory which engenders a professional, dynamic and multi-ethnic work environment. Professor Scheidt will continue to organize and host the annual Chicago Organic Symposium as well as strengthen ties with institutions such as Western Michigan University and Chicago State University. This outreach component is centered on creating an interchange of ideas throughout the Department of Chemistry and between academic and industrial personnel from a variety of backgrounds and is expected to have a unique and significant impact on society.

? DESCRIPTION (provided by applicant): New selective chemical reactions are essential components to advance biology and medicine. The most powerful and efficient chemical reactions commonly use catalysis to control reactivity and selectivity. The discovery of new catalyst concepts with broad utility beyond established reactivity can greatly impact biomedical research by providing unconventional and efficient access to compounds with biological activity. The long-term goal of our catalysis research is to develop new Lewis base-catalyzed transformations with direct application to the syntheses and investigation of bioactive molecules. Our development of N-heterocyclic carbenes (NHCs) as catalysts will continue to uncover new approaches and generate important new concepts of organocatalysis. Our central hypothesis is that new discoveries in the field of carbene catalysis will significantly advance chemical synthesis, bioorganic chemistry and medicine. The specific goals of this proposal are: (1) Develop new cooperative carbene catalysis processes. N-heterocyclic carbenes (Lewis bases) have been discovered to be compatible with Lewis acids to enhance selectivity and reactivity. The combination of Lewis acids, hydrogen bond donors or transition metal complexes with NHCs will provide new opportunities for chemical synthesis; (2) explore azolium-based activation for substitution reactions; (3) investigate carbene catalysis-driven total syntheses. While there has been an explosion of new NHC catalyzed reactions, few target syntheses have employed any of these new reactions as a key step. We will use an NHC-catalyzed intramolecular Michael reaction as the key step in the synthesis of arnamial and related natural products. In addition, a trans-annular NHC-catalyzed lactone formation will be pursued as the main approach to synthesize repin, a potent cytotoxin. Our research in generating new reactivity using organocatalysis will establish new approaches for the efficient synthesis of molecules. This research will also provide important knowledge about nucleophile-catalyzed polarity reversal reactions and cooperative catalysis. These findings will ultimately lead to the development of a powerful collection of stereoselective and related strategies that are useful for medically relevant synthesis and thus further the mission of NIGMS.

DESCRIPTION (provided by applicant): This project will develop and implement a training program in neurotherapeutics discovery and development for faculty members and advanced postdoctoral fellows, centered around a 3-day short course that will provide the trainees with the various knowledge elements required to discover and advance a neurotherapeutic agent to IND. Following the short course, the training program will continue for a two-year period in which students will have individualized mentoring and assessment. The training, which is designed to be applicable to diverse diseases of the nervous system, will equip students with a broad understanding of the various component steps in the neurotherapeutics drug discovery and development process. Students will learn how to identify a good drug discovery target; how to construct an assay; the elements of medicinal chemistry; how to conduct animal efficacy testing; the principles of ADME studies, safety testing, and formulation; the principles of experimental medicine and biomarkers; the steps required to prepare an IND document and the principles for interacting with the FDA; the principles of intellectual property as they relate to neurotherapeutics discovery and development; and how to seek funding for academic drug discovery research. They will also receive training in responsible conduct of research. Students will be equipped with the skills to develop and coordinate an entire drug discovery and development effort, and to work collaboratively with experts in each of the component areas. The training will combine didactic lectures with active engagement activities in which the students will be challenged to utilize the lecture material to work through their own drug discovery project plan with the guidance of the area experts. The 3-day short course (followed by two-years of mentorship and assessment) will be offered annually, a total of five times.

In this project funded by the Chemical Catalysis Program of the Chemistry Division, Professor Karl A. Scheidt, Chemistry Department of Northwestern University, will investigate the synthesis and study of new Lewis bases as catalysts for chemical reactions. A primary focus will be on N-heterocyclic carbenes (NHCs). These Lewis bases have been developed as metal-free catalysts as well as being employed as ligands to generate chiral metal complexes. However, there is a dearth of new, chiral NHCs and there have been few mechanistic investigations of NHC-catalyzed processes. This project will focus on the development of new families of chiral NHCs as ligands and catalysts. The different phases of the investigation include a) synthesis and characterization of new classes of chiral N-heterocyclic carbenes and the evaluation/benchmarking of these NHCs in established catalytic processes, b) exploring/validating carbene catalysis mechanisms, and c) studies geared towards understanding the structure reactivity relationships of new catalysts for the purpose of predicting and controlling the outcome of Lewis base processes. These advances will ultimately expedite the ability to synthesize natural products, pharmaceuticals and fine chemicals with maximum efficiency and minimal impact on the environment.

The development of new catalysts that promote high value reactions is a crucial enterprise that impacts a wide range of scientific endeavors with biological and pharmacological endpoints. The investigations to be carried out on this project will advance our knowledge of Lewis base and metal catalysis, as well as structure reactivity relationships that are the foundation of modern chemical science. These studies provide training for s diverse set of students and postdoctoral fellows. The expected skills acquired by graduate and undergraduate students driving these projects include advanced problem solving, chemical synthesis, and mechanistic organic chemistry/catalysis.

? DESCRIPTION (provided by applicant): Metastatic prostate cancer is not curable, and mortality primarily results from the development of distant metastases. Similarly, over 80% of deaths across all cancer types stem from the formation of metastases, and therefore effective anti-metastatic treatments would have enormous clinical benefit. Unfortunately, therapeutic approaches have been limited by a lack of potent and selective molecules targeting the underlying molecular processes that regulate metastasis. Using genetic and chemical methods in mouse and man, we have identified MAP2K4 as a key regulator of metastasis. The goal of this proposal is to identify and characterize selective MAP2K4 inhibitors that would serve as probes to validate the role of this kinase in an array of invasive cancer disease models. In preliminary work, we developed a functional kinase assay for HTS (Z' 0.58) and performed a pilot screen confirming our ability to identify MAP2K4 inhibitors (1.1% hit rate). We have also developed orthogonal biochemical and cellular assays to characterize the selectivity, mechanism, and anti-metastatic potential of HTS hits. Through this proposal we will: 1) Screen a library of 190,000 diverse compounds to identify functional MAP2K4 inhibitors; 2) Confirm MAP2K4 inhibition and selectivity using biochemical assays and validate promising hit scaffolds through analog synthesis; and 3) evaluate cellular activity of hits to determine potency, selectivity, and anti-metastatic properties. We predict that our integrative approach will enable discovery of new MAP2K4 inhibitors, which will provide the biological community with tools to evaluate the role of metastasis in a range of disease models. Furthermore, such molecules will serve as a starting point in future lead optimization studies to create anti- metastatic clinical candidates.

Project Summary/Abstract This project will develop and implement a training program in neurotherapeutics discovery and development for faculty members and advanced postdoctoral fellows, centered around a 3½-day short course that will provide the trainees with the various knowledge elements required to discover and advance a neurotherapeutic agent to IND. Following the short course, the training program will continue for a two-year period in which students will have individualized mentoring and assessment. The training, which is designed to be applicable to diverse diseases of the nervous system, will equip students with a broad understanding of the various component steps in the neurotherapeutics drug discovery and development process. Students will learn how to identify a good drug discovery target; how to construct an assay; the elements of medicinal chemistry; how to conduct animal efficacy testing; the principles of ADME studies, safety testing, and formulation; the principles of experimental medicine and biomarkers; the steps required to prepare an IND document and the principles for interacting with the FDA; the principles of intellectual property as they relate to neurotherapeutics discovery and development; and how to seek funding for academic drug discovery research. They will also receive training in responsible conduct of research. Students will be equipped with the skills to develop and coordinate an entire drug discovery and development effort, and to work collaboratively with experts in each of the component areas. The training will combine didactic lectures with active engagement activities in which the students will be challenged to utilize the lecture material to work through their own drug discovery project plan with the guidance of the area experts. The 3½-day short course (followed by two-years of mentorship and assessment) will be offered annually, a total of five times.

? DESCRIPTION (provided by applicant): New selective chemical reactions are essential components to advance biology and medicine. The most powerful and efficient chemical reactions commonly use catalysis to control reactivity and selectivity. The discovery of new catalyst concepts with broad utility beyond established reactivity can greatly impact biomedical research by providing unconventional and efficient access to compounds with biological activity. The long-term goal of our catalysis research is to develop new Lewis base-catalyzed transformations with direct application to the syntheses and investigation of bioactive molecules. Our development of N-heterocyclic carbenes (NHCs) as catalysts will continue to uncover new approaches and generate important new concepts of organocatalysis. Our central hypothesis is that new discoveries in the field of carbene catalysis will significantly advance chemical synthesis, bioorganic chemistry and medicine. The specific goals of this proposal are: (1) Develop new cooperative carbene catalysis processes. N-heterocyclic carbenes (Lewis bases) have been discovered to be compatible with Lewis acids to enhance selectivity and reactivity. The combination of Lewis acids, hydrogen bond donors or transition metal complexes with NHCs will provide new opportunities for chemical synthesis; (2) explore azolium-based activation for substitution reactions; (3) investigate carbene catalysis-driven total syntheses. While there has been an explosion of new NHC catalyzed reactions, few target syntheses have employed any of these new reactions as a key step. We will use an NHC-catalyzed intramolecular Michael reaction as the key step in the synthesis of arnamial and related natural products. In addition, a trans-annular NHC-catalyzed lactone formation will be pursued as the main approach to synthesize repin, a potent cytotoxin. Our research in generating new reactivity using organocatalysis will establish new approaches for the efficient synthesis of molecules. This research will also provide important knowledge about nucleophile-catalyzed polarity reversal reactions and cooperative catalysis. These findings will ultimately lead to the development of a powerful collection of stereoselective and related strategies that are useful for medically relevant synthesis and thus further the mission of NIGMS.

ABSTRACT ? MEDICINAL AND SYNTHETIC CHEMISTRY CORE The Medicinal and Synthetic Chemistry Core (ChemCore) is a shared resource facility that provides chemistry services to enable translational programs to advance small molecule candidates from chemical biology to drug discovery. ChemCore supports investigators of the Robert H. Lurie Comprehensive Cancer Center (LCC), Northwestern University, and external organizations by providing advanced cheminformatics and chemical synthesis services. Cheminformatics utilizes many techniques and tools to perform computational chemistry, molecular modeling, and computer-aided drug design techniques. This service provides investigators with unique insights into the design of molecules that are active in cancer biology and guides the selection of candidates that can be synthesized and evaluated for their biological activities. Chemical synthesis provides researchers with access to high-level resources for the custom synthesis of molecular probes and tools, compounds, hit-to-lead chemistry, lead optimization medicinal chemistry, and consulting on drug discovery projects. The ChemCore?s scientific team consists of PhD-level staff chemists with significant experience in pharmaceutical drug discovery. The facility is equipped with modern medicinal chemistry equipment and advanced computational and visualization resources that enable industry-level projects spanning early stages of drug discovery through lead optimization. The daily interaction of computational and medicinal chemists with cancer biologists and clinicians is an essential feature of the core that has contributed to the success of translational projects at the LCC. We have engaged LCC investigators to forge new interdisciplinary research projects and pursue molecular medicine opportunities. During the current funding period, 47 LCC members utilized ChemCore services to investigate the interactions between small molecules and biological systems. We have synthesized and tested more than 1,000 new compounds for nearly 30 different cancer therapeutic projects. ChemCore works closely with several other LCC-supported cores, particularly with the High Throughput Analysis Laboratory (to identify ?hits? via high throughput screening campaigns) and the Developmental Therapeutics Core (to evaluate small molecule candidates in appropriate animal models). The long range goal of ChemCore is to serve as one of the principle conduits by which LCC investigators translate their basic research into new therapeutics.

PROJECT SUMMARY TO OVERALL COMPONENT Despite recent discoveries that explain the molecular pathogenesis of a number of kidney diseases, new therapies have been slow to emerge. With a staggering 30 million Americans suffering from kidney diseases, there is an urgent unmet need to facilitate development of new treatments. The overall theme of the proposed Northwestern George M. O?Brien Kidney Core Center named NU-GoKIDNEY, will focus on Kidney Therapeutics ? to translate discoveries into prevention, treatment and cures. To realize this objective, requires extensive and productive collaborations between multiple scientific and clinical disciplines that do not traditionally interact. Our Center will unite investigators across three Cores: the Pre-Clinical Models Core (Core A), the Therapeutics Development Core (Core B) and the Clinical and Translational Core (Core C). The Center will nucleate unique, unparalleled talent available at Northwestern University to accomplish this goal, including: 1) an exceptional group of interdisciplinary kidney researchers; 2) large collection of relevant animal models and cell lines; 3) a world-leading nanomedicine institute; 4) an innovative and world-class chemistry department devoted to drug discovery; 5) world-leading bio-electronics expertise; 6) a renowned team of experts in pharmacogenomics and pharmacology; 7) a high level Good Manufacturing Practices (GMP) production facility developed by one of the core directors; 8) an electronic data warehouse comprising 6.7M individual patients linked to genomic data; 9) large biorepository of renal specimens; 10) expertise and infrastructure to conduct first-in-human studies; 11) track record of community engagement in the conduct of research and 12) an Innovation and New Ventures office (INVO). In addition to the establishment of the three biomedical cores, the NU-GoKIDNEY Center will support innovative Enrichment programs and Pilot and Feasibility studies designed to enhance cross-disciplinary collaborations, attract new investigators into the kidney diseases field and train the next generation of kidney innovators. An online portal nephro-HUB will provide access to these unique NU resources - for the first time - to the outside world and a Kidney Cure Accelerator will be launched to promote therapeutic innovation and catalyse translation within Northwestern and across the Chicagoland, national and international kidney communities.

PROJECT SUMMARY Natural products continue to be excellent and productive sources of new drug candidates or lead compounds for treatment of neurological disease. This proposal focuses on the synthesis and biological characterization of promising new small molecules known as mellpaladines, which are marine natural products that exhibit specificity for the 5-HT (serotonin) family of G protein-coupled receptors (GPCRs). Serotonin receptors have been successfully targeted for therapeutic treatment of a variety of neurological and non-CNS pathologies. However, the effective assessment of the clinical relevance of several 5-HT receptor family members is stalled due to lack of selective pharmacological tools. To this end, we propose development of mellpaladines A and B, which are antagonists of 5-HT5A and 5-HT7 receptors, to fulfill this role. Our long-term objective is to develop mellpaladines A/B and natural and synthetic analogs as novel pharmacological tools for characterization of 5- HT receptors, and explore their potential as new therapeutic candidates in neuropsychiatric disease. This high risk, high reward project will support a key first step in this process: synthesis of the molecule and initial validation of CNS activity. This proposal brings together the complementary natural products chemistry and neuropharmacological expertise of the Scheidt and Swanson laboratories, respectively, at Northwestern University. The objectives will be to: (1) synthesize and validate the structural assignment of mellpaladines A and B, and (2) validate and optimize interspecies functional inhibition against 5-HT5A/7 receptors. This project will yield novel chemical tools for the pharmacological manipulation of serotonin receptors and may lead to new therapeutic strategies for neurological disease.

Project Summary Advances in 21st century medicine have greatly impacted society, but a serious need persists for new therapeutics that either exploit known biological processes or possess novel mechanisms of action. The development of new, relevant, and selective chemical methodology to drive the investigation of the reactivity and biological activity of natural products and related probes is vital to understanding their mechanism of action and developing new therapeutics for the treatment and/or prevention of disease. A primary goal of our research program is to discover and develop new catalytic, stereoselective reactions that facilitate the efficient construction of heterocyclic targets. The new methods advanced in this proposal have a) significant and highly encouraging preliminary results, and b) been inspired by natural products that will subsequently facilitate the efficient construction of these targets and potential applications towards clinical endpoints. The innovative catalytic tactics we are pursuing should facilitate investigations of biological processes relevant to the discovery of new potential therapies and strategies that generate the targeted natural products structures while providing broad solutions to synthesizing related families of compounds. The specific goals of this research are: a) the exploration of new, stereoselective catalytic carbocation-driven transformations, b) the exploration of new calcium-catalyzed amine conjugate additions, and c) the development of Lewis acid-catalyzed ?-Umpolung type radical reactions. We anticipate that these research activities will fundamentally advance human health by providing innovative tactics and strategies to access many important classes of health relevant compounds.

Project Summary Advances in 21st century medicine have greatly impacted society, but a serious need persists for new therapeutics that either exploit known biological processes or possess novel mechanisms of action. The development of new, selective, and enabling chemical methodology to drive the rapid investigation of the reactivity and biological activity of natural products and related probes is vital to understanding their mechanism of action and developing new therapeutics for the treatment and/or prevention of disease. A primary goal of our research program is to discover and develop new cooperative catalytic, stereoselective transformations that facilitate the highly efficient construction of valuable materials. The new methods advanced in this proposal have a) significant and highly encouraging preliminary results, and b) been inspired by bioactive molecules/natural products that will subsequently facilitate the efficient construction of these targets and potential applications towards clinical endpoints. The innovative cooperative catalytic strategies we are pursuing will power investigations of biological processes relevant to the discovery of new potential therapies and strategies that generate the targeted bioactive molecules while providing broad solutions to synthesizing related families of compounds. The specific goals of this research are: a) the exploration of new, cooperative carbene catalyzed processes, b) the development of stereoselective catalytic carbocation-driven transformations, c) the investigation of Lewis acid-catalyzed ?-Umpolung type radical reactions, and d) the merger of photocatalytically-generated reactivity with biocatalysis. We anticipate that these research activities will fundamentally advance human health by providing innovative tactics and strategies to access many important classes of health relevant compounds.

PROJECT SUMMARY Telomerase has attracted significant attention as a potential target for understanding the aging process and for the treatment of cancer, since telomeres and telomerase have important roles in the transformation and survival of cancer cells. Previous prevailing strategies for targeting telomerase were based on the assumption that in cancer cells, telomere-length maintenance was the sole pro-survival function of this assembly. However, increasingly evidence strongly indicates that a) inhibition of the telomere-lengthening activity of telomerase is not a magic bullet treatment for cancer, and b) there is a much larger role for telomerase in key cellular pathways and these functions are not well understood. Although there have been promising clinical candidates among telomerase inhibitors, the translation of telomerase-targeted therapies to the clinic remains elusive and frustratingly slow. This lack of progress is due in part to the growing list of unanswered questions surrounding telomerase and its role in cancer biology; notably, that hTERT has non-canonical functions separate from its telomere-lengthening activity that are linked to cancer cell survival. This proposal builds on the collaboration between the Scheidt and Kron research groups to bring our expertise in chemical synthesis and cancer biology to bear on key gaps in the knowledge surrounding hTERT, its non-canonical functions, and its involvement in cancer cell survival. We have discovered that small molecules based on the natural product chrolactomycin inhibit telomerase and provide a unique platform for probe development. Based on robust chemical and biological results, we propose to first develop enhanced small molecule probes with improved efficacy. These compounds will enable precise covalent modification of hTERT catalytic function without perturbing the overall complex assembly. The following Aims will focus on exploring the use of these new tools to explore the role(s) of telomerase in DNA damage repair and cell senescence through in-depth analysis of multiple functions of telomerase as a buffer of cell stress and determinant of cell immortality. The long-term goal of this project is to understand and leverage the molecular basis for how these natural product-based molecular tools impact the telomere lengthening and most importantly, non-canonical functions of hTERT. Ultimately, this new knowledge will drive the development of new understanding of telomerase and its biological roles.

PROJECT SUMMARY Natural products are unique sources of new lead compounds for the understanding and ultimate treatment of neurological disease. This proposal focuses on the synthesis and biological characterization of promising new small molecules based on the privileged yohimbine alkaloid scaffold. While these complex natural product alkaloids have been academic targets for synthesis over multiple decades, there is still a surprising lack of efficient, <10 step routes to provide new analogs of these classes of compounds containing high degrees of stereochemical information. Consequently, this dearth has limited the exploration of many yohimbine classes in discovery-based screening of CNS targets and represents a major gap in the knowledge. This high risk, high reward project will support both target and focused library synthesis of new privileged molecules and initial screening/validation of CNS activity in collaboration with a GPCR expert. This proposal brings together the complementary natural products chemistry and neuropharmacological expertise of the Scheidt and McCorvy laboratories. The objectives will be to: (1) synthesize mitragynine to establish the shortest route yet to this compound, and (2) create new mitragynine and yohimbine-like compounds and explore their potential as agonists and/or antagonists in CNS biology. This project will yield novel chemical tools for the pharmacological manipulation of CNS receptors and may lead to new therapeutic strategies for pain management and neurological diseases.

The Center for ChemoEnzymatic Synthesis (C-CES) is supported by the Centers for Chemical Innovation (CCI) Program in the Division of Chemistry. Enzymes are proteins that control and catalyze chemical reactions essential for life. Nature’s ability to employ these highly evolved biological catalysts to generate diverse and complex molecules through selective reactions has inspired chemists for decades and has led to the field of biocatalysis. The potential societal impacts of biocatalysis are significant, yet chemists have only recently begun to leverage these efficient and selective natural processes. C-CES seeks to develop unprecedented transformations and achieve new selectivity strategies by applying novel concepts in biocatalysis to sustainable making of chemicals, which are referred to as chemoenzymatic synthesis. These advances will allow the scientific community to address 21st-century challenges in the production of new medicines and materials. The broader impacts of the Center will focus on convergent, interdisciplinary education of early career scientists in chemoenzymatic synthesis, team building, and communication, all which will build the foundation for their independent careers. The Center will be at the forefront of developing and disseminating resources to integrate biocatalysis into broad practice across university and industrial settings, as well as in chemistry courses and laboratories. Finally, the Center will build up existing institutional resources of each team member to recruit, engage, and educate individuals from underrepresented groups, thereby broadening the impact of chemoenzymatic synthesis. <br/><br/>C-CES will drive an unexplored frontier of organic synthesis by enabling new discoveries in biocatalysis and chemoenzymatic synthesis. The Center will focus on the grand challenge of creating new selective reactions for carbon-carbon and carbon-heteroatom bond formation in a sustainable manner by combining biocatalytic and bioinspired transformations with established chemical synthesis methodologies. Center activities will integrate fundamental concepts and past success of small molecule catalysis with the unique advantages of efficiency and selectivity control available through supramolecular protein-based catalysts. The Center will bring together internationally recognized scientists with complementary areas of expertise in catalysis, organic synthesis, chemoenzymatic synthesis, machine learning, high-throughput experimentation, protein engineering and biocatalysis. The two initial goals of the Center are the biocatalytic formation of high value C–C and C–X bonds and controlling selectivity outcomes currently unobtainable through conventional strategies. The realization of these efforts will be driven by a collaborative and convergent approach to experimental research and student training that combines state-of-the-art strategies for reaction development and biocatalyst design with machine learning and retrosynthesis planning. The Center will oversee coordinated training activities to ensure C-CES participants acquire diverse knowledge and techniques needed to master and then utilize biocatalysis in synthesis. The main broader impacts of this award include: a) the development of biocatalysis workshops to train future scientists on practical strategies and approach to chemoenzymatic synthesis; b) curriculum development around biocatalysis concepts for the broader chemical community; and c) public engagement regarding the sustainable applications of chemoenzymatic synthesis to access innovative materials that impact our everyday lives.<br/><br/>This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.