Most of the natural product targets have been identified by our group for their interesting molecular architecture, but also for their important biological activity. We are developing core strengths in the areas of biomedical and health-related research, which has been enhanced by the number of incoming collaborative opportunities with The Scripps Research Institute, Torrey Pines Institute for Molecular Studies, the Max Planck Florida Institute, and the Harbor Branch Oceanographic Institute, all in the proximity of FAU campuses.
Up to date the first collection of bioactive drug-like molecules (over 50 compounds prepared) was sent for biological testing at McGill University, Eli Lilly (Open Innovation Program) and at the NIH during the summer 2013.
Network of collaborators for Biological testing
Professor Pelletier at McGill University (Canada) is involved in protein synthesis inhibition (eIf4A) related to novel strategies against cancer.
Professor Inglese, Director of NIH center NCATS is involved in drug discovery for rare diseases.
Dr. Ken Dawson-Skully at FAU is involved in small-molecule library screening and behavioral assays on drosophila in relation with neuroprotection.
Dr. Dmitriy Minond at Torrey pines is involved in small-molecule library screening against cancer and metalloprotein inhibitors.
Dr. Minond is a biochemist studying Metalloproteinases and mechanism of actions of small drug-like molecules in proteins interactions and metalloprotein inhibitors. He worked previously at The Scripps Research Institute as a post doctoral associate under Professor Peter S. Hodder. In 2009 he was promoted to a Senior Scientist position. Dr. Minond is currently at the Torrey Pines Institute as an Assistant Member and he is helping us in testing our library of azapodophyllotoxins to refine the most active and selective compounds against human leukemia (over 50 compounds tested).
We initiated a biological screening program, with Professor Jerry Pelletier (McGill University, Canada) targeting anticancer agents which may inhibit protein translation.
Professor Pelletier is particularly interested in small molecule ligands, acting as translation inhibitors to provide novel insight into the complexity of eukaryotic translation. One of his research programs is aimed at identifying inhibitors of mammalian translation, elucidating their mode of action, and characterizing their molecular targets.
Professor Pelletier’s laboratory has screened over 250,000 compounds for chemical inhibitors that specifically target the translation initiation phase under regulation of mTOR signalling and has identified and characterized several novel translation initiation and elongation inhibitors.
We recently launched a medicinal chemistry program on azapodophyllotoxin analogues for novel chemoprevention of invasive cancers. The advent of the synthetic strategy “one pot synthesis of the azapodophyllotoxin core structure” will enable the expedient preparation of a large collection of ‘natural product-like’ compounds bearing a known privileged scaffold. These compounds have also been evaluated for their biological activity and selectivity through collaboration with Dr. James Inglese, associate Investigator within the National Human Genome Research Institute (NCGC).
Dr. Inglese is currently leading a new effort in the development of assays for rare and neglected disease and their subsequent profiling in novel chemical libraries at the NCATS using high throughput techniques for the development of novel assay technologies and small molecule discovery processes. Identification of active compounds such as azapodophyllotoxins displaying selectivity for the Charcot–Marie–Tooth disease with novel chemical chemotypes will be of great utility for the discovery of molecular targets affecting the viability of this disease.
Network of collaborators for Chemical Methodology Advancement
Professor Jacobsen, Chair of the Chemistry Department at Harvard University, is involved in the asymmetric synthesis of non-proteinogenic amino acids.
Dr. Adam Alty, Director of R&D at Synquest (Florida) is involved in developing new reagents for a de novo peptide coupling method using protecting group free amino acids.
Professor West, on studying possible biosynthetic pathways of briareolate esters natural products.
Professor Terentis, starting a collaboration to synthesize tryptophan analogues as mechanism probes in the study of IDO.
One of the best surprises since we started off our research program came from our project on peptide coupling discovery. A single operation for Protection, Activation and Dehydration was discovered to produce α-amino acid building blocks ready to be utilized in a “click” type of peptidic coupling. All the stereo-information is preserved in these new building blocks which required nothing else than another α-amino ester partner to generate the Holly peptidic bonds. In this adventure we are pleased to collaborate closely with the local industry in the name of SynQuest Laboratories. SynQuest’ scientists are helping us developing new perfluorinated chemicals for our specific needs in term of peptidic activation, while advising us in term of fluorine chemistry. At SynQuest, chemists use many complex manufacturing processes in the course of manufacturing over 5,000 chemicals, they are experts at handling hazardous chemicals, providing a strong range of technologies and processes and manufacturing options. Processes are tested prior to production batches to ensure the customers specifications and regulatory requirements are met and on-time.
Professor E. N. Jacobsen moved to Harvard University as full professor in the summer of 1993, and he was named the Sheldon Emory Professor of Organic Chemistry in 2001. He directs a research group of 20-25 graduate students and postdocs at Harvard. He is the Chair of the Department of Chemistry and Chemical Biology and a consultant at Merck, Amgen, Cubist, Firmenich, and PTC Pharmaceuticals. Eric Jacobsen’s research interests lie in the discovery, mechanistic elucidation, and application of new reactions, with special emphasis on asymmetric catalytic processes. Through the development of chiral Schiff base complexes of main group and first row transition metals and of novel urea and thiourea catalysts, Jacobsen has uncovered effective and – in certain cases – highly practical methods for enantioselective catalytic oxidation, hydrolytic, and carbon-carbon bond-forming reactions. Several of the reactions he has devised have been applied successfully, both within his lab and in other academic or industrial settings, to important natural products and pharmaceuticals.
Our research groups embarked together on a collaboration merging total synthesis and enantioselective catalysis to establish new chiral methods for the synthesis of non-proteinogenic α-amino acids (Xaas) incorporated into intricate natural products. We first uncovered a new and highly practical method for accessing a glyoxylate iminium precursor and effecting enantioselective catalytic additions to access α-substituted Xaas with high enantioselectivity. We are currently working to extend this strategy to aryl nucleophiles and ketoiminium precursors for the synthesis of α-arylated and α,α-disubstituted Xaas. In particular, this collaborative effort will aim to 1) enhance the scope and mechanistic understanding of the anion-binding mode of activation applicable to Xaa synthesis, and 2) facilitate a rapid entry to unusual chiral non-proteinogenic Xaas, and 3) apply the new methodologies as the basis for the synthesis of complex, bioactive amino acid derivatives, with a central focus on achieving expedient enantioselective total syntheses campaigns of (+)-sorbicillactone A (1) and (−)-fumimycin (2), natural products with important biological activity against cancer and bacterial infections.