Precise Formation of concise G-Octamer for Construction of Noncovalent and Covalent “Molecular Cube” with enhanced stability
Ying He, Yanbin Zhang, Xiaodong Shi
University of South Florida
Both non-covalent and covalent “molecular cube” was constructed through self-assembly of designated guanosine derivatives, which were characterized by X-ray, NMR and MS. The key design was the analysis of the key steric factors that control G-quartet stacking. With the introduction of 8-aryl and sterically hindered protecting group on ribose, interdigitation of sugar between G-quartet layers was prevented successfully and a concise, discrete self-assembled guanosine octamer was achieved with enhanced stability and unique property on Rb+ recognition.
Unleashing bacterial biosynthetic pathways to expand diketopiperazine chemical diversity
Amy L. Lane
University of North Florida
Natural products with 2,5-diketopiperazine (DKP) scaffolds offer a broad range of bioactivities and chemical structures. The functional and structural diversity of these cyclodipeptides arises via enzyme-catalyzed construction from a variety of amino acids as well as tailoring of DKP cores. For many years, nonribosomal peptide synthetases (NRPSs) were the only enzymes recognized as catalysts for DKP assembly. Cyclodipeptide synthases (CDPSs), employing two aminoacyl-tRNAs as substrates for DKP assembly, were first reported in 2009. Aminoacyl-tRNAs are uncommon players in natural product assembly, making CDPSs intriguing members of Nature’s biosynthetic repertoire. Biochemical and bioinformatics analyses support that CDPSs are found from at least six bacterial phyla and some animals, yet biosynthetic pathways with CDPSs remain understudied relative to pathways featuring NRPSs or other common biosynthetic enzymes. Through studies of bacterial pathways that include CDPSs, my group has unveiled novel biosynthetic capabilities and developed tools for the engineered biosynthesis of DKPs. This presentation will highlight our strategies for the characterization of these pathways to discover uniquely functionalized DKPs and our development of a platform for the CDPS-catalyzed assembly of novel DKPs from unnatural aminoacyl-tRNA precursors. Our results establish the catalytic promise of CDPSs beyond natural cellular aminoacyl-tRNAs, and showcase the utility of biosynthetic strategies for expanding the breadth of chemical space provided natural products.
Development of a practical synthesis of THC and CBD enabling access to novel analogs
Zachary Shultz, James Leahy
University of South Florida, Department of Chemistry
Medicinal use of the cannabis plant dates back to 2700 BC in ancient China. We now have an understanding of the chemical profile of these plants and what molecules are responsible for their observed therapeutic effects. Δ9 Tetrahydrocannabinol (THC) and cannabidiol (CBD) have been identified as the main cannabinoids that contribute to the myriad of effects such as anti-parasitic, antibacterial, analgesic and anti-anxiety effects. It has been recently discovered that these natural derived cannabinoids may play a role in Alzheimer’s disease by disrupting the formation of β-amyloid plaques. Our interest is to probe the therapeutic potential of this class of compounds and to this end we developed a practical modular synthesis of the cannabinoids. A chemoenzymatic approach to access a chiral building block used to control the stereochemistry found in the cannabinoids was successfully employed. This route allows for a scalable and efficient platform for analog development of both natural and unnatural cannabinoid isomers.
Standardizing Complex Terpenoid Synthesis
Alexander J. Grenning
University of Florida
Complex terpenoid natural product synthesis is challenged by scalability, reproducibility, and efficiency (time and yield). My lab aims to develop a chemical strategy to standardize complex cycloheptane synthesis from malonic acid derivatives, ketones/aldehydes, and two different allylic electrophiles. The strategy to be developed is comprised of an operationally simple sequence (2 – 5 steps) to couple the starting materials together yielding the key advanced scaffolds for target (and target-analog) synthesis.1-3
Much like how cross-coupling standardized how biaryl-targets are prepared, we hope to revolutionize how cycloheptane-targets are accessed via standardization. Our route allows for facile recognition of starting materials (retrosynthesis) and efficient synthesis of complex targets. This overall goal also requires significant methodological advancement in the realms of allylic alkylation, [3,3] sigmatropic rearrangements, and malonic acid functional group interconversion.
At the FAME 2018 meeting, I will present an overview of this approach and key recent findings related to new metholodgy and our progress towards various terpenoid natural products.
Representative published work:
(1) Lahtigui, O.; Emmetiere, F.; Zhang, W.; Toledo-Roy, S.; Jirmo, L.; Hershberger, J.; Macho, J.; and Grenning, A. J. “Assembly of Terpenoid Cores by a Simple, Tunable Strategy.” Angew. Chem. Int. Ed. 2016, 55, 15792 –15796.
(2) Fereyduni, E.; Grenning, A. J.; “Factors Governing and Application of the Cope Rearrangement of 3,3-Dicyano-1,5-dienes and Related Studies.” Org. Lett. 2017, 19, 4130.
(3) Scott, S.; Grenning, A. J.; “An Enyne Cope Rearrangement Enables Polycycloalkane Synthesis from Abundant Starting Materials by a Simple Strategy.” Angew. Chem. Int. Ed. 2017, 56, 8125
Ring Distortion of Vincamine Leads to Intriguing Biological Discoveries
Verrill M. Norwood IV and Robert W. Huigens III
Department of Medicinal Chemistry; Center for Natural Products, Drug Discovery and Development (CNPD3); College of Pharmacy, University of Florida
Despite the rich history of natural products as sources of bioactive molecules, the 1990s saw a paradigm shift away from natural products and toward the screening of collections of synthetic compounds (i.e. High-Throughput Screening (HTS)). This shift is due to many factors, including the increasing difficulty of identifying new natural products, the ease of sp2-sp2 coupling reactions, and the rise of combinatorial and parallel synthesis methodology used to rapidly generate large compound libraries. Consequently, current drug screening libraries are highly populated with flat (e.g. sp2 hybridized) molecules. These screening libraries have been effective at targeting protein targets with flat binding pockets (e.g. protein kinases), but ineffective against more complex biological targets (e.g. protein-protein interactions). An indole-based ring distortion approach was used to address this current lack of complexity. Commercially available indole containing natural products (NPs) are used to create diverse screening libraries. Herein we report this indole-based method executed on the NP vincamine to yield a library of >100 highly complex small molecules, which are being screened for biological activities. Progress related to both the chemistry and biology of vincamine ring distorted compounds will be presented at this talk.
Photoassisted synthesis of complex molecular motifs
James H. Frederich
Florida State University
The strategic use of photochemical reactions in chemical synthesis offers a powerful avenue to build complexity. Herein, we report our recent efforts to harness photoinduced ring-opening reactions of pyridazine N-oxides to access natural product frameworks.