Unusual Magnetic Behavior of σ-Dimerizing Organic Radicals
Alina Dragulescu-Andrasi, Hoa Phan, Xiang Li, Yan-Yan Hu, Eugene DePrince, Minyoung Jo, Michael Shatruk
Florida State University, Department of Chemistry and Biochemistry
Many stable organic radicals are well-known to undergo Peierls dimerization in their π-π stacked solid-state structures. Recently, we demonstrated that certain π-radicals, which σ-dimerize upon cooling, can undergo light-induced splitting into the pair of π-radicals in the solid state. The photo-generated paramagnetic structure exhibits remarkable thermal stability, which allows one to interrogated its physical properties using conventional static methods, such as X-ray crystallography, UV-visible spectroscopy, or magnetometry. In this contribution, we report another unconventional phenomenon that leads to abrupt and hysteretic switching between paramagnetic π-radical and diamagnetic σ-dimer states. The switching effect is based on the transition between the plastic-crystal phase with dynamic rotational disorder and a normal crystalline phase in the dimerized form. A comprehensive investigation of this phenomenon with experimental and theoretical methods will be reported.
Ring Distortion of Complex Indole Alkaloids: Reengineering Biological Activity to Address New Disease Areas
Prof. Robert W. Huigens III
University of Florida
Various natural products, such as taxol, morphine and vancomycin, play a prominent role in medicine due to their ability to modulate biological targets critical to human disease. Current drug discovery efforts have shifted away from natural products and to the screening of large collections of compound libraries composed of structurally simple organic molecules. Despite their success against certain biological targets (e.g., kinases), these compound libraries have failed to produce viable leads in certain disease areas (e.g., antibiotics) which have been attributed to a lack of chemical diversity. Our lab aims to address deficiencies in chemical diversity through the development of a unified ring distortion approach targeting available, indole alkaloids as starting points for the rapid generation of an array of diverse complex scaffolds for biological screening in drug discovery. We recently reported a new tryptoline ring distortion approach from yohimbine, an indole alkaloid with a complex fused ring system. In addition, we have utilized vinamine to produce novel complex small molecule scaffolds for drug discovery. Combined, our group has synthesized a library of >200 complex and diverse small molecules using short synthetic sequences and screening campaigns are underway. From these efforts, multiple hit compounds have been identified from various biological screens in diverse disease areas which will be presented during this talk.
A submonomer-based approach towards piperazic acid (Piz) natural products. The total synthesis of L-156,373
Yassin M. Elbatrawi, Chang Won Kang and J. R. Del Valle*
Department of Chemistry, University of South Florida, Tampa, FL 33620, USA
The piperazic acid (Piz) residue is found in a number of biologically active natural products and there exist numerous methods for its synthesis and incorporation into host peptides. Most approaches introduce pre-formed orthogonally protected Piz residues, synthesized in many steps, onto a growing peptide chain. L-156,373, a cyclic hexapeptide and oxytocin antagonist isolated from Streptomyces silvensis, features two consecutive enantiomeric forms of the Piz residue. Here, we present the first total synthesis of L-156,373 and its analogues via a sub-monomer-based electrophilic amination approach. Our strategy relies on a tandem SN2 cyclization to afford both Piz residues in one step and employs l- and d- glutamic acid residues as chiral synthons. This approach provides a means to introduce Piz and δ-oxo piperazic acid (oxoPiz) residues into host peptides using readily available amino acid building blocks.
Anti-infective and Neurodegenerative Drug Discovery – Something Old, Something New…
James W. Leahy
University of South Florida
Recent results from our efforts aimed at the discovery of anti-infective and neurodegenerative results will be discussed. Included in these will be both novel compounds and the discovery of a well-known agent that might be exploited for its activity in both areas.
Investigations in Organobarium Chemistry: Synthesis of 3,4-dihydroxyphenylacetaldehyde (DOPAL): a Potential Target for Neuroprotective Therapy in Parkinson's Disease.
Ralph N. Salvatore*, Nicholas Schofield, Jacob R. Hobby, Josue F. Deslauriers, and Tori Scheffler
Department of Natural Scienes
1000 Longfellow Blvd
Lakeland, FL 33801
3,4-dihydroxyphenylacetaldehyde (DOPAL), an important biogenic aldehyde, serves as a critical endogenous toxin which triggers dopamine (DA) neuron loss in Parkinson’s disease (PD). Despite the immense biochemical significance of DOPAL, attempts to synthesize this compound in pure form have been met with grave difficulty. In fact, most methods lack detailed experimental procedures, full characterization, and suffer from extremely low product yield (~4%). Therefore, considerable effort to produce DOPAL in a higher yield would be clearly warranted. In an effort to mitigate these problems, we have directed our attention toward a more efficient synthesis of DOPAL using organobarium reagents. These novel reagents, standardized against various carbon-carbon bond forming reactions fundamental to organic synthesis, were then applied toward the total synthesis of DOPAL. These studies may provide important insight on future drug action to combat PD and, when the scope of this research is expanded, may aid in the treatment of other neurodegenerative disorders.
Sigma Receptor Ligands: From Discovery to Clinical Translation
Christopher R. McCurdy
Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, Florida, USA 32610
Peripheral nerve injury, as a consequence of trauma, surgery, inflammation, or other causes, is a major medical problem. This type of injury is often associated with chronic pain. About 100 million people suffer from chronic pain in the United States alone. Diagnosis and treatment are still considered as unmet medical needs. Current clinical imaging methods used to evaluate chronic pain are centered on anatomic alterations, which do not necessarily reflect the origin of chronic pain. A potential biomarker associated with nerve injury and neuroinflammation is the sigma-1 receptor (S1R). In addition, S1Rs appear to play an active role in pain modulation, both peripherally and centrally. We recently identified a highly selective S1R antagonist that was transformed into a PET probe candidate and demonstrated high specificity and selectivity for imaging S1Rs in mice, rats, and monkeys. We have utilized this probe in a rat model of nerve injury via PET/MRI. The results have helped promote the clinical use of the agent in identifying peripheral pain generators in patients suffering from neuropathic pain. Furthermore, we have investigated the cold compound and similar derivatives as potential pharmacotherapies for neuropathic pain in mouse models of nerve injury. These compounds have equipotent or superior analgesic efficacy to the clinically utilized gabapentin. The compounds have also been examined for liabilities in locomotor, rotorod, conditioned place preference and in some cases, self-administration assays. The results indicate the analgesic effects produced by S1Rs antagonists are not associated with these potential liabilities. These results confirm the ability of S1Rs to serve as potential diagnostic and analgesic agents for neuropathic pain without CNS liabilities.
Funding provided by NIDA (DA023205), NIGMS (GM104932), US Department of Defense, the Center for Biomedical Imaging at Stanford University, and the State of Florida, Executive Office of the Governor’s Office of Tourism, Trade, and Economic Development.
New Strategies for the C–H Functionalization of Amines
University of Florida
This lecture will cover our recent efforts in the development of reaction cascades for the rapid buildup of molecular complexity via the mild α- and β-C–H bond functionalization of amines. Mechanistically distinct approaches will be discussed.
Hierarchical Self-assembly of Supramolecular Norias
Bo Song, Xiaopeng Li
Department of Chemistry, University of South Florida
In biological systems, the shapes, complexity and functions of DNA- and protein-based assemblies are encoded by the defined sequence of nucleotides and amino acids. Inspired by nature, we herein introduced the concept of “programming of sequence-specific ligands” and designed a series of linear building blocks with specific sequence through bridging terpyridine ligands with Ru(II) coordination. Being different from traditional methods such as controlling the size, angle, dimensionality of the ligand, this strategy allows us to predict and design structures based on the linkage of the building blocks in ligand. Different generations of “Supramolecular Norias” (N1 to N5) with increasing complexity were thus obtained after the self-assembly with different transition metals. The resulting structures were characterized via multi-dimensional mass spectrometry analysis (ESI-MS, TWIM-MS) as well as a series of NMR (1H, COSY, NOESY) analysis. Moreover, the larger size supramolecules N4 and N5 were hierarchically self-assemble into uniform 2D nanostructures on HOPG surface as recorded by STM, or uniform nanotubes, which were observed under TEM.
The dimerization of benzo[1,2-b:4,5-b']dithiophen-4-ol
Ania Sotuyo and Ronald K. Castellano
Department of Chemistry University of Florida
BDT (benzo[1,2-b:4,5-b']dithiophen-4-ol) has been a popular building block for optoelectronic materials. Recently, we decided to remake BDT by adding a hydroxyl group for the purpose of accessing a tautomerically capable BDT. As we delved into benzo[1,2-b:4,5-b']dithiophen-4-ol (BDTOH) as a novel π building block, we found some interesting behavior not mentioned in the original literature. Although tautomerization for BDTOH (pKT = 2.75, 99.8% enol) was comparable theoretically with that of anthrone (pKT = -3.10, 99.9% keto), the tautomeric phenomenon was not observed. Instead, the compound undergoes an irreversible chemical oxidation in 10 mM CDCl3, ushering in a new set biaryl dimers. While the dimerization pathway is unknown, NMR studies done in oxygen-free and radical-free environments did not inhibit the process. Further attempts to derivatize BDTOH through synthesis garnered another new set of π-extended dimers.
Synthetic Explorations with Unsymmetrical Oxyallyl and 2-Amidoallyl Cations
Louisiana State University
We have developed a new strategy that enables carbon-carbon bond formation at the α-position of ketone-derived compounds with an exquisite control of regioselectivity via an intermediacy of unsymmetrical silyloxyallyl and 2-amidoallyl cations that are generated under mild catalytic conditions. This robust chemistry has been applied toward the synthesis of various complex structural motifs, such as all-carbon quaternary centers, 1,4-dicarbonyls, silyldienol ethers, functionalized enamides, heterocyclic compounds, and others. Our results will be discussed in this presentation.
Catalytic enantio- and regioselective alkynylation of pyridines
Kathryn L. Olsen, Mukesh Pappoppula, Aaron Aponick
University of Florida
The α-chiral tetrahydroquinoline (THQ) motif is found in a myriad of natural products and biologically active molecules. Alkynylation of pyridines at the α-position would afford chiral 1,2-dihydropyridines containing multiple synthetic handles allowing for functionalization to more complex systems. We have previously reported a highly enantioselective copper catalyzed alkynylation of quinolinium salts using the atropisomeric imidazole-based biaryl P,N-ligand, StackPhos. Encouraged by these results, we envisioned a catalytic enantioselective alkynylation of pyridines using StackPhos. The development of this methodology and its application will be presented.
New Methods for the Synthesis of Molecules Containing All-Carbon Quaternary Centers
Katelyn M. Chandoa, Ryan E. Michaelb and Tarek Sammakiac
a) Avista Pharma Solutions; b) C4 Therapeutics; c) University of Colorado Boulder
The stereoselectve synthesis of all-carbon quaternary centers has been a long-standing problem in organic synthesis. In this talk, we will describe a new approach to this problem that takes advantage of the reactivity of N-vinyl nitrones and ketenes. When combined, these substrates undergo a cascade reaction that begins with a (3+2) cycloaddition and is followed by a [3,3] sigmatropic rearrangement and a 1,3-shift to produce a 1,4-carbonyl equivalent bearing vicinal stereo centers. Using di-substituted ketenes, products bearing all-carbon quaternary centers are produced with high levels of stereoselectivity. The scope and mechanism of this process will be described in this talk.
Photosensitizers Derived from Chlorophyll
Kevin M. Smith
Louisiana State University
Chlorin-e6 (1) is a degradation product1-3 from chlorophyll-a that possesses three chemically distinct carboxylate sites (at positions 131-, 152-, and 173-) suitable for conjugation with biomolecules. An aspartic acid conjugate (Talaporfin, NPe6 or LS-11) originally identified as the 173-conjugate (2),4 but subsequently revised to be the 152-conjugate (3),3,5 is actively undergoing clinical trials as a photodynamic therapy (PDT) sensitizer.
The presentation will summarize the evidence leading to the reassignment of the structure for Talaporfin,3,5 and report syntheses of numerous amino-acid and non-amino acid mono- and bis-conjugates of chlorin e6.3,6-9 The cellular uptake, dark- and photo-toxicity, and in vitro intracellular localization of the new conjugates will also be discussed.
Figure 1 – Structures of chlorin-e6 (1) and its 173- (2) and 152- (3) aspartic acid conjugates
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Acknowledgements: The author thanks the US National Institutes of Health (grants R01 CA132861 and R01 CA179902) for support of this research.