Modular Approaches to Skeletally Diverse and Stereochemically-rich 7- to 11-membered Ring Sultams

The overarching goal of this dissertation is the development of efficient methods for the generation of medium- and large-sized heterocycles, specifically 7- to 11-membered sultams, for facilitating probe and drug discovery. Chapter One summarizes the structural components that are prevalent in current marketed pharmaceutical agents, highlighting underrepresented rings, rings systems and frameworks, which have the potential to introduce chemical novelty into the existing limited list of chemical ring systems that describe the majority of the drugs. Chapter Two introduces the concept of pairing of a reaction triad, namely sulfonylation, SNAr addition and Mitsunobu alkylation, in varying order via the use of central o-fluorobenzene sulfonyl chloride building blocks that afford rapid access to both bridged- and fused-tricyclic, 7- to 10-membered benzofused sultams. This simple approach obviates the need for the construction of elaborate multi-functional scaffolds and merely requires use of o-fluorobenzene sulfonyl chlorides, amines and alcohols as building blocks. Simple changes in the reaction pair sequence (e.g., sulfonylation–SNAr vs sulfonylation–SNAr–Mitsunobu vs sulfonylation–Mitsunobu– SNAr), or changes in the building blocks (1,2-amino alcohol vs 1,3-amino alcohol), allows access to skeletal and stereochemical diversity. Chapter Three presents the concept of complementary pairing of activated sulfonyl aziridines (simple 6-atom bis-electrophilic synthon) via "chemo- and regioselective" aziridine ring-opening with an amino component of an amino alcohol (bis-nucleophiles). Subsequent intramolecular SNAr cyclization with the alcohol component of the amino alcohol affords unprecedented, functionally rich mediumsized benzofused sultams in overall, chemoselective “6+4” and “6+5” heterocyclization pathways. Moreover, the use of primary amines for the sulfonyl aziridine ring-opening step, whereby the resulting secondary amines cyclize via a subsequent intramolecular SNAr reaction, enables the generation of 7-membered benzofused sultams via an overall “6+1” atom cyclization sequence Chapter Four describes efforts aimed at the use of one-pot, sequential 3- or 4- component sulfonylation–aza-Michael–amide cyclization protocols to generate a library of skeletally and stereochemically diverse 7/4, 7/5 and 7/6-fused bicyclic acyl sultams. In this library effort, sulfonylation of different amines with 2-chloroethane sulfonyl chloride, followed by Michael reaction with a variety of amino acids, and subsequent amide cyclization provides access to the titled bicyclic sultams, which are currently being screened for biological activity as well as unique chemical properties

High-Load, Hybrid Si-ROMP Reagents

The combination of norbornenyl-tagged (Nb-tagged) silica particles and functionalized Nb-tagged monomers for the generation of hybrid Si-ROMP reagents and scavengers is reported. Specifically Si-ROMP-derived bis-acid chloride, dichlorotriazine and triphenylphosphine scavenger/reagents have been grafted from the surface of silica particles utilizating surface-initiated, ring-opening metathesis polymerization (ROMP). These hybridpolymeric materials combine the physical properties of current immobilized silica reagents and represent a key advancement in load by merging the inherent tunable properties of the ROMP-derived oligomers with silica supports for application in parallel synthesis

Select cognitive deficits in Vasoactive Intestinal Peptide deficient mice

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Rapid, Scalable Assembly of Stereochemically Rich, Mono- and Bicyclic Acyl Sultams

A one-pot, sequential protocol is reported that involves complementary ambiphile pairing (CAP) of a vinyl sulfonamide with a variety of unprotected amino acids via aza-Michael addition and subsequent intramolecular amidation. The method generates diverse, sp3-rich mono- and bicyclic acyl sultams in a highly scalable manner. Modular pairing of stereochemically rich building blocks allows quick access to all possible isomers. Extension to include one-pot, sequential 3-, 4- and 5-multicomponent protocols is also discussed

Reaction Pairing: A Diversity-Oriented Synthesis Strategy for the Synthesis of Diverse Benzofused Sultams

A reaction pairing strategy centered on utilization of a reaction triad (sulfonylation, SNAr addition and Mitsunobu alkylation) generating skeletally diverse benzofused tricyclic and bicyclic sultams is reported. Pairing sulfonylation and SNAr reactions yields bridged, tricyclic and bicyclic benzofused sultams. Application of the Mitsunobu reaction in a sulfonylation–Mitsunobu–SNAr pairing allows access to benzo-oxathiazocine-1,1-dioxides, while a simple change in the order of pairing to sulfonylation–SNAr–Mitsunobu affords structurally different, benzofused bridged tricyclic sultams

Reduced physiological plasticity in a fish adapted to stable temperatures

Publisher Copyright: Copyright © 2022 the Author(s).Plasticity can allow organisms to maintain consistent performance across a wide range of environmental conditions. However, it remains largely unknown how costly plasticity is and whether a trade-off exists between plasticity and performance under optimal conditions. Biological rates generally increase with temperature, and to counter that effect, fish use physiological plasticity to adjust their biochemical and physiological functions. Zebrafish in the wild encounter large daily and seasonal temperature fluctuations, suggesting they should display high physiological plasticity. Conversely, laboratory zebrafish have been at optimal temperatures with low thermal fluctuations for over 150 generations. We treated this domestication as an evolution experiment and asked whether this has reduced the physiological plasticity of laboratory fish compared to their wild counterparts. We measured a diverse range of phenotypic traits, from gene expression through physiology to behavior, in wild and laboratory zebrafish acclimated to 15 temperatures from 10 °C to 38 °C. We show that adaptation to the laboratory environment has had major effects on all levels of biology. Laboratory fish show reduced plasticity and are thus less able to counter the direct effects of temperature on key traits like metabolic rates and thermal tolerance, and this difference is detectable down to gene expression level. Rapid selection for faster growth in stable laboratory environments appears to have carried with it a trade-off against physiological plasticity in captive zebrafish compared with their wild counterparts.Peer reviewe

Exploring chemical diversity via a modular reaction pairing strategy

The efficient synthesis of an 80-member library of unique benzoxathiazocine 1,1-dioxides by a microwave-assisted, intermolecular nucleophilic aromatic substitution (SNAr) diversification pathway is reported. Eight benzofused sultam cores were generated by means of a sulfonylation/SNAr/Mitsunobu reaction pairing protocol, and subsequently diversified by intermolecular SNAr with ten chiral, non-racemic amine/amino alcohol building blocks. Computational analyses were employed to explore and evaluate the chemical diversity of the library.Financial support of this work was provided by the National Institute of General Medical Sciences and is gratefully acknowledged (P50-GM069663 and P41-GM076302). In addition, funding from The University of Kansas for an Undergraduate Research Award (S.Y.) is gratefully acknowledged

Using Mathematical Models In A Unified Approach To Predicting The Next Emerging Infectious Disease

Emerging infectious diseases (EIDs) pose a significant threat to human health, global economies, and conservation (Smolinski et al. 2003). They are defined as diseases that have recently increased in incidence (rate of the development of new cases during a given time period), are caused by pathogens that recently moved from one host population to another, have recently evolved, or have recently exhibited a change in pathogenesis (Morse 1993; Krause 1994). Some EIDs threaten global public health through pandemics with large-scale mortality (e.g., HN/AIDS). Others cause smaller outbreaks but have high case fatality ratios or lack effective therapies or vaccines (e.g. Ebola virus or methicillin-resistant Staphylococcus aureus). As a group, EIDs cause hundreds of thousands of deaths each year, and some outbreaks (e.g., SARS, H5N1) have cost the global economy tens of billions of dollars. Emerging diseases also affect plants, livestock, and wildlife and are recognized as a Significant threat to the conservation of biodiversity (Daszak et al. 2000). Approximately 60% of emerging human disease events are zoonotic, and over 75% of these diseases originate in wildlife (Jones et al. 2008). The global response to such epidemics is frequently reactive, and the effectiveness of conventional disease control operations is often too little, too late\u27: With rising globalization, the ease with which diseases spread globally has increased dramatically in recent times. Also, interactions between humans and wildlife have intensified through trade markets, agricultural intensification, logging and mining, and other forms of development that encroach into wild areas. Rapid human population growth, land use change, and change in global trade and travel require a shift toward a proactive, predictive, and preventive approaches for the next zoonotic pandemic

A Novel SALL4/OCT4 Transcriptional Feedback Network for Pluripotency of Embryonic Stem Cells

Background: SALL4 is a member of the SALL gene family that encodes a group of putative developmental transcription factors. Murine Sall4 plays a critical role in maintaining embryonic stem cell (ES cell) pluripotency and self-renewal. We have shown that Sall4 activates Oct4 and is a master regulator in murine ES cells. Other SALL gene members, especially Sall1 and Sall3 are expressed in both murine and human ES cells, and deletions of these two genes in mice lead to perinatal death due to developmental defects. To date, little is known about the molecular mechanisms controlling the regulation of expressions of SALL4 or other SALL gene family members. Methodology/Principal Findings: This report describes a novel SALL4/OCT4 regulator feedback loop in ES cells in balancing the proper expression dosage of SALL4 and OCT4 for the maintenance of ESC stem cell properties. While we have observed that a positive feedback relationship is present between SALL4 and OCT4, the strong self-repression of SALL4 seems to be the “break” for this loop. In addition, we have shown that SALL4 can repress the promoters of other SALL family members, such as SALL1 and SALL3, which competes with the activation of these two genes by OCT4. Conclusions/Significance: Our findings, when taken together, indicate that SALL4 is a master regulator that controls its own expression and the expression of OCT4. SALL4 and OCT4 work antagonistically to balance the expressions of other SALL gene family members. This novel SALL4/OCT4 transcription regulation feedback loop should provide more insight into the mechanism of governing the “stemness” of ES cells