1,721,005 research outputs found
Exploring intramolecular interactions, structure, and dynamics in a series of 24-membered triazine macrocycles
No full textIn 2020, Vishal Sharma synthesized a glycine-containing triazine macrocycle in yields exceeding 93%.1 In the solid-state, the macrocycle adopts a folded, compact structure, however, no solution structure was rigorously assigned. Three areas of investigation are born out of these observations: what is the source of the quantitative yields, what is the solution structure, and what is the dynamic behavior in solution.
These observations are general: triazine macrocycles of varying compositions are made in high yields. 1H NMR spectroscopy shows macrocycles form as a singular isomer in solution along with evidence for rotamers found in the intermediates. In total, 17 macrocycles were made and characterized.
The quantitative dimerization of these macrocycles occurs through a templated intermediate. Crystal structures of the macrocycles exhibit the hypothesized hydrogen bonding network. DFT calculations provide evidence for the hydrogen bonding pattern. The pKa of the triazines are determined using titration data and is confirmed by 1H NMR spectroscopy.
Xray crystallography and NMR spectroscopy elucidates the three-dimensional conformation of these triazine-containing macrocycles. 1H-1H rOesy spectroscopy provides relevant correlations for structure determination that are present in solid-state structures. Additionally, using subtle differences in downfield chemical shifts and the network of correlations to a singular proton, nuanced differences in structure can be quickly determined. The role of protonation on structure is probed by variable temperature NMR.
The dynamic motion of some triazine-containing macrocycles can be examined through computational modeling and variable temperature NMR experiments. Here, the macrocycles hinge from one closed state to another closed state. Internal (steric bulk) and external (solvent polarity) factors influence the hinge barrier. Isosteric and isomorphic macrocycles with shared dynamic behavior are investigated.
Altogether, this work focused on expanding the library of 24-membered triazine macrocycles to probe quantitative yields, conformation, and dynamics through a variety of computational methods and NMR spectroscopic techniques
Synthesis and Characterization of an Isoleucine-Containing Macrocycle
No full textLarge drugs-including macrocycles-are receiving more attention due to the belief that there may be therapeutic targets available to them that are unavailable to small molecules. Here, the synthesis of an isoleucine-containing macrocycle comprising 24 atoms utilizes a three-step synthesis with intermediates that can all be isolated, purified, and characterized. The choice of isoleucine reflects a desire to understand how a large, beta-branched amino acid affects synthesis and conformation. The monomer is available in two reactions. First, a sequential substitution of cyanuric chloride with BOC-protected hydrazine, isoleucine, and dimethylamine gives the carboxylic acid intermediate. The three reactions are performed in a single reaction vessel and are monitored by thin-layer chromatography to ensure that each substitution was successful. The carboxylic acid intermediate is purified using silica gel chromatography. Then, an EDC-mediated coupling reaction between the acetal and an aminoacetal gives the monomer. The monomer can be envisioned to be crescent-shaped. Spontaneous dimerization is initiated by treating the monomer with trifluoracetic acid. Oligomeric and polymeric materials are not observed in synthesis. NMR spectroscopy confirms the successful synthesis of each intermediate and the macrocycle. Both COSY and rOesy spectra are used to probe the change in conformation as a function of solvent. Finally, NMR spectra are measured at various temperatures to help understand the dynamic behavior of the macrocycle
Synthesis of Novel Architectures from Triazinyl Hydrazines and Various Carbonyl Compounds
No full textThe pH labile nature of hydrazones has made them useful in various fields from material to medical science. Here, explorations of triazinyl hydrazones are reported. Three different projects will be described; the hydrolysis of novel triazinyl hydrazones, the synthesis of remarkably stable hemiaminals, and the creation of macrocycles derived from hydrazone dimers. Novel triazinyl hydrazones. Elaborating on previous work, the role of N -alkylation on hydrazone hydrolysis was studied using ArNHNH 2 , ArN(CH 3 )NH 2 and ArN(Ph)NH 2 wherein Ar is a triazine ring. The study relied on four different carbonyl donors. The use of diketones affords an opportunity to study the effects of intramolecular hydrogen bonding when N -alkylhydrazines (which preclude pyrazole formation) are employed. Hydrolysis rates were measured by high performance liquid chromatography (HPLC) using an established competitive exchange reaction relying the presence of an excess of formaldehyde. The studies show that the presence of methyl group increases hydrolysis rates when compared to phenyl (which is similar) and to unalkylated hydrazones which proceed most slowly. Stable hemiaminals. During the synthesis of hydrazones, stable cyclic hemiaminals were observed. Cyclic hemiaminals are obtained from acidic conditions using an aromatic ring containing hydrogen bond acceptor and diketones with strong electron withdrawing groups. Triazine ring provides three hydrogen bond acceptors and, hence, used to create stable cyclic hemiaminals under acidic conditions. By surveying a range of 1,3-diketones, stability is attributed to the effect of hydrogen bonding and the presence of a strong electron withdrawing group (trifluoromethyl). Using resistance to dehydration as a surrogate for stability, these hemiaminals survives in ambient, neat glacial acetic acid for long periods of time and requiring reflux for conversion to the corresponding pyrazole. DFT calculations corroborate design criteria that are crucial for the stability. Macrocycles. Finally, an earlier report from the Simanek group identified three macrocycles that derive from dimerization of a protected triazinyl hydrazine bearing an acetal when exposed to acid.8 The resulting bishydrazone presented 24 atoms in a ring. The simplicity of monomer preparation and the nearly quantitative yields of product led to the question of whether rings of varying sizes could be prepared. Ring size is readily manipulated by changing the tether between the acetal and triazine ring which contains an amino acid and an amino acetal. For these studies, 6 monomers were prepared using glycine and ?-alanine along with acetals including the 2-carbon aminoethyl acetal, the 3-carbon aminopropyl acetal, and the 4-carbon aminobutyl acetal. Treatment with trifluoroacetic acid and slow evaporation of solvent yielded macrocycles that are characterized by x-ray diffraction, 1 H and 13 C NMR spectroscopy, mass spectrometry and HPLC. Macrocyclic homodimers of ring sizes of 22-28 atoms were obtained in high yield. In addition, when a 1:1 mole ratio of different monomers were mixed, heterodimeric macrocycles with odd-numbered ring sizes (23-27 atoms) were also made. Solid state structures and solution state NMR studies suggest that these macrocycles form networks of hydrogen bonds and might be templated by protonation
Design, Synthesis, and Characterization of a Threonine-Rich Macrocycle; A Review of “Introduction to Research”
No full textThis work describes the synthesis of a 24-atom, threonine-rich macrocycle homodimer, T-T. Syntheses of macrocycles are of interest due to their potential applications as drugs. If the synthesis design allows for a wide variety of different groups to be incorporated without affecting the structure itself, classical drug design strategies can be adopted. The benefits of macrocycles derive from their large and flexible structures that can adopt different conformations. This flexibility is important when the macrocycle is required to present either hydrophilic or hydrophobic surfaces when it is inside and outside the cell or crossing the membrane, respectively. The synthesis of T-T is done in three steps and relied on making changes to a previously studied macrocycle synthesis pathway. First, a threonine acid intermediate is prepared by substituting a triazine ring with dimethyl amine, a t-butyl protected threonine and a BOC-protected hydrazine. Then, the acid is reacted to create the threonine acetal monomer. The final step involves treating the monomer with acid to yield the homodimer, T-T. The macrocycle and its intermediates were purified through column chromatography and characterized via 1H NMR, 13C NMR, COSY NMR, rOesy NMR, and HSQC NMR. What emerges from these studies is the three-dimensional shape of T-T. 1H NMR and 13C NMR were also used to characterize the acid intermediate and the acetal monomer. Mass spectrometry also corroborated these assignments. This research adds to a growing library of similar macrocycles that vary in amino acid in the position of threonine with the eventual goal of creating a library of macrocycles for future research in the area of synthetic drug design. Separately, during the spring semester of the 2020-2021 academic year at Texas Christian University a group of 12 undergraduate students participated in a group project given the title Introduction to Research. These students chose to participate in this project after their organic chemistry II laboratory course was moved to an online format two weeks into the start of the semester. The goal of the project was to provide undergraduate students the opportunity to participate in faculty led organic chemistry research which would supplement their laboratory course being moved online. This review seeks to cover what the undergraduate students were able to accomplish over the course of the semester while meeting weekly to work on this project. Additionally, a survey was given to the students after they completed the semester in order to get their opinion on how the structure of the course operated as well as areas which could be improved if the opportunity was offered to students again in the future. The opinions received from the survey demonstrated that the undergraduate students felt that the experience was extremely positive with only a few areas in which the operations could have been improved. This review takes the summary of student activities through this project as well as their perspectives gained through the survey in order to provide guidelines on how a similarly styled opportunity could be offered in the future as a class course at TCU
Functionalization of small triazine dendrons with maleimides and hydrazines on the periphery and DOTA group at the core
No full textIn this work, we functionalized small triazine dendrons with maleimides (maleimide dendrimer) and triazine substituted hydrazines (hydrazine dendrimer) for potential use as theranostics in the presence of DOTA group as the reporter domain that can host metals for diagnostic applications. The model maleimide dendrimer displays four maleimides on the periphery that can readily react with thiols in a variety of solvents. Reactions of maleimide dendrimer with oligopeptides that contain cysteine have been examined. We began the work of hydrazine dendrimer with the study of hydrolytic stability of triazine substituted hydrazones (triazinyl hydrazones) and acyl hydrazones. At pH 5 and 7, triazinyl hydrazones showed higher hydrolysis rates. However, at pH 4, an inversion was observed in hydrolytic stability with triazinyl hydrazones more stable towards hydrolysis in comparison to corresponding acyl hydrazones due to the protonation of the triazine moiety. The experimental data is consistent with computation prediction. Then the success of synthesis of hydrazine dendrimer offers a model platform for targeted delivery of drugs containing ketone or aldehyde group. Specifically, the conjugation of hydrazine dendrimer with water insoluble drug bruceantin has been examined and produced water soluble model theranostics
Efforts Toward The Synthesis Of Phenylalanine-Containing Macrocycles Derived From Dimerization Of Triazine Monomers To Explore Bro5 Properties
No full textA revival of attention paid to large drugs, such as cyclic macrocycles, has been fueled by the idea that there may be therapeutic targets available to them that are unavailable to smaller molecules. The pharmaceutical space that includes large, cyclic molecules has long been ignored by drug developers. This phenomenon is because, based on Lipinski's Rule of 5, orally absorptive drugs shouldn't exist there. Additionally, the chemistry of synthesizing such large molecules is complex, time intensive, and unpredictable. The Simanek group aims to establish a novel and straightforward synthesis. Establishing this approach allows for investigation into why large drugs, like the immunosuppressant cyclosporin, are so successful. Additionally, this research creates opportunities to design large cyclic drugs with intentionality and flexibility. This intentional design includes the addition of specific functional groups and amino acids. The long-term goal of this project is the synthesis of the complete macrocycle. The short-term accomplishment of this experiment is the synthesis of the trisubstituted triazine ring, called Intermediate 3 or I-3 . To create the target molecule, I-3, three groups were substituted onto a triazine ring. The target molecule has a triazine with a BOC-protected hydrazine group, a morpholine, and phenylalanine. This synthesis occurred in a stepwise substitution process. The product was purified through silica column chromatography. Upon examination by 13C and 1H NMR, the spectra reveal resonances that are diagnostic for macrocycle formation. Thus, it was determined that the trisubstituted molecule was successfully synthesized
Progress Toward Biodegradable Triazine Dendrimers Using Triazinyl Hydrazone Linkages
No full textThis research aims to synthesize a triazine dendrimer with labile arms through the incorporation of hydrazone linkages. This dendrimer should be susceptible to hydrolysis in acidic conditions, be soluble in water, relatively non-toxic, and be degradable into molecules small enough for excretion. The synthesis uses trichlorotriazines as branching molecules and different types of diamines to connect the branches
Synthesis Of 2,4,6-Trisubstituted-1,3,5-Triazine Using Sertraline As One Of The Substituents
No full textBesides its commercial use as an anti-depressant, sertraline is also known to behave as an efflux pump inhibitor which impedes bacteria's ability to extrude antibiotic. This property explains why sertraline can potentiate clinically relevant antibiotics and make them effective against some resistant strains of bacteria. Exploiting this characteristic, a library of 2,4,6-trisubstituted-1,3,5-triazines were synthesized, using sertraline as one of the substituents while the other substituent groups were varied. The synthesized compounds were screened for antibacterial activities using Kirby-Bauer disk diffusion method. Of the seven new compounds prepared, three showed noteworthy activity against both Gram negative and Gram positive bateria, Staphylococcus aureus and Escherichia coli, respectively
Synthesis and applications of novel nitrogen heterocycles
No full textPyridines and triazines are nitrogen heterocycles found in all fields of the chemical realm. These aromatic compounds readily undergo nucleophilic aromatic substitution reactions. Nitrogen heterocycles appear in therapeutics, reactive dyes, herbicides, catalysts, and others. Exploration of pyridines and triazines in our laboratory, resulted in novel compounds with potential applications. A triazine ligand was developed containing pyrazolone and hydrazine groups, capable of binding to first row transition metals. Copper (II), nickel (II), and zinc (II) formed chelates through a unique 6,5 oxygen to metal binding ring systems. The chelating ability of this ligand led to promising results in its antioxidant ability, and cellular toxicity. (Chapter 1). Homo- and heterodimeric peptide macrocycles were synthesized and characterized. The facile route for the preparation of these compounds enable for rapid and selective transformations of diverse dimeric macrocycles. Analysis via mass spectrometry, NMR spectroscopy, and X-ray diffractometry determined the formation of 24-membered macrocycles. Glycine, and Lphenylalanine amino acid residues were incorporated into the macrocycles as well as substituted hydrazines as amino acid side chain mimics. These compounds find potential applications in a broad field of biological sciences. (Chapter 2). Finally, four members of a class of pyridine containing macrocycles bearing electron withdrawing groups in the 4-position (CN, NO2, Cl, CF3), were synthesized as targets for metal chelation and catalysis. (Chapter 3)
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