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The effect of local chain stiffness on oligomer crystallization from a melt
No full textWhile the process by which a polymer crystal nucleates from the melt has been extensively studied via molecular simulation, differences in polymer models and simulated crystallization conditions have led to seemingly contradictory results. We make steps to resolve this controversy by computing low-temperature phase diagrams of oligomer melts using Wang-Landau Monte Carlo simulations. Two qualitatively different crystallization mechanisms are possible depending on the local bending stiffness potential. Polymers with a discrete bending potential crystallize via a single-step mechanism, whereas polymers with a continuous bending potential can crystallize via a two-step mechanism that includes an intermediate nematic phase. Other model differences can be quantitatively accounted for using an effective volume fraction and a temperature scaled by the bending stiffness. These results suggest that at least two universality classes of nucleation exist for melts and that local chain stiffness is a key determining factor in the mechanism of nucleation
Heteroaryl derivatives of suvorexant as OX1R selective PET ligand candidates: Cu-mediated 18F-fluorination of boroxines, in vitro and initial in vivo evaluation
No full textBackground: The orexin receptor (OXR) plays a role in drug addiction and appears as a tumor marker in colon carcinoma. Subtype-selective OXR PET ligands have not yet been reported. The present work deals with the development of 18F-labeled OXR ligands dervived from selective OX1R antagonist JH112.
Methods: Applying computational analysis, medicinal chemistry, integrated OXR binding studies, Cu-mediated 18F-fluorination and initial small animal PET studies, we evaluated a series of OXR ligands (1a-1f), varying the heteroarene scaffold of FH112 by 5-fluorobenzoxazole, 5-/6-fluorobenzthiazole and 6-fluoroquinoxaline. Receptor binding studies were preformed on HEK293T cells transiently expressing the OX1R and OX2R. Cu-mediated 18F-fluorination was performed on BPin and boroxine precursors. In vitro assays for logD7.4, stability in plasma, plasma-protein binding and potential P-gp-mediated transport in the Caco-2 monolayer model were performed. The brain uptake of 18F-labeled ligands was studied by dynamic PET imaging in rats.
Results: Computational analysis predicted that fluorine substitution (1e) and introduction of the fluorobenzothiazole scaffold (1f) would be suitable for maintaining high OX1R affinity. After multi-step synthesis of 1a-1f, in vitro OXR binding studies confirmed molecular dynamics calculations and revealed single-digit nanomolar OX1R affinities for 1a-f, ranging from 0.69 nM-2.5 nM. The benzothiazole 1f showed high OX1R affinity (Ki = 0.69 nM), along with 77-fold subtype selectivity over OX2R. Cu-mediated 18F-fluorination of the nonselective OXR ligands benzothiazole [18F]1c and quinoxaline [18F]1d yielded RCY of 44% and 56%, respectively, after 10 min, compared to low RCY for benzoxazole [18F]1a of 12% after 20 min. The nonselective OXR ligand [18F]1c and the selective OX1R ligand [18F]1f gave total activity yields of 14% and 22%, respectively, using boroxine precursors for Cu-mediated 18F-fluorination with 5 min reaction time and a total synthesis time of 50-60 min. [18F]1c and [18F]1f were stable in plasma and serum in vitro, with logD7.4 of 2.28 ([18F]1c) and 2.37 ([18F]1f), and high plasma-protein binding of 66% and 77%, respectively, reflecting only marginal differences in brain uptake of [18F]1c (0.17 %ID/g) and [18F]1f (0.15 %ID/g). 1c showed higher passive permeability than 1f in vitro, which was consistent with the faster brain clearance of [18F]1c compared to [18F]1f. However, preinjection of the OXR antagonist suvorexant did not significantly block [18F]1c or [18F]1f uptake in the rat brain. Pretreatment with cyclosporin A to study the role of P-gp in limiting brain accumulation moderately increased brain uptake of [18F]1c and [18F]1f. Accordingly, in vitro experiments demonstrated that the P-gp inhibitor zosuquidar only moderately inhibited polarized, basal to apical transport of 1c (p<0.05) and had no influence on transport of 1f (n.s.), indicating that P-gp does not play a relevant role in brain accumulation of [18F]1c and [18F]1f in vivo.
Conclusions: The in vitro and in vivo results of [18F]1c and [18F]1f provide a solid basis for further development of suitable OXR PET ligands for brain imaging. This could be achieved through structural changes that would result in lower blood protein binding and 18F labeling methods that would allow for improved molar activities
Sulfonate group improves the solubility and electrocatalytic performance of Ru-based bda- and pda-type water oxidation catalysts under neutral conditions
No full textFour ruthenium water oxidation catalysts that bear carboxylate and sulfonate groups in the active site have been synthesized and analyzed for their catalytic activity. The developed catalysts are modified from highly active species that traditionally have two carboxylate groups in the active site and are used to probe the effects of sulfonate substitution as well as the effects of other structural changes of the catalyst. The sulfonate-containing catalysts show higher electrochemical activity in pH 7 phosphate buffer with 3-5 times larger catalytic current, improved durability with sacrificial oxidant, and increased solubility compared to their dicarboxylate counterparts. Density functional theory calculations suggest that the sulfonate group provides more favorable geometry for water nucleophilic attack, of which is both the most energetically favorable mechanism calculated and experimentally predicted mechanism under electrochemical conditions. Further experimental studies have been performed to show that under certain conditions catalysts can perform well electrochemically under pH conditions as low as 1.6 and that various structural components can greatly change solubility and catalytic operation
Selective copper-mediated cross-coupling of pyroglutamate post-translational modifications
No full textPyroglutamate is a cyclic N-terminal posttranslational modifica-tion that occurs in both proteins and peptide hormones. The prevalence and biological roles of pyroglutamate are little under-stood, in part due to limited tools to identify, quantify, and ma-nipulate its pyrrolidinone structure. Selective modification of pyroglutamate residues in complex polypeptides may provide unique tools to better understand its biological roles, and to al-low late-stage diversification of biologically active pyrogluta-mate-containing sequences. This work describes a copper-catalyzed N–H cross-coupling of unprotected peptides that is selective for N-terminal pyroglutamate residues. The reaction is operationally simple under mild conditions, and tolerates almost all canonical residues. Mechanistic studies point to a key role for a multidentate copper-binding mode of the extended polypeptide structure in delivering the observed reactivity. The reaction al-lows direct labeling and identification of a pyroglutamate hormone present in porcine intestinal extracts
Synthesis and Application of Robust Spiro [Fluorene 9] CAAC Ruthenium Alkylidene Complexes to the „One-Pot“ Conversion of Allyl Acetate to Butane-1,4-diol
No full textA series of a novel CAAC ligands featuring a spiro-fluorene group have been synthesized and complexed with ruthenium alkylidenes, yielding the corresponding Hoveyda-type derivatives as a new family of olefin metathesis catalysts. The novel complexes have been characterized by XRD, HRMS and NMR measurements. The synthetized complexes were tested in catalysis and showed good activity in olefin metathesis, as demonstrated on diethyl diallylmalonate and allyl acetate substrates. The unique backbone in the ligand system with the large, yet inflexible condensed system renders interesting properties to the catalyst, exemplified by the good catalytic performance and improved Z selectivity. In addition, the catalyst can also serve as a hydrogenation catalyst in a consecutive (one-pot) reaction. The latter reaction can convert allyl acetate to butane 1,4 diol, a valuable chemical intermediate for biodegradable polybutylene succinate (PBS)
Screening the ToxCast Chemical Libraries for Binding to Transthyretin
No full textTransthyretin (TTR) is one of the serum binding proteins responsible for transport of thyroid hormones (TH) to target tissue and for maintaining the balance of available TH. Chemical binding to TTR and subsequent displacement of TH has been identified as an endpoint in screening chemicals for potential disruption of the thyroid system. To address the lack of data regarding chemicals binding to TTR, we optimized an in vitro assay utilizing the fluorescent probe 8-anilino-1-napthalenesulfonic acid (ANSA) and the human protein TTR to screen over 1,500 chemicals from the U.S. EPA’s ToxCast ph1_v2, ph2, and e1k libraries utilizing a tiered approach. Testing of a single high concentration (target 100 µM) resulted in 888 chemicals with 20% or greater activity based on displacement of ANSA from TTR. Of these, 282 chemicals had activity of 85% or greater and were further tested in 12-point concentration-response with target concentrations ranging from 0.015-100µM. An EC50 was obtained for 276 of these 282 chemicals. To date, this is the largest set of chemicals screened for binding to TTR. Utilization of this assay is a significant contribution towards expanding the suite of in vitro assays used to identify chemicals with the potential to disrupt thyroid hormone homeostasis
Rapid interpretation of protein backbone rotation dynamics directly from spin relaxation data
No full textBesides structure, protein dynamics is pivotal for their functions, particularly for intrinsically disordered proteins (IDPs) that do not fold to a fixed 3D structure. Rapid rotations of chemical bonds in proteins can be detected measuring NMR spin relaxation rates, but interpretation of protein dynamics from the experimental data is arduous for IDPs or molecular assemblies with complex dynamic landscape. Here we demonstrate numerically that the total effective correlation times of protein backbone N-H bond rotations, τeff , can be calculated from experimentally measured transverse 15N spin relaxation rates, R2, using linear relation. Using molecular dynamics (MD) simulations, we show this for wide range of proteins, from short peptides to partially dis- ordered proteins and peptides in micelles. Significant practical advance of the result is demonstrated by interpreting dynamics of partially disordered proteins that are beyond the scope of current approaches to interpret spin relaxation rate experiments
Crystals of Organic Acid-Bases Complexes Defy the pKa Rule Under Compression
No full textCrystals of organic acid-base adducts are major components in the active pharmaceutical ingredients (API). These 1:1 adducts either form a co-crystal with a hydrogen-bonded motif or a salt by transfer of proton from the acid to the base. As a rule of thumb if the difference in pKa between the protonated base and the acid (ΔpKa) is ≤ 1, a co-crystal is expected while ΔpKa > 3 leads to a salt. The preferred crystalline form for 1:1 adducts of pyridine, pyridazine, pyrazine and furan with formic acid are elucidated using genetic algorithm assisted first-principles crystal structure predictions (CSP). In agreement with the ΔpKa rule, all the adducts stabilize as H-bonded co-crystals under ambient pressure. However, under isotropic pressure formic acid transfers the protons to the three nitrogenous bases forming salts of pyridinium formate, pyridazinium formate and pyrazinium formate. External pressure is found to dictate the co-crystal – salt equilibrium. The critical pressure (Pc) required to induce co-crystal → salt conversion for formic acid… pyridine/pyridazine/pyrazine is 3 GPa, 5 GPa and 15 GPa respectively. Compression is shown to enhance the electrostatic interactions between the molecules leading to additional stabilization of the ionic configurations namely, N+-H…O- in salts vis-à-vis the neutral N-H…O motifs in the co-crystals. Violating the ΔpKa rule, Pc overcomes the free-energy required for the proton-transfer (ΔGPT) to stabilize the salts. The very high ΔGPT = 177.9 kcal/mol for the furan…formic acid adduct prevents salt formation even at 30 GPa. Apart from the thermodynamic and kinetic control during crystallization, pressure acts as a key control for organic acid-base adducts
Excited state dynamics of intramolecular charge transfer excited state in thermally activated delayed fluorescence carbazole dendrimer
No full textOrganic light-emitting diodes (OLEDs) using dendrimers as emitting layers are gathering attention due to their ability of precise molecular structuring. Carbazole dendrimers have been utilized in luminescent devices demonstrating thermally activated delayed fluorescence (TADF), which efficiently converts non-emissive triplet states to emissive singlet states, enhancing OLED performance. Our research examined triazine-cored carbazole TADF dendrimers with three generations, assessing their photofunctional properties through time-resolved photoluminescence and transient absorption spectroscopy. We revealed significant generation-dependent charge-transfer characteristics, with higher generations showing enhanced charge-transfer character in the singlet excited state. On the contrary, while the transient absorption spectra of the singlet excited state were modified sensitively by elongation of the dendron, those of the triplet excited state were insensitive to the generation. This study underscores the importance of molecular design in dendrimers for optimizing electronic properties, providing insights into their unique photophysical behaviors, and potentially guiding future developments in OLED technology
Quick Reference (QR) Instructional Videos for Common Organic Chemistry Laboratory Equipment and Techniques
No full textMultimedia approaches, including short instructional videos, are complementary to traditional modes of instruction such as in-person lecture and written procedures. We describe the creation and implementation of Quick Reference (QR) instructional videos in an undergraduate organic chemistry laboratory (OCL) setting for non-chemistry majors. The QR videos were designed to address specific, recurring questions about equipment, procedure, and concepts that students in our OCL courses find continually challenging. Quick-response barcodes for each video were located close to related glassware, equipment, and chemicals during the teaching laboratory, which could be scanned by a mobile device. Students indicated that the QR videos were easily accessible, increased their confidence in the chosen technique, and answered questions that they would otherwise have asked their TA. With respect to student engagement, we found that students engaged the most with video sections relating directly to hands-on procedure ("how"), but disengaged during conceptual explanations ("why"). A specific template for outlining, scripting, recording, and editing QR videos is included so that similar QR videos can be prepared at other institutions