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Subcellular targeted anion transporters
No full textSynthetic anion transporters that mediate electroneutral (H+/Cl–) transport have demonstrated anti-cancer activity due to their ability to disrupt subcellular homeostatic environments. Elucidation of the cell death mechanism revealed the transporters’ ability to neutralize lysosomal pH gradients and inhibit autophagy. However, their effect on other subcellular compartments is unknown. Herein, we disclose the first subcellular targeted anionophores that accumulate in various membrane bound organelles to bias their natural propensity to depolarize lysosomes. Confocal microscopy revealed the ability of the naphthalimide-based transporters to localize within their intended membrane-bound organelles. Analogues that contained endoplasmic reticulum (ER) and lysosomal targeting motifs showed an enhanced H+/Cl– transport ability and cytotoxicity compared to non-targeted analogues. Moreover, ER and mitochondrial localization was found to enhance apoptosis in cancerous cells. Our work provides an alternative approach to the design of therapeutically focused synthetic anion transporters and an insight into possible subcellular compartment-specific effects on homeostasis
Scoring Methods in Lead Optimization of Molecular Glues
No full textEfficiency metrics are a simple and effective medicinal chemistry tool to track small molecule progress toward a preferred profile in lead optimization. Targeted protein degradation can be mediated by small molecules that act as a molecular glue between an E3 ligase and a protein target. Molecular glue compounds are characterized by the potency and the depth of their protein degradation dose response measurement, representing additional complexity toward identifying drug candidates. We developed degradation efficiency metrics that are based on both potency and depth of degradation. They serve as basic scoring functions to effectively track lead optimization objectives. In recent years, applying machine learning (ML) has effectively accelerated lead optimization. We established a comprehensive scoring function to guide molecular glue design. This manuscript describes how such a merit score was retrospectively applied to track optimization of a clinical molecular glue degrader series that resulted in the identification of Golcadomide (CC-99282). The application of these efficiency metrics in conjunction with a ML based merit score may accelerate identification of glue molecules development candidates
Insight into selectivity differences of glycerol electro-oxidation on Pt(111) and Ag(111)
No full textElectro-oxidation is a way to utilize glycerol, a byproduct of biodiesel production, to produce fuels and feedstock chemicals for the chemical industry. A significant challenge is to get products with high selectivity, so it is desirable to understand the glycerol oxidation mechanisms in further details. Using density functional theory calculations, we investigate possible glycerol oxidation intermediates on Pt(111) and Ag(111). We find that the different adsorption preferences of the intermediates on Pt (adsorption via carbon atoms) and on Ag (adsorption via oxygen atoms) lead to different preferred reaction pathways, resulting in different products. The reaction pathways on both surfaces involve glyceraldehyde as a key intermediate, however, upon further oxidation, Pt(111) preferentially produces glyceric acid (CH2OH-CHOH-COOH), while on Ag(111) C-C bonds are broken and leads to production of glycolaldehyde and formic acid (CH2OH-CHO and HCOOH). These predictions agrees well with the experimental outcome of electro-oxidation of glycerol on Pt and Ag surfaces. Our study therefore provides useful insights for optimizing the selectivity of glycerol oxidation and improving the utilization of glycerol
Visualization of membrane localization and functional state of CB2R pools by matched agonist and inverse agonist probe pairs
No full textThe diversity of physiological roles of the endocannabinoid system has turned it into an attractive yet elusive therapeutic target. However, chemical probes with various functionalities could pave the way for a better understanding of the endocannabinoid system at the cellular level. Notably, inverse agonists of CB2R – a key receptor of the endocannabinoid system - lagged behind despite the evidence regarding the therapeutic potential of its antagonism. Herein, we report a matched fluorescent probe pair based on a common chemotype to address and visualize both the active and inactive states of CB2R, selectively. Alongside with extensive cross-validation by flow cytometry and confocal microscopy, we successfully visualize the intracellular localization of CB2R pools in live cells. The synthetic simplicity together with the high CB2R-selectivity and specificity of our probes, turn them into valuable tools in chemical biology and drug development that can benefit the clinical translatability of CB2R-based drug
Optimized 13C-TrEnDi enhances the sensitivity of plasmenyl ether glycerophospholipids and demonstrates compatibility with other derivatization strategies
No full textThe identification and quantitation of plasmalogen glycerophospholipids is challenging due to their isobaric overlap with plasmanyl ether-linked glycerophospholipids, susceptibility to acid degradation, and their typically low abundance in biological samples. Trimethylation enhancement using diazomethane (TrEnDi) can be used to significantly enhance the signal of glycerophospholipids through the creation of quaternary ammonium groups producing fixed positive charges using 13C-diazomethane in complex lipid extracts. Although TrEnDi requires a strong acid for complete methylation, we report an optimized protocol using 9.6 mM HBF4 with the subsequent addition of a buffer solution that prevents acidic hydrolysis of plasmalogen species and enables the benefits of TrEnDi to be realized for this class of lipids. These optimized conditions were applied to aliquots of bovine liver extract (BLE) to achieve permethylation of plasmalogen lipids within a complex mixture. Treating aliquots of unmodified and TrEnDi-derivatized BLE samples with 80% formic acid and comparing their liquid chromatography mass spectrometry (LCMS) results to analogous samples not treated with formic acid, enabled the identification of 29 plasmalogen species. On average, methylated plasmalogen species from BLE demonstrated 2.81-fold and 28.1-fold sensitivity gains over unmodified counterparts for phosphatidylcholine and phosphatidylethanolamine plasmalogen species, respectively. Furthermore, the compatibility of employing 13C-TrEnDi and a previously reported iodoacetalization strategy was demonstrated to effectively identify plasmenyl-ether lipids in complex biological extracts at greater levels of sensitivity. Overall, we detail an optimized 13C-TrEnDi derivatization strategy that enables the analysis of plasmalogen glycerophospholipids with no undesired cleavage of radyl groups, boosting their sensitivity in LCMS and LCMS/MS analyses
Multigram Synthesis of 4,4-disubstituted-3-oxopyrrolidones – efficient starting material for diverse 3 functionalized pyrrolidones
No full textThe practical rapid development of chemical leads for drug discovery is strongly dependent on scalable procedures for building block synthesis. N-heterocyclic moieties, especially unsaturated ones, remain essential tools in the hands of screening and medicinal chemists. Here, we report four novel chemical block families and the interconversions between them. 4,4-disubstituted-3-oxopyrrolidones synthesis was an essential milestone in the diversity-oriented production of 3-aminopyrrolidones, 3-hydroxypyrrolidones and 3,3’-difluoropyrrolidines. Those can be functionalized with conformationally flexible spirocyclic substituents. We developed the multigram procedure for 4,4-disubstituted-3-oxopyrrolidones from commercially accessible and cost-saving reagents via the short three-step procedure. Also, here we are reporting the robust conversion procedure of 3-oxopyrrolidones to 3-aminopyrrolidones, 3,3’-difluoropyrrolidones and 3-hydroxypyrrolidones, involving a minimal amount of steps. We demonstrate the scope and limitations and further perspectives for such synthetic approaches
Lessons Learned from Semi-Empirical Methods for the Li-Ion Battery Solid Electrolyte Interphase
No full textStudying the chemical reactivity related to the solid electrolyte interphase (SEI) in lithium-ion batteries is challenging due to system heterogeneity (spatial and compositional). Semi-empirical methods have the potential to reduce the computational cost compared to the computationally costly DFT computations. In this study, we have first assessed the performance of four semi-empirical methods (GFN-xtb, GFN2-xtb, PM6-D3 and PM7-D3) to model major reactions for SEI formation and growth. We have included the major decomposition reactions of the most used solvent (ethylene carbonate), most used salt (lithium hexafluorophosphate) and other electrolyte species like the co-solvent 1,3-dioxolane and the additive vinylene carbonate. We have found that PM7-D3 and GFN-xtb are the two best performing methods for the 32 tested reactions. Finally, we have performed PM7-D3 and GFN-xtb -based molecular dynamics for inorganic/organic interfaces. We have found that LiF is the most rigid salt, which barely reconstructs. In contrast, Li2O is subject to severe reconstruction at the GFN-xtb level of theory, but significantly less when using PM7-D3. Still, even at the PM7-D3 level of theory Li2O readily reacts with alkyl carbonates, leading to CO2 dissociation and thus the formation of surface carbonates. When in contact with ethylene carbonate, the organic molecules undergo partial dehydrogenation reactions and ring openings. This suggests that Li2O is overly reactive to be in direct contact with such organic molecules. Rather, it is surrounded by a passivating (mono-)layer of Li2CO3. Indeed, our simulations suggest that such a hybrid system (core of Li2O, shell of Li2CO3, solvated with ethylene carbonate) the organic solvent remains intact
Influence of Acid Strength on Olefin Selectivity of Chabazite (CHA) Framework Zeolite/Zeotypes during Tandem CO2 Hydrogenation
No full textThe role of the Brønsted acid sites (BAS) strength of chabazite (CHA) framework on olefin selectivity during methanol-to-olefin (MTO) and tandem CO2 hydrogenation was investigated over an aluminosilicate, SSZ-13 and a silicoaluminophospate, SAPO-34 and their bifunctional admixtures with In2O3. During MTO, SSZ-13 and SAPO-34 yielded primarily olefins (cumulative selectivity of ~60% and ~90%, respectively at cumulative turn-over number, TON over 500). Interestingly, an interpellet admixture of In2O3/SSZ-13 (distance between redox sites and BAS of 260-900 µm)) predominantly yielded paraffins (cumulative selectivity of ~93% at cumulative TON over 40) via the secondary hydrogenation of olefins as seen from the cumulative paraffin-to-olefin (P/O) ratio of ~21 during CO2 hydrogenation. In comparison, an interpellet In2O3/SAPO-34 admixture yielded majority olefins (cumulative selectivity of ~67% at cumulative TON over 60) due to a lesser degree of secondary hydrogenation (cumulative P/O ratio of ~0.2) on the BAS in SAPO-34, which has a lower acid strength as compared to SSZ-13. Interestingly, both interpellet admixtures of In2O3/SSZ-13 and In2O3/SAPO-34 remained stable during tandem CO2 hydrogenation by favoring the olefin cycle and suppressing the formation of deactivation-inducing-aromatics, unlike MTO, where both admixtures showed fast deactivation. Ion-exchange of BAS (H+) with Inδ+ (from In2O3) in intrapellet admixtures (distance between redox sites and BAS of 270-1500 nm) of In2O3/SSZ-13, and In2O3/SAPO-34, inhibited C-C coupling and predominantly formed CH4. Overall, our study related to the product selectivity and deactivation in MTO and tandem CO2 hydrogenation over CHA framework zeolite/zeotype to the aromatic and olefin pool in the hydrocarbon pool mechanism. These underpinnings will help with rational catalyst design for tandem CO2 hydrogenation
The interplay between calcite crystal nucleation on polydiacetylene template and its amorphization by phosphoserine
No full textOrganisms use a diverse range of organic-inorganic hybrid materials for a variety of purposes, including mechanical support, navigation and protection. These materials are mostly crystalline and are characterized by unique composition, polymorph, crystallite size, shape and crystallographic orientation. The crystalline biominerals are generally formed through amorphous, hydrated transient minerals, but in some, the amorphous phases are stable and persist. Using a biomimetic approach, we address aspects of biological mineralization in vitro and gain insight into the processes and interactions that play roles in the natural systems, in-vivo. In this work, we demonstrate two essential but conflicting methods that are likely to act simultaneously in many mineralizing systems. These are directed crystal nucleation on organic templates, and on the other hand, crystal inhibition to produce the transient amorphous phase. The experimental method in this project mimics aspects of biomineralization processes of calcium carbonate (CaCO3) nucleation. Polydiacetylene (PDA) – a robust, linear conjugated polymer, made from amphiphilic long-chain diacetylene monomers, which upon surface compression, followed by UV polymerization form an ultrathin, stable monolayer structure. PDA simulates the organic template for the CaCO3 crystallization in our experimental system in that it exposed a dense array of acidic groups in well-defined orientation and being a semi-rigid template surface. On PDA templates, calcite crystals nucleate from a (01.2) face and in every single domain of the PDA film they are all coaligned with the crystals\u27 a-axes oriented parallel to the polymer backbone. Supersaturated solutions for CaCO3were prepared either by mixing CaCl2 and Na2CO3, or by bubbling CO2 into CaCO3 suspension, or by slow diffusion of ammonium carbonate into CaCl2 solution in a desiccator. Phosphoserine (P-ser) was added to CaCO3 deposition systems as a crystallization inhibitor, which results in amorphous calcium carbonate (ACC) deposition. The phosphate groups substitute a part of the carbonate groups during the deposition and this way, inhibit the crystallization process. Various concentrations of P-ser in deposition system on PDA templates result in different morphologies and degrees of crystallinity of CaCO3. In this biomimetic system, we demonstrate the conflicting, yet simultaneous influences on biological crystal formation, namely the ordered template and crystal nucleation and crystal inhibition
Utilizing Machine Learning to Model Interdependency of Bulk Molecular Weight, Solution Concentration, and Thickness of Spin Coated Polystyrene Thin Films
No full textSpin coating is a wide-spread, quick, and inexpensive method to create nanometer-thick thin films of various polymers, such as polystyrene, on top of solid substrates. Since the film thickness determines the mechanical, optical, and degradation properties of the coated film, it is essential to develop a simple method to predict thickness based on other manipulatable factors. In this study, a three-dimensional manifold relating initial solution concentration, thin film coverage thickness, and monodisperse bulk molecular weight is developed utilizing curve-fit machine learning. The model is able to receive polystyrene bulk molecular weight and desired thin film thickness as input and output an accurate prediction of initial solution concentration required to generate a coating of a desired thickness