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STAR Protocols Dec 2023In this protocol, we describe highly (E)-selective alkyne semihydrogenation employing commercially available iridium complex and a bidentate phosphine ligand. We provide...
In this protocol, we describe highly (E)-selective alkyne semihydrogenation employing commercially available iridium complex and a bidentate phosphine ligand. We provide steps for (E)-stilbene synthesis, remaining formic acid neutralization, and determination of the (Z)/(E) ratio using gas chromatography analysis. We then detail (E)-stilbene purification using a short pad of silica and NMR analysis. The protocol is compatible with a wide range of functionalities and different types of alkynes. For complete details on the use and execution of this protocol, please refer to Kusy et al. (2022)..
Topics: Iridium; Alkynes; Stilbenes
PubMed: 37733598
DOI: 10.1016/j.xpro.2023.102579 -
Beilstein Journal of Organic Chemistry 2023A library of 19 differently substituted 3-iodoindoles is generated by a consecutive four-component reaction starting from -haloanilines, terminal alkynes,...
A library of 19 differently substituted 3-iodoindoles is generated by a consecutive four-component reaction starting from -haloanilines, terminal alkynes, -iodosuccinimide, and alkyl halides in yields of 11-69%. Initiated by a copper-free alkynylation, followed by a base-catalyzed cyclizive indole formation, electrophilic iodination, and finally electrophilic trapping of the intermediary indole anion with alkyl halides provides a concise one-pot synthesis of 3-iodoindoles. The latter are valuable substrates for Suzuki arylations, which are exemplified with the syntheses of four derivatives, some of them are blue emitters in solution and in the solid state, in good yield.
PubMed: 37736394
DOI: 10.3762/bjoc.19.99 -
Biomacromolecules May 2024Linear-dendritic block copolymers assemble in solution due to differences in the solubility or charge properties of the blocks. The monodispersity and multivalency of...
Modular Synthesis of PEG-Dendritic Block Copolymers by Thermal Azide-Alkyne Cycloaddition with Internal Alkynes and Evaluation of their Self-Assembly for Drug Delivery Applications.
Linear-dendritic block copolymers assemble in solution due to differences in the solubility or charge properties of the blocks. The monodispersity and multivalency of the dendritic block provide unparalleled control for the design of drug delivery systems when incorporating poly(ethylene glycol) (PEG) as a linear block. An accelerated synthesis of PEG-dendritic block copolymers based on the click and green chemistry pillars is described. The tandem composed of the thermal azide-alkyne cycloaddition with internal alkynes and azide substitution is revealed as a flexible, reliable, atom-economical, and user-friendly strategy for the synthesis and functionalization of biodegradable (polyester) PEG-dendritic block copolymers. The high orthogonality of the sequence has been exploited for the preparation of heterolayered copolymers with terminal alkenes and alkynes, which are amenable for subsequent functionalization by thiol-ene and thiol-yne click reactions. Copolymers with tunable solubility and charge were so obtained for the preparation of various types of nanoassemblies with promising applications in drug delivery.
Topics: Alkynes; Azides; Click Chemistry; Cycloaddition Reaction; Dendrimers; Drug Delivery Systems; Polyethylene Glycols; Polymers
PubMed: 38613487
DOI: 10.1021/acs.biomac.3c01429 -
ACS Catalysis Nov 2023Two bench-stable Fe(II) alkyl complexes [Fe(κPCP-PCP-Pr)(CO)(R)] (R = CHCHCH, CH) were obtained by the treatment of [Fe(κPCP-PCP-Pr)(CO)(H)] with NaNH and subsequent...
Two bench-stable Fe(II) alkyl complexes [Fe(κPCP-PCP-Pr)(CO)(R)] (R = CHCHCH, CH) were obtained by the treatment of [Fe(κPCP-PCP-Pr)(CO)(H)] with NaNH and subsequent addition of CHCHCHBr and CHI, respectively. The reaction proceeds via the anionic Fe(0) intermediate Na[Fe(κPCP-PCP-Pr)(CO)]. The catalytic performance of both alkyl complexes was investigated for the transfer hydrogenation of terminal and internal alkynes utilizing PhSiH and PrOH as a hydrogen source. Precatalyst activation is initiated by migration of the alkyl ligand to the carbonyl C atom of an adjacent CO ligand. In agreement with previous findings, the rate of alkyl migration follows the order Pr > Me. Accordingly, [Fe(κPCP-PCP-Pr)(CO)(CHCHCH)] is the more active catalyst. The reaction takes place at 25 °C with a catalyst loading of 0.5 mol%. There was no overhydrogenation, and in the case of internal alkynes, exclusively, -alkenes are formed. The implemented protocol tolerates a variety of electron-donating and electron-withdrawing functional groups including halides, nitriles, unprotected amines, and heterocycles. Mechanistic investigations including deuterium labeling studies and DFT calculations were undertaken to provide a reasonable reaction mechanism.
PubMed: 37942266
DOI: 10.1021/acscatal.3c04156 -
ACS Omega Dec 2023The catalytic activity of methyltrifluoromethanesulfonate (MeOTf) has been explored toward direct nucleophilic substitution of the hydroxyl group of nonmanipulated...
The catalytic activity of methyltrifluoromethanesulfonate (MeOTf) has been explored toward direct nucleophilic substitution of the hydroxyl group of nonmanipulated alcohols such as benzylic, allylic, propargylic, and tertiary alcohols with a wide range of uncharged nucleophiles such as 1,3-dicarbonyl compounds, amides, alkynes, and indoles to generate functionalized 1,3-dicarbonyl compounds, amides, alkynes, and indoles, respectively. Thus, the present protocol defines an alternate pathway to construct new C-C, C-N, and C-O bonds with the formation of water as the byproduct under mild conditions without any acids or metals. A completely different mechanism was established through several control experiments to explain the reaction methodology. As an application of the reported protocol, 1-indene derivatives have been synthesized in one pot when benzylic alcohols were subjected to react with internal alkynes. The scope of the reaction has been further extended toward a tandem benzylation-cyclization-dehydration of 1,3-dicarbonyl compounds with 2-hydroxybenzyl alcohols, which furnish biologically important 4-chromene derivatives.
PubMed: 38107960
DOI: 10.1021/acsomega.3c05619 -
Molecules (Basel, Switzerland) May 2024A versatile family of quaternary propargylamines was synthesized employing the KA multicomponent reaction, through the single-step coupling of a number of amines,...
A versatile family of quaternary propargylamines was synthesized employing the KA multicomponent reaction, through the single-step coupling of a number of amines, ketones, and terminal alkynes. Sustainable synthetic procedures using transition metal catalysts were employed in all cases. The inhibitory activity of these molecules was evaluated against human monoaminoxidase (hMAO)-A and hMAO-B enzymes and was found to be significant. The IC values for hMAO-B range from 152.1 to 164.7 nM while the IC values for hMAO-A range from 765.6 to 861.6 nM. Furthermore, these compounds comply with Lipinski's rule of five and exhibit no predicted toxicity. To understand their binding properties with the two target enzymes, key interactions were studied using molecular docking, all-atom molecular dynamics (MD) simulations, and MM/GBSA binding free energy calculations. Overall, herein, the reported family of propargylamines exhibits promise as potential treatments for neurodegenerative disorders, such as Parkinson's disease. Interestingly, this is the first time a propargylamine scaffold bearing an internal alkyne has been reported to show activity against monoaminoxidases.
Topics: Alkynes; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Humans; Molecular Docking Simulation; Molecular Dynamics Simulation; Pargyline; Propylamines; Structure-Activity Relationship; Molecular Structure
PubMed: 38893361
DOI: 10.3390/molecules29112486 -
Organic Letters Feb 2024Sulfoximines and pyrazoles are both important motifs in medicinal compounds. Here we report the synthesis and reactivity of sulfoximine diazo compounds as new reagents...
Sulfoximines and pyrazoles are both important motifs in medicinal compounds. Here we report the synthesis and reactivity of sulfoximine diazo compounds as new reagents for the incorporation of sulfoximines. The use of -silyl sulfoximines enabled formation of monosubstituted diazo compounds. Their application is demonstrated in a [3 + 2] cycloaddition with alkynes to form pyrazole sulfoximines in a new combination of these important chemotypes. Further derivatization of the pyrazole sulfoximines is demonstrated, including silyl deprotection to form unprotected pyrazolesulfoximines.
PubMed: 38306458
DOI: 10.1021/acs.orglett.3c04274 -
Biomedicine & Pharmacotherapy =... May 2024Parkinson's disease (PD) is a complex neurodegenerative disorder with an unclear etiology. Despite significant research efforts, developing disease-modifying treatments...
Parkinson's disease (PD) is a complex neurodegenerative disorder with an unclear etiology. Despite significant research efforts, developing disease-modifying treatments for PD remains a major unmet medical need. Notably, drug repositioning is becoming an increasingly attractive direction in drug discovery, and computational approaches offer a relatively quick and resource-saving method for identifying testable hypotheses that promote drug repositioning. We used an artificial intelligence (AI)-based drug repositioning strategy to screen an extensive compound library and identify potential therapeutic agents for PD. Our AI-driven analysis revealed that efavirenz and nevirapine, approved for treating human immunodeficiency virus infection, had distinct profiles, suggesting their potential effects on PD pathophysiology. Among these, efavirenz attenuated α-synuclein (α-syn) propagation and associated neuroinflammation in the brain of preformed α-syn fibrils-injected A53T α-syn Tg mice and α-syn propagation and associated behavioral changes in the C. elegans BiFC model. Through in-depth molecular investigations, we found that efavirenz can modulate cholesterol metabolism and mitigate α-syn propagation, a key pathological feature implicated in PD progression by regulating CYP46A1. This study opens new avenues for further investigation into the mechanisms underlying PD pathology and the exploration of additional drug candidates using advanced computational methodologies.
Topics: Cyclopropanes; Alkynes; Benzoxazines; Drug Repositioning; Animals; alpha-Synuclein; Parkinson Disease; Artificial Intelligence; Mice; Caenorhabditis elegans; Mice, Transgenic; Humans; Nevirapine; Disease Models, Animal; Mice, Inbred C57BL
PubMed: 38513596
DOI: 10.1016/j.biopha.2024.116442 -
Organic Letters Mar 2024A carboxylate-catalyzed, metal-free -silylation protocol for terminal alkynes is reported using a quaternary ammonium pivalate as the catalyst and commercially available...
A carboxylate-catalyzed, metal-free -silylation protocol for terminal alkynes is reported using a quaternary ammonium pivalate as the catalyst and commercially available ,-bis(silyl)acetamides as silylating agents. The reaction proceeds under mild conditions, tolerates a range of functionalities, and enables concomitant - or -silylation of acidic OH or NH groups. A Hammett ρ value of +1.4 ± 0.1 obtained for -substituted 2-arylalkynes is consistent with the proposed catalytic cycle involving a turnover-determining deprotonation step.
PubMed: 38428925
DOI: 10.1021/acs.orglett.3c04213 -
Structure-Inherent Tumor-Targeted IR-783 for Near-Infrared Fluorescence-Guided Photothermal Therapy.International Journal of Molecular... May 2024IR-783, a commercially available near-infrared (NIR) heptamethine cyanine dye, has been used for selective tumor imaging in breast, prostate, cervical, and brain cancers...
IR-783, a commercially available near-infrared (NIR) heptamethine cyanine dye, has been used for selective tumor imaging in breast, prostate, cervical, and brain cancers in vitro and in vivo. Although the molecular mechanism behind the structure-inherent tumor targeting of IR-783 has not been well-demonstrated, IR-783 has unique properties such as a good water solubility and low cytotoxicity compared with other commercial heptamethine cyanine dyes. The goal of this study is to evaluate the phototherapeutic efficacy of IR-783 as a tumor-targeted photothermal agent in human colorectal cancer xenografts. The results demonstrate that IR-783 shows both the subcellular localization in HT-29 cancer cells and preferential accumulation in HT-29 xenografted tumors 24 h after its intravenous administration. Furthermore, the IR-783 dye reveals the superior capability to convert NIR light into heat energy under 808 nm NIR laser irradiation in vitro and in vivo, thereby inducing cancer cell death. Taken together, these findings suggest that water-soluble anionic IR-783 can be used as a bifunctional phototherapeutic agent for the targeted imaging and photothermal therapy (PTT) of colorectal cancer. Therefore, this work provides a simple and effective approach to develop biocompatible, hydrophilic, and tumor-targetable PTT agents for targeted cancer phototherapy.
Topics: Humans; Photothermal Therapy; Animals; Mice; Xenograft Model Antitumor Assays; HT29 Cells; Carbocyanines; Mice, Nude; Infrared Rays; Colorectal Neoplasms; Fluorescent Dyes; Fluorescence; Mice, Inbred BALB C
PubMed: 38791347
DOI: 10.3390/ijms25105309