Alkyne Moiety Research Articles

Heat-guided drug delivery via thermally induced crosslinking of polymeric micelles

Targeted drug delivery in response to external stimuli is therapeutically desirable, but long-term drug retention at the target site after stimulation is turned off remains a challenge. Herein, we present a targeted-delivery strategy via irreversible aggregation of drug carriers in response to mild external heating. We constructed two types of polymeric micelles, DBCO-TRM and Az-TRM, having a thermo-responsive polymer shell based on N-isopropylacrylamide (NIPAAm) and incorporating alkyne and azide moieties, respectively. Upon heating at 42 °C, the micelles aggregated through hydrophobic interaction between their dehydrated shells. Further, the azide moieties of Az-TRM become exposed on the surface due to the thermally shrinkage of the shells, thereby enabling crosslinking between the two types of micelles via azide-alkyne click chemistry to form irreversible aggregates. These aggregates were efficiently accumulated at tumor sites in mice by local heating after intravenous administration of a mixture of the micelles, and were well retained after cessation of heating due to their increased size. As proof of concept, we show that delivery of doxorubicin in this heat-guided drug delivery system dramatically improved the anti-tumor effect in a mouse model after a single treatment. Our results suggest that this platform could be an efficient tool for on-demand drug delivery.

Versatile immobilization of mimicking peptides on additively manufactured functionalized α-amino acid based poly(ester amide)s

α-Amino acid based polyester amides (AA-PEAs) exhibit remarkable properties, including biocompatibility, biodegradability, flexibility, thermal stability, and mechanical integrity. The incorporation of α-amino acids enhances cytocompatibility, hydrogen bonding, and favorable cell-polymer interactions, making AA-PEAs appealing for biomedical applications, notably tissue engineering. However, addressing complex tissue regeneration requires additional enhancements. Introducing biologically instructive factors, like growth factors and peptides, becomes essential to facilitate cell growth, proliferation, and differentiation.This study explores α-amino acid based functionalized polyester amides (AA-FPEAs) for their potential in tissue engineering, focusing on their underexplored role as thermoplastic resources for fused deposition modeling (FDM). Novel AA-FPEAs with alkyne moieties were synthesized and additively manufactured via FDM, highlighting their structure–property correlation. Employing a facile copper-free click chemistry strategy, we successfully attached a CGRGDS mimicking peptide to AA-FPEAs using UV light and a photoinitiator with water as a solvent. UV–Vis analysis confirmed the feasibility of the click reaction, and TOF-SIMS analysis verified CGRGDS attachment on AA-FPEA films and AM scaffolds. In vitro evaluation further demonstrated that AA-FPEAs support cell growth and proliferation, highlighting their biocompatibility. These findings underscore the potential of AA-FPEAs as versatile functionalized biomaterials for tissue engineering applications.

Profiling of i-motif-binding proteins reveals functional roles of nucleolin in regulation of high-order DNA structures.

Non-canonical DNA structures, such as the G-quadruplex (G4) and i-motif (iM), are formed at guanine- and cytosine-rich sequences, respectively, in living cells and involved in regulating various biological processes during the cell cycle. Therefore, the formation and resolution of these non-canonical structures must be dynamically regulated by physiological conditions or factors that can bind G4 and iM structures. Although many G4 binding proteins responsible for tuning the G4 structure have been discovered, the structural regulation of iM by iM-binding proteins remains enigmatic. In this study, we developed a protein-labeling DNA probe bearing an alkyne moiety through a reactive linker, for proximity-labeling of nucleic acid-binding proteins, and searched for new iM-binding proteins. Alkyne-modified proteins in the nuclear extract of HeLa cells were labeled with biotin via a click reaction and then captured with streptavidin-coated magnetic beads. This fingerprint-targeting enrichment, followed by proteome analyses, identified new candidate proteins that potentially bind to the iM structure, in addition to the reported iM-binding proteins. Among the newly identified candidates, we characterized a nucleolar protein, nucleolin, that binds to the iM structure and relaxes it, while nucleolin stabilizes the G4 structure.

Synthesis, Characterization, and Thin-Film Properties of Post-Functionalized N,N-Dimethylanilinoethynyl-Substituted Cyclobutenofullerenes.

A π-extended cyclobutenofullerene containing an N,N-dimethylanilinoethynyl group was synthesized via a one-pot cascade reaction of C60 with the corresponding propargylic phosphate. The cyclobutenofullerene was further modified using either one-pot or sequential post-functionalization methods, yielding derivatives containing altered addend structures. During one-pot post-functionalization, hydration reaction of the alkyne moiety continued after the formation of cyclobutenofullerenes. The sequential post-functionalization approach involved introducing the tetracyanobutadiene structure through formal [2 + 2] cycloaddition and a subsequent retroelectrocyclization reaction with tetracyanoethylene. The electronic and optical properties of the derivatives in solution, as well as their field-effect transistor behavior in thin films, were thoroughly assessed to elucidate the optoelectronic differences arising from various addend structures. The properties of the three characteristic cyclobutenofullerene derivatives in the solution and thin films significantly varied depending on the addends. Among the three derivatives studied, only cyclobutenofullerene, featuring a folded structure induced by the hydration of the alkyne moiety, exhibited n-type semiconductor behavior in the thin films. The findings of this study present a novel methodology for synthesizing and functionalizing fullerene derivatives, together with a conceptual framework for tailoring molecular properties.

Synthesis of Cyclic 2-Aminodienes and Aminobenzofulvenes by Rhodium-Catalyzed Hydroaminative Cyclization of Diynes.

Regioselective hydroaminative cyclizations of 1,5- and 1,6-diynes via double functionalization of an alkyne carbon were achieved using a phosphine-quinolinolato (PNO) rhodium catalyst. While the reaction of 1,6-diynes with secondary amines provided cyclic 2-aminodienes, phenylene-tethered 1,5-diynes were transformed into benzofulvene derivatives. The reaction is considered to proceed via in situ construction of an aminocarbene ligand, [2 + 2] addition with an internal alkyne moiety, and isomerization to an aminodiene structure. This hydroaminative cyclization proceeds just by heating the substrate with the rhodium catalyst without adding any additive and provides a convenient route to access cyclic 2-aminodiene and aminobenzofulvene derivatives.

Enhancing the Cumulene Character of One-Dimensional Acetylene-Based Systems by Stimuli-Induced Planarization of Their Two Pro-diradicaloid Cyclopenta[h,i]aceanthrylene Units.

Acetylene/polyynes -(C≡C-)n and cumulenes =(C=)n are connectors widely used for the realization of one-dimensional (1-D) π-conjugates. Although both π-moieties are constituted by sp carbon atoms, their different bond connectivity confers distinct physicochemical properties to the resulting systems. In this context, while many acetylene/polyyne- and cumulene-based derivatives have been prepared and studied, no reports have tackled the possibility to reversibly alter the acetylene/polyyne-cumulene electronic character of these derivatives using mild conditions. Herein, we present a novel approach to enhance the cumulene character of 1-D acetylene-based conjugates consisting in the preparation of derivatives featuring an acetylene moiety connecting two pro-diradicaloid species, namely cyclopenta[h,i]aceanthrylene (CPA), at their pro-radical positions. A thoughtful spectroscopic study of the prepared dimers, complemented by theoretical calculations, suggest a high π-electronic delocalization of the pro-diradicaloid CPAs through the central acetylene spacer upon the dimers' planarization which, in turn, increases the cumulenic character of the acetylenic π-bridge, a feature enhanced for one of the two dimers at low temperature and in methylcyclohexane due to an aggregation-induced planarization process. We reckon that the proposed approach offers an interesting avenue towards the realization of 1-D systems which cumulenic character of the acetylenic π-connector could be altered in response to external stimuli.

Enhancing the Cumulene Character of One‐Dimensional Acetylene‐Based Systems by Stimuli‐Induced Planarization of Their Two Pro‐diradicaloid Cyclopenta[h,i]aceanthrylene Units

Acetylene/polyynes –(C≡C–)n and cumulenes =(C=)n are connectors widely used for the realization of one‐dimensional (1‐D) π‐conjugates. Although both π‐moieties are constituted by sp carbon atoms, their different bond connectivity confers distinct physicochemical properties to the resulting systems. In this context, while many acetylene/polyyne‐ and cumulene‐based derivatives have been prepared and studied, no reports have tackled the possibility to reversibly alter the acetylene/polyyne‐cumulene electronic character of these derivatives using mild conditions. Herein, we present a novel approach to enhance the cumulene character of 1‐D acetylene‐based conjugates consisting in the preparation of derivatives featuring an acetylene moiety connecting two pro‐diradicaloid species, namely cyclopenta[h,i]aceanthrylene (CPA), at their pro‐radical positions. A thoughtful spectroscopic study of the prepared dimers, complemented by theoretical calculations, suggest a high π‐electronic delocalization of the pro‐diradicaloid CPAs through the central acetylene spacer upon the dimers’ planarization which, in turn, increases the cumulenic character of the acetylenic π‐bridge, a feature enhanced for one of the two dimers at low temperature and in methylcyclohexane due to an aggregation‐induced planarization process. We reckon that the proposed approach offers an interesting avenue towards the realization of 1‐D systems which cumulenic character of the acetylenic π‐connector could be altered in response to external stimuli.

Cascade Reactions of Alkynyl Ketones and Amides to Generate Unsaturated Oxacycles and Aromatic Carbocycles.

We describe novel amine-mediated transformation of alkynyl ketones and amides to generate 2-methylene-2H-pyrans, substituted 3-hydroxy-9H-fluoren-9-ones, and amine-incorporated arenes. These cascade processes are initiated by conjugate addition of secondary amine followed by hydrolysis of the enamine/vinylogous amide intermediates. The product distribution is highly sensitive to the steric and electronic effects of the substituents on both the alkyne moieties, the tether structure connecting them, and the nature of the amine. Alkynyl amide participates in the Alder-ene reaction favorably to generate more reactive allene amide that reacts with amine to generate amine-incorporated arene products. These metal-free cascade reactions are a useful synthetic method that can be exploited for the construction of various hetero- and carbocyclic systems.

Targeting the Plasmodium falciparum IspE Enzyme.

The enzyme IspE in Plasmodium falciparum is considered an attractive drug target, as it is essential for parasite survival and is absent in the human proteome. Yet it still has not been addressed by a small-molecule inhibitor. In this study, we conducted a high-throughput screening campaign against the PfIspE enzyme. Our approach toward a PfIspE inhibitor comprises in vitro screening, structure-activity relationship studies, examining the docking position using an AlphaFold model, and finally target verification through probe binding and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis. The newly synthesized probe containing a diazirine and an alkyne moiety (23) allowed us to demonstrate its binding to IspE in the presence of a lysate of human cells (HEK293 cells) and to get evidence that both probe 23 and the best inhibitor of the series (19) compete for the same IspE binding site.

Cyclohexanediamine Triazole (CHDT) Functionalization Enables Labeling of Target Molecules with Al18F/68Ga/111In.

The Al18F-labeling approach offers a one-step access to radiofluorinated biomolecules by mimicking the labeling process for radiometals. Although these labeling conditions are considered to be mild compared to classic radiofluorinations, improvements of the chelating units have led to the discovery of (±)-H3RESCA, which allows Al18F-labeling already at ambient temperature. While the suitability of (±)-H3RESCA for functionalization and radiofluorination of proteins is well established, its use for small molecules or peptides is less explored. Herein, we advanced this acyclic pentadentate ligand by introducing an alkyne moiety for the late-stage functionalization of biomolecules via click chemistry. We show that in addition to Al18F-labeling, the cyclohexanediamine triazole (CHDT) moiety allows stable complexation of 68Ga and 111In. Three novel CHDT-functionalized PSMA inhibitors were synthesized and their Al18F-, 68Ga-, and 111In-labeled analogs were subjected to a detailed in vitro radiopharmacological characterization. Stability studies in vitro in human serum revealed among others a high kinetic inertness of all radiometal complexes. Furthermore, the Al18F-labeled PSMA ligands were characterized for their biodistribution in a LNCaP derived tumor xenograft mouse model by PET imaging. One radioligand, Al[18F]F-CHDT-PSMA-1, bearing a small azidoacetyl linker at the glutamate-urea-lysine motif, provided an in vivo performance comparable to that of [18F]PSMA-1007 but with even higher tumor-to-blood and tumor-to-muscle ratios at 120 min p.i. Overall, our results highlight the suitability of the novel CHDT moiety for functionalization and radiolabeling of small molecules or peptides with Al18F, 68Ga, and 111In and the triazole ring seems to entail favorable pharmacokinetic properties for molecular imaging purposes.

Axial Ligand Enables Synthesis of Allenylsilane through Dirhodium(II) Catalysis.

Described herein is a dirhodium(II)-catalyzed silylation of propargyl esters with hydrosilanes, using tertiary amines as axial ligands. By adopting this strategy, a range of versatile and useful allenylsilanes can be achieved with good yields. This reaction not only represents a SN2'-type silylation of the propargyl derivatives bearing a terminal alkyne moiety to synthesize allenylsilanes from simple hydrosilanes, but also represents a new application of dirhodium(II) complexes in catalytic transformation of carbon-carbon triple bond. The highly functionalized allenylsilanes that are produced can be transformed into a series of synthetically useful organic molecules. In this reaction, an intriguing ON-OFF effect of the amine ligand was observed. The reaction almost did not occur (OFF) without addition of Lewis base amine ligand. However, the reaction took place smoothly (ON) after addition of only catalytic amount of amine ligand. Detailed mechanistic studies and density functional theory (DFT) calculations indicate that the reactivity can be delicately improved by the use of tertiary amine. The fine-tuning effect of the tertiary amine is crucial in the formation of the Rh-Si species via a concerted metalation deprotonation (CMD) mechanism and facilitating β-oxygen elimination.

Axial Ligand Enables Synthesis of Allenylsilane through Dirhodium(II) Catalysis

AbstractDescribed herein is a dirhodium(II)‐catalyzed silylation of propargyl esters with hydrosilanes, using tertiary amines as axial ligands. By adopting this strategy, a range of versatile and useful allenylsilanes can be achieved with good yields. This reaction not only represents a SN2′‐type silylation of the propargyl derivatives bearing a terminal alkyne moiety to synthesize allenylsilanes from simple hydrosilanes, but also represents a new application of dirhodium(II) complexes in catalytic transformation of carbon‐carbon triple bond. The highly functionalized allenylsilanes that are produced can be transformed into a series of synthetically useful organic molecules. In this reaction, an intriguing ON‐OFF effect of the amine ligand was observed. The reaction almost did not occur (OFF) without addition of Lewis base amine ligand. However, the reaction took place smoothly (ON) after addition of only catalytic amount of amine ligand. Detailed mechanistic studies and density functional theory (DFT) calculations indicate that the reactivity can be delicately improved by the use of tertiary amine. The fine‐tuning effect of the tertiary amine is crucial in the formation of the Rh−Si species via a concerted metalation deprotonation (CMD) mechanism and facilitating β‐oxygen elimination.

Rapid Access to Divergent Fused Polycycles Via One-Pot A3 Coupling and Intramolecular Diels-Alder Reaction.

Divergent nitrogen-containing fused polycyclic ring systems are constructed from simple starting materials via a one-pot aldehyde-alkyne-amine (A3) coupling and intramolecular Diels-Alder reaction. This domino reaction directly furnishes linear 5/5/5 and 5/5/6, or nonlinear 5/5/6/5, polycyclic rings containing an oxa-bridged fused 5/5 bicycle and a 1,6-enyne substructure. One-step derivation of the oxa-bridged 5/5 bicycle leads to a polyfunctionalized 5/5 bicycle with tetrahydrofuran fused back-to-back to pyrroline or a 6/5 bicycle with the hexahydro-1H-isoindole structure, while cycloisomerizing the enyne substructure adds an extra fused 5-membered ring to afford functionalized linear 5/5/5/5 or 5/5/5/5/5 fused ring systems from selected substrates. In addition, the one-pot product can be designed so that the alkyne moiety is hydroalkoxylated to form an additional heterocyle in a linear 5/5/5/6 or nonlinear 5/5/6/5/5 ring system. This diversity-oriented synthetic approach thus allows rapid access to an under-explored structural space for discovery of new biological or non-biological activities or functions.

On the Auxetic Potential of Synthesizable Calix[4]arene Polymers

Materials exhibiting auxetic behavior have garnered significant interest due to their potential applications across various fields, with synthetic auxetic materials being one such group. Theoretical studies have demonstrated the potential for various organic polymeric systems to exhibit auxetic behavior. However, to date, only a few synthesized molecular systems have shown some degree of auxetic behavior. Among the theoretical classes of molecular systems that have attracted attention are calix[4]arene systems in the “egg‐rack” conformation. While the theoretical systems proposed in the literature have been deemed difficult to synthesize, calix[4]arene chemistry has advanced tremendously in recent years. In fact, a number of molecular systems with configurations similar to those predicted to exhibit a negative Poisson's ratio have been synthesized, albeit with different chemical moieties. Consequently, it is deemed valuable to study the potential of these synthesized systems to exhibit a negative Poisson's ratio through force‐field‐based simulations. This study is extended to include theoretical calix[4]arene systems linked by acetylene moieties, which are also potentially synthesizable through known methods. It is suggested that these materials can exhibit auxetic behavior when subjected to on‐axis loading in the [001] direction. A detailed mechanistic study of these systems is also conducted.

Constructing Pd and Cu Crowding Single Atoms by Protein Confinement to Promote Sonogashira Reaction.

For multicenter-catalyzed reactions, it is important to accurately construct heterogeneous catalysts containing multiple active centers with high activity and low cost, whichis more challenging compared to homogeneous catalysts because of the low activity and spatial confinement of active centers in the loaded state. Herein, a convenient protein confinement strategy is reported to locate Pd and Cu single atoms in crowding state on carbon coated alumina for promoting Sonogashira reaction, the most powerful method for constructing the acetylenic moiety in molecules. The single-atomic Pd and Cu centers take advantage in not only the maximized atomic utilization for low cost, but also the much-enhanced performance by facilitating the activation of aryl halides and alkynes. Their locally crowded dispersion brings them closer to each other, which facilitates the transmetallation process of acetylide intermediates between them. Thus, the Sonogashira reaction is drove smoothly by the obtained catalyst with a turnover frequency value of 313 h-1, much more efficiently than that by commercial Pd/C and CuI catalyst, conventional Pd and Cu nanocatalysts, and mixed Pd and Cu single-atom catalyst. The obtained catalyst also exhibits the outstanding durability in the recycling test.

Migration of Condensed Aromatic Hydrocarbons During Alkyne-Vinylidene Rearrangements.

Diarylacetylenes ArC≡CAr featuring condensed aromatic hydrocarbon fragments (Ar) such as naphthalene, anthracene, phenanthrene and pyrene were converted into vinylidene ligands by 1,2-migration reactions within the coordination sphere of half-sandwich complexes [MII(dppe)Cp]+ (MII = RuII, FeII). Comparison of the extent of conversion of the alkyne substrates to the vinylidene complexes [Ru{=C=CAr2}(dppe)Cp]+ with those obtained from acetylenes functionalized by smaller groups (H, CH3, Ph) show that the molecular volume (VM) of the migrating group and relief of steric congestion plays a role during the rearrangement process. Conversely, the H-atoms from the larger condensed ring aryl groups that are in close proximity to the migrating sites also have a significant influence on the efficacy and extent of the reaction by restricting access of the alkyne to the metal center, resulting in a less effective migration reaction. This combination of competing steric factors (acceleration due to relief of steric congestion and restricted access of the alkyne moiety to the reaction site) is exemplified by the facile migration of 1-pyryl entities and the low yields of vinylidene products formed from 1,2-bis(9-anthryl)acetylene.

A β-Glucosyl Sterol Probe for in situ Fluorescent Labelling in Neuronal Cells to Investigate Neurodegenerative Diseases.

A β-glucosyl sterol probe bearing a terminal alkyne moiety for fluorescent tagging enables the investigation of the neuronal and intracellular localization of this class of compounds involved in neurodegenerative diseases. The compound showed localization in the neuronal cells, with marked differences in the uptake and metabolism leading to enhanced persistence with respect to the un-glycosylated sterol analogue. In addition, a different impact was observed towards lysosomes, with the simple sterol probe showing the enlargement of the lysosome structures, while the β-glucosyl sterol was less capable to alter the morphology of this specific organelle.

Synthesis of mannose conjugated biodegradable polyester-based nanocarriers and their binding study with Concanavalin A

In this paper, we aim to create fully biodegradable glyconanoparticles formed via self-assembly of glycopolymers, comprising of biodegradable aliphatic polyester conjugated with mannose moiety. To accomplish the goal, a series of random copolymers comprised of poly(propargyl glycolide-co-lactide) were synthesized. Alkyne moiety of the poly (propargyl glycolide) component was then clicked with mannose ethyl azide to produce amphiphilic glycopolymers in good yield (60–75 %). The glycopolymers were then self-assembled to form glyconanoparticles of 15–23 nm size in dry state and 78–88 nm size in hydrated state (hydrodynamic diameter). The copolymers were characterized by NMR and FTIR, whereas the nanoparticles were thoroughly characterized by DLS, FESEM, and HR-TEM and explored for their lectin binding efficiency. Isothermal calorimetry (ITC) experiments suggest a stronger binding efficiency of glyconanoparticles towards mannose-specific lectin such as Concanavalin A, as compared to its corresponding glycopolymers (∼2 fold) and monomeric mannose unit (∼7-fold) as well. Moreover, curcumin was selected as the model drug to be encapsulated (∼76 % encapsulation efficiency) and released (74 % in 24 h) from the glyconanoparticles. Apart from these, excellent haemocompatibility, cell viability, and cellular uptake of the nanoparticles (more than 80 % cells showed uptake of the nanoparticles), further supported their potential as drug carriers having sugar as a targeting moiety.

Optical Fiber-Assisted Printing: A Platform Technology for Straightforward Photopolymer Resins Patterning and Freeform 3D Printing.

Light-based 3D printing techniques represent powerful tools, enabling the precise fabrication of intricate objects with high resolution and control. An innovative addition to this set of printing techniques is Optical Fiber-Assisted Printing (OFAP) introduced in this article. OFAP is a platform utilizing an LED-coupled optical fiber (LOF) that selectively crosslinks photopolymer resins. It allows change of parameters like light intensity and LOF velocity during fabrication, facilitating the creation of structures with progressive features and multi-material constructs layer-by-layer. An optimized formulation based on allyl-modified gelatin (gelAGE) with food dyes as photoabsorbers is introduced. Additionally, a novel gelatin-based biomaterial, alkyne-modified gelatin (gelGPE), featuring alkyne moieties, demonstrates near-visible light absorption thus fitting OFAP needs, paving the way for multifunctional hydrogels through thiol-yne click chemistry. Besides 2D patterning, OFAP is transferred to embedded 3D printing within a resin bath demonstrating the proof-of-concept as a novel printing technology with potential applications in tissue engineering and biomimetic scaffold fabrication, offering rapid and precise freeform printing capabilities.

Ytterbium(II) Complex-Catalyzed Selective Single and Double Hydrophosphination of 1,3-Enynes.

1,3-Enynes with conjugated alkene and alkyne moieties are attractive building blocks in synthetic chemistry. However, neither 4,1-hydrophosphination nor dihydrophosphination of 1,3-enynes has been reported. In this paper, the divalent ytterbium and calcium amide complexes supported by silaimine-functionalized cyclopentadienyl ligands (C5Me4-Si(L)=NR) were developed, which successfully catalyzed the efficient single and double hydrophosphination of 1,3-enynes with diarylphosphines. The hydrophosphination reactions selectively produced homoallenyl phosphines and (E)-propenylene diphosphines, respectively. This work demonstrated the potential of hemilabile silaimine-Cp ligands in the supporting the efficient and selective rare- and alkaline-earth catalysts.