Versatile Scaffold Research Articles

Advances in the Synthesis of 3‐Acyl‐2‐Pyridones: Strategies and Methods for Accessing the Versatile Scaffold

ABSTRACTThe syntheses and bioevaluation of 3‐acyl‐2‐pyridones have garnered significant interest in recent years as a novel class of compounds with diverse biological activities. The bioactivities cover a wide range of therapeutic areas including antimicrobial, antitumor, anti‐inflammatory, antifungal, antibiotic, neuritogenic, cytotoxic, and antiviral activities. Therefore, 3‐acyl‐2‐pyridone scaffold offers a versatile platform for the development of new molecules with potential applications in medicinal chemistry. The recent exploration on synthesis and bioevaluation of 3‐acyl‐2‐pyridones has yielded promising results, making them attractive targets for further optimization and development of new therapeutic agents. This review summarizes the available information on total synthesis of 3‐acyl‐2‐pyridone containing natural products, and the other synthetic strategies developed for accessing the 3‐acyl pyridones such as multicomponent synthesis, condensation reaction, microwave‐assisted synthesis, catalytic hydrogenation reactions, metalation reaction, Michael addition, and formylation reactions. The presented information may serve as a valuable resource for researchers working in the field of medicinal chemistry and drug discovery, stimulating further exploration and development of this intriguing scaffold.

Finely tunable NIR‐II organic scaffolds for fluorescence/photoacoustic duplex imaging–guided noninvasive photothermal therapy of glioblastoma

AbstractOrganic agents possessing NIR‐II and photoacoustic duplex imaging capabilities, coupled with high‐efficiency photothermal conversion, offer significant potential for noninvasive and precise phototheranostics of glioblastoma, which is further augmented when these agents can concurrently exhibit tumor targeting and blood–brain barrier (BBB) permeability. This study reports a series of finely tunable NIR‐II molecular luminophores based on the aza‐BODIPY scaffold, featuring unique twisted and rotatable structures. They are further constructed to folate‐decorated polymeric nanoparticles, exhibiting remarkable NIR‐II/photoacoustic imaging performance and superior photothermal conversion efficiency (49.7%). Folate modification enables tumor targeting and BBB permeability through receptor‐mediated transcytosis, allowing for precise and efficient phototherapy in 4T1‐/glioblastoma‐bearing mice after a single intravenous injection and irradiation. This study presents a rational molecular engineering approach and a versatile structural scaffold for designing NIR‐II emitters with tailored photophysical properties and desirable phototherapeutic efficacy, thereby offering novel perspectives on the development of advanced depth imaging probes and brain tumor therapeutics.

Indole Derivatives: A Versatile Scaffold in Modern Drug Discovery-An Updated Review on Their Multifaceted Therapeutic Applications (2020-2024).

Indole derivatives have become an important class of compounds in medicinal chemistry, recognized for their wide-ranging biological activities and therapeutic potential. This review provides a comprehensive overview of recent advances in the evaluation of indole-based compounds in the last five years, highlighting their roles in cancer treatment, infectious disease management, anti-inflammatory therapies, metabolic disorder interventions, and neurodegenerative disease management. Indole derivatives have shown significant efficacy in targeting diverse biological pathways, making them valuable scaffolds in designing new drugs. Notably, these compounds have demonstrated the ability to combat drug-resistant cancer cells and pathogens, a significant breakthrough in the field, and offer promising therapeutic options for chronic diseases such as diabetes and hypertension. By summarizing recent key findings and exploring the underlying biological mechanisms, this review underscores the potential of indole derivatives in addressing major healthcare challenges, thereby instilling hope and optimism in the field of modern medicine.

A biodegradable piezoelectric scaffold promotes spinal cord injury nerve regeneration

Neural repair and regeneration remain one of the greatest challenges in regenerative medicine. The incorporation of intelligent scaffolds with noninvasive in vivo electrical stimulation illustrates considerable potential for tissue repair and regeneration. Nevertheless, the development of biomaterials that possess both biodegradable tissue scaffolds and electrical stimulation capabilities at a high level remains a significant obstacle. In this study, we effectively integrated the organic piezoelectric material poly-L-lactic acid (PLLA) with inorganic piezoelectric nanowires (potassium sodium niobate coated with polydopamine, KNN@PDA) to fabricate PLLA/KNN@PDA piezoelectric composite fibers. These fibers exhibit in-situ electrical stimulation capabilities, rendering them suitable for direct application in living tissues. The PLLA/KNN@PDA piezoelectric composite fibers not only function as biodegradable scaffolds for regenerative tissue engineering and platforms for in-situ electrical stimulation to enhance dorsal root ganglion axon growth, proliferation, and neuronal differentiation but also serve as versatile scaffolds for broader tissue engineering applications. In the complete spinal cord transection rat model, the piezoelectric scaffold enabled the recovery of rat motor function, indicating its significant ability to promote tissue formation and regeneration. Therefore, combining biodegradable piezoelectric tissue scaffolds with in situ electrical stimulation has significant therapeutic advantages for spinal cord injury repair and may be extended to other damaged tissues regeneration.

Chalcone and derived natural products: versatile scaffolds for multiple targets in treatment of Type 2 diabetes

Chalcone and derived natural products: versatile scaffolds for multiple targets in treatment of Type 2 diabetes

In vitro and in silico DNA interaction studies of a series of 3-carboxamide-4-quinolone derivatives prepared from an one-pot stepwise synthesis (OPSS) method

The 3-carboxamide-4-quinolone framework is highly regarded in the fields of Medicinal and Bioorganic Chemistry mainly due to its widespread bioactive properties. This versatile scaffold allows for the development of compounds with various pharmacological effects. In this sense, the present work explores a novel one-pot stepwise (OPPS) method for synthesizing fifteen 3-carboxamide-4-quinolone derivatives, some of which exhibit antitumor profiles in previous works. These compounds were synthesized using the OPPS methodology with yields ranging from 35 % to 88 %, streamlining the synthetic process and reducing solvent usage. Furthermore, interaction studies with calf-thymus DNA were done by UV–Vis absorption and steady-state fluorescence measurements combined with molecular docking calculations. Compounds 10a-b, 10d-g, 10k, and 10n were selected for the CT-DNA interaction assays, from which it was possible to demonstrate their DNA-binding property through peripheral secondary interactions. Molecular docking results suggested van der Waals and hydrogen bonds as the main binding forces responsible for the interactive profile between the nucleobases and the 3-carboxamide-4-quinolone derivatives. All these results unveiled promising insights into their role as DNA replication inhibitors, highlighting their potential in developing antiproliferative drugs.

Suspension electrospinning of decellularized extracellular matrix: A new method to preserve bioactivity

Decellularized extracellular matrices (dECM) have strong regenerative potential as tissue engineering scaffolds; however, current clinical options for dECM scaffolds are limited to freeze-drying its native form into sheets. Electrospinning is a versatile scaffold fabrication technique that allows control of macro- and microarchitecture. It remains challenging to electrospin dECM, which has led researchers to either blend it with synthetic materials or use enzymatic digestion to fully solubilize the dECM. Both strategies reduce the innate bioactivity of dECM and limit its regenerative potential. Herein, we developed a new suspension electrospinning method to fabricate a pure dECM fibrous mesh that retains its innate bioactivity. Systematic investigation of suspension parameters was used to identify critical rheological properties required to instill “spinnability,” including homogenization, concentration, and particle size. Homogenization enhanced particle interaction to impart the requisite elastic behavior to withstand electrostatic drawing without breaking. A direct correlation between concentration and viscosity was observed that altered fiber morphology; whereas, particle size had minimal impact on suspension properties and fiber morphology. The versatility of this new method was demonstrated by electrospinning dECM with three common decellularization techniques (Abraham, Badylak, Luo) and tissue sources (intestinal submucosa, heart, skin). Bioactivity retention after electrospinning was confirmed using cell proliferation, angiogenesis, and macrophage polarization assays. Collectively, these findings provide a framework for researchers to electrospin dECM for diverse tissue engineering applications.

Nanoparticles in Bone Regeneration: A Narrative Review of Current Advances and Future Directions in Tissue Engineering.

The rising demand for effective bone regeneration has underscored the limitations of traditional methods like autografts and allografts, including donor site morbidity and insufficient biological signaling. This review examines nanoparticles (NPs) in tissue engineering (TE) to address these challenges, evaluating polymers, metals, ceramics, and composites for their potential to enhance osteogenesis and angiogenesis by mimicking the extracellular matrix (ECM) nanostructure. The methods involved synthesizing and characterizing nanoparticle-based scaffoldsand integrating hydroxyapatite (HAp) with polymers to enhance mechanical properties and osteogenic potential. The results showed that these NPs significantly promote cell growth, differentiation, and bone formation, with carbon-based NPs like graphene and carbon nanotubes showing promise. NPs offer versatile, biocompatible, and customizable scaffolds that enhance drug delivery and support bone repair. Despite promising results, challenges with cytotoxicity, biodistribution, and immune responses remain. Addressing these issues through surface modifications and biocompatible molecules can improve the biocompatibility and efficacy of nanomaterials. Future research should focus on long-term in vivo studies to assess the safety and efficacy of NP-based scaffolds and explore synergistic effects with other bioactive molecules or growth factors. This review underscores the transformative potential of NPs in advancing BTE and calls for further research to optimize these technologies for clinical applications.

Foam fractionation studies of recombinant human apolipoprotein A-I

Apolipoprotein A-I (apoA-I), the primary protein component of plasma high-density lipoproteins (HDL), is comprised of two structural regions, an N-terminal amphipathic α-helix bundle domain (residues 1–184) and a hydrophobic C-terminal domain (residues 185–243). When a recombinant fusion protein construct [bacterial pelB leader sequence – human apoA-I (1–243)] was expressed in Escherichia coli shaker flask cultures, apoA-I was recovered in the cell lysate. By contrast, when the C-terminal domain was deleted from the construct, large amounts of the truncated protein, apoA-I (1–184), were recovered in the culture medium. Consequently, following pelB leader sequence cleavage in the E. coli periplasmic space, apoA-I (1–184) was secreted from the bacteria. When the pelB-apoA-I (1–184) fusion construct was expressed in a 5 L bioreactor, substantial foam production (~30 L) occurred. Upon foam collection and collapse into a liquid foamate, SDS-PAGE revealed that apoA-I (1–184) was the sole major protein present. Incubation of apoA-I (1–184) with phospholipid vesicles yielded reconstituted HDL (rHDL) particles that were similar in size and cholesterol efflux capacity to those generated with full-length apoA-I. Mass spectrometry analysis confirmed that pelB leader sequence cleavage occurred and that foam fractionation did not result in unwanted protein modifications. The facile nature and scalability of bioreactor-based apolipoprotein foam fractionation provide a novel means to generate a versatile rHDL scaffold protein.

Single-Walled Carbon Nanotubes As Fluorescent Probes for Supramolecular Self-Assembly Complexes

Semiconducting single-walled carbon nanotubes (SWCNTs) are distinguished by their fluorescence in the near-infrared range, which overlaps with the transparency window of biological samples, and they do not photobleach or blink. Utilizing their unique optical properties, SWCNTs can be rendered optical probes for the characterization and analysis of bio-inspired peptide-based hydrogels. Peptide hydrogels, formed through the supramolecular self-assembly of conjugated amino acids, provide versatile three-dimensional scaffolds for applications in cell culture, tissue engineering, and regenerative medicine. The inherent properties of these amino acids or peptides, notably their limited solubility in water, drive them to self-assemble into elongated fibrillary nanostructures, ultimately creating self-supporting hydrogel matrices. We integrate near-infrared fluorescent SWCNTs into these peptide hydrogels as dynamic fluorescent probes, offering real-time insights into the morphological and structural evolution of the hydrogels. This approach not only enhances our understanding of the self-assembly mechanisms at play but also opens new avenues in supramolecular science. The integration of SWCNTs into the supramolecular structures showcases their potential as a powerful tool for long-term, non-invasive monitoring, with immense promise for numerous biomedical applications.

Artificial Channels Based on Bottlebrush Polymers: Enhanced Ion Transport Through Polymer Topology Control.

Synthetic structures mimicking the transport function of natural ion channel proteins have a wide range of applications, including therapeutic treatments, separation membranes, sensing, and biotechnologies. However, the development of polymer-based artificial channels has been hampered due to the limitation on available models. In this study, we demonstrate the great potential of bottlebrush polymers as accessible and versatile molecular scaffolds for developing efficient artificial ion channels. Adopting the bottlebrush configuration enhanced ion transport activity of the channels compared to their linear analogs. Matching the structure of lipid bilayers, the bottlebrush channel with a hydrophilic-hydrophobic-hydrophilic triblock architecture exhibited the highest activity among the series. Functionalized with urea groups, these channels displayed high anion selectivity. Additionally, we illustrated that the transport properties could be fine-tuned by modifying the chemistry of ion binding sites. This work not only highlights the importance of polymer topology control in channel design, but also reveals the great potential for further developing bottlebrush channels with customized features and diverse functionalities.

Artificial Channels Based on Bottlebrush Polymers: Enhanced Ion Transport Through Polymer Topology Control

AbstractSynthetic structures mimicking the transport function of natural ion channel proteins have a wide range of applications, including therapeutic treatments, separation membranes, sensing, and biotechnologies. However, the development of polymer‐based artificial channels has been hampered due to the limitation on available models. In this study, we demonstrate the great potential of bottlebrush polymers as accessible and versatile molecular scaffolds for developing efficient artificial ion channels. Adopting the bottlebrush configuration enhanced ion transport activity of the channels compared to their linear analogs. Matching the structure of lipid bilayers, the bottlebrush channel with a hydrophilic‐hydrophobic‐hydrophilic triblock architecture exhibited the highest activity among the series. Functionalized with urea groups, these channels displayed high anion selectivity. Additionally, we illustrated that the transport properties could be fine‐tuned by modifying the chemistry of ion binding sites. This work not only highlights the importance of polymer topology control in channel design, but also reveals the great potential for further developing bottlebrush channels with customized features and diverse functionalities.

Rationalizing Diverse Binding Mechanisms to the Same Protein Fold: Insights for Ligand Recognition and Biosensor Design.

The engineering of novel protein-ligand binding interactions, particularly for complex drug-like molecules, is an unsolved problem, which could enable many practical applications of protein biosensors. In this work, we analyzed two engineered biosensors, derived from the plant hormone sensor PYR1, to recognize either the agrochemical mandipropamid or the synthetic cannabinoid WIN55,212-2. Using a combination of quantitative deep mutational scanning experiments and molecular dynamics simulations, we demonstrated that mutations at common positions can promote protein-ligand shape complementarity and revealed prominent differences in the electrostatic networks needed to complement diverse ligands. MD simulations indicate that both PYR1 protein-ligand complexes bind a single conformer of their target ligand that is close to the lowest free-energy conformer. Computational design using a fixed conformer and rigid body orientation led to new WIN55,212-2 sensors with nanomolar limits of detection. This work reveals mechanisms by which the versatile PYR1 biosensor scaffold can bind diverse ligands. This work also provides computational methods to sample realistic ligand conformers and rigid body alignments that simplify the computational design of biosensors for novel ligands of interest.

Conformational and Electron Density Analysis of Bicyclo[3.1.0] hexanes: All Roads Lead to Boats

In view of the existence of an optimal conformation for molecular recognition and bearing in mind that nucleosides exhibit a broad range of pharmaceutical properties, whereby their conformation has a key role in molecular recognition, the tendency of the pseudosugar moiety in carbanucleosides to adopt a boat‐like conformation has been studied on the basis of a bicyclo[3.1.0]hexane system, resulting in versatile druglike scaffolds to increase molecular recognition. It is already known that using this system as a pseudosugar can fix the conformation in the northern or southern geometry required for biological activity, according to the relative position of the three‐membered ring. By mapping their energy potential surface, we investigated the preference for boat‐like conformers in bicyclo[3.1.0]hexanes. DFT was utilized alongside NBO analysis to explore the enhanced stability of boat‐like conformers, also considering the influence of oxygen, sulfur, and selenium heteroatoms. Additionally, charge density distribution analysis using QTAIM identified key atoms contributing to stability changes. These findings will help to comprehend this behavior in the drug discovery process when conformationally restricted nucleosides are involved.

Mobilizing Endogenous Progenitor Cells Using pSDF1α-Activated Scaffolds Accelerates Angiogenesis and Bone Repair in Critical-Sized Bone Defects.

Mobilizing endogenous progenitor cells to repair damaged tissue in situ has the potential to revolutionize the field of regenerative medicine, while the early establishment of a vascular network will ensure survival of newly generated tissue. In this study, a gene-activated scaffold containing a stromal derived factor 1α plasmid (pSDF1α), a pro-angiogenic gene that is also thought to be involved in the recruitment of mesenchymal stromal cells (MSCs) to sites of injury is described. It is shown that over-expression of SDF1α protein enhanced MSC recruitment and induced vessel-like structure formation by endothelial cells in vitro. When implanted subcutaneously, transcriptomic analysis reveals that endogenous MSCs are recruited and significant angiogenesis is stimulated. Just 1-week after implantation into a calvarial critical-sized bone defect, pSDF1α-activated scaffolds are recruited MSCs and rapidly activate angiogenic and osteogenic programs, upregulating Runx2, Dlx5, and Sp7. At the same time-point, pVEGF-activated scaffolds are recruited a variety of cell types, activating endochondral ossification. The early response induced by both scaffolds leads to complete bridging of the critical-sized bone defects within 4-weeks. The versatile cell-free gene-activated scaffold described in this study is capable of harnessing and enhancing the body's own regenerative capacity and has immense potential in a myriad of applications.

Exploring the potential therapeutic role of benzofuran derivatives in cancer treatment

Benzofuran serves as the primary active pharmaceutical ingredient (API) in a plethora of both naturally occurring and synthetic drugs known for their potent biological activities. The diverse array of biological effects demonstrated by benzofuran and its analogues encompasses anticancer, anti-microbial, anti-inflammatory, anti-fungal, analgesic, anti-parasitic, anti-hyperglycemic, anti-hyperlipidemic, anti-convulsant, antipyretic, anti-tubercular, anti-Alzheimer, and antioxidant properties, among others. Given this extensive range of therapeutic potentials, benzofuran and its derivatives have garnered significant attention and are extensively utilized in pharmaceutical research and development. This review article focuses specifically on the anti-cancer properties of benzofuran and its derivatives, underscoring the pivotal role of benzofuran as a prominent and versatile scaffold for designing and developing novel therapeutic agents.

Expanding the Scope of C-Glycoside Synthesis from Unstable Organolithium Reagents Using Flow Microreactors.

C-glycosides are versatile scaffolds for drugs and bioactive compounds. The common organolithium-based synthesis of C-glycosides is limited by low reaction temperatures and a restricted substrate scope. To address these issues, a flow microreactor (FMR) was utilized for rapid mixing and precise temperature control, enabling C-glycoside synthesis at temperatures up to 40 °C and expanding the substrate scope. Continuous C-glycoside synthesis was achieved with a throughput of 21.9 g h-1, demonstrating the industrial potential of FMRs.

Enzyme‐Assisted Activation Technique for Producing Versatile Hydrogel Microparticle Scaffolds with High Surface Chemical Reactivity

AbstractAdvancing the integration of nonliving and living components relies heavily on functional hydrogel materials with biocompatibility and customizability. In this study, an enzyme‐assisted surface activation method is developed to produce reactive hydrogel microparticles (HMPs) comprising thiolated hyaluronic acid and hyperbranched poly(β‐hydrazide esters). Fluorescence labeling analysis reveals an over six‐fold increase in surface‐active functional group density on the hydrogels and three‐fold on HMPs after enzyme activation. This enhancement improves accessibility of active elements, facilitating post‐functionalization and optimizing their capacity to support initial cell adhesion and spreading as carriers for cell cultures. Additionally, by utilizing the exposed reactive double bonds on the HMP surfaces post‐enzymatic treatment, thiolated HMPs are produced through a thiol‐ene coupling reaction with thiolated polymers. These thiolated HMPs bond together spontaneously, resulting in the formation of annealed granular hydrogels with interconnected large‐pore networks and a tunable storage modulus (G’) from tens to hundreds of pascals, compatible with most soft tissues. Integrated with 3D bioprinting, this hydrogel ink generates prints that foster cell adhesion, migration, growth, and network formation. Moving forward, integrating various granular hydrogel scaffold systems with the enzyme‐assisted activation technique holds significant promise for enhancing performance and expanding applications in regenerative medicine and innovative living materials.

Discovery and Synthesis of Hydroxy-l-Proline Blockers of the Neutral Amino Acid Transporters SLC1A4 (ASCT1) and SLC1A5 (ASCT2).

As a conformationally restricted amino acid, hydroxy-l-proline is a versatile scaffold for the synthesis of diverse multi-functionalized pyrrolidines for probing the ligand binding sites of biological targets. With the goal to develop new inhibitors of the widely expressed amino acid transporters SLC1A4 and SLC1A5 (also known as ASCT1 and ASCT2), we synthesized and functionally screened synthetic hydroxy-l-proline derivatives using electrophysiological and radiolabeled uptake methods against amino acid transporters from the SLC1, SLC7, and SLC38 solute carrier families. We have discovered a novel class of alkoxy hydroxy-pyrrolidine carboxylic acids (AHPCs) that act as selective high-affinity inhibitors of the SLC1 family neutral amino acid transporters SLC1A4 and SLC1A5. AHPCs were computationally docked into a homology model and assessed with respect to predicted molecular orientation and functional activity. The series of hydroxyproline analogs identified here represent promising new agents to pharmacologically modulate SLC1A4 and SLC1A5 amino acid exchangers which are implicated in numerous pathophysiological processes such as cancer and neurological diseases.

Albumin-capped gold nanocluster-integrated human albumin scaffolds: A traceable, xeno-free and customizable template for autogenic tissue engineering applications

Albumin has attracted interest in the field of tissue engineering for fabricating three-dimensional scaffolds due to its stability, unique ligand-binding property, biocompatibility, high solubility and low cost. This study aimed to develop a versatile fluorescent scaffold using human serum albumin (HSA), HSA-capped gold nanoclusters (HSA@AuNCs) and oxidized dextran. The morphological, structural, mechanical and physical properties of the constructs were evaluated using FTIR, SEM, thermogravimetric analysis, swelling, compression, in vitro biocompatibility and degradation tests. Traceability was demonstrated by fluorescence imaging, while Au release from scaffolds was determined by inductively coupled plasma-optical emission spectroscopy. Cell adhesion and proliferation on scaffolds were evaluated using mesenchymal stem cells (MSCs), cellular metabolic activity was assessed by alamarBlue assay for 10 days. The alkaline phosphatase activity of MSCs was followed for up to 21 days. The findings revealed that the HSA/AuNC scaffolds are fluorescent, biodegradable and exhibit good in vitro biocompatibility. In addition, the nanocomposite scaffolds provide a suitable environment for MSCs to adhere, proliferate and maintain their metabolic activities. This work is expected to pave the way for the design of albumin-based scaffolds with different bioactive agents that can be conjugated to the albumin backbone.