Mimetic Scaffolds Research Articles

4-Connected azabicyclo[5.3.0]decane Smac mimetics-Zn2+ chelators as dual action antitumoral agents

Putative dual action compounds (DACs 3a–d) based on azabicyclo[5.3.0]decane (ABD) Smac mimetic scaffolds linked to Zn2+-chelating 2,2′-dipicolylamine (DPA) through their 4 position are reported and characterized. Their synthesis, their target affinity (cIAP1 BIR3, Zn2+) in cell-free assays, their pro-apoptotic effects, and their cytotoxicity in tumor cells with varying sensitivity to Smac mimetics are described. A limited influence of Zn2+ chelation on in vitro activity of DPA-substituted DACs 3a–d was sometimes perceivable, but did not lead to strong cellular synergistic effects. In particular, the linker connecting DPA with the ABD scaffold seems to influence cellular Zn2+-chelation, with longer lipophilic linkers/DAC 3c being the optimal choice.

Investigating cellulose derived glycosaminoglycan mimetic scaffolds for cartilage tissue engineering applications.

Articular cartilage has a limited capacity to heal and, currently, no treatment exists that can restore normal hyaline cartilage. Creating tissue engineering scaffolds that more closely mimic the native extracellular matrix may be an attractive approach. Glycosaminoglycans, which are present in native cartilage tissue, provide signalling and structural cues to cells. This study evaluated the use of a glycosaminoglycan mimetic, derived from cellulose, as a potential scaffold for cartilage repair applications. Fully sulfated sodium cellulose sulfate (NaCS) was initially evaluated in soluble form as an additive to cell culture media. Human mesenchymal stem cell (MSC) chondrogenesis in pellet culture was enhanced with 0.01% NaCS added to induction media as demonstrated by significantly higher gene expression for type II collagen and aggrecan. NaCS was combined with gelatine to form fibrous scaffolds using the electrospinning technique. Scaffolds were characterized for fibre morphology, overall hydrolytic stability, protein/growth factor interaction and for supporting MSC chondrogenesis in vitro. Scaffolds immersed in phosphate buffered saline for up to 56days had no changes in swelling and no dissolution of NaCS as compared to day 0. Increasing concentrations of the model protein lysozyme and transforming growth factor-β3 were detected on scaffolds with increasing concentrations of NaCS (p<0.05). MSC chondrogenesis was enhanced on the scaffold with the lowest NaCS concentration as seen with the highest collagen type II production, collagen type II immunostaining, and expression of cartilage-specific genes. These studies demonstrate the feasibility of cellulose sulfate as a scaffolding material for cartilage tissue engineering. Copyright © 2016 John Wiley & Sons, Ltd.

Development of Selective CBP/P300 Benzoxazepine Bromodomain Inhibitors.

CBP (CREB (cAMP responsive element binding protein) binding protein (CREBBP)) and P300 (adenovirus E1A-associated 300 kDa protein) are two closely related histone acetyltransferases (HATs) that play a key role in the regulation of gene transcription. Both proteins contain a bromodomain flanking the HAT catalytic domain that is important for the targeting of CBP/P300 to chromatin and which offeres an opportunity for the development of protein-protein interaction inhibitors. Here we present the development of CBP/P300 bromodomain inhibitors with 2,3,4,5-tetrahydro-1,4-benzoxazepine backbone, an N-acetyl-lysine mimetic scaffold that led to the recent development of the chemical probe I-CBP112. We present comprehensive SAR of this inhibitor class as well as demonstration of cellular on target activity of the most potent and selective inhibitor TPOP146, which showed 134 nM affinity for CBP with excellent selectivity over other bromodomains.

Autologous Circulating Progenitor Cells Transplanted with Hybrid Scaffold Accelerate Diabetic Wound Healing in Rabbit Model

Background: Currently, various approaches employed for treating diabetic wounds face several limitations. Since diabetic ischemia-related non-healing wounds cause economic burden and social problems world-wide, newer methods need to be developed to address the crisis. Objective: In this study, we tested a novel strategy of applying hybrid scaffold developed from synthetic biodegradable electro-spun poly[Lactide-glycolidecaprolactone] and bio-mimetic fibrin based matrix combined with autologous circulating progenitor cells on wounds in diabetic rabbits. Methods: The wounds created in rabbit ear were grouped into three categories: (i) untreated open wounds [control]; (ii) covered with hybrid scaffold [test1]; and (iii) applied with autologous progenitor cell suspension and covered with hybrid scaffold [test 2]. Replicate wounds were explanted at 3 time periods ending 28 days, gross tissue and histological sections were compared between control and tests. Healing parameters assessed were collagen organization, angiogenesis and epithelial coverage. Survival of transplanted cells at the wound site was tracked. Results: All wounds healed by 28 days; but, fastest epithelial healing and least scar formations were achieved when wounds were applied with progenitors and scaffold together. Collagen organization and angiogenesis were the best in Test2 followed by Test1 and was minimal in Control as compared to normal skin. Upon cell transplantation, healed skin thickness was near normal with appendage-like structures. Conclusion: Transplanted cells could be tracked till the end of the study through fluorescence imaging. The transplanted cells seemed important for dermal and epidermal regeneration. Even though a mixture of cells was transplanted, all of them can be harvested easily from autologous source and could be committed to respective lineage within few days. Therefore, it could be a potential strategy for regeneration of wounds in human subjects. Keywords: Autologous cell transplantation, bio mimetic scaffolds, circulating progenitors, diabetic wound regeneration.

Dual action Smac mimetics–zinc chelators as pro-apoptotic antitumoral agents

Dual action compounds (DACs) based on 4-substituted aza-bicyclo[5.3.0]decane Smac mimetic scaffolds (ABDs) linked to a Zn2+-chelating moiety (DPA, o-hydroxy, m-allyl, N-acyl (E)-phenylhydrazone) through their 10 position are reported and characterized. Their synthesis, their target affinity (XIAP BIR3, Zn2+) in cell-free assays, their pro-apoptotic effects and cytotoxicity in tumor cells with varying sensitivity to Smac mimetics are described. The results are interpreted to evaluate the influence of Zn2+ chelators on cell-free potency and on cellular permeability of DACs, and to propose novel avenues towards more potent antitumoral DACs based on Smac mimetics and Zn2+ chelation.

The characterization of decellularized human skeletal muscle as a blueprint for mimetic scaffolds

The use of decellularized skeletal muscle (DSM) as a cell substrate and scaffold for the repair of volumetric muscle loss injuries has shown therapeutic promise. The performance of DSM materials motivated our interest in exploring the chemical and physical properties of this promising material. We suggest that these properties could serve as a blueprint for the development of next generation engineered materials with DSM mimetic properties. In this study, whole human lower limb rectus femoris (n=10) and upper limb supraspinatus muscle samples (n=10) were collected from both male and female tissue donors. Skeletal muscle samples were decellularized and nine property values, capturing key compositional, architectural, and mechanical properties, were measured and statistically analyzed. Mean values for each property were determined across muscle types and sexes. Additionally, the influence of muscle type (upper vs lower limb) and donor sex (male vs female) on each of the DSM material properties was examined. The data suggests that DSM materials prepared from lower limb rectus femoris samples have an increased modulus and contain a higher collagen content then upper limb supraspinatus muscles. Specifically, lower limb rectus femoris DSM material modulus and collagen content was approximately twice that of lower limb supraspinatus DSM samples. While muscle type did show some influence on material properties, we did not find significant trends related to sex. The material properties reported herein may be used as a blueprint for the data-driven design of next generation engineered scaffolds with muscle mimetic properties, as well as inputs for computational and physical models of skeletal muscle.

Rational Structure-Based Rescaffolding Approach to De Novo Design of Interleukin 10 (IL-10) Receptor-1 Mimetics.

Tackling protein interfaces with small molecules capable of modulating protein-protein interactions remains a challenge in structure-based ligand design. Particularly arduous are cases in which the epitopes involved in molecular recognition have a non-structured and discontinuous nature. Here, the basic strategy of translating continuous binding epitopes into mimetic scaffolds cannot be applied, and other innovative approaches are therefore required. We present a structure-based rational approach involving the use of a regular expression syntax inspired in the well established PROSITE to define minimal descriptors of geometric and functional constraints signifying relevant functionalities for recognition in protein interfaces of non-continuous and unstructured nature. These descriptors feed a search engine that explores the currently available three-dimensional chemical space of the Protein Data Bank (PDB) in order to identify in a straightforward manner regular architectures containing the desired functionalities, which could be used as templates to guide the rational design of small natural-like scaffolds mimicking the targeted recognition site. The application of this rescaffolding strategy to the discovery of natural scaffolds incorporating a selection of functionalities of interleukin-10 receptor-1 (IL-10R1), which are relevant for its interaction with interleukin-10 (IL-10) has resulted in the de novo design of a new class of potent IL-10 peptidomimetic ligands.

The effect of sulfation in glycosaminoglycan (GAG)-mimetic scaffolds on promoting chondrogenesis

Event Abstract Back to Event The effect of sulfation in glycosaminoglycan (GAG)-mimetic scaffolds on promoting chondrogenesis Gloria Portocarrero Huang1, Roseline Menezes1, Richard Vincent1, Willis Hammond1, George Collins1 and Treena Livingston Arinzeh1 1 New Jersey Institute of Technology, Department of Biomedical Engineering, United States Introduction: Articular cartilage has a limited ability to heal. Current surgical procedures to repair cartilage result in the formation of fibrocartilage instead of hyaline cartilage. The presence of fibrocartilage may suggest deficient bioactivity to promote the chondrocyte phenotype. Glycosaminoglycans (GAGs) have been shown to interact and maintain the bioactivity of growth factors due to their level and spatial distribution of sulfate groups[1]. Cellulose sulfate, a semi-synthetic derivative of cellulose, is a sulfated polysaccharide with structural similarity to GAGs and has yet to be explored for cartilage repair. It is a cost-effective alternative to the use of naturally occurring GAGs for cartilage repair applications. This study evaluated the effect of varying the degree of sulfation in cellulose sulfate on human mesenchymal stem cell (MSC) chondrogenesis and its effect on maintaining the bioactivity of transforming growth factor-β3 (TGF-β3), a potent driver of chondrogenesis, in comparison to other sulfated GAGs. Materials and Methods: Cellulose sulfate was combined with bovine gelatin, electrospun to form fibrous scaffolds and characterized for fiber dimension, interfiber spacing, and interactions with TGF-β3. Interactions with TGF-β3 were additionally evaluated in solutions of cellulose sulfate. Partially sulfated cellulose (pSC) and fully sulfated cellulose (NaCS) were evaluated at 0.1% and 5% dry weight of the scaffold. Gelatin (Gel) with no cellulose sulfate was used as a control. MSCs were seeded onto the scaffold and chondrogenesis was evaluated after 56 days through the production of collagen type 2, cell morphology, and gene expression of chondrogenic markers. Results and Discussion: NaCS had significantly higher amounts of complexed TGF-β3 than chondroitin 6-sulfate (CSC) and pSC in solution (Figure 1A) and increasing the cellulose sulfate on the scaffold bound more TGF-β3 (Figure 1B). Yet, MSCs on pSC-gel scaffolds had the highest production of collagen type II (Figure 2A & 2B) and greatest gene expression for chondrocyte markers (aggrecan, collagen type II, chondroadherin, and Sox9). On scaffolds with cellulose sulfate, cells had a lower production of collagen type I per cell, a protein found in fibrocartilage, compared to gelatin alone (Figure 3). The cells on the scaffolds had lower gene expression of collagens type X and I as indicators of hypertrophic chondrocytes and MSCs, respectively, when compared to cells in MSC chondrogenic control cultures. Conclusion: The findings suggest that pSC-gel scaffolds, having partial sulfation, may support a more homogeneous cartilage tissue formation. Future studies will understand the interactions of the growth factors and GAGs to improve scaffold design and further promote tissue formation. National Science Foundation; Musculoskeletal Transplant Foundation

Engineering of a collagen-based extracellular matrix mimetic scaffold via electrospinning

Event Abstract Back to Event Engineering of a collagen-based extracellular matrix mimetic scaffold via electrospinning Jorge Almodovar1 and David Castilla1 1 University of Puerto Rico Mayaguez, Department of Chemical Engineering, Puerto Rico Nanofibrous scaffolds have been extensively used in tissue engineering due to its resemblance to native extracellular matrix (ECM) in scale, orientation, and geometry. Collagen is one of the biological polymers more suitable to be used in the fabrication of scaffolds. Collagen is the most abundant protein in the human body, providing strength and structure to tissues. Electrospun collagen nanofibrous scaffolds have been previously investigated using harsh solvents that disrupt collagen’s secondary structure and limits its applications as implantable devices. Our work focuses on the generation of a nanofibrous structure that mimics the morphology, organization, nanoscale and composition of native ECM. Type II collagen from cow tendon, was used to fabricate a nanofibrous structure via the electrospinning technique using a mild aqueous solvent. Scanning Electron Microscope (SEM) was used to confirm the morphology of the nanofibrous structure. SEM revelead that it was possible to fabricate an aligned or randomly oriented nanofibrous structure of type II collagen, with a range of diameters between from 36 to 130 nm. To utilize the collagen membranes in aqueous environment, crosslinking was performed by: 1) immersion in a 25% glutaraldehyde solution and 2) exposure to glutaraldehyde vapor. The chemical composition of the nanofibers was assessed using Fourier transform infrared spectroscopy (FT-IR). Secondary structure determination was based on the amide I band (1700–1600 cm-1), which is commonly used to study the secondary structure proteins. FTIR confirms that the secondary structure of collagen is preserved after the electrospinning process and after crosslinking. Un-crosslinked and crosslinked type II collagen membranes were mechanically tested with an Instron ElectroPuls model E3000 in tension mode at a constant displacement of 1.0 mm/s. Measurements for the un-crosslinked samples were performed in air at room temperature whereas the crosslinked samples were submerged in deionized water and tested at 37 degrees C using a BioPlus Temperature Controlled Bath. The crosslinking process allows for the fabrication of collagen scaffolds with mechanical properties in the range of soft tissues such as cartilage, and stable in water environments at body temperature. Young's Moduli (MPa) of 12.2 ± 3.3 for un-crosslinked nanofibers, 4.1 ± 0.5, for crosslinked - by immersion and 2.7 ± 0.7 for crosslinked – vapor were obtained. In conclusion, we developed a nanofibrous scaffold of type II collagen that preserves its chemical and secondary structure. Nanofibrous membranes were obtained with morphological and mechanical features similar to that found in soft tissues in the human body, which may be suitable as scaffolds for tissue regeneration. Keywords: Extracellular Matrix, biomaterial, nanofiber, material design Conference: 10th World Biomaterials Congress, Montréal, Canada, 17 May - 22 May, 2016. Presentation Type: General Session Oral Topic: Electrospinning and related technologies Citation: Almodovar J and Castilla D (2016). Engineering of a collagen-based extracellular matrix mimetic scaffold via electrospinning. Front. Bioeng. Biotechnol. Conference Abstract: 10th World Biomaterials Congress. doi: 10.3389/conf.FBIOE.2016.01.00762 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 27 Mar 2016; Published Online: 30 Mar 2016. Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Jorge Almodovar David Castilla Google Jorge Almodovar David Castilla Google Scholar Jorge Almodovar David Castilla PubMed Jorge Almodovar David Castilla Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Structural Mimetic Silk Fiber-Reinforced Composite Scaffolds Using Multi-Angle Fibers.

The fabrication of structural mimetic scaffolds reinforced with multi-angle silk fibers is described. Degummed silk fibers with a parallel arrangement of the fibers in a planar format were overlapped with successive layers organized at 0°, 30°, 60° and 90°, respectively. The overlapped silk fiber layers were coated with silk solution (6 wt%) containing sodium dodecyl sulfate (SDS). The morphology, mechanical properties, structure and biocompatibility of the scaffolds were investigated. The mechanical properties of the scaffolds (tensile and burst) were characterized based on the angles of the fibers. Layers with an overlapping angle at 30° exhibited better mechanical performance (18 MPa) than the other groups. The results of Fourier Transform (FT) IR Spectroscopy (FT-IR) and X-ray Differentiation (XRD) analyses indicated that the presence of degummed silk fibers with different angles did not significantly impact secondary structure or crystallization of the fiber reinforced scaffolds. The attachment and growth of a human fibroblast cell line (HS-865-SK) on the reinforced scaffolds supported good cell compatibility. These new scaffolds have potential applications in tissue repairs where superior mechanical strength and cell compatibility are important.

Selective Bisubstrate Inhibitors with Sub‐nanomolar Affinity for Protein Kinase Pim‐1

Potent and selective: The unique nature of the ATP binding pocket structure of Pim family protein kinases (PKs) was used for the development of bisubstrate inhibitors and a fluorescent probe with sub-nanomolar affinity. Conjugates of arginine-rich peptides with two ATP mimetic scaffolds were synthesized and tested as inhibitors of Pim-1. Against a panel of 124 protein kinases, a novel ARC-PIM conjugate selectively inhibited PKs of the Pim family.

Collagen-Based Substrates with Tunable Strength for Soft Tissue Engineering.

Through the use of mechanical reinforcement of collagen matrices, mechanically strong and compliant 3D tissue mimetic scaffolds can be generated that act as scaffolds for soft tissue engineering. Collagen has been widely used for the development of materials for repair, augmentation or replacement of damaged or diseased tissue. Herein we describe a facile method for the layer-by-layer fabrication of robust planar collagen fiber constructs. Collagen gels cast in a phosphate buffer were dried to form dense collagen mats. Subsequent gels were layered and dried atop mats to create multilayer constructs possessing a range of tunable strengths (0.5 - 11 MPa) and stiffness (1 - 115 MPa). Depending on processing conditions and crosslinking of constructs, strain to failure ranged between 9 to 48%. Collagen mats were constructed into hernia patches that prevented hernia recurrence in Wistar rats.

Amyloid Inspired Self-Assembled Peptide Nanofibers

Amyloid peptides are important components in many degenerative diseases as well as in maintaining cellular metabolism. Their unique stable structure provides new insights in developing new materials. Designing bioinspired self-assembling peptides is essential to generate new forms of hierarchical nanostructures. Here we present oppositely charged amyloid inspired peptides (AIPs), which rapidly self-assemble into nanofibers at pH 7 upon mixing in water caused by noncovalent interactions. Mechanical properties of the gels formed by self-assembled AIP nanofibers were analyzed with oscillatory rheology. AIP gels exhibited strong mechanical characteristics superior to gels formed by self-assembly of previously reported synthetic short peptides. Rheological studies of gels composed of oppositely charged mixed AIP molecules (AIP-1 + 2) revealed superior mechanical stability compared to individual peptide networks (AIP-1 and AIP-2) formed by neutralization of net charges through pH change. Adhesion and elasticity properties of AIP mixed nanofibers and charge neutralized AIP-1, AIP-2 nanofibers were analyzed by high resolution force-distance mapping using atomic force microscopy (AFM). Nanomechanical characterization of self-assembled AIP-1 + 2, AIP-1, and AIP-2 nanofibers also confirmed macroscopic rheology results, and mechanical stability of AIP mixed nanofibers was higher compared to individual AIP-1 and AIP-2 nanofibers self-assembled at acidic and basic pH, respectively. Experimental results were supported with molecular dynamics simulations by considering potential noncovalent interactions between the amino acid residues and possible aggregate forms. In addition, HUVEC cells were cultured on AIP mixed nanofibers at pH 7 and biocompatibility and collagen mimetic scaffold properties of the nanofibrous system were observed. Encapsulation of a zwitterionic dye (rhodamine B) within AIP nanofiber network was accomplished at physiological conditions to demonstrate that this network can be utilized for inclusion of soluble factors as a scaffold for cell culture studies.

Thick Acellular Heart Extracellular Matrix with Inherent Vasculature: A Potential Platform for Myocardial Tissue Regeneration

The decellularization of porcine heart tissue offers many opportunities for the production of physiologically relevant myocardial mimetic scaffolds. Earlier, we reported the successful isolation of a thin porcine cardiac extracellular matrix (pcECM) exhibiting relevant bio-mechanical properties for myocardial tissue engineering. Nevertheless, since native cardiac tissue is much thicker, such thin scaffolds may offer limited regeneration capacity. However, generation of thicker myocardial mimetic tissue constructs is hindered by diffusion limitations (~100 μm), and the lack of a proper vascular-like network within these constructs. In our present work, we focused on optimizing the decellularization procedure for thicker tissue slabs (10-15 mm), while retaining their inherent vasculature, and on characterizing the resulting pcECM. The trypsin/Triton-based perfusion procedure that resulted in a nonimmunogenic and cell-supportive pcECM was found to be more effective in cell removal and in the preservation of fiber morphology and structural characteristics than stirring, sonication, or sodium dodecyl sulfate/Triton-based procedures. Mass spectroscopy revealed that the pcECM is mainly composed of ECM proteins with no apparent cellular protein remains. Mechanical testing indicated that the obtained pcECM is viscoelastic in nature and possesses the typical stress-strain profile of biological materials. It is stiffer than native tissue yet exhibits matched mechanical properties in terms of energy dissipation, toughness, and ultimate stress behavior. Vascular network functionality was maintained to the first three-four branches from the main coronary vessels. Taken together, these results reaffirm the efficiency of the decellularization procedure reported herein for yielding thick nonimmunogenic cell-supportive pcECM scaffolds, preserving both native tissue ultra-structural properties and an inherent vascular network. When reseeded with the appropriate progenitor cells, these scaffolds can potentially serve as ex vivo screening platforms for new therapeutics, as models for human cardiac ECM, or as biomedical constructs for patch or transmural transplantation strategies.

Abstract 3834: 3-ethynyl-1H-indazoles as inhibitors of PI3k signaling pathway

Abstract A new series of 3-ethynyl-1H-indazoles has been synthesized and evaluated in both biochemical and cell-based assays as potential kinase inhibitors. Interestingly, a selected group of compounds identified from this series exhibited low micromolar inhibition against critical components of the PI3K pathway, targeting PI3K, PDK1 and mTOR kinases. Combination of computational modeling and structure-activity relationships studies reveal a possible novel mode for PI3K inhibition, resulting in a PI3Kα isoform specific compound. Hence, by targeting the most oncogenic mutant isoform of PI3K, the compound displays anti-proliferative activity both in monolayer human cancer cell cultures and in three-dimensional tumor models. Because of its favorable physicochemical, in vitro ADME and drug-like properties, we propose that this novel ATP mimetic scaffold could result useful in deriving novel selecting and multi-kinase inhibitors for clinical use. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3834. doi:10.1158/1538-7445.AM2011-3834

Design, Synthesis, and Structure−Activity Relationships of 3-Ethynyl-1H-indazoles as Inhibitors of the Phosphatidylinositol 3-Kinase Signaling Pathway

A new series of 3-ethynyl-1H-indazoles has been synthesized and evaluated in both biochemical and cell-based assays as potential kinase inhibitors. Interestingly, a selected group of compounds identified from this series exhibited low micromolar inhibition against critical components of the PI3K pathway, targeting PI3K, PDK1, and mTOR kinases. A combination of computational modeling and structure-activity relationship studies reveals a possible novel mode for PI3K inhibition, resulting in a PI3Kα isoform-specific compound. Hence, by targeting the most oncogenic mutant isoform of PI3K, the compound displays antiproliferative activity both in monolayer human cancer cell cultures and in three-dimensional tumor models. Because of its favorable physicochemical, in vitro ADME and drug-like properties, we propose that this novel ATP mimetic scaffold could prove useful in deriving novel selecting and multikinase inhibitors for clinical use.

ChemInform Abstract: Investigations on the Synthesis of Indole‐Based Constrained Mimetic Scaffolds Through 1,3‐Dipolar Cycloadditions of the C‐3‐(3‐Indolyl)‐N‐phenylnitrone with a Variety of Olefinic and Allenic Dipolarophiles under Microwave Irradiation.

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Investigations on synthesis of indole based constrained mimetic scaffolds through 1,3-dipolar cycloadditions of the C-(3-indolyl)- N-phenylnitrone with a variety of olefinic and allenic dipolarophiles under microwave irradiation

Monomode microwave assisted regio- and stereo-selective 1,3-dipolar cycloadditions of C-(3-indolyl)- N-phenylnitrone ( 19) with a number of olefinic dipolarophiles ( 20a– f) afford isoxazolidines ( 21– 26) in high yields, which are conformationally constrained mimetics of indole-3-propionic acid of biological significance. Similar cycloadducts derived from addition of nitrone ( 19) to allenic esters ( 27a– c) undergo domino reorganization to afford potentially biologically active bis-indole derivatives ( 28, 29). The observed regio- and stereo-selectivities are analysed, inter alia, in terms of HOMO-dipole–LUMO-dipolarophile and involved secondary orbital/steric interactions in the transition states intervening these cycloadditions.

Biphenyls as potent vitronectin receptor antagonists. Part 3: Squaric acid amides

Vitronectin receptor (α Vβ 3) antagonists have been implicated as a possible new treatment of restenosis following balloon angioplasty. In this work we investigate a series of novel arginine mimetic scaffolds leading to new insight of the α Vβ 3/ligand interaction. Squaric acid amide 10 is a subnanomolar α Vβ 3 antagonist with improved potency on human smooth muscle cell migration.

Enhanced osteoblast‐like cell adhesion and proliferation using sulfonate‐bearing polymeric scaffolds

Orthopedic malfunction, degeneration, or damage remains a serious healthcare issue despite advances in medical technology. Proactive extracellular matrix (ECM)-mimetic scaffolds are being researched to orchestrate the activation of diverse osteogenic signaling cascades, facilitating osteointegration. We hypothesized that sulfonated functionalities incorporated into synthetic hydrogels would simulate anionic, sulfate-bearing proteoglycans, abundant in the ECM. Using this rationale, we successfully developed differentially sulfonated hydrogels, polymerizing a range of sulfopropyl acrylate potassium-acrylamide (SPAK-AM) mole ratios as monomer feeds under room temperature conditions. For anchorage-dependent cells, such as osteoblasts, adhesion is a critical prerequisite for subsequent osteointegration and cell specialization. The introduction of the sulfonated monomer, SPAK, resulted in favorable uptake of serum proteins with proportional increase in adhesion and proliferation rates of model cell lines, which included NIH/3T3 fibroblasts, MG-63 osteoblasts, and MC3T3-E1 subclone 4 preosteoblasts. In fact, higher proportions of sulfonate content (pSPAK75, pSPAK100) exhibited comparable or even higher degrees of adhesion and proliferation, relative to commercial grade tissue culture polystyrene in vitro. These results indicate promising potentials of sulfonated ECM-mimetic hydrogels as potential osteogenic tissue engineering scaffolds.