Versatile Scaffold Research Articles

Recent Advances in β-lactam Derivatives as Potential Anticancer Agents.

Cancer, accounts for around 10 million deaths annually, is the second leading cause of death globally. The continuous emergency of drug-resistant cancers and the low specificity of anticancer agents are the main challenges in the control and eradication of cancers, so it is imperative to develop novel anticancer agents. Immense efforts have been made in developing new lead compounds and novel chemotherapeutic strategies for the treatment of various forms of cancers in recent years. β-Lactam derivatives constitute versatile and attractive scaffolds for the drug discovery since these kinds of compounds possess a variety of pharmacological properties, and some of them exhibited promising potency against both drug-sensitive and drug-resistant cancer cell lines. Thus, β-lactam moiety is a useful template for the development of novel anticancer agents. This review will provide an overview of β-lactam derivatives with the potential therapeutic application for the treatment of cancers covering articles published between 2000 and 2020. The mechanisms of action, the critical aspects of design and structureactivity relationships are also discussed.

Unsymmetrical 2,4,6‐Triarylpyridines as Versatile Scaffolds for Deep‐Blue and Dual‐Emission Fluorophores

AbstractPyridines substituted with different aromatic groups at C‐2, C‐4 and C‐6 were prepared following a Kröhnke synthetic route. Introducing ortho‐anisole at C‐2 resulted in deep blue emitters in solution, with quantum yields up to 74 %. On the other hand, when ortho‐phenol was introduced, forming a strong hydrogen bond with the pyridine nitrogen, excited‐state intramolecular proton transfer was witnessed by the dual emission of the fluorophores, which is sensitive to the dye environment. The phenyl ring at C‐4 was used to introduce electron‐donating or withdrawing groups, to fine‐tune the photophysical properties of the dyes. Crystal structures of the fluorophores, together with theoretical studies using DFT/TD‐DFT calculations, were used to rationalize the experimental photophysical properties of the two families of dyes. Unsymmetrical 2,4,6‐triarylpyridines are therefore versatile scaffolds for the preparation of deep‐blue and dual emission fluorophores, and are promising building blocks for luminescent devices and sensors.

Metal-Free Synthesis of Indolopyrans and 2,3-Dihydrofurans Based on Tandem Oxidative Cycloaddition.

The synthesis of versatile scaffold indolopyrans based on C-C radical-radical cross-coupling under metal-free conditions is described. The reaction involving single electron transfer between coupling partners followed by cage collapse allows highly selective cross-coupling while employing only equimolar amounts of coupling partners. Moreover, the mechanistic manifold was expanded for the functionalization of enamines to give the stereoselective synthesis of 2,3-dihydrofurans. This iodine-mediated oxidative coupling features mild conditions and fast reaction kinetics.

Mimochrome, a metalloporphyrin-based catalytic Swiss knife†.

Over the years, mimochromes, a class of miniaturized porphyrin-based metalloproteins, have proven to be reliable but still versatile scaffolds. After two decades from their birth, we retrospectively review our work in mimochrome design and engineering, which allowed us developing functional models. They act as electron-transfer miniproteins or more elaborate artificial metalloenzymes, endowed with peroxidase, peroxygenase, and hydrogenase activities. Mimochromes represent simple yet functional synthetic models that respond to metal ion replacement and noncovalent modulation of the environment, similarly to natural heme-proteins. More recently, we have demonstrated that the most active analogue retains its functionality when immobilized on nanomaterials and surfaces, thus affording bioconjugates, useful in sensing and catalysis. This review also briefly summarizes the most important contributions to heme-protein design from leading groups in the field.

Effective Pharmacophore for CDC25 Phosphatases Enzyme Inhibitors: Newly Synthesized Bromothiazolopyrimidine Derivatives.

Thiazolopyrimidine analogues are versatile synthetic scaffold possessing wide spectrum of biological interests involving potential anticancer activity. To report the synthesis of novel bromothiazolopyrimidine derivatives and the study of both molecular modeling and in-vitro anticancer activity. Novel bromothiazolopyrimidine derivatives 5-18 have been prepared from 2-bromo-3-(4- chlorophenyl)-1-(3,4-dimethylphenyl)-propenone 3 as a key starting compound. The anti-cancer activities of the new compounds were evaluated against HepG2, MCF-7, A549 and HCT116 cell lines. The compounds 16, 17 and 18 showed cytotoxic and growth inhibitory activities on both colon and lung cells. The cytotoxic activities of the novel synthetic compounds 8, 9, 11, 16, 17 and 18 were due to CDC25 phosphatases inhibition as shown by the enzymatic binding assay. Although compounds 8, 9 and 11 have only demonstrated CDC25B phosphatases inhibition. The novel bromothiazolopyrimidine derivatives showed promising in vitro anticancer activities against colon cancer HCT116 and lung cancer A549 cell lines comparable to the anticancer drug doxorubicin.

Silk Fibroin Processing from CeCl3 Aqueous Solution: Fibers Regeneration and Doping with Ce(III)

AbstractSilk fibroin (SF) obtained from Bombyx mori cocoon is a very promising biopolymer. It can be processed from aqueous solutions to obtain many versatile scaffolds useful in optoelectronics, photonics, and biomedicine. Aqueous solutions are prepared by dissolving degummed fibroin with chaotropic agents and then purifying by dialysis. This work presents, for the first time, a solubilization protocol, involving CeCl3·7H2O as chaotropic salt in water and ethanol, that allows to regenerate SF under a fibrous form, unlike the standard Ajisawa’s method, which uses CaCl2 and allows to obtain aqueous gels. All the experimental analyses performed (SEM, XPS, WAXS, ATR‐FTIR, NMR) suggest that the fiber recovered preserves most of the morphological and structural features of the pristine SF and is doped with Ce(III) ions, that interact mainly with the oxygen atoms of CO moieties and side‐chains of amino acids. Ce(III) doped SF could be the base for new luminescent materials.

1,8,10-Trisubstituted anthracenyl hydrocarbons: Towards versatile scaffolds for multiple-H-bonded recognition arrays

In this work, we describe the synthesis of 1,8,10-trisubstituted anthracenyl scaffolds that, bearing boronic acid functionalities, can act as multiple H-bonding donor systems. The trisubstituted anthracenyl derivatives are synthesized following two main synthetic pathways. Whereas in the first approach trisubstituted anthracenyl derivatives are prepared through the regioselective addition of the relevant organomagnesium nucleophile to 1,8-dichloroanthraquinone, in the second avenue a triflate-bearing anthracene is prepared by reduction of the anthraquinone into the anthrone precursor and functionalized through metal-catalysed cross-coupling reactions. Complementary studies of the Na 2 S 2 O 4 -mediated reduction of 1,8-dichloroanthraquinone allowed to shed further light on the possible mechanism of formation of the anthrone precursor, suggesting the presence of a cis -diol intermediate undergoing antiperiplanar elimination. Solid-state X-ray diffraction investigations of the bisboronic acids show that the molecules self-assemble into dimers through the formation of four H-bonds established between the anti - syn conformers of the boronic acid moieties. 1 H-NMR titrations between bisboronic acids and tetra H-bond acceptor, diisoquinolino-naphthyridine, showed a significant shift of the -B(O H ) 2 proton resonances, suggesting the presence of H-bonding interactions between both molecules.

Size-dependent soft epitaxial crystallization in the formation of blend nanofiber shish kebabs

Hierarchical structures called nanofiber shish-kebabs (NFSKs) have been studied as a means to decorate or functionalize electrospun nanofibers. Blending natural and synthetic polymers together into the electrospun fiber NFSK backbones offers the opportunity to design materials with finely tuned mechanical and biological properties. However, it is not known how homopolymer and copolymer kebab formation will be impacted by these blend compositions. NFSKs made from polycaprolactone (PCL) and gelatin blend fibers with PCL homopolymer and PCL-block-poly (acrylic acid) (PCL-b-PAA) block copolymer crystalline kebabs were successfully formed. The blend fibers templated crystal growth on the surface, but with a highly irregular kebab orientation and periodicity that was attributed to the large fiber diameter for the blend. Acetic acid was then incorporated into the fibers and shown to improve the phase mixing between PCL and gelatin, leading to smaller diameter electrospun fibers and more regular and periodic kebab NFSK morphology. The study further confirmed the size-dependent soft-epitaxy mechanism in the formation of crystalline shish kebab structures, with the electrospun nanofiber diameter leading to more oriented PCL chains within the fiber and subsequent orientation of the crystallizing kebab polymer. These NFSKs with multicomponent shish and kebabs have potential to be versatile scaffolds for biomineralization and cellular engineering purposes.

A Supramolecular Platform Technology for Bacterial Cell Surface Modification.

In an era of antimicrobial resistance, a better understanding of the interaction between bacteria and the sentinel immune system is needed to discover new therapeutic targets for combating bacterial infectious disease. Sentinel immune cells such as macrophages phagocytose intact bacteria and thereby initiate ensuing immune responses. The bacterial surface composition is a key element that determines the macrophage signaling. To study the role of the bacterial cell surface composition in immune recognition, we developed a platform technology for altering bacterial surfaces in a controlled manner with versatile chemical scaffolds. We show that these scaffolds are efficiently loaded onto both Gram-positive and -negative bacteria and that their presence does not impair the capacity of monocyte-derived macrophages to phagocytose bacteria and subsequently signal to other components of the immune system. We believe this technology thus presents a useful tool to study the role of bacterial cell surface composition in disease etiology and potentially in novel interventions utilizing intact bacteria for vaccination.

(Invited) Near-Infrared Optical Probes for Imaging Neuromodulators with High Spatiotemporal Resolution

Dopamine neurotransmission plays critical roles in brain function in both health and disease and aberrations in dopamine neurotransmission are implicated in several psychiatric and neurological disorders, including schizophrenia, depression, anxiety, and Parkinson’s disease. Until recently, measuring the dynamics of dopamine and other neurotransmitters of this class could not be achieved at spatiotemporal resolutions necessary to understand how dopamine regulates the plasticity and function of neurons and neural circuits, and how dysfunctions in this regulation lead to disease. Probes that satisfy critical attributes in spatial and temporal resolution, and chemical selectivity are needed to facilitate investigations of brain neurochemistry.To address this need, we developed an ultrasensitive near-infrared “turn-on” nanosensor (nIRCat) for the catecholamines dopamine and norepinephrine and implemented nIRCat to study endogenous dopamine dynamics in brain tissue. nIRCats are synthesized from photostable and near infrared emissive functionalized single wall carbon nanotubes (SWCNT) and exhibit maximal relative change in fluorescence intensity (ΔF/F0) of up to 35-fold, with a dynamic range that spans physiological concentrations of their target brain analytes. We demonstrate that nIRCat can detect electrically and optogenetically evoked release of dopamine in brain tissue, revealing putative hotspots of activity that exhibited a log-normal distribution in size, ranging from 2 – 10 µm for mice brain tissue in the dorsomedial striatum. Furthermore, the synthetic nature of the molecular recognition platform afforded compatibility with dopamine-receptor targeting antipsychotics and psychoactive drugs and permitted studies of how such receptor-targeting drugs modulate evoked dopamine release. This assay revealed presynaptic correlates of drug activity at the level of putative dopamine release sites, which had heretofore been inaccessible to probe with existing tools. Our results suggest that nIRCat technology may uniquely support similar explorations of processes that regulate dopamine neuromodulation at the level of individual synapses, and exploration of the effects of receptor agonists and antagonists that are commonly used as psychiatric drugs as well as drugs that lead to substance use disorder. We conclude that SWCNTs can serve as versatile synthetic optical scaffolds for monitoring interneuronal chemical signaling in the brain extracellular space at spatial and temporal scales pertinent with the encoded neurochemical information.

Poly-β-Ketoester Particles as a Versatile Scaffold for Lanthanide-Doped Colorless Magnetic Materials

The present report describes the preparation of lanthanide-doped colorless magnetic materials based on poly-β-ketoester particles. Monodisperse poly(2-acetoacetoxy ethyl methacrylate) (PAAEM) parti...

Bacterial Phytochrome as a Scaffold for Engineering of Receptor Tyrosine Kinases Controlled with Near-Infrared Light

Optically controlled receptor tyrosine kinases (opto-RTKs) allow regulation of RTK signaling using light. Until recently, the majority of opto-RTKs were activated with blue-green light. Fusing a photosensory core module of Deinococcus radiodurans bacterial phytochrome (DrBphP-PCM) to the kinase domains of neurotrophin receptors resulted in opto-RTKs controlled with light above 650 nm. To expand this engineering approach to RTKs of other families, here we combined the DrBpP-PCM with the cytoplasmic domains of EGFR and FGFR1. The resultant Dr-EGFR and Dr-FGFR1 opto-RTKs are rapidly activated with near-infrared and inactivated with far-red light. The opto-RTKs efficiently trigger ERK1/2, PI3K/Akt, and PLCγ signaling. Absence of spectral crosstalk between the opto-RTKs and green fluorescent protein-based biosensors enables simultaneous Dr-FGFR1 activation and detection of calcium transients. Action mechanism of the DrBphP-PCM-based opto-RTKs is considered using the available RTK structures. DrBphP-PCM represents a versatile scaffold for engineering of opto-RTKs that are reversibly regulated with far-red and near-infrared light.

Nitric oxide as a source for bacterial triazole biosynthesis

The heterocycle 1,2,3-triazole is among the most versatile chemical scaffolds and has been widely used in diverse fields. However, how nature creates this nitrogen-rich ring system remains unknown. Here, we report the biosynthetic route to the triazole-bearing antimetabolite 8-azaguanine. We reveal that its triazole moiety can be assembled through an enzymatic and non-enzymatic cascade, in which nitric oxide is used as a building block. These results expand our knowledge of the physiological role of nitric oxide synthase in building natural products with a nitrogen–nitrogen bond, and should also inspire the development of synthetic biology approaches for triazole production.

First Synthesis for Bis-Spirothiazolidine Derivatives as a Novel Heterocyclic Framework and Their Biological Activity.

Spirothiazolidines are versatile synthetic scaffold possessing wide spectrum of biological interests involving potential anticancer activity. To report the first synthesis of Bis Spiro-thiazolidine as a novel heterocyclic ring system. One-pot three-component reaction including condensation of p-phenyllene diamine; cyclohexanone and thioglycolic acid produced Spiro-thiazolidine 4, which underwent further condensation with cyclohexanone and thioglycolic acid with equimolar ratio to introduce Bis-Spiothiazolidine 5 as the first synthesis. Also, bis spiro-thiazolidine arylidene derivatives 6-13 were synthesized by the reaction of Bis-Spiothiazolidine 5 with different aromatic benzaldehydes. Four compounds 13, 12, 9 and 11 have shown highly significant anticancer activity compared to Doxorubicin® (positive control) against Human liver carcinoma (HepG2) and Human Normal Retina pigmented epithelium (RPE-1) cell lines. The novel bis-spirothiazolidine deriviatives have been synthesized for the first time and showed excellent anticancer activities compare with the corresponding spirothiazolidine derivatives.

Hexaarylbutadiene: A Versatile Scaffold with Tunable Redox Properties towards Organic Near-Infrared Electrochromic Material.

When the 1,1,4,4-tetraanilinobutadiene skeleton is attached with two halogenated aryl units at the 2,3-positions, they undergo facile two-electron oxidation to give stable dicationic dyes which exhibit a near-infrared (NIR) absorption whereas the neutral dienes show only pale color. Therefore, a distinct electrochromic response with an absorption change in the NIR region is achieved, which is attracting considerable recent attention from the viewpoint of bioimaging. Herein, we demonstrate that the redox potentials of the 1,1,4,4-tetraanilinobutadiene can be precisely controlled by the donating properties of the amino group on the aniline unit as well as the number of halogen atoms on the aryl units at 2,3-positions on the butadiene. In contrast, the NIR absorption bands mainly depend on the number of halogen atoms irrespective to the donating properties of aniline unit. Thus, the hexaarylbutadiene skeleton is proven to be a versatile scaffold to develop less-explored organic NIR electrochromic materials, whose redox and spectroscopic properties can be finely tuned by modifying/attaching the proper substituents.

Biocatalytic cascades operating on macromolecular scaffolds and in confined environments

Biocatalytic cascades guide complex, efficient and selective intracellular transformations. These unique features originate from the spatial organization of the biocatalysts in confined cellular environments that allow the directional channelling of reaction intermediates across the cells. Here we address efforts directed towards the development of synthetic cell analogues and supramolecular ensembles acting as nano/microenvironments for operating biocatalytic cascades. Multienzyme systems are integrated within metal–organic frameworks, polymersomes, lipid-stabilized microdroplets and hydrogel microparticles acting as cell-like containments. Also, multienzyme systems are spatially positioned on one-dimensional DNA wires, two-dimensional DNA strips or origami tiles, and three-dimensional DNA origami bundles or cages, and specific protein–protein interactions or peptide–protein complexes provide versatile scaffolds for engineering enzyme assemblies. Biocatalytic cascades operating on these scaffolds or in confined nano/microenvironments reveal substantially enhanced reaction yields compared with the analogous diffusional mixtures of the biocomponents. Mechanistic pathways accounting for the enhanced biocatalytic activities and future challenges in developing and applying biocatalytic cascades are presented. Spatial organization of biocatalytic cascades can improve their performance. In this Review Article, Itamar Willner and colleagues discuss technologies to artificially confine and localize enzyme cascades, the origin of observed rate enhancements and potential applications of such designed systems.

Styrylquinoline - A Versatile Scaffold in Medicinal Chemistry.

Styrylquinolines are characteristic fully aromatic compounds with flat, rather lipophilic structures. The first reports on their synthesis and biological activity were published roughly a century ago. However, their low selectivity, unfavorable toxicity and problems with their mechanism of action significantly hampered their development. As a result, they have been abandoned for most of the time since they were discovered. Their renaissance was observed by the antiretroviral activity of several styrylquinoline derivatives that have been reported to be HIV integrase inhibitors. Subsequently, other activities such as their antifungal and anticancer abilities have also been revisited. In the present review, the spectrum of the activity of styrylquinolines and their use in drug design is presented and analyzed. New properties and applications that were reported recently have re-established styrylquinolines within medicinal and material chemistry. The considerable increase in the number of published papers regarding their activity spectrum will ensure further discoveries in the field. Styrylquinolines have earned a much stronger position in medicinal chemistry due to the discovery of their new activities, profound mechanisms of action and as drug candidates in clinical trials.

Synthesis of Coumarin Derivatives as Versatile Scaffolds for GSK-3β Enzyme Inhibition.

Glycogen synthase kinase-3 (GSK-3) is involved in the phosphorylation and inactivation of glycogen synthase. GSK-3 inhibitors have been associated with a variety of diseases, including Alzheimer´s disease (AD), diabetes type II, neurologic disorders, and cancer. The inhibition of GSK-3β isoforms is likely to represent an effective strategy against AD. The present work aimed to design and synthesize coumarin derivatives to explore their potential as GSK-3β kinase inhibitors. The through different synthetic methods were used to prepare coumarin derivatives. The GSK-3β activity was measured through the ADP-Glo™ Kinase Assay, which quantifies the kinasedependent enzymatic production of ADP from ATP, using a coupled-luminescence-based reaction. A docking study was performed by using the crystallographic structure of the staurosporine/GSK-3β complex [Protein Data Bank (PDB) code: 1Q3D]. The eleven coumarin derivatives were obtained and evaluated as potential GSK-3β inhibitors. Additionally, in silico studies were performed. The results revealed that the compounds 5c, 5d, and 6b inhibited GSK-3β enzymatic activity by 38.97-49.62% at 1 mM. The other coumarin derivatives were tested at 1 mM, 1 µM, and 1 nM concentrations and were shown to be inhibitor candidates, with significant IC50 (1.224-6.875 µM) values, except for compound 7c (IC50 = 10.809 µM). Docking simulations showed polar interactions between compound 5b and Lys85 and Ser203, clarifying the mechanism of the most potent activity. The coumarin derivatives 3a and 5b, developed in this study, showed remarkable activity as GSK-3β inhibitors.

Quinazoline and phthalazine derivatives as novel melatonin receptor ligands analogues of agomelatine

For further development of successors of Agomelatine through modulation of its pharmacokinetic properties, we report herein the design, synthesis and pharmacological results of a new family of melatonin receptor ligands. Issued from the introduction of quinazoline and phthalazine scaffolds carrying an ethyl amide lateral chain and a methoxy group as bioisosteric ligands analogues of previously developed Agomelatine. The biological activity of the prepared analogues was compared with that of Agomelatine. Quinazoline and phthalazine rings proved to be a versatile scaffold for easy feasible MT1 and MT2 ligands. Potent agonists with sub-micromolar binding affinity were obtained. However, the presence of two nitrogen atoms resulted in compounds with lower affinity for both MT1 and MT2, in comparison with the parent compound, balanced by the exhibition of good pharmacokinetic properties.

Recent advances in the catalytic synthesis of 3-aminooxindoles: an update.

3-Substituted-3-aminooxindoles are versatile scaffolds and they are common core structural motifs found in many natural products and biologically active compounds. In the last few years, a variety of synthetic methodologies have been developed for the synthesis of this moiety. In this review, we are presenting the recent advances in the catalytic synthesis of 3-aminooxindole derivatives.