Dynamic Multicomponent Reactions-Directed Self-Assembled G-quadruplex Inherent Antibacterial Hydrogel.

Nowadays, inherent antibacterial hydrogels have gained significant attention due to their utilization against infectious bacteria. Herein, we focus on the development of an injectable, self-healable, dynamic, and G-quadruplex hydrogel with inherent antibacterial activity. The dynamic self-assembled hydrogel is constructed upon multicomponent reactions (MCR) among guanosine, 2-formylphenylboronic acid, and amino acid/peptides in the presence of potassium ions. The role of amino acid/peptides in the formation of the G-quadruplex hydrogel is studied in detail. The G-quadruplex structure is formed via the π-π stacking of G-quartets. The formation of G-quadruplex is investigated by thioflavin T binding assay, CD spectroscopy, and PXRD. The formation of the dynamic imino-boronate bond in the hydrogels is well characterized by temperature-dependent 11B NMR (VT-NMR) and FT-IR spectroscopy. Furthermore, HR-TEM images and rheological experiments reveal the fibrillar networks and viscoelastic property of the hydrogels. The presence of the dynamic imino-boronate ester bonds makes the hydrogel injectable and self-healable in nature. These dynamic G-quadruplex hydrogels show potential antibacterial activity against a series of Gram-positive and Gram-negative bacteria. The hydrogels have been used for the entrapment and sustained release of an anticancer drug doxorubicin over 48 h at different pHs (4.8, 7.4, and 8.5) and temperature without the influence of any external stimuli. Such injectable and self-healable hydrogels could be used in various applications in the field of biomedical science.

Gold-catalyzed hydroarylation reactions: a comprehensive overview.

The hydroarylation of alkynes, alkenes, and allenes is a cost-effective and efficient way to incorporate unsaturated moieties into aromatic substrates. This review focuses on gold-catalyzed hydroarylation, which produces aromatic alkenes, diaryl-alkanes, heterocycles, carbocycles, and arylbutadienes by directly functionalizing C-H bonds. Without the need for prefunctionalization, direct functionalization of aromatic C-H bonds with unsaturated moieties (alkyne, alkene, allene) provides an efficient synthetic strategy with fewer reaction steps. This review offers an overview of the recently developed hydroarylation processes catalyzed by gold. Mechanisms of hydroarylation via alkyne, alkene, allene, and arene activation receive special attention.

A family of amphiphilic dioxidovanadium(V) hydrazone complexes as potent carbonic anhydrase inhibitors along with anti-diabetic and cytotoxic activities.

A family of dioxidovanadium(V) complexes (1-4) of the type [Na(H2O)x]+[VVO2(HL1-4)]- (x = 4, 4.5 and 7) where HL2- represents the dianionic form of 2-hydroxybenzoylhydrazone of 2-hydroxyacetophenone (H2L1, complex 1), 2-hydroxy-5-methylacetophenone (H2L2, complex 2), 2-hydroxy-5-methoxyacetophenone (H2L3, complex 3) and 2-hydroxy-5-chloroacetophenone (H2L4, complex 4), have been synthesized and characterized by analytical and spectral methods. These complexes exhibited the potential abilities to suppress the erythrocytes carbonic anhydrase enzymatic activity in type 1 and type 2 diabetic patients (in vitro), promising antidiabetic activity against T2 diabetic mice (in vivo). They also exhibited significant cytotoxic activity against cervical cancer (SiHa) cells (in vitro) as the IC50 value of complexes 1, 2 and 4 is substantially lower than the value found for cisplatin while that of 3 is comparable and follow the order: 4 < 1 < 2 < 3 and can kill the cells by apoptosis via the generation of reactive oxygen species (ROS). The complexes are soluble both in water and octanol media and also non-toxic at working concentrations. The antidiabetic activity of these four complexes follows the order: 4 > 2 > 1 > 3 while both the carbonic anhydrase and cytotoxic activity follow the order: 4 > 1 > 2 > 3 suggesting that complex 4, containing electron withdrawing Cl atom is the most reactive while 3 with electron donating OCH3 group is the least reactive species. The molecular docking study on hCA-I and hCA-II demonstrates that complexes interact via hydrogen bonding as well as different types of π-stacking.

A novel heterozygous mutation in the hydroxymethylbilane synthase gene in a case with acute intermittent porphyria.

Porphyrias are rare metabolic disorders caused by inherited or acquired enzymatic defects in the heme biosynthetic pathway. They are grouped into acute hepatic porphyrias and photocutaneous porphyrias. Acute intermittent porphyria, the most prevalent subtype of acute hepatic porphyrias, is caused by a mutation in the hydroxymethylbilane synthase gene. In this work, a case of a 13 year-old Indian female presenting with multi-organ involvement (Neurological: episodic seizures, behavioral abnormalities, acute onset progressive flaccid-motor quadriparesis, multiple cranial nerve palsies, respiratory paralysis, dysautonomia, and posterior reversible encephalopathy syndrome; Gastrointestinal: recurrent attacks of abdominal pain, nausea/vomiting, isolated transaminitis, and acute pancreatitis; and Renal: metabolic alkalosis and refractory dyselectrolytemia) which resulted in significant diagnostic dilemmas. She was eventually diagnosed as a case of acute intermittent porphyria harboring a novel hydroxymethylbilane synthase gene mutation (p.Arg173Trp).

Bicomponent Coassembled Hydrogel as a Template for Selective Enzymatic Generation of DOPA.

In living organisms, tyrosinase selectively produces l-DOPA from l-tyrosine. Here, a bicomponent hydrogel is used as a template for tyrosinase-catalyzed selective generation of l-DOPA from tyrosine. An amphiphilic molecule 1,5-diaminonaphthalene (DAN) coassembles with 1,3,5-benzenetricarboxylic acid (BTC) to form a self-supporting hydrogel. After alteration of complementary acids, DAN does not coassemble to form a hydrogel. The coassembly mechanism is investigated using spectroscopic techniques. The transmission electron microscopy and scanning electron microscopy images reveal the morphology details. The l-DOPA is kept from being oxidized when the hydrogel is used as a template. The enzymatically synthesized l-DOPA can also be separated from the mixture by easy tuning of the bicomponent coassembly.

Free Space in Liquid Crystals-Molecular Design, Generation, and Usage.

In the last 50 years, an important aim of molecular and materials design has been the generation of space for the uptake of guest molecules in macrocycles and cryptands, in dendrimers as monomolecular containers, and recently in porous networks like metal-organic and covalent organic frameworks. Such molecular, oligomeric, and polymeric materials can be applied for sensing, separation, catalysis, drug delivery, and gas storage, among others. The common goal is the recognition of molecules and their uptake into and release from an appropriate space. Typically, completely empty space is unfavorable in crystalline materials. Therefore, the elimination of molecules from the cavities is often accompanied by the collapse of the cavities, that is, by a change in the molecular conformation. In contrast to this solid matter, in which the cavities are rationally designed by covalent or coordinative bonds, liquid crystals (LCs) are fluid materials with high molecular mobility. Thus, the proposal of empty space in LCs is certainly a scientific provocation. However, various recent publications on columnar mesophases claim the existence of pores with low electron density or even completely empty space on the basis of X-ray and solid-state NMR studies. Although the latter may be debated, there are many examples in which LCs take up dopants such as polymerizable monomers in disclination lines, perdeuterated chains in the interstices between columns, or electron acceptors to fill mesogens with incommensurate building blocks, which eventually stabilize the LC phases. It seems that in LC science the generation and usage of free space has been studied only occasionally and were lucky discoveries rather than investigations based on rational design. This Account summarizes the research on the formal generation of void in LCs and highlights that rational design of molecules can lead to unconventional mesophases by efficient filling of the provided space, as was shown with shuttlecock mesogens and discotic mesogens related to the concept of complementary polytopic interactions. The topic was recently further developed by the investigation of shape-persistent star mesogens. Despite the formally empty space between their arms, they all form columnar liquid crystals. Such shape-persistent oligo(phenylenevinylene) molecules fill the void and efficiently nanosegregate by helical packing in columns and deformation of the molecular scaffold at the expense of the torsional energy. This inspired us to fill the intrinsic free space by guest molecules either via supramolecular or covalent bonds or just by physical mixing in order to avoid the increase in torsional energy and to stabilize the structure. This strategy led to complex filled liquid-crystalline matter with high structural control and may in the future be used for the design of organic electronic materials that are easily alignable for device applications.

Engineered Dynamic Boronate Ester-Mediated Self-Healable Biocompatible G-Quadruplex Hydrogels for Sustained Release of Vitamins.

Injectable, self-healable, and biocompatible dynamic hydrogels prepared from the molecular self-assembly and reversible covalent bond formation of low-molecular-weight hydrogelators are increasing in the field of drug delivery. Herein, we report the formation of G-quadruplex hydrogels via the multicomponent self-assembly and reversible bond formation between guanosine (G) and 1-naphthaleneboronic acid in the presence of the monovalent cation K+. The cation-templated stacking interaction of G4 quartets and the formation of dynamic cyclic boronate esters are responsible for the construction of dynamic G-quadruplex assembly. The in situ-synthesized dynamic cyclic boronate esters are well characterized by 11B nuclear magnetic resonance and Fourier transform infrared spectroscopy methods. The formation and morphology of the G-quadruplex hydrogel are well supported by several spectroscopic and microscopic techniques. The injectability and self-healing ability of the G-quadruplex hydrogel are also investigated. The in vivo cytotoxicity of the G-quadruplex hydrogel is extensively evaluated over different cell lines (HeLa, MCF-7, and HEK293) to observe the biostability and broad-spectrum biocompatibility of the hydrogel. Further, this injectable, biocompatible G-quadruplex hydrogel has been used for encapsulation and sustained release of two important vitamins (B2 and B12) over 40 h at physiological pH (7.46) and temperature (37 °C) without the influence of any external stimuli.

Fullerene-Filled Stilbene Stars: The Balance between Isolated C60 Helices and 3D Networks in Liquid-Crystal Self-Assemblies.

A series of shape-persistent star-shaped oligo(phenylene vinylene) liquid crystals and derivatives with fullerene tethered through spacers of different lengths to one arm were successfully synthesized. Solution studies by NMR, UV/Vis and fluorescence spectroscopy revealed the preferential location of the C60 acceptor in the vicinity of the peripheral donor unit, which affects the quenching of the emission of the conjugated stilbenoid scaffold in the donor-acceptor dyad. The fluorescence was completely absent in the liquid crystal phase due to the extraordinary hierarchical self-assembly. In this family of mesogens, the intrinsic free space has to be filled either by an extremely tight packing of the stars or by the fullerenes as guests. The spacer lengths control the nanosegregation of the C60 units in the cavities of the stars in either independent triple helices or unprecedented 3D networks, in which fullerenes are positioned at the interface of neighboring columns. Eventually, the clearing temperature of such large complex donor-acceptor systems can be tuned by an entropy effect defined by the length of the spacer. The accessibility of the isotropic phase without decomposition is an important prerequisite for future alignment studies associated with potential material applications in organic electronics.

Binding affinity and in vitro cytotoxicity of harmaline targeting different motifs of nucleic acids: An ultimate drug designing approach.

The work focuses towards interaction of harmaline, with nucleic acids of different motifs by multispectroscopic and calorimetric techniques. Findings of this study suggest that binding constant varied in the order single-stranded (ss) poly(A) > double-stranded calf thymus (CT) DNA > double-stranded poly(G)·poly(C) > clover leaf tRNAPhe . Prominent structural changes of ss poly(A), CT DNA, and poly(G)· poly(C) with concomitant induction of optical activity in the bound achiral alkaloid molecule was observed, while with tRNAPhe , very weak induced circular dichroism perturbation was seen. The interaction was predominantly exothermic, enthalpy driven, and entropy favored with CT DNA and poly(G)·poly(C), while it was entropy driven with poly(A) and tRNAPhe . Intercalated state of harmaline inside poly(A), CT DNA, and poly(G)·poly(C) was shown by viscometry, ferrocyanide quenching, and molecular docking. All these findings unequivocally pointed out preference of harmaline towards ss poly(A) inducing self-structure formation. Furthermore, harmaline administration caused a significant decrease in proliferation of HeLa and HepG2 cells with GI50 of 28µM and 11.2µM, respectively. Nucleic acid fragmentation, cellular ultramorphological changes, decreased mitochondrial membrane potential, upregulation of p53 and caspase 3, generation of reactive oxygen species, and a significant increase in the G2 /M population made HepG2 more prone to apoptosis than are HeLa cells.

Expression Pattern Similarities Support the Prediction of Orthologs Retaining Common Functions after Gene Duplication Events.

The identification of functionally equivalent, orthologous genes (functional orthologs) across genomes is necessary for accurate transfer of experimental knowledge from well-characterized organisms to others. This frequently relies on automated, coding sequence-based approaches such as OrthoMCL, Inparanoid, and KOG, which usually work well for one-to-one homologous states. However, this strategy does not reliably work for plants due to the occurrence of extensive gene/genome duplication. Frequently, for one query gene, multiple orthologous genes are predicted in the other genome, and it is not clear a priori from sequence comparison and similarity which one preserves the ancestral function. We have studied 11 organ-dependent and stress-induced gene expression patterns of 286 Arabidopsis lyrata duplicated gene groups and compared them with the respective Arabidopsis (Arabidopsis thaliana) genes to predict putative expressologs and nonexpressologs based on gene expression similarity. Promoter sequence divergence as an additional tool to substantiate functional orthology only partially overlapped with expressolog classification. By cloning eight A. lyrata homologs and complementing them in the respective four Arabidopsis loss-of-function mutants, we experimentally proved that predicted expressologs are indeed functional orthologs, while nonexpressologs or nonfunctionalized orthologs are not. Our study demonstrates that even a small set of gene expression data in addition to sequence homologies are instrumental in the assignment of functional orthologs in the presence of multiple orthologs.

Tilt boundary induced heteroepitaxy in chemically grown dendritic silver nanostructures on germanium and their optical properties.

Dendritic silver nanostructures were prepared by a simple dip-and-rinse galvanic displacement reaction directly on germanium surfaces. The formation and evolution of these dendrites were investigated using scanning electron microscopy (SEM), high-resolution transmission electron microscopy (HRTEM) and energy-dispersive X-ray spectroscopy (EDX). The present results clearly show a new type of heteroepitaxy, where the large lattice mismatch between silver and germanium is accommodated at the interface by the formation of low-energy asymmetric tilt boundaries. The overgrown samples reduce the strain by introducing crystal defects. Additionally, by employing cathodoluminescence (CL) spectroscopy and imaging with a field emission gun scanning electron microscope (FEG-SEM), we provide information on the surface plasmon assisted photon emission of a stack of Ag hexagonal nanostructures. Surface enhanced Raman scattering (SERS) studies show the suitability of such Ag nanodendritic structures as SERS active substrates.

A mini review on human serum albumin - natural alkaloids interaction and its role as drug carrier.

Human serum albumin (HSA) is one of the main protein components of the circulatory system. It's well characterized physiological role is to carry numerous ligands to their target site. Overall pharmacokinetic profile of a drug is deliberately influenced by its affinity towards plasma proteins, especially with albumins. Alkaloids as small molecules are natural nitrogenous organic compounds that have significant medicinal properties that bind to HSA. There are three sites viz., I, II and III, on HSA molecule where the drug/small molecule binds based on their molecular size, structure and hydrophobicity. The major driving forces for the interaction of alkaloids-HSA are non-covalent interactions. Drug-HSA interaction is an admired area of research since it has been lately employed for both therapeutic and investigative reasons and is one of the main elements determining the pharmacokinetic and pharmacodynamic profiles of the therapeutic molecules. Displacement and drug-drug interactions, clinical alteration of drug-albumin affinity in diseases affecting the therapeutic role of the drugs, use of HSA nanoparticles for the delivery of drug in cancer are the major significant issues that have been discussed in this review. This article provides an overview of the multifunctional properties of HSA as a drug carrier, as well as how knowledge of these properties is currently being used to improve the bioavailability of drugs with the ability to bind to albumin for future pharmaceutical, clinical, and commercial applications of the albumin protein.Communicated by Ramaswamy H. Sarma.

N-Heterocyclic Carbene-Catalyzed Facile Synthesis of Phthalidyl Sulfonohydrazones: Density Functional Theory Mechanistic Insights and Docking Interactions.

N-heterocyclic carbene catalysis reaction protocol is disclosed for the synthesis of phthalidyl sulfonohydrazones. A broad range of N-tosyl hydrazones react effectively with phthalaldehyde derivatives under open-air conditions, enabling the formation of a new C-N bond via an oxidative path. The reaction proceeds under mild reaction conditions with broad substrate scopes, wide functional group tolerance, and good to excellent yields. The mechanistic pathway is studied successfully using control experiments, competitive reactions, ESI-MS spectral analyses of the reaction mixture, and computational study by density functional theory. The potential use of one of the phthalidyl sulfonohydrazone derivatives as the inhibitor of ß-ketoacyl acyl carrier protein synthase I of Escherichia coli is investigated using molecular docking.

Nucleopeptide-Coupled Injectable Bioconjugated Guanosine-Quadruplex Hydrogel with Inherent Antibacterial Activity.

The multicomponent reaction-directed self-assembled hydrogels offer the opportunities to fabricate materials with ubiquitous properties which sometimes are not possible to generate from single components. Therefore, multicomponent-derived hydrogels have enormous applications in biomedical fields, and the number of such systems is increasing day by day. Herein, the multicomponent self-assembly techniques have been employed to develop a biomimetic low-molecular-weight G-quadruplex hydrogel under physiological conditions. The bioconjugation of guanosine, 4-formylphenylboronic acid, and cytosine-functionalized nucleopeptide (NP) is important to generate the multicomponent self-assembled dynamic imino-boronate ester-mediated bioconjugated G-quadruplex hydrogels. Using thioflavin T fluorescence assay, powder X-ray diffraction, and circular dichroism spectroscopic techniques, we confirm the existence of a G-quartet-like structure as the key parameter for the formation of nanofibrillar hydrogels. The multicomponent self-assembled G-quadruplex hydrogel possesses excellent inherent antibacterial activity against a broad range of bacterial species. The in vitro cytocompatibility of the synthesized hydrogel was evaluated on MCF-7 and HEK 293T cell lines to study the biocompatibility of the hydrogel. The proposed injectable, biocompatible, and NP-coupled G-quadruplex hydrogel with inherent antibacterial efficiency holds promising importance to prevent localized bacterial infections.

Synthesis and Structural Studies of Nucleobase Functionalized Hydrogels for Controlled Release of Vitamins.

The development of biomolecule-derived biocompatible scaffolds for drug delivery applications is an emerging research area. Herein, we have synthesized a series of nucleobase guanine (G) functionalized amino acid conjugates having different chain lengths to study their molecular self-assembly in the hydrogel state. The gelation properties have been induced by the correct choice of chain lengths of fatty acids present in nucleobase functionalized molecules. The effect of alkali metal cations, pH, and the concentration of nucleobase functionalized amino acid conjugates in the molecular self-assembly process has been explored. The presence of Hoogsteen hydrogen bonding interaction drives the formation of a G-quadruplex functionalized hydrogel. The DOSY nuclear magnetic resonance is also performed to evaluate the self-assembling behavior of the newly formed nucleobase functionalized hydrogel. The nanofibrillar morphology is responsible for the formation of a hydrogel, which has been confirmed by various microscopic experiments. The mechanical behaviors of the hydrogel were evaluated by rheological experiments. The in vitro biostability of the synthesized nucleobase amino acid conjugate is also investigated in the presence of hydrolytic enzymes proteinase K and chymotrypsin. Finally, the nucleobase functionalized hydrogel has been used as a drug delivery platform for the control and sustained pH-responsive release of vitamins B2 and B12. This synthesized nucleobase functionalized hydrogel also exhibits noncytotoxic behavior, which has been evaluated by their in vitro cell viability experiment using HEK 293 and MCF-7 cell lines.

Headache as the presenting manifestation of Gorlin-Goltz syndrome with diastematomyelia: A case report.

Gorlin-Goltz syndrome (GGS) is an autosomal dominant multisystemic disease with high penetrance. Headache heralding GGS has been previously reported but without discussing potential sources. We report a patient with headache and a novel association (diastematomyelia), which helped with the diagnosis. A 46-year-old woman presented with persistent holocranial headache. On examination, countless hyperpigmented basal cell nevi over the face, pits over the palmar/plantar surface, and palmar and plantar keratosis were observed. A magnetic resonance imaging (MRI) of the spinal cord revealed diastematomyelia. Diagnosis of GGS was finally made. Headache and diastematomyelia should be included in the clinical picture of GGS.

Palladium-catalyzed Synthesis of Fused Carbo- and Heterocycles.

The use of palladium catalysts in fused ring synthesis has been increasingly noteworthy in recent years in organic synthesis. It has a lot of potential compared to other transition metal catalysts, because of its one-of-a-kind feature that makes them more widely applicable in a variety of disciplines application. Palladium is important in a variety of Heck processes, including intramolecular, intermolecular, and reductive Heck reactions, which produce diverse carbocycles and heterocycles of biological importance. Under optimal reaction conditions, carbocyclization or heterocyclization occurs, resulting in the production of numerous structural building blocks of naturally occurring compounds. Beside intramolecular Heck-type reactions, cycloaddition, cycloalkylation, oxidative coupling, C-H functionalization, cross-coupling reactions, and carboamidation reactions have also been employed extensively to access fused carbo- and heterocycles of immense biological importance. This review article provides a well-summarized discussion (since 2001) on fused carbo- and heterocycle ring synthesis using palladium catalysts, overviewing their applications, and mechanistic insights.

Insights into the transformation of VO2+ motif to VO3+, V2O34+ and VO2+ motifs and their interconversion along with a detailed mechanistic study of their anti-cancer activity in SiHa cervical cancer cells.

The basic criteria for the formation of complexes with VO3+, V2O34+ and VO2+ motifs from the VO2+ motif and their interconversion were explored utilizing two multidentate O,N-donor hydrazone ligands namely, E-2-Hydroxy-N'-(4-oxopentan-2-ylidine)benzohydrazide (H3L1) and E-2-Hydroxy-N'-(4-oxo-4-phenylbutan-2-ylidine)benzohydrazide (H3L2), derived from the condensation of 2-hydroxybenzoylhydrazide with acetylacetone and benzoylacetone respectively. Under aerobic condition, the possibility of forming complexes with different motifs in different solvents with varying pH was examined theoretically by computational methods with results that were verified experimentally. This study reveals that under aerobic condition, complexes with VO3+ (1,2) and V2O34+ (3, 4) motifs were formed in protic CH3OH and neutral CHCl3 solvent respectively while the formation of complexes (5-14) with VO2+ motif required protic CH3OH solvent and higher pH (≥ 7). Interconversion of VO3+, V2O34+ and VO2+ motifs are associated with specific acid-base equilibria, substantiated by 51V NMR titrations. Complexes containing these three motifs exhibited promising in vitro anticancer activity in SiHa cervical cancer cells without affecting healthy cells; among them complexes (5-14) with VO2+ motif are more potent. A detailed systematic mechanistic study was carried out, utilizing the two most potent complexes 5 and 6 (IC50 = 13, 6 µM respectively), which indicates that cytotoxicity and anti-proliferative activity of these complexes are manifested through oxidative stress induced apoptotic pathways (caspase mediated).