Single Molecular Scaffold Research Articles

Tyramine Derivatives as Versatile Pharmacophores With Potent Biological Properties: Sex Hormone-Binding Globulin Inhibition, Colon Cancer Antimigration, and Antimicrobial Activity.

Guided by the idea that the presence of a heterocyclic aromatic core and tyramine moiety, under the umbrella of a single molecular scaffold could bring interesting biological properties, herein we present synthesis, characterization, with two crystal structures reported, and biological evaluation of some tyramine derivates. Cytotoxic and antimigratory potential was addressed by using a colorectal cancer cell line as a model system. Although possessing no cytotoxic effects, two compounds have shown strong antimigratory potential in low doses, with no effect on healthy MRC-5 cells. Evaluation of their antimicrobial activities suggested prominent antimicrobial activity, where Compound 4 outperformed streptomycin against Escherichia coli and Proteus mirabilis. Hormone-dependent types of cancer, such as prostate, ovary, and breast, are highly dependent on human sex hormone-binding globulin (SHBG) blood levels. A molecular docking study has shown that 1 has high affinity to bind and therefore compete with natural steroids for the SHBG steroid-binding site. DNA-binding study have shown that 4 interacts with CT-DNA in a groove-binding mode. In silico ADME/T study revealed that all compounds have suitable physicochemical properties for oral bioavailability and druglikeness, while toxicity tests for 1, 4, and 6 suggested potential for mutagenicity (4, 6), hepatotoxicity (6), and skin sensation (1).

Design of an Acidic pH-Activated NIR Fluorescent Convertible Rhodamine-Hemicyanine Probe-Peptide Conjugate for Living Cancer Cell Active Targeted Selective Tracking of Lysosomes.

We have synthesized an acidic pH-activatable dual targeting ratiometric fluorescent probe-peptide conjugate using the SPPS protocol on Rink amide AM resin. Living carcinoma cell specific active targeting, successive cell penetration, and selective staining of lysosomes are accomplished. Real-time monitoring of lysosomes, 3D, and multicolor cancer cell imaging are also attained. The de novo design consists of the integration of multifunctionality into a single molecular scaffold, e. g., RGDS peptide residue to target cancer cell surface overexpressed receptor αVβ3 integrin, live-cell penetrating organic unsymmetrical rhodamine-hemicyanine chromophore comprising a lysosome targeting morpholine group, and an acidic pH openable spiro-lactam ring for a visible-to-NIR switchable ratiometric response. Water-soluble fluorescent probe-peptide conjugate exhibits intramolecular spirolactamization at basic pH through Arg amide N. The visible spirolactam state predominantly exists at physiological and basic pH and can be switched to the highly conjugated NIR open amide state (λem=735 nm) through spiro-lactam ring opening triggered by acidic pH with a huge bathochromic shift (Δλabs=336 nm, ΔλFL=265 nm). Moreover, pH-sensitive ratiometric optical switching is achieved. This in situ acidic cancer cell lysosome activatable multifunctional fluorophore-peptide conjugate shows augmented molar absorptivity, enhanced quantum yield, and improved fluorescence lifetime at acidic lysosomal pH; negligible cytotoxicity; and dual targeted ratiometric imaging capability of living cancer cell selective lysosomes with a pKa value of 5.1.

Switchable supramolecular helices for asymmetric stereodivergent catalysis

Despite recent developments on the design of dynamic catalysts, none of them have been exploited for the in-situ control of multiple stereogenic centers in a single molecular scaffold. We report herein that it is possible to obtain in majority any amongst the four possible stereoisomers of an amino alcohol by means of a switchable asymmetric catalyst built on supramolecular helices. Hydrogen-bonded assemblies between a benzene-1,3,5-tricarboxamide (BTA) achiral phosphine ligand coordinated to copper and a chiral BTA comonomer are engaged in a copper-hydride catalyzed hydrosilylation and hydroamination cascade process. The nature of the product stereoisomer is related to the handedness of the helices and can thus be directed in a predictable way by changing the nature of the major enantiomer of the BTA comonomer present in the assemblies. The strategy allows all stereoisomers to be obtained one-pot with similar selectivities by conducting the cascade reaction in a concomitant manner, i.e. without inverting the handedness of the helices, or sequentially, i.e. by switching the handedness of the supramolecular helices between the hydrosilylation and hydroamination steps. Supramolecular helical catalysts appear as a unique and versatile platform to control the configuration of molecules or polymers embedding several stereogenic centers.

Formylation as a Chemical Tool to Modulate the Performance of Photosensitizers Based on Boron Dipyrromethene Dimers.

Heavy-atom-free photosensitizers are envisioned as the next generation of photoactive molecules for photo-theragnosis. In this approach, and after suitable irradiation, a single molecular scaffold is able to visualize and kill tumour cells by fluorescence signalling and photodynamic therapy (PDT), respectively, with minimal side effects. In this regard, BODIPY-based orthogonal dimers have irrupted as suitable candidates for this aim. Herein, we analyse the photophysical properties of a set of formyl-functionalized BODIPY dimers to ascertain their suitability as fluorescent photosensitizers. The conducted computationally aided spectroscopic study determined that the fluorescence/singlet oxygen generation dual performance of these valuable BODIPY dimers not only depends on the BODIPY-BODIPY linkage and the steric hindrance around it, but also can be modulated by proper formyl functionalization at specific chromophoric positions. Thus, we propose regioselective formylation as an effective tool to modulate such a delicate photonic balance in BODIPY-based dimeric photosensitizers. The taming of the excited-state dynamics, in particular intramolecular charge transfer as the key underlying process mediating fluorescence deactivation vs. intersystem crossing increasing, could serve to increase fluorescence for brighter bioimaging, enhance the generation of singlet oxygen for killing activity, or balance both for photo-theragnosis.

Novel Structural Hybrids of Pyrrole and Thiazole Moieties: Synthesis and Evaluation of Antibacterial and Antifungal Activities.

One of the best ways to design new biocidal agents is synthesizing hybrid molecules by combining two or more bioactive moieties in a single molecular scaffold. So, new series of pyrroles bearing a thiazole moiety were synthesized using 1-methyl-1H-pyrrole-2-carbaldehyde thiosemicarbazones 1a-c. Cyclization of thiosemicarbazone derivatives 1a-c with ethyl chloroacetate, ethyl 2-chloropropanoate, chloroacetone and phenacyl bromide afforded the corresponding thiazolidin-4-ones 2a-c, 5-methylthiazolidin-4-ones 3a-c, 4-methyl-2,3-dihydrothiazoles 4a-c, and 4-phenyl-2,3-dihydrothiazoles 5a-c, respectively. The antimicrobial activity of the new thiazole derivatives was evaluated.

Site-Selective Artificial Ribonucleases: Renaissance of Oligonucleotide Conjugates for Irreversible Cleavage of RNA Sequences.

RNA-targeting therapeutics require highly efficient sequence-specific devices capable of RNA irreversible degradation in vivo. The most developed methods of sequence-specific RNA cleavage, such as siRNA or antisense oligonucleotides (ASO), are currently based on recruitment of either intracellular multi-protein complexes or enzymes, leaving alternative approaches (e.g., ribozymes and DNAzymes) far behind. Recently, site-selective artificial ribonucleases combining the oligonucleotide recognition motifs (or their structural analogues) and catalytically active groups in a single molecular scaffold have been proven to be a great competitor to siRNA and ASO. Using the most efficient catalytic groups, utilising both metal ion-dependent (Cu(II)-2,9-dimethylphenanthroline) and metal ion-free (Tris(2-aminobenzimidazole)) on the one hand and PNA as an RNA recognising oligonucleotide on the other, allowed site-selective artificial RNases to be created with half-lives of 0.5–1 h. Artificial RNases based on the catalytic peptide [(ArgLeu)2Gly]2 were able to take progress a step further by demonstrating an ability to cleave miRNA-21 in tumour cells and provide a significant reduction of tumour growth in mice.

Novel structural hybrids of quinoline and thiazole moieties: Synthesis and evaluation of antibacterial and antifungal activities with molecular modeling studies

One of the best ways to design new biocidal agents is synthesizing hybrid molecules by combining two or more bioactive moieties in a single molecular scaffold. So, new series of quinolines bearing a thiazole moiety were synthesized using thiosemicarbazones 2a–f. Cyclization of 2a–f with ethyl chloroacetate, ethyl 2-chloropropanoate or chloroacetone afforded the corresponding thiazoles 3–5. The antimicrobial activity of the new quinoline derivatives was evaluated. The most of tested compounds revealed potent both of the antibacterial and antifungal activities. Fourfold potency of amphotericin B for the inhibition the growth of the A. fumigatus was displayed by ccompound 5e. The latter compound displayed twofold potency of gentamycin for inhibition the growth of N. gonorrhoeae. Moreover, this compound showed equipotent potency of references drugs for inhibition of the growth of S. flexneri, S. pyogenes, P. vulgaris, A. clavatus, G. candidum and P. marneffei. So, quinolines bearing a thiazole moiety can be suggested as interesting scaffolds for the development both of the novel antibacterial and antifungal agents. Some new derivatives were studied as peptide deformylase enzyme inhibitors. Thiazolidin-4-one derivative 3d and 2,3-dihydrothiazole derivative 5c had shown good PDF inhibition activity, which had been supported by the docking results with highest binding affinity and lowest docking energy score. These results suggested that the most potent compounds might be possible agents as novel bacterial PDF inhibitor.

Imaging mitochondria and plasma membrane in live cells using solvatochromic styrylpyridines

Investigating the dynamics of different biomolecules in the cellular milieu through microscopic imaging has gained paramount importance in the last decade. Continuous developments in the field of microscopy are paralleled by the design and synthesis of fluorophores that target specific compartments within a cell. In this study, we have synthesized four fluorescent styrene derivatives, a neutral styrylpridine, three cationic styrylpyridinium probes with and without cholesterol tether, and investigated their absorption, emission, and cellular imaging properties. The fluorophores show solvatochromic emission attributed to intramolecular charge transfer from donor to acceptor with an emission range of 500–600 nm. The fluorescent cholesterol conjugate labels plasma membrane effectively while the fluorophores devoid of the cholesterol tether label mitochondria. Cholesterol conjugate also shows strong interaction with liposome membrane. Furthermore, the fluorophores alsotrack the mitochondria in live cells with high specificity. Cell viability assay showed overall non-toxic nature of the probes even at higher fluorophore concentrations. Through sidearm modifications, keeping the fluorescent core intact, we successfully targeted specific subcellular compartments of neuronal (N2a) and non-neuronal (HeLa) mammalian cell lines. This strategy of using a single molecular scaffold with subtle substitutions could be ideal in generating a variety of fluorophores targeting other subcellular compartments.

A strategic approach to the synthesis of ferrocene appended chalcone linked triazole allied organosilatranes: Antibacterial, antifungal, antiparasitic and antioxidant studies.

A series of ferrocene appended chalcone allied triazole coupled organosilatranes (FCTSa 7-FCTSa 12) were synthesised with the aim of amalgamating the pharmacological action of the constituting moieties into a single molecular scaffold. All the synthesised silatranes were well characterized by various spectroscopic techniques like IR, 1H NMR, 13C NMR and elemental analysis. Organosilatranes were then evaluated for their biological alacrity against bacterial and fungal strains compared with the standard drugs Rifampicin and Amphotericin B respectively. The ferrocene conjugates were found to be only moderately effective against the tested microbes. However, the organosilatranes conceded excellent efficacy against parasite G. lamblia with FCTSa 11 arraying the leading results. On the other hand against another parasite T. vaginalis, FCTSa 8 has emerged as an outstanding composite. Further, Total Antioxidant Assay (TAA) with 2,2'-azino-bis-3-(ethylbenzothiazoline-6-sulphonic acid) revealed FCTSa 10 to be the best claimant for radical scavenging activity. Along these lines, introducing some different substituents in the synthesised hybrids may act as a useful strategy for increasing the biological profile of the drugs.

Solvent Induced Morphological Evolution of Cholesterol Based Glucose Tailored Amphiphiles: Transformation from Vesicles to Nanoribbons.

Supramolecular self-assembly of low molecular mass amphiphiles is of topical interest with the urge to achieve precise control over the formation of various self-aggregated structures. Particularly, fabrication of multifarious nanostructures from single molecular backbone would be highly advantageous for task specific applications of the self-aggregates. To this end, the present study reports the solvent triggered evolution of hierarchical self-assembled structures of cholesterol based glucose appended amphiphiles and the pathway of structural transition. The amphiphiles formed bilayered vesicles in water and gels in different organic solvents. In DMSO-water solvent mixture, it showed gradual transition in the morphology of self-aggregates from vesicle-to-fiber and intermediate morphologies depending on the solvent compositions. Microscopic and spectroscopic investigations showed that morphological transformation took place through fusion, elongation and twisting of self-aggregates owing to the reorganization of the amphiphiles (H-type to J-type) in varied solvent polarity. Moreover, sheetlike molecular organization originating from hydrogen bonding and solvophobic interaction played a vital role in the formation of nanoribbons that led to the formation of gel fibril network. This study endows a new strategy to develop solvent induced multistructured self-aggregates from a single molecular scaffold, unraveling the route of forming hierarchical self-assembly.

First example of a modular porphyrinoid assembly capable of stabilizing different metal ions in a single molecular scaffold.

We report the synthesis and characterization of porphyrin-corrole-porphyrin (Por-Cor-Por) hybrids directly linked at the meso-meso positions for the first time. The stability and solubility of the trimer are carefully balanced by adding electron-withdrawing substituents to the corrole ring and sterically bulky groups on the porphyrins. The new hybrids are capable of stabilizing more than one metal ion in a single molecular scaffold. The versatility of the triad has been demonstrated by successfully stabilizing homo- (Ni) and heterotrinuclear (Ni-Cu-Ni) coordination motifs. The solid-state structure of the NiPor-CuCor-PorNi hybrid was revealed by single-crystal X-ray diffraction studies. The Ni(II) porphyrins are significantly ruffled and tilted by 83° from the plane of corrole. The robustness of the synthesized hybrids was reflected in the electrochemical investigations and the redox behaviour of the hybrids show that the oxidation processes are mostly corrole-centred. In particular it is worth noting that the Por-Cor-Por hybrid can further be manipulated due to the presence of substituent-free meso-positions on both the terminals.

Discovery of new coumarin substituted quinazolines as potential bioactive agents

In view of the biological importance of some important pharmacophores such as quinazoline, coumarin, and benzothiazole, we frame these moieties in a single molecular scaffold to be screened in vitro for their antimicrobial activity. The newly synthesized analogs have been examined for their in vitro biological efficacy against two Gram-positive bacteria, three Gram-negative bacteria, two fungi, and for antimycobacterial activity against M. tuberculosis H37Rv. The bioassay results revealed that the majority of final analogs exhibited potential bio efficacies with the remarkable level of MICs comparable to control drugs. The new synthesized compounds were characterized by FT-IR, 1H NMR, 13C NMR, and MS analysis.

ChemInform Abstract: 1,3‐Dipolar Cycloaddition in the Synthesis of Novel Isoxazoline/Pyrazole Derivatives Bearing 1,2,3‐Triazoles Moiety.

1,3-Dipolar cycloaddition of α,β-unsaturated ketones bearing 1,2,3-triazole moiety with nitrile oxides and sydnones obtained a series of novel 3,4,5-trisubstituted isoxazolines (5a, 5b, 5c, 5d, 5e, 5f, 5g, 5h) and 1,3,4-trisubstituted pyrazoles (7a, 7b, 7c, 7d, 7e, 7f, 7g, 7h) with different active pharmacophores in a single molecular scaffold. The structure of the target compounds was confirmed on the basis of IR, 1H NMR, mass spectral, elemental analysis, and X-ray crystallographic analysis.

1,3-Dipolar Cycloaddition in the Synthesis of Novel Isoxazoline/Pyrazole Derivatives Bearing 1,2,3-Triazoles Moiety

1,3-Dipolar cycloaddition of α,β-unsaturated ketones bearing 1,2,3-triazole moiety with nitrile oxides and sydnones obtained a series of novel 3,4,5-trisubstituted isoxazolines (5a, 5b, 5c, 5d, 5e, 5f, 5g, 5h) and 1,3,4-trisubstituted pyrazoles (7a, 7b, 7c, 7d, 7e, 7f, 7g, 7h) with different active pharmacophores in a single molecular scaffold. The structure of the target compounds was confirmed on the basis of IR, 1H NMR, mass spectral, elemental analysis, and X-ray crystallographic analysis.

Reconstitution of Collective Transport by Defined Numbers of Kinesin-1 and Kinesin-14, Two Opposing Motor Proteins

Intracellular transport is usually driven by the collective operation of molecular motors that move along cytoskeletal filaments. Recent studies have reported that the movements include dynamic changes in velocity and direction along the filaments, which may be explained as a result of interplay between teams of opposing motors. In these movements, the number of participating motors is so small that its stochastic behavior dominates. Therefore, to reveal the mechanisms of motor coordination, it is essential to build and test mechanical models that explicitly incorporate the number and geometry of engaged motors. Here, we develop an experimental system to control the number and geometry of motors, i.e. 1, 2, 3, and 4 molecules, at specific sites on a single DNA scaffold. The covalent bonds throughout the whole complex allow us to precisely quantify the number of engaged molecules by SDS-PAGE, and ensure the stable linkages between motors for motion tracking and force measurement. First, we constructed complexes that engage teams of either kinesin-1 or kinesin-14. The travel distances of both kinesins were greatly extended when the number of molecules was increased, whereas the velocities were only slightly affected. Next, we linked together two opposing kinesin motors, kinesin-1 and kinesin-14, by a single molecular scaffold, which leads to a tug-of-war on microtubules. In the tug-of-war, reversals of direction and periodical, step-like movements were frequently observed. The combination of quantitative in vitro and in silico experiments using this simplified system will provide fundamental knowledge of motor coordination.

Dendrimers as a Scaffold for Nitric Oxide Release

The preparation and characterization of nitric oxide (NO)-releasing dendrimer conjugates are reported. Generation 3 and 5 polypropylenimine dendrimers (DAB-Am-16 and DAB-Am-64) were modified at the exterior to impart different amine functionalities. The ability to store NO on a dendritic scaffold using N-diazeniumdiolate NO donors was examined via the reaction of primary amine, secondary amine, and amide functionalities with high pressures of NO (5 atm). The secondary amine dendrimer conjugates exhibited a high storage capacity for NO (up to 5.6 micromol NO/mg), greatly increasing the "payload" of released NO over existing macromolecular NO donors. The mechanism of diazeniumdiolate decomposition was proton initiated, generating NO spontaneously under physiological conditions (pH 7.4, 37 degrees C). The NO release durations (>16 h) observed for the secondary amine dendrimers were significantly longer compared to small molecule alkyl secondary amine diazeniumdiolates, thus illustrating a dendritic effect on NO release kinetics. The multivalent exterior of dendrimers allows for the future combination of NO donors and other functionalities on a single molecular scaffold, enabling diverse utility as NO storage/delivery systems.

Synthesis of luminescent heterometallic bis-lanthanide complexes via selective, sequential metallation

A modular synthetic method for the differential incorporation of two lanthanide ions into a single molecular scaffold is reported; the mixed bimetallic Tb/Eu complex displays an interesting solvent polarity-dependent ratiometric luminescence.

Reactive Dendronized Copolymer of Styryl Dendron and Maleic Anhydride: A Single Molecular Scaffold

Novel dendronized copolymers bearing reactive anhydride groups along the backbones are reported in this paper. They were synthesized through copolymerizations of styryl macromonomers bearing Fréchet-type dendrons of the first to the fourth generation and maleic anhydride (MAn) through conventional radical polymerization. The dendritic macromonomers were prepared by an accelerated convergent approach, i.e., a reaction of the dendritic bromide of lower generation with a styrene derivative bearing a 3,5-dihydroxybenzyl group. The dendronized copolymers with rather high molar masses were obtained under mild conditions, even for the fourth-generation dendritic monomer as determined by static light scattering (SLS). For example, the degree of copolymerization for the third-generation monomer reached 487. Owing to the reactivity of the anhydride, functional groups, which were buried by the grafted dendrons along the backbone, could be easily introduced as follows: (1) by the hydrolysis under acid conditions, the amphiphilic copolymers with a structure of dendron-alt-2COOH were prepared; (2) by reacting with alkyl primary amine, the copolymers with dendron-alt-linear alkyl chain were obtained in a quantitatively yields; (3) when reacted with a primary amino dendron of its generation different from the pendent dendron, a series of new dendronized copolymers with their side dendrons grafted in an alternative generation structure were produced. Therefore, the novel reactive dendronized copolymer presented herein can be a single molecular scaffold to be applied in nanomaterials and nanotechnologies of one dimension.

Single Framework Recombinant Antibody Fragments Designed for Protein Chip Applications

High-throughput proteomics, based on the microarray platform, requires stable, highly functional components that will yield a highly sensitive read-out of low abundance proteins. Although antibodies are the best characterized binding molecules for this purpose, only a fraction of them appear to behave satisfactorily in the chip format. Therefore, high demands need to be placed on their molecular design. In the present study, we have focused on recombinant antibody design based on a single framework for protein chip applications, aiming at defining crucial molecular probe parameters. Our results show that engineered human recombinant scFv antibody fragments that displayed appropriate biophysical properties (molecular [functional] stability in particular) can be generated, making them prime candidates for high-density antibody arrays. In fact, a superior framework that displays both multifaceted adsorption properties and very high functional stability over several months on chips (stored in a dried-out state) was identified. Taken together, designed scFv fragments based on a single molecular scaffold, readily accessible in large phage display libraries, can undoubtedly meet the requirements of probe content in antibody microarrays, particularly for global proteome analysis.