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Isothiazolo[4,3- b ]pyridines have been extensively explored as inhibitors of cyclin G-associated kinase (GAK). In order to expand the structure-activity relationship study and to discover other chemotypes that act as GAK inhibitors, the closely related isothiazolo[4,5- b ]pyridine scaffold was explored. An easy and efficient synthetic procedure to access 3,5- and 3,6-dihalogenated isothiazolo[4,5- b ]pyridines as key building blocks was developed. Regioselective functionalization with various substituents was performed. None of the newly synthesized isothiazolo[4,5- b ]pyridines were active as GAK inhibitors. Molecular modeling was applied to rationalise their inactivity as GAK binders.

A one-pot microwave assisted telescopic approach is reported for the chemo-selective synthesis of substituted 1,3-thiazetidines using readily available 2-aminopyridines/pyrazines/pyrimidine, substituted isothiocyanates and 1,2-dihalomethanes. The procedure involves thiourea formation from 2-aminopyridines/pyrazines/pyrimidine with the substituted isothiocyanates followed by a base catalysed nucleophilic attack of the CS bond on the 1,2-dihalomethane. Subsequently, a cyclization reaction occurs to yield substituted 1,3-thiazetidines. These four membered strained ring systems are reported to possess broad substrate scope with high functional group tolerance. The above synthetic sequence for the formation of four membered heterocycles is proven to be a modular and straightforward approach. Further the mechanistic pathway for the formation of 1,3-thiazetidines was supported by computational evaluations and X-ray crystallography analyses. The relevance of these thiazetidines in biological applications is evaluated by studying their ability to bind bio-macromolecules like proteins and nucleic acids.

A mild and eco-friendly visible-light-induced synthesis of 2-(2-hydrazinyl) thiazole from readily accessible thiosemicarbazide, carbonyl, and phenacyl bromide in the absence of a metal catalyst and/or any extrinsic photosensitizer is reported. This approach only requires a source of visible light and a green solvent at room temperature to produce the medicinally privileged scaffolds of hydrazinyl-thiazole derivatives in good to outstanding yields. Experimental studies support the in situ formation of a visible-light-absorbing, photosensitized colored ternary EDA complex. The next step is to prepare a pair of radicals in an excited state, which makes it easier to prepare thiazole derivatives through a SET and PCET process. DFT calculations additionally supported the mechanistic analysis of the course of the reaction. The antioxidant and antidiabetic properties of some of the compounds in the synthesized library were tested in vitro . All the investigated compounds demonstrated appreciable antioxidant activity, as evidenced by the reducing power experiment and the IC 50 values of the DPPH radical scavenging experiment. Furthermore, the IC 50 values for 4c, 4d, and 4g also demonstrated a strong α-amylase inhibitory effect.

Azlactones and thiazoles are common structural motifs and possess diverse applications. A new method for the efficient and straightforward syntheses of 2,4-disubstituted thiazoles from azlactones has been developed. The reaction proceeded via deoxygenation of azlactones by Lawesson's reagent without metal or external additives. A variety of 2,4-disubstituted thiazoles were synthesized with up to 92% yield. Furthermore, the importance of this methodology was also justified by a gram-scale synthesis.

An effective method for the synthesis of 8-aryl-4,5-dihydrothiazolo[4',5':3,4]benzo[1,2- c ]isoxazol-2-amines was developed. This method includes the α-keto bromination of 3-aryl-6,7-dihydrobenzo[ c ]isoxazol-4(5 H )-ones followed by the condensation of the obtained bromo derivatives with thiourea in acetonitrile. Using virtual screening, a series of acylated derivatives of the obtained compounds were selected as potential HSP90 inhibitors. These compounds were prepared and evaluated as antiproliferative agents against three cancer cell lines (A431, 22Rv1, and MCF-7). Compounds 8b, 8c and 8q exhibiting high antiproliferative potency against MCF-7 breast cancer cells with IC 50 values ranging from 2.3 to 9.5 μM were chosen for in-depth evaluation. The selected compounds had remarkable effects on HSP90 client proteins, including steroid hormone receptors and the anti-apoptotic factor BCL2. The obtained compounds are of interest for anticancer drug development.

Rho-associated coiled-coil-containing protein kinase (ROCK) is a serine-threonine kinase whose inhibitors are useful for the regulation of the actomyosin system. Here, we developed a photoswitchable ROCK inhibitor based on a phenylazothiazole scaffold. The reversible trans - cis isomerization by visible light stimuli enabled us to manipulate ROCK activities in vitro and in cells.

We herein present the synthesis of diversely functionalized pyrimidine fused thiazolino-2-pyridones via K 2 S 2 O 8 -mediated oxidative coupling of 6-amino-7-(aminomethyl)-thiazolino-2-pyridones with aldehydes. The developed protocol is mild, has wide substrate scope, and does not require transition metal catalyst or base. Some of the synthesized compounds have an ability to inhibit the formation of Amyloid-β fibrils associated with Alzheimer's disease, while others bind to mature amyloid-β and α-synuclein fibrils.

Recently, phototherapy has attracted much attention due to its negligible invasiveness, insignificant toxicity and excellent applicability. The construction of a newly proposed nanosystem with synergistic photothermal and photodynamic tumor-eliminating properties requires a delicate structure design. In this work, a novel therapeutic nanoplatform (denoted as BCS-Ce6) based on defective cobalt hydroxide nanosheets was developed, which realized hypoxia-relieved photothermal-enhanced photodynamic therapy against cancer. Defective cobalt hydroxide exhibited high photothermal conversion efficacy at the near-infrared region (49.49% at 808 nm) as well as enhanced catalase-like activity to produce oxygen and greatly boost the singlet oxygen generation by a photosensitizer, Ce6, realizing efficacious dual-modal phototherapy. In vivo and in vitro experiments revealed that BCS-Ce6 can almost completely extinguish implanted tumors in a mouse model and present satisfactory biocompatibility during the treatment. This work sets a new angle of preparing photothermal agents and constructing comprehensive therapeutic nanosystems with the ability to modulate the hypoxic tumor microenvironment for efficient cancer therapy.

Because of their excellent capacity to significantly improve the bioavailability and solubility of chemotherapy drugs, block copolymer micelles are widely utilized for chemotherapy drug delivery. In order to further improve the anti-tumor ability and reduce unwanted side effects of drugs, tumor-targeting peptides were used to functionalize the surface of polymer micelles so that the micelles can target tumor tissues. Herein, we synthesized a kind of PEG-PLA that is maleimide-terminated and then conjugated with a specific peptide F3 which revealed specific capacity binding to nucleolin that is overexpressed on the surface of many tumor cells. Then, F3 conjugated, paclitaxel loaded nanoparticles (F3-NP-PTX) were prepared as stable micelles that displayed an enhanced accumulation via a peptide-mediated cellular association in human breast cancer cells (MCF-7). Furthermore, F3-NP-PTX showed a prominent anti-tumor efficacy compared with non-targeting nanoparticles (NP-PTX) both in vitro and in vivo, and showed great potential as an efficacious targeting drug delivery system for breast cancer treatment.

We analyzed the near-degenerate states of the firefly dioxetanone anion (FDO-) and its prototypes, especially in the biradical region, using multi-configurational approaches. The importance of utilizing full valence active spaces by means of density-matrix renormalization group self-consistent field (DMRG-SCF) calculations was described. Our results revealed that the neglect of some valence orbitals can affect the quantitative accuracy in later multi-reference calculations or the qualitative conclusion when optimizing conical intersections. Using all of the relevant valence orbitals of FDO-, we confirmed that there were two conical intersections, as reported in previous work, and that the intersecting states were changed when the active space was enlarged. Beyond these, we found that there were strong interactions between states in the biradical regions, in which the changes in entanglements can be used to visualize the interacting state evolution.

The design of glycogen phosphorylase (GP) inhibitors targeting the catalytic site of the enzyme is a promising strategy for a better control of hyperglycaemia in the context of type 2 diabetes. Glucopyranosylidene-spiro-heterocycles have been demonstrated as potent GP inhibitors, and more specifically spiro-oxathiazoles. A new synthetic route has now been elaborated through 1,3-dipolar cycloaddition of an aryl nitrile oxide to a glucono-thionolactone affording in one step the spiro-oxathiazole moiety. The thionolactone was obtained from the thermal rearrangement of a thiosulfinate precursor according to Fairbanks' protocols, although with a revisited outcome and also rationalised with DFT calculations. The 2-naphthyl substituted glucose-based spiro-oxathiazole 5h, identified as one of the most potent GP inhibitors (K i = 160 nM against RMGPb) could be produced on the gram-scale from this strategy. Further evaluation in vitro using rat and human hepatocytes demonstrated that compound 5h is a anti-hyperglycaemic drug candidates performing slightly better than DAB used as a positive control. Investigation in Zucker fa/fa rat model in acute and subchronic assays further confirmed the potency of compound 5h since it lowered blood glucose levels by ∼36% at 30 mg kg -1 and ∼43% at 60 mg kg -1 . The present study is one of the few in vivo investigations for glucose-based GP inhibitors and provides data in animal models for such drug candidates.

Covering: January 2013 to September 2018Sulfur-containing natural products are a large class of significant functional molecules. Many of these compounds exhibit potent biological activities and pharmacological properties; in fact, some of them have been developed into important drugs. The total synthesis of sulfur-containing natural products is a subject that has long attracted significant attention from synthetic organic chemists; to achieve this goal, various methods have been developed over the past years. This review surveys total syntheses of sulfur-containing natural products that introduce sulfur atoms using different sulfurization agents to construct related sulfur-containing moieties.

We developed a new method for the de novo formation of fluorophores based on citrate (DNFC) in biological samples. Use of an amide coupling reagent and microwave irradiation greatly facilitates the fluorophore formation on peptides and proteins with N-terminal cysteine or serine. Since N-terminal cysteine and serine can form thiazolopyridone- or oxazolopyridone-based fluorophores emitting blue and green fluorescence, respectively, by the DNFC staining, each organelle, cell and tissue exhibited a characteristic fluorescence distribution. The DNFC staining is able to provide a new potential protocol for future cell imaging, histology and diagnosis.

CF 2 H-Pseudoprolines obtained from difluoroacetaldehyde hemiacetal and serine are stable proline surrogates. The consequence of the incorporation of the CF 2 H group is an important decrease of the trans to cis amide bond isomerization energy and a remarkable stabilisation of the cis conformer by an hydrogen bond.

Photodynamic therapy (PDT), as an essential tumor treatment method, has received great attention; however, there are still some challenges such as hydrophobicity of most of the photosensitizers, safety of in vivo transport, and characteristics of oxygen consumption. Herein, we used albumin as the nanocarrier for the loading of Chlorin e6 (Ce6) photosensitizer. In the meantime, tirapazaming (TPZ) was co-loaded onto the nanocomposite, which could be activated by hypoxia caused by PDT for enhanced therapy. Considering the over irradiation problem, a strategy for measuring PDT degree by ratio fluorescence was utilized. The PDT monitoring design relies on ratio emissions of C6 (Coumarin 6) and Ce6 molecules since the red emission of Ce6 is dependent on the PDT capability. Based on the characterization of the albumin nanocomposites, we further explored the combined therapy effect at both the in vitro and in vivo levels and attained the corresponding results.

More than 10% of all men will be given the diagnosis "prostate cancer" during their lifetime. Most of the current radio-diagnostic vehicles involve both expensive and localized production with cyclotrons as well as the use of bulky chelators for the radiometal. We report the use of a new multifunctional cyclopentadiene (Cp) platform to prepare difunctional and monofunctional, PSMA-targeting rhenium and technetium-99m complexes. The Cp-complexes and the free ligands are prepared by straightforward functionalization with either one or two Lys-urea-Glu (LuG) PSMA binding motifs. Cell binding assays revealed that the difunctional rhenium complex displays a dissociation constant (KD = 2.1 nM) that is an order of magnitude lower than the monofunctional compound (KD = 24.2 nM). The 99mTc complexes can be prepared in one step and ≤15 min in high yields. These difunctional Cp-Re(i)/99mTc(i) complexes represent a new class of imaging agents with binding affinities comparable to clinically evaluated compounds. Additionally, this study demonstrates that the Cp-platform can readily be derivatized with amine-containing biomolecules. Extending this work to incorporate both targeting and therapeutic moieties could lead to theranostic systems with Re/99mTc.

Cancer is a global health issue and a leading cause of death. The discrimination of cancer cells from normal cells is of significant importance for the early diagnosis of cancers. As one of the useful biomarkers for developing cancer diagnosis and chemotherapy resistance systems, biothiols not only play an essential role in physiological and pathological processes but also exhibit cytoprotective effects in the susceptibility to carcinogenesis. It would be highly desirable to explore near-infrared biothiol-specific fluorescent probes for cancer diagnosis with outstanding specificity. In this study, a novel near-infrared fluorescent probe BPO-THAZ decorated with thiazole as a recognition site was presented for sensitive and selective detection of endogenous biothiols. BPO-THAZ can be used to not only evaluate the biothiol level in living HeLa cells upon treatment with H2O2 or anti-cancer drugs but also assess endogenous biothiols in stem cells. Furthermore, BPO-THAZ was successfully utilized to discriminate cancer cells from normal cells showing great promise for cancer diagnosis.

Numerous studies demonstrate the promise of opioid peptides as analgesics, but poor oral bioavailability has limited their therapeutic development. This study sought to increase the oral bioavailability of opioid peptides by cyclization, using Hantzsch-based macrocyclization strategies to produce two new series of cyclized DAMGO and Leu/Met-enkephalin analogs. Opioid receptor affinity and selectivity for compounds in each series were assessed in vitro with radioligand competition binding assays. Compounds demonstrated modest affinity but high selectivity for the mu, delta, and kappa opioid receptors (MOR, DOR and KOR), while selectivity for mu opioid receptors varied by structure. Antinociceptive activity of each compound was initially screened in vivo following intracerebroventricular (i.c.v.) administration and testing in the mouse 55 °C warm-water tail-withdrawal test. The four most active compounds were then evaluated for dose- and time-dependent antinociception, and opioid receptor selectivity in vivo. Cyclic compounds 1924-10, 1936-1, 1936-7, and 1936-9 produced robust and long- lasting antinociception with ED 50 values ranging from 0.32-0.75 nmol following i.c.v. administration mediated primarily by mu- and delta-opioid receptor agonism. Compounds 1924-10, 1936-1 and 1936-9 further displayed significant time-dependent antinociception after oral (10 mg kg -1 , p.o.) administration. A higher oral dose (30 mg kg -1 . p.o.) of all four cyclic peptides also reduced centrally-mediated respiration, suggesting successful penitration into the CNS. Overall, these data suggest cyclized opioid peptides synthesized by a Hantzsch-based macrocyclization strategy can retain opioid agonist activity to produce potent antinociception in vivo while conveying improved bioavailability following oral administration.

Oral chemotherapy of docetaxel (DTX) is restricted by active P-glycoprotein (P-gp) efflux, hepatic first-pass metabolism and then poor oral absorption. Herein, a lipophilic thioether-bridged oleate prodrug (DTX-S-OA) and an ester-bond linked oleate prodrug of docetaxel (DTX-OA) were synthesized and efficiently incorporated into a self-nanoemulsifying drug delivery system (SNEDDS) using core-matching technology with a high drug-loading rate. DTX-S-OA SNEDDS produced a uniform droplet size of about 30 nm and a significantly high drug loading capability (60 mg mL-1), compared with DTX SNEDDS (20 mg mL-1). Additionally, DTX-S-OA SNEDDS exhibited a markedly slower drug release property and higher (>2-fold) drug solubilization in the aqueous phase after 60 min lipolysis compared with DTX SNEDDS. In situ single-pass intestinal perfusion and intestinal biodistribution studies demonstrated that the membrane permeability and intestinal bioadhesion of SNEDDS were significantly increased. Moreover, DTX-S-OA showed a comparable ability with verapamil in inhibiting P-gp efflux. Lymphatic transport studies confirmed that DTX-S-OA SNEDDS could significantly enhance intestinal lymphatic transport. Notably, the bioavailability of DTX-S-OA SNEDDS was 6.2-fold and 2.0-fold higher than that of the DTX solution and DTX SNEDDS, respectively. Furthermore, DTX-S-OA achieved a more rapid release of free DTX from the prodrug in systemic circulation than DTX-OA. Therefore, such a unique combination strategy of the single thioether-bridged DTX-oleate prodrug and SNEDDS is a promising platform to enable effective oral delivery of DTX.

A main objective in the synthesis of prebiotic compounds is to remain consistent with reasonable geochemical scenarios, while avoiding concomitant formation of undesirable by-products. In this context, 2-aminothiazole has shown enhanced selectivity in the addition reaction with sugars promoting interest in this sulfur species compared to its oxygenated analogue, 2-aminooxazole. More generally, the role of sulfur in prebiotic chemistry needs to be widely investigated with regard to the numerous sulfur-containing molecules detected recently in different astrophysical environments. However, in parallel to the problematic formation of building blocks of life, how prebiotic molecules could survive under extreme astrophysical conditions remains an open question. Intense UV radiation or ion bombardment may indeed lead to fragmentation and the specific behaviour of sulfur compounds has to be addressed. Focusing on its potentiality in prebiotic multistep synthesis, a detailed analysis of the proton impact on 2-aminothiazole has been investigated theoretically in a wide collision energy range chosen to model various astrophysical environments. The comparison with its oxygenated analogue may suggest qualitative trends on their respective stability under such processes which could be of crucial interest for prebiotic synthesis.

The aggregation of Aβ1-40 was monitored by solution NMR, which showed a trend complementary to the one observed by ThT-fluorescence. The NMR data support a kinetic model where Aβ1-40 initially aggregates with the reversible formation of oligomeric species, which then irreversibly convert into fibrils.

Fluorine is often incorporated into the aromatic moieties of synthetic bioactive molecules such as pharmaceuticals and disease diagnostics in order to alter their physicochemical properties. Fluorine substitution may increase a molecule's lipophilicity, thereby enabling its diffusion across cell membranes to enhance bioavailability or to exert a direct physiological effect from within the lipid bilayer. Understanding the structure, dynamics and orientation of fluoroaromatic molecules in lipid bilayers can provide useful insight into the effect of fluorine on their mode of action, and their interactions with membrane-embedded targets or efflux proteins. Here we demonstrate that NMR measurements of 19F chemical shift anisotropy combined with 1H-19F dipolar coupling measurements together report on the average orientation of a lipophilic fluoroaromatic molecule, 4-(6-fluorobenzo[d]thiazol-2-yl)aniline (FBTA), rapidly rotating within a lipid bilayer. The 19F chemical shift tensor orientation in the molecular frame was calculated by density functional theory and corroborated by 1H-19F PISEMA NMR. It was then possible to analyse the line shapes of proton-coupled and proton-decoupled 19F spectra of FBTA in chain perdeuterated dimyristoylphosphatidylcholine (DMPC-d54) bilayers to restrict the average axis of molecular reorientation of FBTA in the bilayer to a limited range orientations. This approach, which exploits the high sensitivity and gyromagnetic ratios of 19F and 1H, will be useful for comparing the membrane properties of related bioactive fluoroaromatic compounds.

Herein, palladium-catalyzed Miyaura borylation of 4-bromo-2,4'-bithiazoles followed by Suzuki-Miyaura cross-coupling reaction (named the MBSC process) with (hetero)aryl- and alkenyl halides is reported. This methodology offers rapid access to various 2',4-disubstituted 2,4'-bithiazole features including naturally-occurring 4-alkenylated and 4-pyridinylated 2,4'-bithiazoles. To prove its application, a concise approach for the synthesis of a heterocyclic cluster of the thiopeptide d-series antibiotic GE2270 is reported through a late-stage MBSC strategy.

We proposed a terminal deoxynucleotidyl transferase (TdT)-assisted rolling circle amplification (RCA) strategy for the amplified detection of genome-containing biological targets. The synergetic signal amplification of DNase I-mediated genomic DNA fragmentation and subsequent RCA allow the sensing platform to have extraordinarily high sensitivity.

Biocatalysis is a fast developing field in which an enzyme's natural capabilities are harnessed or engineered for synthetic chemistry. The enzyme PatG is an extremely promiscuous macrocyclase enzyme tolerating both non-natural amino acids and non-amino acids within the substrate. It does, however, require a proline or thiazoline at the C-terminal position of the core peptide which means the final product must contain this group. Here, we show guided by structural insight we have identified two synthetic routes, triazole and a double cysteine, that circumvent this requirement. With the triazole, we show PatGmac can macrocyclise substrates that do not contain any amino acids in the final product.

Concise total syntheses of smenothiazoles A (1) and B (2), two distinguished vinyl chloride containing natural products isolated from the marine sponge S. aurea, have been developed. Silastannation, Stille reaction and a carefully controlled desilylchlorination were employed as key steps to construct unique polyketide acid fragments, and the optimized reaction conditions avoided migration of 2,5-diene to a 2,4-conjugated system. This report unambiguously confirmed the structures of both natural products.

Six new copper(ii) complexes with 2,2':6',2''-terpyridine (4'-R n -terpy) [1 (R 1 = furan-2-yl), 2 (R 2 = thiophen-2-yl), and 3 (R 3 = 1-methyl-1H-pyrrol-2-yl)] and 2,6-di(thiazol-2-yl)pyridine derivatives (R n -dtpy) [4 (R 1 ), 5 (R 2 ), and 6 (R 3 )] have been synthesized by a reaction between copper(ii) chloride and the corresponding ligand. The complexes have been characterized by UV-vis and IR spectroscopy, and their structures have been determined by X-ray analysis. The antiproliferative potential of copper(ii) complexes of 2,2':6',2''-terpyridine and 2,6-di(thiazol-2-yl)pyridine derivatives towards human colorectal (HCT116) and ovarian (A2780) carcinoma as well as towards lung (A549) and breast adenocarcinoma (MCF7) cell lines was examined. Complex 1 and complex 6 were found to have the highest antiproliferative effect on A2780 ovarian carcinoma cells, particularly when compared with complex 2, 3 with no antiproliferative effect. The order of cytotoxicity in this cell line is 6 > 1 > 5 > 4 > 2 ≈ 3. Complex 2 seems to be much more specific towards colorectal carcinoma HCT116 and lung adenocarcinoma A549 cells. The viability loss induced by the complexes agrees with Hoechst 33258 staining and typical morphological apoptotic characteristics like chromatin condensation and nuclear fragmentation. The specificity towards different types of cell lines and the low cytotoxic activity towards healthy cells are of particular interest and are a positive feature for further developments. Complexes 1-6 were also tested in the oxidation of alkanes and alcohols with hydrogen peroxide and tert-butyl-hydroperoxide (TBHP). The most active catalyst 4 gave, after 120 min, 0.105 M of cyclohexanol + cyclohexanone after reduction with PPh 3 . This concentration corresponds to a yield of 23% and TON = 210. Oxidation of cis-1,2-dimethylcyclohexane with m-CPBA catalyzed by 4 in the presence of HNO 3 gave a product of a stereoselective reaction (trans/cis = 0.47). Oxidation of secondary alcohols afforded the target ketones in yields up to 98% and TON = 630.

Pyochelin (PCH) is a siderophore (extracellular chelator) produced by the pathogenic bacterium Pseudomonas aeruginosa (PAO). PCH is implicated in iron (Fe 3+ ) transport to PAO, and is crucial for its metabolism and pathogenicity. Due to the chemical similarity with Fe 3+ , gallium (Ga 3+ ) interferes with vital iron-dependent processes in bacterial cells, thereby opening new perspectives for the design of specific metal-based antibacterial drugs. However, the structural basis for the Fe 3+ -mimetic properties of Ga 3+ complexed with the PCH siderophore is still lacking. A precise knowledge of the coordination chemistry at the metal site is one of the topmost issues in the production of novel biomimetic metal-based drugs. Elucidation of this issue by means of a deep structural spectroscopic investigation could lead to an improved interference with, or a specific inhibition of, relevant biological pathways. For this reason, we applied Synchrotron Radiation induced X-ray Photoelectron Spectroscopy (SR-XPS) and X-ray Absorption Spectroscopy (XAS) to probe the electronic nature and coordination chemistry of Fe 3+ and Ga 3+ coordinative sites in PCH metal complexes. Combined XAFS and SR-XPS studies allow us to demonstrate that both Fe and Ga have the same valence state in Fe-PCH and Ga-PCH, and have the same octahedral coordination geometry. Moreover, a similar next neighbour distribution for Fe and Ga, resulting from the EXAFS data analysis, strongly supports similar coordination chemistry at the origin of the biomimetic behaviour of Ga.

More than thirty human proteins and/or peptides can fold incorrectly to form amyloid deposits associated with several protein aggregation diseases. No cure is currently available for treating these diseases. This work is aimed at examining the inhibitory potency of fast green FCF, a biocompatible dye, toward the fibrillogenesis/aggregation of lysozyme. As verified by ThT binding assay along with transmission electron microscopy, fast green FCF was observed to suppress the generation of lysozyme fibrils in a concentration-dependent manner. We next used circular dichroism absorption spectroscopy, ANS fluorescence spectroscopy, and SDS-PAGE to characterize the structural alterations in lysozyme samples upon the addition of fast green FCF. Furthermore, experiments with the addition of fast green FCF at different time points of incubation showed that fast green FCF also exhibited disaggregating activity against the preformed/existing lysozyme fibrils. We believe that the results from this study suggest a potential therapeutic role of biocompatible molecules in treating or preventing protein aggregation diseases.

Hepatitis C virus (HCV) is a serious cause of liver inflammation, cirrhosis and the development of hepatocellular carcinoma. Its NS3/4A serine protease functions to cleave a specific peptide bond, which is an important step in HCV replication. Thus the NS3/4A protease has become one of the main drug-targets in the design and development of anti-HCV agents. Unfortunately, high mutation rates in HCV have been reported due to the lack of RNA proofreading activity resulting in drug resistance. Herein, all-atom molecular dynamics simulations were employed to understand and illustrate the effects of the NS3/4A D168V mutation on faldaprevir (FDV) and danoprevir (DNV) binding efficiency. The D168V mutation was shown to interrupt the hydrogen bonding network of Q80R155D168R123 embedded in the extended S2 and partial S4 subsites of the NS3 protein and as a result the R123 side chain was displaced and moved out from the binding pocket. By means of MM/PBSA and MM/GBSA binding free energy calculations, the FDV and DNV binding affinities were shown to be significantly reduced by ∼10-15 kcal mol -1 and ∼4-9 kcal mol -1 relative to the wild-type complexes, respectively, which somewhat agrees with the experimental resistance folds.

PicoGreen, a cyanine based ultrafast molecular rotor, shows high affinity towards amyloid fibrils and scores a much better sensitivity than Thioflavin-T, a gold standard probe for amyloid fibrils. Detailed spectroscopic and molecular docking studies have been performed to understand the mode of interaction between PicoGreen and amyloid fibrils.

Bacteroides vulgatus is a member of the human microbiota whose abundance is increased in patients with Crohn's disease. We show that a B. vulgatus glycoside hydrolase from the carbohydrate active enzyme family GH123, BvGH123, is an N-acetyl-β-galactosaminidase that acts with retention of stereochemistry, and, through a 3-D structure in complex with Gal-thiazoline, provide evidence in support of a neighbouring group participation mechanism.

Nuclear magnetic resonance (NMR) spectroscopy has been established as a potent method for the determination of foldamer structures in solution. However, the NMR techniques could be limited by averaging, so additional experimental techniques are often needed to fully endorse the folding properties of a sequence. We have recently demonstrated that oligo-γ-peptides composed of 4-amino(methyl)-1,3-thiazole-5-carboxylic acids (ATCs) adopt an original helical fold stabilized by hydrogen bonds forming C 9 pseudocycles. The main objective of the present work is to reinvestigate the folding of ATC oligomer 1 in order to identify reliable FT-IR and NMR structural markers that are of value for tracking the degree of organization of ATC-based peptides.

The generation of Aβ amyloid aggregates in the form of senile plaques in the brain is one of the pathological hallmarks of Alzheimer's disease (AD). There is no cure for AD and one of the recent treatment strategies is focused on the inhibition of amyloid fibrillization of Aβ peptide. Fullerene C60 has been proposed as a candidate for destroying Aβ aggregates but it is not soluble in water and its toxicity to cells remains largely ambiguous. To overcome these drawbacks, we synthesized and studied the effect of water-soluble fullerenol C60(OH)16 (fullerene C60 carrying 16 hydroxyl groups) on the amyloid fibrillization of Aβ40 peptide in vitro. Using a Thioflavin T fluorescent assay and atomic force microscopy it was found that C60(OH)16 effectively reduces the formation of amyloid fibrils. The IC50 value is in the low range (μg ml(-1)) suggesting that fullerenol interferes with Aβ40 aggregation at stoichiometric concentrations. The in silico calculations supported the experimental data. It was revealed that fullerenol tightly binds to monomer Aβ40 and polar, negatively charged amino acids play a key role. Electrostatic interactions dominantly contribute to the binding propensity via interaction of the oxygen atoms from the COO(-) groups of side chains of polar, negatively charged amino acids with the OH groups of fullerenol. This stabilizes contact with either the D23 or K28 of the salt bridge. Due to the lack of a well-defined binding pocket fullerenol is also inclined to locate near the central hydrophobic region of Aβ40 and can bind to the hydrophobic C-terminal of the peptide. Upon fullerenol binding the salt bridge becomes flexible, inhibiting Aβ aggregation. In order to assess the toxicity of fullerenol, we found that exposure of neuroblastoma SH-SY5Y cells to fullerenol caused no significant changes in viability after 24 h of treatment. These results suggest that fullerenol C60(OH)16 represents a promising candidate as a therapeutic for Alzheimer's disease.

We present theoretical characterization of fluorescent non-natural nucleobases, (tz)A, (tz)G, (tz)C, and (tz)U, derived from the isothiazolo[4,3-d]pyrimidine heterocycle. Consistent with the experimental evidence, our calculations show that the non-natural bases have minimal impact on the geometry and stability of the classical Watson-Crick base pairs, allowing them to accurately mimic natural bases in a RNA duplex, in terms of H-bonding. In contrast, our calculations indicate that H-bonded base pairs involving the Hoogsteen edge are destabilized relative to their natural counterparts. Analysis of the photophysical properties of the non-natural bases allowed us to correlate their absorption/emission peaks to the strong impact of the modification on the energy of the lowest unoccupied molecular orbital, LUMO, which is stabilized by roughly 1.0-1.2 eV relative to the natural analogues, while the highest occupied molecular orbital, HOMO, is not substantially affected. As a result, the HOMO-LUMO gap is reduced from 5.3-5.5 eV in the natural bases to 4.0-4.4 eV in the modified ones, with a consequent bathochromic shift in the absorption and emission spectra.

Herein, a label-free fluorescent adenosine triphosphate (ATP) aptasensor is fabricated with a DNA hairpin and an overhanging aptamer. In the presence of ATP, the overhanging sequences of the aptamer may form preferred substrates of exo III, and thus trigger the enzyme-assisted amplification, which results in the release of G-rich sequences. Free G-rich sequences subsequently generate an enhanced flourescent signal by binding with thioflavin T. However, if ATP is absent, the overhanging sequence can induce steric hindrance and protect the DNA hairpin against the digestion of exo III, significantly reducing the noise of this biosensor. Accordingly, the signal-to-noise ratio of the sensing system is greatly improved, which ensures the desirable analytical performance of the proposed aptasensor both in pure samples and real samples.

We recently identified 6-hydroxy-3[R],7a[S]-dimethyl-7-oxo-2,3-dihydropyrrolo[2,1-b]thiazole-3-calboxylic acid, a novel pyrrolothiazole derivative carrying a carboxy group and named pyrrolothiazolate, as a Mallard pigment formed from l-cysteine and d-glucose. Here we described the formation of its enantiomer, the plausible formation scheme of pyrrolothiazolate, and its antioxidant activity. When d-cysteine was used instead of l-cysteine in the reaction mixture, the enantiomer of pyrrolothiazolate was obtained. The carbon at position 1 of glucose was incorporated into two methyl groups of pyrrolothiazolate. The pigment was considered to be formed through 1-deoxyglucosone (1-DG). The dehydrated isomer of 1-DG would be condensed with the thiol and amino groups of cysteine. This condensate was dehydrated and cyclized to form pyrrolothiazolate. This compound was an antioxidant showing radical scavenging activity.

Pateamine A is a naturally occurring metabolite extracted from the marine sponge Mycale hentscheli. It exhibits potent cytotoxicity towards cancer cell lines and has been shown to target protein translation initiation via inhibition of the function of eukaryotic initiation factor 4A proteins. We have synthesised a simplified analogue of pateamine A, consisting of the skeletal core of the natural product but with the thiazole heterocycle replaced by a triazole. The convergent design of the synthesis features a base-induced opening of a δ-valerolactone to access the Z,E-dienoate moiety, Julia-Kocienski olefination and copper-catalysed azide-alkyne cycloaddition. Bioactivity testing of the simplified pateamine A analogue (3) indicated a significant reduction in cytotoxicity, compared to natural pateamine A. We propose that this reduced activity is due mainly to the substitution of the thiazole for the triazole heterocycle. This supports the hypothesis that the thiazole of pateamine A is important for binding to its biological target.

The anti-adhesive strategy, consisting of disrupting bacterial attachment to the host cells, is widely explored as an alternative to antibiotic therapies. Recently, thiazolylmannosides (TazMans) have been identified as strong anti-adhesives of E. coli strains implied in the gut inflammation of patients with Crohn's disease. In this work, we developed a second generation of TazMans with improved chemical stability. The anomeric nitrogen was substituted by short linkers and the compounds were assessed against the bacterial adhesin FimH and the clinically isolated LF82 E. coli strain in four in vitro assays. The results obtained on the FimH adhesin alone and the whole bacteria enabled the identification of a candidate for further in vivo evaluations.

On-off photoswitching of circularly polarized luminescence was achieved using a pyrene-bearing helical tetrathiazole, in which two pyrene fluorophores stack in a chiral fashion (folded state). The pyrene-excimer based CPL was reversibly controlled by a geometrical change of the tetrathiazole upon photoisomerization.

Two isomorphous cocrystals of nitazoxanide (NTZ) with p-aminosalicylic acid (PASA) and p-aminobenzoic acid (PABA) as well as their alloys were prepared by slurry and grinding techniques. The cocrystals exhibit faster dissolution rates and higher pharmacokinetic properties compared to the reference drug, and surprisingly the cocrystal alloy NTZ-PABA : NTZ-PASA (0.75 : 0.25) exhibited 4 fold higher bioavailability of NTZ in Sprague Dawley rats. This study opens the opportunity for cocrystal alloys as improved medicines.

4-Thiazolidinone is regarded as a privileged structural unit in bioactive compounds. However, there is still no example of a catalytic method for the synthesis of chiral 4-thiazolidinone until now. We reported herein a facile and efficient method for the construction of chiral spirooxindole-based 4-thiazolidinone. This methodology is based on the asymmetric formal [3+2] annulation of 1,4-dithiane-2,5-diol to ketimines which is followed by simple oxidation, featuring a broad substrate scope with high enantioselectivity (up to 98% ee). The method has been successfully applied to the synthesis of a novel class of mycobacterium tuberculosis inhibitor-spirooxindole based 4-thiazolidinone.

Sixteen new isothiazoloisoxazole 1,1-dioxides, one new isothiazolotriazole and one new isothiazolopyrazole have been synthesised by using 1,3-dipolar cycloadditions to isothiazole 1,1-dioxides. One sub-set of these isothiazoloisoxazoles showed low μM activity against a human breast carcinoma cell line, whilst a second sub-set plus the isothiazolotriazole demonstrated an interesting restricted rotation of sterically hindered bridgehead substituents. A thiazete 1,1-dioxide produced from one of the isothiazole 1,1-dioxides underwent conversion into an unknown 1,2,3-oxathiazolin-2-oxide upon treatment with Lewis acids, but was inert towards 1,3-dipoles and cyclopropenones. Six supporting crystal structures are included.

Thirty two new binaphthyl-based, functionalized oxazole and thiazole peptidomimetics and over thirty five novel leucine-containing intermediate oxazoles and thiazoles were prepared in this study. This includes the first examples of the direct C-5 arylation of an amino acid dipeptide-derived oxazole. Moderate to excellent antibacterial activity was observed for all new compounds across Gram positive isolates with MICs ranging from 1-16 μg mL(-1). Results for Gram negative E. coli and A. baumannii were more variable, but MICs as low as 4 μg mL(-1) were returned for two examples. Significantly, the in vitro results with a fluoromethyl-oxazole derivative collectively represent the best obtained to date for a member of our binaphthyl peptide antimicrobials.

A Ca(2+)-specific chemosensor involving acyclic non-ether and non-carboxylato-type metal chelating ligands is rare. The tetradentate OONO artificial receptor, HL, possessing a sulfur-containing intermediate siderophore aeruginic acid, tethered to a rhodamine 6G based signalling unit in a single molecule has been synthesized. The fluoroionophore required excitation in the visible wavelength (510 nm) and showed highly selective and sensitive detection of Ca(2+) ions in 100% water solution in HEPES buffer at physiological pH (7.4). The probe HL, with LOD as low as 70 nM, behaves reversibly and showed nearly 17-fold enhanced selectivity for Ca(2+) over other cell abundant alkali and alkaline metal ions such as Na(+), K(+), Li(+), and Mg(2+) without any intervention. Job's plot, (1)H NMR titration and ESI-MS data provided corroborative evidence in support of 1 : 1 association between HL and Ca(2+). From a wide range of transition and heavy metal ions series, HL also binds Cu(2+). However, the use of l-cysteine removes the interference from Cu(2+) and results in highly selective detection specificity of HL for Ca(2+). As a reversible "off-on-off" fluorescent chemosensor, it is possible to detect Ca(2+) at as low as 5 μM in the midgut region of the gastrointestinal tract of the live animal Artemia, a brine shrimp.

Monitoring the aggregation of the tau protein is a key protocol for elucidating the pathogenic mechanism of Alzheimer's disease. In the present article, [Ru(phen)2dppzidzo](2+), a "light switch" ruthenium(ii) complex, was presented as a new monitoring probe for the aggregation of a tau R3 peptide, the third repeat unit of the tau microtubule-binding domain. Having little impact on the aggregation process, large fixed Stokes shift and small background luminescence made the complex a better probe for monitoring the aggregation process and quantitatively detecting tau filaments compared to thioflavin S, a commonly used fluorescent dye for staining neurofibrillary tangles and monitoring tau aggregation. Furthermore, a long luminescence lifetime of this complex could also expand its potential usage in the detection of tau filaments in the presence of short-lived fluorescent backgrounds.

In this communication, using sub-picosecond resolved fluorescence upconversion spectroscopy, we discover that despite a large fluorescence enhancement observed for thioflavin-T in insulin fibrils, the majority of fibril bound thioflavin-T undergoes efficient ultrafast conformational relaxation, and thus does not contribute to the characteristic fluorescence enhancement.

We report on transiently responsive protein-polymer conjugates that temporarily change their protein conformation from the soluble to the particle-like state. 'Grafting-from' RAFT polymerization of a dioxolane-containing acrylamide with a protein macroCTA is used to design polymer-protein conjugates that self-assemble into nanoparticles at physiological temperature and pH. Acid triggered hydrolysis of the dioxolane units into diol moeities rendered the conjugates fully water soluble irrespective of temperature.

In this work, we present a new type of functional organic/inorganic hybrid supraparticle that spontaneously assembles from silver ions (Ag(+)), iodide ions (I(-)) and thioflavin T (ThT) under aqueous solution conditions. ThT alone in aqueous solution was weakly fluorescent with an emission band at 494 nm, which was related to the monomer. However, in the above-mentioned hybrid supraparticle (i.e., ThT@AgI SP) structure, the ThT monomer can form a dimer with a new emission band. The new band shifted to 546 nm and the emission intensity increased. We further present a facile strategy of reversible fluorescence switching of ThT by a simple cation (Ag(+)) and anions (I(-) and S(2-)), which can be employed for the ratiometric fluorescence detection of Ag(+) with high sensitivity and selectivity. The linear range of detecting Ag(+) was from 100 nM to 10 μM, with a limit of detection as low as approximately 50 nM. Moreover, it can be successfully applied for the operation of a logic gate system and to the sensing of Ag(+) in real water samples.

A simple and practical method has been developed for the regioselective nitrosylation of imidazopyridines via C(sp(2))-H bond functionalization using tert-butyl nitrite under mild reaction conditions in a short time. A library of 3-nitrosoimidazopyridines with broad functionalities was synthesized in near quantitative yields. The present protocol is also applicable to imidazo[2,1-b]thiazole and benzo[d]imidazo[2,1-b]thiazole.