Versatile Synthetic Route Research Articles

Highly Cytotoxic Cryptophycin Derivatives with Modification in Unit D for Conjugation.

Cytotoxic payloads for drug conjugates suitable for directed tumor therapy need to be highly potent and require a functional group for conjugation with the homing device (antibody, peptide, or small molecule). Cryptophycins are cyclodepsipeptides that stand out from the realm of natural products due to their extraordinarily high cytotoxicity. However, the installation of a suitable conjugation handle without compromising the toxicity is highly challenging. The unit D, natively 2-hydroxyisocaproic acid (leucic acid), was envisaged as a promising attachment site based on structural information from X-ray analysis. A versatile, scalable and efficient synthetic route towards conjugable cryptophycins with modification in unit D was developed and an array of new cryptophycin analogues was synthesized. Several derivatives, especially those containing lipophilic groups with low steric demand such as alkylated amino groups, exhibit low picomolar cytotoxicity often combined with efficacy against multidrug-resistant tumor cells. The newly established cryptophycin analogues comprise a broad range of relevant functional groups used as conjugation handles, among them amino, hydroxy, carboxy, as well as sulfur-containing derivatives. X-ray crystallographic analysis of a tubulin-bound cryptophycin together with quantitative structure activity relationship manifested rationales for the synthesis of most potent cryptophycin derivatives and further confirmed the suitability of modifications in unit D.

Highly Selective Electrosynthesis of 1H-1-Hydroxyquinol-4-ones-Synthetic Access to Versatile Natural Antibiotics.

1H-1-Hydroxyquinolin-4-ones represent a broad class of biologically active heterocycles having an exocyclic N,O motif. Electrosynthesis offers direct, highly selective, and sustainable access to 1-hydroxyquinol-4-ones by nitro reduction. A versatile synthetic route starting from easily accessible 2-nitrobenzoic acids was established. The broad applicability of this protocol was demonstrated on 26 examples with up to 93% yield, highlighted by the naturally occurring antibiotics Aurachin C and HQNO. The practicability and technical relevance were underlined by multigram scale electrolysis.

Synthesis of Soluble High Molar Mass Poly(Phenylene Methylene)-Based Polymers.

Poly(phenylene methylene) (PPM) is a multifunctional polymer that is also active as an anticorrosion fluorescent coating material. Although this polymer was synthesized already more than 100 years ago, a versatile synthetic route to obtain soluble high molar mass polymers based on PPM has yet to be achieved. In this article, the influence of bifunctional bis-chloromethyl durene (BCMD) as a branching agent in the synthesis of PPM is reported. The progress of the reaction was followed by gel permeation chromatography (GPC) and NMR analysis. PPM-based copolymers with the highest molar mass reported so far for this class of materials (up to Mn of 205,300 g mol-1) were isolated. The versatile approach of using BCMD was confirmed by employing different catalysts. Interestingly, thermal and optical characterization established that the branching process does not affect the thermoplastic behavior and the fluorescence of the material, thus opening up PPM-based compounds with high molar mass for applications.

Acetylacetonate Ruthenium Nitrosyls: A Gateway to Nitric Oxide Release in Water under Near-Infrared Excitation by Two-Photon Absorption.

A fundamental challenge for phototriggered therapies is to obtain robust molecular frameworks that can withstand biological media. Photoactivatable nitric oxide (NO) releasing molecules (photoNORMs) based on ruthenium nitrosyl (RuNO) complexes are among the most studied systems due to several appealing features that make them attractive for therapeutic applications. Nevertheless, the propensity of the NO ligand to be attacked by nucleophiles frequently manifests as significant instability in water for this class of photoNORMs. Our approach to overcome this limitation involved enhancing the Ru-NO π-backbonding to lower the electrophilicity at the NO by replacing the commonly employed 2,2'-bipyridine (bpy) ligand by an anionic, electron-rich, acetylacetonate (acac). A versatile and convenient synthetic route is developed and applied for the preparation of a large library of RuNO photoNORMs with the general formula [RuNO(tpy)(acac)]2+ (tpy = 2,2':6',2″-terpyridine). A combined theoretical and experimental analysis of the Ru-NO bonding in these complexes is presented, supported by extensive single-crystal X-ray diffraction experiments and by topological analyses of the electron charge density by DFT. The enhanced π-back-bonding, systematically evidenced by several techniques, resulted in a remarkable stability in water for these complexes, where significant NO release efficiencies were recorded. We finally demonstrate the possibility of obtaining sophisticated water-stable multipolar NO-delivery platforms that can be activated in the near-IR region by two-photon absorption (TPA), as demonstrated for an octupolar complex with a TPA cross section of 1530 GM at λ = 800 nm and for which NO photorelease was demonstrated under TPA irradiation in aqueous media.

Fabrication of ZnO-SnO2 heterojunction inverse opal photonic balls for chemiresistive acetone sensing

The development of metal oxide semiconductor-based chemiresistive gas sensors with ultra-fast response/recovery for toxic and flammable gases is of great importance, but still challenging. Here, ZnO-SnO2 heterojunction three-dimensional (3D) inverse opal photonic crystal balls (IOPBs) were fabricated based on rapid and liquid waste-free spray drying. The spherical three-dimensional (3D) ordered macroporous skeleton can provide more active sites and faster gas diffusion channels. Furthermore, the n-n heterojunction established by ZnO and SnO2 is favorable for electron transport. The response (Ra/Rg) of IOPBs to 50 ppm acetone reaches 40.3 at an optimal operating temperature of 260 °C when the Zn/Sn atomic ratio is 1:4, which is 5 times higher than that of the pure SnO2 sensor. Response/recovery time also reduces from 23/47 s for pure SnO2 to 6/10 s. In addition, the IOPBs gas sensors also exhibit good selectivity and excellent long-term stability. This work provides a straightforward and versatile synthetic route for the preparation of 3D IOPBs to explore novel gas sensors with ultra-fast response speed.

FeN4 active sites generated on dipyridylpyridazine functionalized reduced graphene oxide for high-performance air electrode in a Zn-air battery

The growing global electricity demand requires the development of cost-effective energy conversion and storage systems, integrating inexpensive, eco-friendly, and high-efficiency catalysts. Oxygen reduction reaction (ORR) is considered crucial process to achieve high-power-density fuel cells and Zn-air batteries (ZABs). The latter have attracted the attention of scientific community due to its high theoretical energy density, reliable safety and low-cost. However, several limitations must be overcome, designing ORR catalysts thought versatile and economical synthetic routes. In this sense, the non-noble iron–nitrogen-carbon materials (FeNC) have been reported as the most potential candidates for attaining superior activity toward ORR in substitution of the high-priced commercial Pt-C catalysts. Herein, Diels-Alder surface adducts based on dipyridylpyridazine units have been created along 2D surface of reduced graphene oxide (rGO) nanosheets for the controlled generation of FeN4 active sites at the edges through successive solvent-free mechanochemical reactions and an additional thermal treatment. The optimized catalyst provided high content of pyridinic-N, graphitic-N and Fe2+ species, contributing to the excellent activity delivered as electrocatalyst for ORR processes. In addition, a flooded ZAB assembled with this material as cathodic/air electrode exhibited excellent specific capacities of 4.94 and 2.77 A·h·g−1 at -1 and -5 mA, respectively, improving the catalytic performance obtained for the 10 wt% Pt-C benchmark electrocatalyst.

Room-Temperature, Multigram-Scale Synthesis and Conversion Mechanism of Highly Luminescent Lead Sulfide Quantum Dots.

PbS quantum dots (QDs) are attractive near-infrared (NIR) materials, but traditional synthetic methods require inert atmosphere and/or high temperature. Herein we develop a facile, room-temperature synthetic route for in situ halide passivated PbS QDs through controllable reactions between lead halide, N,N'-diphenyl thiourea, and oleyamine (OLA) in toluene. Contrast experiments and theoretical calculations reveal that the OLA plays a bifunctional role as a mild base to initiate the formation of PbS monomers and as a dynamic ligand to control the crystallization of PbS QDs and further ligand exchange. The oleic acid-capped PbS QDs exhibit high photoluminescence quantum yields up to 45%. The scaled-up synthesis on multigram scales shows great batch-to-batch consistency. We further demonstrate high-power NIR light-emitting diodes using the PbS QDs as color converters, delivering NIR optical power of 9.2 mW at 160 mA. This work provides a simple and versatile synthetic route for high-quality PbS QDs and boosts the applications of NIR materials.

Synthesis and Exploration of New Imidazo[4,5‐c]Pyrazoles as Potent α‐Amylase Inhibitors

AbstractTo identify new leads of small molecules as α‐amylase inhibitors, the current research is focused on the assessment of imidazopyrazoles. Hence, a set of novel imidazo[4,5‐c]pyrazoles was synthesized via simple versatile straightforward synthetic routes and was estimated for their in vitro α‐amylase inhibition activity. The findings revealed that diphenylaminomethyl and phenylcarbamodithioate derivatives elicited potent α‐amylase inhibition activities with IC50 values of 0.071 and 0.083 μM, respectively that were comparable to acarbose (IC50 0.060 μM). Molecular docking and in silico studies were performed for the most active derivatives and demonstrated that docked compounds have good binding affinities toward α‐amylase with binding free energies that are very similar to that of acarbose. Furthermore, these compounds demonstrated not only significant biological activity but also noteworthy physicochemical properties, drug‐likeness, and good pharmacokinetics. As a result, such compounds offered a robust opportunity for further development and optimization of the imidazopyrazole scaffold for the potential management of Type II Diabetes Mellitus.

NO2-sensing proprieties of WS2/WO3 heterostructures obtained by hydrothermal treatment of tungsten oxide seed materials

This work reports on the preparation of WS2/WO3 heterostructures for the development of nitrogen dioxide (NO2) sensors via a novel wet-chemical hydrothermal route approach. Different tungsten oxides were used as seed materials, and the heterostructure were formed using thioacetamide as a source of sulfur during a second hydrothermal treatment step. Structural and morphological characterizations demonstrated that the heterostructures can be described as WS2 nanosheets deposited over the tungsten oxide phase. Compared against the respective tungsten oxide seed materials, the heterostructures exhibited significant enhancement of the sensor response to NO2. High sensor signal to a 5 ppm exposure level was observed for the WS2/WO3 microplates at a working temperature of 200 °C, with good selectivity against reducing gases and a sub 2 ppm lower detection limit. To explain the enhancement of the sensor signal, we proposed an electronic sensitization mechanism based on the electronic barriers introduced by the p-n semiconductor junctions. Overall, this work introduces a low-cost, low-temperature, versatile wet-chemical synthetic route for the fabrication of transition metal dichalcogenide-metal oxide heterostructures with potential applications for the development of sensors capable of detecting NO2 at ppm levels.

Versatile Synthesis of Trisphosphines Bearing Phenylene and Vinylene Backbones Useful for Metal Catalysis and Materials Applications

AbstractTrisphosphines, in which two phenylene or vinylene backbones connect three phosphine atoms, belong to an emerging class of ligands in metal-catalyzed organic synthesis and materials applications. However, these ligands were previously known only in a small variety because of the synthetic limitations. We report herein two versatile synthetic routes to a hitherto unavailable variety of trisphosphines. The compounds bearing phenylene backbones were synthesized by sequential addition of two different organolithium reagents to triphenyl phosphite and that with vinylene backbones by stereoretentive addition of lithium diarylphosphide to a cis-bromoalkene. The new trisphosphine compounds will serve as valuable tools for the development of transition-metal-catalyzed reactions and functional materials.

Phospholipid metabolites of GHB as potential biomarkers in whole blood: Synthesis, analytics, and in vitro formation of homolog 16:0/18:1.

Gamma-hydroxybutyric acid (GHB) is a common drug of abuse, and the detection of a consumption or administration is a longstanding research objective in clinical and forensic toxicology. However, until now, the short detection window of GHB could not be enlarged by the use of GHB metabolites. Therefore, new biomarkers for the detection of a GHB intake are needed. In analogy to phosphatidylethanols as long-time biomarkers of ethanol, phospholipids with GHB might represent a promising compound class. While the availability of reference compounds often represents a bottleneck in clinical and forensic toxicological research, two phospholipids-phosphatidyl-GHB (16:0/18:1) and its isomer phosphatidyl beta-hydroxybutyric acid (16:0/18:1)-were successfully synthesized by a new highly versatile synthetic route. Structural characterization data, together with 1 H-, 13 C-, and 31 P-NMR and high-resolution mass spectrometry (HRMS) spectra, are reported. Subsequently, a HPLC-MS/MS method was established for the determination of both compounds (limits of detection [LOD] ≤ 2ng/ml), and the formation of these metabolites was investigated in two in vitro experiments. The formation of phosphatidyl-GHB (16:0/18:1) was observed in an incubation experiment by converting phosphatidylcholine (16:0/18:1) and GHB with phospholipase D and in whole blood samples spiked with 50 mM GHB, respectively. Therefore, phosphatidyl-GHB (16:0/18:1) might represent a valuable new metabolite of GHB with the potential for an extension of the detection window as GHB biomarker.

DNA-Liposome Hybrid Carriers for Triggered Cargo Release.

The design of simple and versatile synthetic routes to accomplish triggered-release properties in carriers is of particular interest for drug delivery purposes. In this context, the programmability and adaptability of DNA nanoarchitectures in combination with liposomes have great potential to render biocompatible hybrid carriers for triggered cargo release. We present an approach to form a DNA mesh on large unilamellar liposomes incorporating a stimuli-responsive DNA building block. Upon incubation with a single-stranded DNA trigger sequence, a hairpin closes, and the DNA building block is allowed to self-contract. We demonstrate the actuation of this building block by single-molecule Förster resonance energy transfer (FRET), fluorescence recovery after photobleaching, and fluorescence quenching measurements. By triggering this process, we demonstrate the elevated release of the dye calcein from the DNA–liposome hybrid carriers. Interestingly, the incubation of the doxorubicin-laden active hybrid carrier with HEK293T cells suggests increased cytotoxicity relative to a control carrier without the triggered-release mechanism. In the future, the trigger could be provided by peritumoral nucleic acid sequences and lead to site-selective release of encapsulated chemotherapeutics.

Smart construction of MnCo2O4 microspheres with multiple interiors: Morphological evolution and structure-performance relationship for supercapacitor electrodes

The development of a simple and general approach for manufacturing complex hollow structures is essential to achieve rapid dynamic response and high energy density storage for supercapacitor electrodes. Herein, we report a versatile heating rate-controlled synthetic route to prepare MnCo2O4 microspheres with multiple interiors. Comparative study reveals that MnCo2O4 microspheres with core–shell structure (MCO-CSS) process the highest specific surface area (91.6 m2 g−1) and oxygen vacancy density (0.16), which can provide more electroactive sites for surface Faradic reaction and further facilitate the kinetics of rapid charge storage. While the porous shell and well-defined gap endow MCO-CSS with excellent permeability and low-resistance pathways for electrolyte ions, as well as enhanced volume change accommodation. Benefiting from the structural advantages, MCO-CSS displays an excellent specific capacitance of 1064.4F g−1 at 1 A g−1, remarkable rate capability, and satisfactory cycle stability (89.1% capacitance retention at 2 A g−1 over 1000 cycles). Additionally, an asymmetric supercapacitor device, with an MCO-CSS cathode and porous carbon spheres anode, delivers a remarkable energy density of 33.9 Wh kg−1 at a power density of 187.4 W kg−1, as well as 84.13% capacitance retention over 3000 cycles at 1 A g−1.

DESIGN, SYNTHESIS AND EVALUATION OF NOVEL AZETIDINONYL/ FORMAZONYL/ THIAZOLIDINONYLPHENOTHIAZINES AS POTENTIAL ANTI-INFLAMMATORY AGENTS

The present study describes the synthesis, full characterization and biological evaluation of novel azetidinonyl/formazonyl/thiazolidinonylphenothiazines. The synthesis of these compounds as potential anti-inflammatory agents was carried out using a more efficient and versatile synthetic route. Various 4-substituted phenyl-1-(10’-acetylaminophenothiazinyl)-azetidin-2-ones (9-13), 1-(10’-acetyliminophenothiazinyl)-3-substituted phenyl formazans (14-18) and 3-(10’- acetylamino-phenothiazinyl) -2-substituted phenyl-4-thiazolidinones (19-23) were synthesized by reacting 10-(various substituted phenylmethyleneimino) aminoacetylphenothiazines (4-8) with triethylamine / acetyl chloride, benzene diazonium chloride and thioglycolic acid / anhydrous zinc chloride, respectively. The structures of these compounds have been interpreted by elemental (C, H, N) and spectral (I.R., 1 H-NMR and mass) analysis. All the compounds were evaluated for their anti-inflammatory activity using rat paw oedema inhibition test and were compared with standard drugs. These compounds were also screened for acute toxicity studies. Compound 22 was the most potent compound of the series, exhibiting 82.44% oedema inhibition, interestingly more potent than the standard drug - phenylbutazone. All compounds showed ALD50 > 1000 mg kg -1 p.o. except compound 22, which exhibited ALD50 > 2000 mg kg -1 p.o.

Rhodium catalyzed asymmetric synthesis of Chiraphos derivatives

Herein, we report a highly efficient versatile synthetic route to Chiraphos derivatives through Rh/Ph-bod catalyzed asymmetric addition of aryl boronic acids to phosphinyl dienes. Various substituted phosphinyl dienes, both on the parent skeleton and the phosphine atoms, were well tolerated with this method and provided chiral phosphine oxides in satisfied yield and up to 95% ee. The corresponding Chiraphos derivative displayed an advantage over Chiraphos in the representative Pd-catalyzed asymmetric 1,4-addition reaction.

Green Synthesis of Novel Triazolothiadiazine‐Coumarins Catalyzed by Agro Waste Extract: An Approach towards In‐Silico and In‐Vitro Anti‐Fungal Activity

AbstractA green, commodious, immensely versatile synthetic route for agro waste extract WELPSA catalyzed cyclocondensation of biologically active triazolothiadiazine‐coumarin hybrid derivatives has been studied. A proficient synthesis offused heterocycles 9 i–wvia dehydrative condensation with cyclization of4‐((4‐amino‐5‐mercapto‐4H‐1,2,4‐triazol‐3‐yl)methyl)‐2‐aryl‐2,4‐dihydro‐3H‐1,2,4‐triazol‐3‐one (5 a‐‐c) and substituted bromoacyl coumarins (8 d‐‐h)has been incorporated in presence of different catalysts including WELPSA, a green catalyst. The in silico docking studies of these previously unknown compounds revealed favorable C score and Chemscore values and the in vitro antifungal assay against three fungal strains showed excellent to good activity.

Current developments of hypercrosslinked polymers as green carbon resources

Carbons and their composites are the most valuable materials in the modern field of catalysis, energy storage/conversion, and environments. In past decades, breakthroughs have been made in preparing carbon materials, such as fullerenes, carbon nanotubes, and graphene. Meanwhile, the carbon materials with high surface areas, tunable pore size, heteroatom doping, and controlled morphologies also can promote their application performances in heterogeneous catalysis, drug encapsulation, electrode, and photonic devices. Hypercrosslinked polymers (HCPs) generally have high surface areas versatile synthetic routes, well-defined chemical-physical stability, and have emerged as excellent candidates for carbon precursors. More and more green and sustainable chemical synthetic methodologies have become possible to directly control particle size, surface area, chemical composition, and morphologies of carbons from the carbonization of HCPs. This graphical review demonstrates current approaches toward the synthesis of HCPs as carbon precursors following green and sustainable principles. And we also discussed the challenges and future directions of green HCPs production as carbon resources.

A versatile synthetic route towards gelatin-silica hybrids and magnetic composite colloidal nanoparticles

A versatile synthetic route towards gelatin-silica hybrids and magnetic composite colloidal nanoparticles

Ligand Influence on Structural and Spectroscopic Properties of Beryllium Oxocarboxylates.

Aluminum-based adjuvants for vaccines and beryllium ions interact with the same immune receptor. The Be4O core, which is also found in beryllium oxocarboxylates, has been proposed to be the binding species in the latter case. However, this is not proven due to a lack of suitable probes for the Be4O moiety. Therefore, a versatile synthetic route to beryllium oxocarboxylates has been developed to investigate the steric and electronic influence of the ligands onto their molecular and spectroscopic properties. The oxocarboxylates exhibit extremely narrow line widths in 9Be NMR spectroscopy, and the chemical shift is only influenced by the sterics of the ligands. The mean variation of the atomic distances in the central Be4O building block is extremely small over all investigated compounds, and even the C-C distances are only little perturbed by the properties of the ligands. Vibrational spectroscopy showed Be-O bands; however, further distinctions could not be drawn.

Cover Image, Volume 138, Issue 42

The cover designed by Wanida Janvikul and co-authors displays an SEM micrograph of a digital light processing (DLP)-printed porous scaffold consisted of poly(caprolactone-co-glycidyl methacrylate). The copolymer was synthesized via sequential ring-opening polymerization of ε-caprolactone and glycidyl methacrylate, which bypassed the usages of substantial chemicals and complicated purification steps. This versatile neat synthetic route explicitly opens up a new method to prepare biodegradable light-assisted 3D printing materials from other biodegradable cyclic ester monomers. DOI: 10.1002/app.51391