Structural basis of human monocarboxylate transporter 1 inhibition by anti-cancer drug candidates.

Proton-coupled monocarboxylate transporters MCT1-4 catalyze the transmembrane movement of metabolically essential monocarboxylates and have been targeted for cancer treatment because of their enhanced expression in various tumors. Here, we report five cryo-EM structures, at resolutions of 3.0-3.3 Å, of human MCT1 bound to lactate or inhibitors in the presence of Basigin-2, a single transmembrane segment (TM)-containing chaperon. MCT1 exhibits similar outward-open conformations when complexed with lactate or the inhibitors BAY-8002 and AZD3965. In the presence of the inhibitor 7ACC2 or with the neutralization of the proton-coupling residue Asp309 by Asn, similar inward-open structures were captured. Complemented by structural-guided biochemical analyses, our studies reveal the substrate binding and transport mechanism of MCTs, elucidate the mode of action of three anti-cancer drug candidates, and identify the determinants for subtype-specific sensitivities to AZD3965 by MCT1 and MCT4. These findings lay out an important framework for structure-guided drug discovery targeting MCTs.

Inhibition of retrograde transport protects mice from lethal ricin challenge.

Bacterial Shiga-like toxins are virulence factors that constitute a significant public health threat worldwide, and the plant toxin ricin is a potential bioterror weapon. To gain access to their cytosolic target, ribosomal RNA, these toxins follow the retrograde transport route from the plasma membrane to the endoplasmic reticulum, via endosomes and the Golgi apparatus. Here, we used high-throughput screening to identify small molecule inhibitors that protect cells from ricin and Shiga-like toxins. We identified two compounds that selectively block retrograde toxin trafficking at the early endosome-TGN interface, without affecting compartment morphology, endogenous retrograde cargos, or other trafficking steps, demonstrating an unexpected degree of selectivity and lack of toxicity. In mice, one compound clearly protects from lethal nasal exposure to ricin. Our work discovers the first small molecule that shows efficacy against ricin in animal experiments and identifies the retrograde route as a potential therapeutic target.

Domino Reaction Protocol to Synthesize Benzothiophene-Derived Chemical Entities as Potential Therapeutic Agents.

An efficient synthesis of 3-amino-2-formyl-functionalized benzothiophenes by a domino reaction protocol and their use to synthesize a library of novel scaffolds have been reported. Reactions of ketones and 1,3-diones with these amino aldehyde derivatives formed a series of benzothieno[3,2-b]pyridine and 3,4-dihydro-2H-benzothiopheno[3,2-b]quinolin-1-one, respectively. A plausible mechanism for the formation of fused pyridine derivatives by the Friedlander reaction has been elucidated by density functional theory (DFT) calculations. Furthermore, hydrazones were obtained by reacting the aldehyde functional group of benzothiophenes with different hydrazine derivatives. Preliminary screening of these compounds against several bacterial strains and cancer cell lines led to the discovery of several hit molecules. Hydrazone and benzothieno[3,2-b]pyridine derivatives are potent cytotoxic and antibacterial agents, respectively. One of the potent compounds effected ∼97% growth inhibition of the LOX IMVI cell line at 10 µM concentration.

Chemoenzymatic total synthesis of rotigotine via IRED-catalyzed reductive amination.

A short and chemoenzymatic synthesis of rotigotine using an IR-36-M5 mutant is reported. Focusing on the residues that directly contact the 2-tetralone moiety, we applied structure-guided semi-rational design to obtain a double-mutant F260W/M147Y, which showed a good isolated yield and S-stereoselectivity >99% toward 2-aminotetralin synthesis. Furthermore, the utility of this biocatalytic protocol was successfully demonstrated in the enantioselective synthesis of rotigotine via enzymatic reductive amination as the key step.

Supported-amine-catalyzed cascade synthesis of spiro-thiazolone-tetrahydrothiophenes: assessing HSA binding activity.

We have devised a supported-amine-catalyzed efficient synthesis of spiro-thiazolone-tetrahydrothiophenes via a sulfa-Michael/aldol cascade approach. The catalyst demonstrated sustained efficacy over 21 cycles. These derivatives were found to exhibit excellent binding abilities with purified human serum albumin as indicated by both in silico and in vitro-based experiments.

Discovery of thiophen-2-ylmethylene bis-dimedone derivatives as novel WRN inhibitors for treating cancers with microsatellite instability.

Microsatellite instability (MSI) is a hypermutable condition caused by DNA mismatch repair system defects, contributing to the development of various cancer types. Recent research has identified Werner syndrome ATP-dependent helicase (WRN) as a promising synthetic lethal target for MSI cancers. Herein, we report the first discovery of thiophen-2-ylmethylene bis-dimedone derivatives as novel WRN inhibitors for MSI cancer therapy. Initial computational analysis and biological evaluation identified a new scaffold for a WRN inhibitor. Subsequent SAR study led to the discovery of a highly potent WRN inhibitor. Furthermore, we demonstrated that the optimal compound induced DNA damage and apoptotic cell death in MSI cancer cells by inhibiting WRN. This study provides a new pharmacophore for WRN inhibitors, emphasizing their therapeutic potential for MSI cancers.

Correlating Molar Mass, π-Conjugation, and Optical Properties of Narrowly Distributed Anionic Polythiophenes in Aqueous Solutions.

Polythiophene-based conjugated polyelectrolytes (CPE) are attracting increasing attention as sensor or interface materials in chemistry and biology. While cationic polythiophenes are better understood, limited structural information is available on their anionic counterparts. Limited access to well-defined polymers has made the study of structure-property relationships difficult and clear correlations have remained elusive. By combining controlled Kumada catalyst transfer polymerization with a polymer-analog substitution, regioregular and narrowly distributed poly(6-(thiophen-3-yl)hexane-1-sulfonate)s (PTHS) with tailored chain length are prepared. Analysis of their aqueous solution structures by small-angle neutron scattering (SANS) revealed a cylindrical conformation for all polymers tested, with a length close to the contour length of the polymer chains, while the estimated radii remain too small (<1.5 nm) for extensive π-stacking of the chains. The latter is particularly interesting as the longest polymer exhibits a concentration-independent structured absorption typical of crystalline polythiophenes. Increasing the ionic strength of the solution diminishes these features as the Coulomb repulsion between the charged repeat units is shielded, allowing the polymer to adopt a more coiled conformation. The extended π-conjugation, therefore, appears to be a key parameter for these unique optical features, which are not present in the corresponding cationic polythiophenes.

Thienoisoindigo-Based Conjugated Polymers Synthesized by Direct Arylation Polycondensation.

A series of thienoisoindigo (TIG)-based conjugated polymers (CPs) with high molecular weights are synthesized by direct arylation polycondensation (DArP) by using TIG derivatives as CBr monomer and multi-halogenated thiophene derivatives, i.e., (E)-1,2-bis(3,4-difluorothien-2-yl)ethene (4FTVT), (E)-1,2-bis(3,4-dichlorothien-2-yl)ethene (4ClTVT), 3,3',4,4'-tetrafluoro-2,2'-bithiophene (4FBT), and 3,3',4,4'-tetrachloro-2,2'-bithiophene (4ClBT), as CH monomers. Density functional theory (DFT) calculations reveal the high selectivity between α-CH bonds in 4FTVT, 4ClTVT, 4FBT, and 4ClBT and ß-CH bonds in TIG CBr monomer. All four resulting CPs exhibit low optical bandgaps of ca. 1.20 eV and ambipolar transport characteristics with both electron and hole mobility above 0.1 cm2  V-1  s-1 as elaborated with organic thin-film transistors (OTFTs). The polymer TIG-4FTVT delivers the best device performance. With this polymer, n-channel OTFTs with electron mobility up to 1.67 cm2  V-1  s-1 and p-channel OTFTs with hole mobility up to 0.62 cm2  V-1  s-1 are fabricated by modifying source/drain electrodes with polyethylenimine ethoxylated (PEIE) and MoO3 , respectively, to selectively inject electrons and holes.

Highly Stretchable Conjugated Polymer/Elastomer Blend Films with Sandwich Structure.

The physical blending of high-mobility conjugated polymers with ductile elastomers provides a simple way to realize high-performance stretchable films. However, how to control the morphology of the conjugated polymer and elastomer blend film and its response to mechanical fracture processes during stretching are not well understood. Herein, a sandwich structure is constructed in the blend film based on a conjugated polymer poly[(5-fluoro-2,1,3-benzothiadiazole-4,7-diyl)(4,4-dihexadecyl-4H-cyclopenta[2,1-b:3,4-b″]dithiophene-2,6-diyl)(6-fluoro-2,1,3-benzothiadiazole-4,7-diyl)(4,4-dihexadecyl-4H-cyclopenta[2,1-b:3,4-b″]dithiophene-2,6-diyl)] (PCDTFBT) and an elastomer polystyrene-block-poly(ethylene-ran-butylene)-block-polystyrene (SEBS). The sandwich structure is composed of a PCDTFBT:SEBS mixed layer laminated with a PCDTFBT-rich layer at both the top and bottom surfaces. During stretching, the external strain energy can be effectively dissipated by the deformation of the crystalline PCDTFBT domains and amorphous SEBS phases and the recrystallization of the PCDTFBT chains. This endows the blend film with excellent ductility, with a large crack onset strain exceeding 1100%, and minimized the electrical degradation of the blend film at a large strain. This study indicates that the electrical and mechanical performance of conjugated polymer/elastomer blend films can be improved by manipulating their microstructure.

Blocking potential metabolic sites on NAT to improve its safety profile while retaining the pharmacological profile.

The number of opioid-related overdose deaths and individuals that have suffered from opioid use disorders have significantly increased over the last 30 years. FDA approved maintenance therapies to treat opioid use disorder may successfully curb drug craving and prevent relapse but harbor adverse effects that reduce patient compliance. This has created a need for new chemical entities with improved patient experience. Previously our group reported a novel lead compound, NAT, a mu-opioid receptor antagonist that potently antagonized the antinociception of morphine and showed significant blood-brain barrier permeability. However, NAT belongs to thiophene containing compounds which are known structural alerts for potential oxidative metabolism. To overcome this, 15 NAT derivatives with various substituents at the 5'-position of the thiophene ring were designed and their structure-activity relationships were studied. These derivatives were characterized for their binding affinity, selectivity, and functional activity at the mu opioid receptor and assessed for their ability to antagonize the antinociceptive effects of morphine in vivo. Compound 12 showed retention of the basic pharmacological attributes of NAT while improving the withdrawal effects that were experienced in opioid-dependent mice. Further studies will be conducted to fully characterize compound 12 to examine whether it would serve as a new lead for opioid use disorder treatment and management.

Discovery of novel thiophene-3-carboxamide derivatives as potential VEGFR-2 inhibitors with anti-angiogenic properties.

VEGFR-2 is an attractive target for the development of anti-tumor drugs and plays a crucial role in tumor angiogenesis. This study reports a series of novel thiophene-3-carboxamide derivatives based on PAN-90806 as VEGFR-2 inhibitors, among which compound 14d exhibits excellent anti-proliferative activity against HCT116, MCF7, PC3, and A549 cell lines, and has effective VEGFR-2 inhibitory activity with an IC50 value of 191.1 nM. Additionally, CETSA results indicated that VEGFR-2 was a relevant target of compound 14d in the cell lines, and compound 14d could also inhibit VEGFR-2 protein phosphorylation in A549 cell line. Furthermore, compound 14d inhibited colony formation, cell migration, and HUVECs tube formation in a dose-dependent manner. The mechanism by which 14d induced cancer cell death involves blocking the cell cycle, increasing ROS production, inducing apoptosis, and dose-dependently reducing the levels of phosphorylated ERK and MEK. Molecular docking and molecular dynamics simulations had shown that compound 14d could stably bind to the active site of VEGFR-2. These results confirmed that compound 14d might be a promising lead compound for anti-angiogenesis.

Discovery of a potent Gilteritinib-based FLT3-PROTAC degrader for the treatment of Acute myeloid leukemia.

Fms-like tyrosine receptor kinase 3 (FLT3) proteolysis targeting chimeras (PROTACs) emerge as a promising approach to overcome the limitations of FLT3 inhibitors, while the development of orally bioavailable FLT3-PROTACs faces great challenges. Here, we report the rational design and evaluation of a series of Gilteritinib-based FLT3-PROTACs. Among them, B3-2 exhibited the strongest antiproliferative activity against FLT3-ITD mutant AML cells, and significantly induced FLT3-ITD protein degradation. Mechanistic investigations demonstrated that B3-2 induced FLT3-ITD degradation in a ubiquitin-proteasome-dependent manner. More importantly, B3-2 exhibited an oral bioavailability of 5.65%, and oral administration of B3-2 showed good antitumor activity in MV-4-11 xenograft models. Furthermore, B3-2 showed strong antiproliferative activity against FLT3 resistant mutations, highlighting its potential in overcoming drug resistance.

A selective bis-thiophene chalcone-based spectrofluorimetric sensor for Fe3.

A highly selective bis thiophene-based chalcone as a chemosensor for detecting Fe3+ metal ions in DMF: H2O (9:1). This sensor was selective toward ferric ions over other metal ions with a detection limit in micromolar range.

Synthesis of Some Novel Thiophene Analogues as Potential Anticancer Agents.

The aim of this study involves the synthesis novel thiophene analogues that can be used as anticancer medications through a strategic multicomponent reaction connecting ethyl 4-chloroacetoacetate (1), phenyl isothiocyanate, and a series of active methylene reagents, including ethyl acetoacetate (2), malononitrile, ethyl cyanoacetate, cyanoacetamide 6a-c, N-phenyl cyanoacetamide derivatives 13a-c, and acetoacetanilide derivatives 18. This reaction was facilitated by dry dimethylformamide with a catalytic quantity of K2CO3. The resultant thiophene derivatives were identified as 4, 8a-b, 9, 12a-d, 15a-c, and 20a-b. Further reaction of compound 4 with hydrazine hydrate yielded derivative 5, respectively. When compound 1 was refluxed with ethyl 3-mercapto-3-(phenylamino)-2-(p-substituted phenyldiazenyl)acrylate 10a-e in the presence of sodium ethoxide, it produced thiophene derivatives 12a-d. Comprehensive structural elucidation of these newly synthesized thiophene-analogues was accomplished via elemental and spectral analysis data. Furthermore, the study delves into the cytotoxicity of the newly synthesized thiophenes was evaluated using the HepG2, A2780, and A2780CP cell lines. The amino-thiophene derivative 15b exhibited an increased growth inhibition of A2780, and A2780CP with IC50 values 12±0.17, and 10±0.15 µM, respectively compared to Sorafenib with IC50 values 7.5±0.54 and 9.4±0.14. This research opens new avenues for developing thiophene-based anticancer agents.

Anticancer Potential of the S-Heterocyclic Ring Containing Drugs and its Bioactivation to Reactive Metabolites.

Sulfur-containing heterocyclic derivatives have been disclosed for binding with a wide range of cancer-specific protein targets. Various interesting derivatives of sulfur-containing heterocyclics such as benzothiazole, thiazole, thiophene, thiazolidinedione, benzothiophene, and phenothiazine, etc have been shown to inhibit diverse signaling pathways implicated in cancer. Significant progress has also been made in molecular targeted therapy against specific enzymes such as kinase receptors due to potential binding interactions inside the ATP pocket. Sulfur-containing heterocyclic ring metal complexes i. e., benzothiazole, thiazole, thiophene, benzothiophene and phenothiazines are among the most promising active anticancer compounds. However, sulfur heteroaromatic rings, particularly thiophene, are of high structural alert due to their metabolism to reactive metabolites. The mere presence of a structural alert itself does not determine compound toxicity therefore, this review focuses on some specific findings that shed light on factors influencing the toxicity. In the current review, synthetic strategies of introducing the sulfur core ring in the synthesized derivatives are discussed with their structure-activity relationships to enhance our understanding of toxicity mechanisms and develop safer therapeutic options. The sulfur-containing marketed anticancer drugs included in this review direct the synthesis of novel compounds and will help in the development of potent, safer sulfur-based anticancer drugs in near future.

A PEDOT: PSS/GO fiber microelectrode fabricated by microfluidic spinning for dopamine detection in human serum and PC12 cells.

Rapid and accurate in situ determination of dopamine is of great significance in the study of neurological diseases. In this work, poly (3,4-ethylenedioxythiophene): poly (styrenesulfonic acid) (PEDOT: PSS)/graphene oxide (GO) fibers were fabricated by an effective method based on microfluidic wet spinning technology. The composite microfibers with stratified and dense arrangement were continuously prepared by injecting PEDOT: PSS and GO dispersion solutions into a microfluidic chip. PEDOT: PSS/GO fiber microelectrodes with high electrochemical activity and enhanced electrochemical oxidation activity of dopamine were constructed by controlling the structure composition of the microfibers with varying flow rate. The fabricated fiber microelectrode had a low detection limit (4.56 nM) and wide detection range (0.01-8.0 µM) for dopamine detection with excellent stability, repeatability, and reproducibility. In addition, the PEDOT: PSS/GO fiber microelectrode prepared was successfully used for the detection of dopamine in human serum and PC12 cells. The strategy for the fabrication of multi-component fiber microelectrodes is a new and effective approach for monitoring the intercellular neurotransmitter dopamine and has high potential as an implantable neural microelectrode.

A decade's overview of 2-aminothiophenes and their fused analogs as promising anticancer agents.

Over the past decades, cancer has been a challenging domain for medicinal chemists as it is an international health concern. In association, small molecules such as 2-aminothiophenes and their derivatives showed significant antitumor activity through variable modes of action. Therefore, this article aims to review the advances regarding these core scaffolds over the past 10 years, where 2-aminothiophenes and their fused analogs are classified and discussed according to their biological activity and mode of action, in the interest of boosting new design pathways for medicinal chemists to develop targeted antitumor candidates.

Chemiresistors Based on Hybrid Nanostructures Obtained from Graphene and Conducting Polymers with Potential Use in Breath Methane Detection Associated with Irritable Bowel Syndrome.

This paper describes the process of producing chemiresistors based on hybrid nanostructures obtained from graphene and conducting polymers. The technology of graphene presumed the following: dispersion and support stabilization based on the chemical vapor deposition technique; transfer of the graphene to the substrate by spin-coating of polymethyl methacrylate; and thermal treatment and electrochemical delamination. For the process at T = 950 °C, a better settlement of the grains was noticed, with the formation of layers predominantly characterized by peaks and not by depressions. The technology for obtaining hybrid nanostructures from graphene and conducting polymers was drop-casting, with solutions of Poly(3-hexylthiophene (P3HT) and Poly[(9,9-dioctylfluorenyl-2,7-diyl)-co-bithiophene] (F8T2). In the case of F8T2, compared to P3HT, a 10 times larger dimension of grain size and about 7 times larger distances between the peak clusters were noticed. To generate chemiresistors from graphene-polymer structures, an ink-jet printer was used, and the metallization was made with commercial copper ink for printed electronics, leading to a structure of a resistor with an active surface of about 1 cm2. Experimental calibration curves were plotted for both sensing structures, for a domain of CH4 of up to 1000 ppm concentration in air. A linearity of the curve for the low concentration of CH4 was noticed for the graphene structure with F8T2, presenting a sensitivity of about 6 times higher compared with the graphene structure with P3HT, which makes the sensing structure of graphene with F8T2 more feasible and reliable for the medical application of irritable bowel syndrome evaluation.

Promising Molecular Architectures for Two-Photon Probes in the Diagnosis of α-Synuclein Aggregates.

The abnormal deposition of protein in the brain is the central factor in neurodegenerative disorders (NDs). These detrimental aggregates, stemming from the misfolding and subsequent irregular aggregation of α-synuclein protein, are primarily accountable for conditions such as Parkinson's disease, Alzheimer's disease, and dementia. Two-photon-excited (TPE) probes are a promising tool for the early-stage diagnosis of these pathologies as they provide accurate spatial resolution, minimal intrusion, and the ability for prolonged observation. To identify compounds with the potential to function as diagnostic probes using two-photon techniques, we explore three distinct categories of compounds: Hydroxyl azobenzene (AZO-OH); Dicyano-vinyl bithiophene (DCVBT); and Tetra-amino phthalocyanine (PcZnNH2). The molecules were structurally and optically characterized using a multi-technique approach via UV-vis absorption, Raman spectroscopy, three-dimensional fluorescence mapping (PLE), time-resolved photoluminescence (TRPL), and pump and probe measurements. Furthermore, quantum chemical and molecular docking calculations were performed to provide insights into the photophysical properties of the compounds as well as to assess their affinity with the α-synuclein protein. This innovative approach seeks to enhance the accuracy of in vivo probing, contributing to early Parkinson's disease (PD) detection and ultimately allowing for targeted intervention strategies.

Synthesis of 2-Ethylhexyl 5-Bromothiophene-2-Carboxylates; Antibacterial Activities against Salmonella Typhi, Validation via Docking Studies, Pharmacokinetics, and Structural Features Determination through DFT.

A new class of thiophene-based molecules of 5-bromothiophene-2-carboxylic acid (1) have been synthesized in current research work. All analogs 4A-4G were synthesized with optimized conditions by coupling reactions of 2-ethylhexyl 5-bromothiophene-2-carboxylate (3) with various arylboronic acids. The results indicated that the majority of compounds showed promising effective in vitro antibacterial activity. Herein, 2-ethylhexyl-5-(p-tolyl)thiophene-2-carboxylate (4F), in particular among the synthesized analogs, showed outstanding antibacterial action (MIC value 3.125 mg/mL) against XDR Salmonella Typhi compared to ciprofloxacin and ceftriaxone. The intermolecular interaction was investigated by using a molecular docking study of thiophene derivatives 4A-4G against XDR S. Typhi. The values of the binding affinity of functionalized thiophene molecules and ciprofloxacin were compared against bacterial enzyme PDB ID: 5ztj. Therefore, 4F appears to be a promising antibacterial agent and showed the highest potential value. Density functional theory (DFT) calculations were executed to examine the electronic, structural, and spectroscopic features of the newly synthesized molecules 4A-4G.