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A solvent-controlled divergent thiocyanation of carbazoles and di/triphenylamines has been developed. Using either CH3 CN/H2 O (3:1) or DMSO as the solvent, a facile and efficient protocol for the solvent-controlled divergent synthesis of mono- and di-thiocyanation of carbazoles and di/triphenylamines was achieved. The salient features of this transformation include simple and mild reaction conditions, easily available substrates, and broad substrate scope. [ABSTRACT FROM AUTHOR]

Organic phosphorescent materials are excellent candidates for use in tumor imaging. However, a systematic comparison of the effects of the intensity, lifetime, and wavelength of phosphorescent emissions on bioimaging performance has not yet been undertaken. In addition, there have been few reports on organic phosphorescent materials that specifically distinguish tumors from normal tissues. This study addresses these gaps and reveals that longer lifetimes effectively increase the signal intensity, whereas longer wavelengths enhance the penetration depth. Conversely, a strong emission intensity with a short lifetime does not necessarily yield robust imaging signals. Building upon these findings, an organo‐phosphorescent material with a lifetime of 0.94 s was designed for tumor imaging. Remarkably, the phosphorescent signals of various organic nanoparticles are nearly extinguished in blood‐rich organs because of the quenching effect of iron ions. Moreover, for the first time, we demonstrated that iron ions universally quench the phosphorescence of organic room‐temperature phosphorescent materials, which is an inherent property of such substances. Leveraging this property, both the normal liver and hepatitis tissues exhibit negligible phosphorescent signals, whereas liver tumors display intense phosphorescence. Therefore, phosphorescent materials, unlike chemiluminescent or fluorescent materials, can exploit this unique inherent property to selectively distinguish liver tumor tissues from normal tissues without additional modifications or treatments. [ABSTRACT FROM AUTHOR]

The minimization of pain in research animals is a scientific and ethical necessity. Carprofen is commonly used for pain management in mice; however, some data suggest that the standard dosage of 5 mg/kg may not provide adequate analgesia after surgery. We hypothesized that a higher dose of carprofen in mice would reduce pain-associated behaviors and improve analgesia without toxic effects. A pharmacokinetic study was performed in mice given carprofen subcutaneously at 10 or 20 mg/kg. Plasma concentrations were measured at 0.25, 0.5, 1, 2, 4, 8, 12, 24, and 48 h after dosing (n = 3 per time point and treatment). At these doses, plasma levels were above the purported therapeutic level for at least 12 and 24 h, respectively, with respective half-lives of 14.9 and 10.2 h. For the efficacy study, 10 mice per group received anesthesia with or without an ovariectomy. Mice were then given 5 or 10 mg/kg of carprofen, or saline subcutaneously every 12 h. Orbital tightening, arched posture, wound licking, rearing, grooming, nesting behavior, and activity were assessed before surgery and at 4, 8, 12, 24, and 48 h after surgery. The von Frey responses were assessed before and at 4, 12, 24, and 48 h after surgery. The efficacy study showed that all surgery groups had significantly higher scores for orbital tightening, arched posture, and wound licking than did the anesthesia-only groups at 4, 8, 12, and 24-h time points. At the 8 h time point, the surgery groups treated with carprofen had significantly lower arched posture scores than did the surgery group treated with saline only. No significant differences were found between carprofen treatment groups for rearing, grooming, von Frey, activity, or nesting behavior at any time point. These results indicate that subcutaneous carprofen administered at these doses does not provide sufficient analgesia to alleviate postoperative pain in female CD1 mice.

What is this summary about?This is a summary of the results of the ALLEGRO phase 2b/3 clinical trial, originally published in The Lancet. ALLEGRO-2b/3 looked at how well and safely the study medicine, ritlecitinib, works in treating people with alopecia areata ('AA' for short). The immune system protects your body from outside invaders such as bacteria and viruses. AA is an autoimmune disease, meaning a disease in which one's immune system attacks healthy cells of the body by mistake. In AA, the immune system attacks hair follicles, causing hair to fall out. AA causes hair loss ranging from small bald patches to complete hair loss on the scalp, face, and/or body. Ritlecitinib is a medicine taken as a pill every day, by mouth, that is approved for the treatment of severe AA. It blocks processes that are known to play a role in causing hair loss in patients with AA.What were the results of the study?Adults and adolescents (12 years and older) took part in the ALLEGRO-2b/3 study. They either took ritlecitinib for 48 weeks or took a placebo (a pill with no medicine) for 24 weeks. Participants taking placebo later switched to taking ritlecitinib for 24 weeks. The study showed that participants taking ritlecitinib had more hair regrowth on their scalp after 24 weeks than those taking the placebo. Hair regrowth was also seen on the eyebrows and eyelashes in participants taking ritlecitinib. Hair regrowth continued to improve to week 48 with continued ritlecitinib treatment. In addition, more participants taking ritlecitinib reported that their AA had 'moderately' or 'greatly' improved after 24 weeks than those taking the placebo. Similar numbers of participants taking ritlecitinib or placebo had side effects after 24 weeks. Most side effects were mild or moderate.What do the results of the study mean?Ritlecitinib was an effective and well-tolerated treatment over 48 weeks for people with AA. Clinical Trial Registration: NCT03732807 (phase 2b/3 ALLEGRO study).

Although helicenes are promising molecules, the synthetic difficulty and tediousness have often been problems, and only small amounts of optically pure helicenes have been obtained by using chiral HPLC in most cases. Herein, aza[7]helicenes or closed‐aza[7]helicenes with (1R)‐menthyl substituents were selectively synthesized via the intramolecular Scholl reaction, and the diastereomeric pairs were separated by silica gel column chromatography. The optically pure helicenes were further transformed into the corresponding cyclic dimers, and the chiroptical properties were investigated. The rigid π‐frameworks of the dimers led to the high molar extinction coefficients and fluorescence quantum yields, while the twisted helicene moieties induced clear Cotton effects and CPL in the visible region, and the high CPL brightness (BCPL) was achieved. Furthermore, the cyclic dimers were found to have the macrocyclic cavity with the two NH groups suitable for the selective binding of a fluoride anion, which induced significantly redshifted fluorescence and CPL in the red region. [ABSTRACT FROM AUTHOR]

Four different carbazole‐based self‐assembled molecules (SAMs) with different terminal groups have been designed and synthesized as hole‐selective contacts for inverted perovskite solar cells to investigate their interfacial interactions and, consequently, the performance of the devices. Using the carbazole core as a reference, the effect of the thiophen‐2‐yl phenyl, or the hydroxymethyl phenyl attached to the core through a phenyl moiety, with that of the thiophene directly linked to the carbazole is compared. These new SAMs have been successfully synthesized using cost‐effective starting materials and a straightforward synthetic method, eliminating the need for expensive and complex purification processes. Subsequently, they have been applied as efficient hole‐selective contact in inverted perovskite solar cells, leading to an outstanding power conversion efficiency of 19.67% in the case of SAM5, containing a carbazole‐core substituted with double 2‐phenylthiophene side arms as functional group. The detailed characterization of the interface and the charge kinetics has allowed to determine the effect of each substituent. [ABSTRACT FROM AUTHOR]

This review centers on the synthetic strategies employed with indolyl‐ynones. Indolyl‐ynone, owing to its highly reactive ynone moiety, frequently partakes in dearomatizing spirocyclization reactions and subsequent rearrangement reactions when subjected to various reaction conditions. Hence, various heterocycles such as densely functionalized spiroindolenines, carbazoles, quinolines and carbo‐and hetero‐cycle substituted indoles are synthesized from indolyl‐ynones. In addition to this, the versatile spirocyclic indole scaffold exhibits the capability to produce tetracyclic and polyclic structures through intricate skeletal rearrangement processes. Moreover, the total synthesis of natural products using the indolyl‐ynone moiety was also compiled in this review. [ABSTRACT FROM AUTHOR]

Herein we have described the Pd-catalyzed sonochemistry driven by [BMIM]-IL as re-useable solvent to synthesize various carbazole scaffolds from 2,2′-dibromodiphenyl. Diverse primary amines were utilised as coupling partners in the presence of [PAIM][NTf2], which exhibits an impactful promoter in the IL medium, thereby avoiding the need for hazardous VOC's. The recyclability of ionic liquids highlights the green approach of the reaction. Further, the synthesized carbazole scaffolds were assessed for antimicrobial activity. Compounds 3e and 3g are found to be highly active. The most probable binding sites for these scaffolds were screened through a computer-simulated docking method with targeted protein.

N-Acyl carbazoles can be efficiently produced through a single-step process using amides and cyclic diaryliodonium triflates. This convenient reaction is facilitated by copper iodide in p-xylene, using the commonly found activating ligand diglyme. We have tested this method with a wide range of amides and iodonium triflates, proving its versatility with numerous substrates. Beyond carbazoles, we also produced a variety of other N-heterocycles, such as acridines, phenoxazines, or phenazines, showcasing the robustness of our technique. In a broader sense, this new method creates two C–N bonds simultaneously based on a mono-halogenated starting material, thus allowing heterocycle formation with diminished halogen waste.

IntroductionIn COVID-19 pneumonia, there is a massive increase in fatty acid levels and lipid mediators with a predominance of cyclooxygenase metabolites, notably TxB2 ≫ PGE2 > PGD2 in the lungs, and 11-dehydro-TxB2, a TxA2 metabolite, in the systemic circulation. While TxA2 stimulates thromboxane prostanoid (TP) receptors, 11-dehydro-TxB2 is a full agonist of DP2 (formerly known as the CRTh2) receptors for PGD2. Anecdotal experience of using ramatroban, a dual receptor antagonist of the TxA2/TP and PGD2/DP2 receptors, demonstrated rapid symptomatic relief from acute respiratory distress and hypoxemia while avoiding hospitalization.Areas coveredEvidence supporting the role of TxA2/TP receptors and PGD2/DP2 receptors in causing rapidly progressive lung injury associated with hypoxemia, a maladaptive immune response and thromboinflammation is discussed. An innovative perspective on the dual antagonism of TxA2/TP and PGD2/DP2 receptor signaling as a therapeutic approach in COVID-19 is presented. This paper examines ramatroban an anti-platelet, immunomodulator, and antifibrotic agent for acute and long-haul COVID-19.Expert opinionRamatroban, a dual blocker of TP and DP2 receptors, has demonstrated efficacy in animal models of respiratory dysfunction, atherosclerosis, thrombosis, and sepsis, as well as preliminary evidence for rapid relief from dyspnea and hypoxemia in COVID-19 pneumonia. Ramatroban merits investigation as a promising antithrombotic and immunomodulatory agent for chemoprophylaxis and treatment.

SP 1 sp H NMR (400 MHz, CDCl SB 3 sb ): = 12.46 (s, 1 H), 9.12-9.10 (m, 2 H), 8.84 (dd, I J i SB 1 sb = 4.2, I J i SB 2 sb = 1.7 Hz, 1 H), 8.14-8.10 (m, 2 H), 7.62-7.58 (m, 1 H), 7.49 (dd, I J i SB 1 sb = 8.2, I J i SB 2 sb = 1.1 Hz, 1 H), 7.42-7.39 (m, 2 H), 7.32 (d, I J i = 8.1 Hz, 1 H), 7.28-7.24 (m, 1 H), 6.83 (s, 1 H), 4.29-4.23 (m, 5 H), 1.43 (t, I J i = 7.3 Hz, 3 H). SP 1 sp H NMR (400 MHz, CDCl SB 3 sb ): = 7.98 (d, I J i = 7.7 Hz, 1 H), 7.94 (dd, I J i SB 1 sb = 8.0, I J i SB 2 sb = 0.9 Hz, 1 H), 7.40-7.36 (m, 1 H), 7.33 (d, I J i = 7.8 Hz, 1 H), 7.21-7.17 (m, 1 H), 6.84-6.82 (m, 2 H), 4.27 (q, I J i = 7.2 Hz, 2 H), 3.91 (s, 3 H), 1.39 (t, I J i = 7.2 Hz, 3 H). SP 1 sp H NMR (400 MHz, CDCl SB 3 sb ): = 8.64 (s, 1 H), 8.03 (d, I J i = 7.7 Hz, 1 H), 7.41-7.37 (m, 1 H), 7.32 (d, I J i = 8.1 Hz, 1 H), 7.19-7.16 (m, 1 H), 7.12 (s, 1 H), 4.34 (q, I J i = 7.2 Hz, 2 H), 4.28 (q, I J i = 7.2 Hz, 2 H), 3.10 (t, I J i = 8.0 Hz, 2 H), 1.65-1.57 (m, 2 H), 1.40-1.35 (m, 8 H), 1.28-1.19 (m, 16 H), 0.79 (t, I J i = 6.5 Hz, 3 H). SP 1 sp H NMR (400 MHz, CDCl SB 3 sb ): = 8.70 (s, 1 H), 8.11 (d, I J i = 7.7 Hz, 1 H), 7.96-7.96 (m, 1 H), 7.93-7.90 (m, 1 H), 7.56-7.53 (m, 1 H), 7.49-7.43 (m, 2 H), 7.39 (d, I J i = 8.2 Hz, 1 H), 7.27-7.22 (m, 2 H), 4.32 (q, I J i = 7.3 Hz, 2 H), 4.08 (q, I J i = 7.2 Hz, 2 H), 2.58 (s, 3 H), 1.38 (t, I J i = 7.2 Hz, 3 H), 1.00 (t, I J i = 7.1 Hz, 3 H). [Extracted from the article]

A wide variety of regioselectively substituted carbazole derivatives can be synthesized by the gold‐catalyzed cyclization of alkynols bearing an indol‐3‐yl and an additional group at the homopropargylic positions. The regioselectivity of the process can be controlled by both the oxidation state of the gold catalyst and the electronic nature of the substituents of the alkynol moiety. The 1,2‐alkyl migration in the spiroindoleninium intermediate, generated after indole attack to the activated alkyne, is favored with gold(I) complexes and for electron‐rich aromatic substituents at the homopropargylic position, whereas the 1,2‐alkenyl shift is preferred when using gold(III) salts and for alkyl or non‐electron‐rich aromatic groups. [ABSTRACT FROM AUTHOR]

An efficient and scalable Pd‐catalyzed decarboxylative cross‐coupling strategy for the synthesis of carbazoles has been developed by using N‐aryl anthranilic acids. By employing a well‐designed catalytic system, this protocol access diverse carbazole derivatives via a C−C bond‐formation in one‐pot. The substituted carbazoles were obtained in good to excellent yields with high functional‐group tolerance. We have also demonstrated the gram‐scale synthesis of the anti‐cancer drug Ellipticine by utilizing this methodology. This concise and scalable total synthesis of ellipticine exemplifies the efficiency of our methodology in producing this significant anti‐cancer compound. [ABSTRACT FROM AUTHOR]

Mechanoluminescence (ML) is the emission of light caused by mechanical stresses on solid, usually crystalline substances. Recently, it has been observed that a specific class of organic crystals, N‐alkyl carbazoles, have both low melting points and high proclivity for self‐assembly, making them easily renewable for long‐term device applications. To develop new carbazole‐based ML materials for device applications, it is necessary to be able to tune their emission to desirable wavelengths. In this study, we computationally investigated using chemical substituents with electron‐withdrawing/donating character to tune the emission wavelength of N‐alkyl carbazoles. We find that strongly electron‐withdrawing substituent groups can be used as one controlling factor for tuning emission wavelengths for N‐alkyl carbazoles. This finding provides materials scientists with a new family of derivatives for designing effective organic materials with desirable ML emission properties. [ABSTRACT FROM AUTHOR]

The Zhidan area in the Ordos Basin is enriched with unconventional hydrocarbon resources. However, there is a lack of research on oil–source correlation and specific petroleum secondary migration paths in the Chang 10 member, which restricts the exploration and development of petroleum resources in the area. Gas chromatography–mass spectrometry was used to determine the biomarker characteristics of 28 samples and the carbazole ratios of 14 oil sand extracts. Inductively coupled plasma–mass spectrometry was used to determine the rare earth element (REE) compositions of the oil sands and source rock extracts. Oil–source correlation analyses based on biomarkers and REE compositions were cross-validated, and the results showed that the Chang 10 oil in the study area originated from mixed source rocks of the Chang 7 and Chang 9 members, or from separate source rocks in either the Chang 7 or Chang 9 member. Based on the oil–source correlation, 11 secondary migration paths of Chang 10 oil were determined by applying carbazole parameters. The secondary migration path of oil shows that the Zhidan area's eastern part is the preferential oil accumulation area. [ABSTRACT FROM AUTHOR]

A series of carbazole‐dendronized tris(2,4,6‐trichlorophenyl)methyl (TTM) radicals have been synthesized. The photophysical properties of dendronized radicals up to the fourth generation were compared systematically to understand how structure–property relationships evolve with generation. The photoluminescence quantum yield (PLQY) was found to increase with the increasing generation, and the fourth generation (G4TTM) in cyclohexane solution showed a PLQY as high as 63 % at a wavelength of 627 nm (in the deep‐red region) from the doublet state. The dendron modification strategy also showed a blue‐shift of the emission on increasing the generation number, and the photostability was also increased compared to the bare TTM radical. [ABSTRACT FROM AUTHOR]

1,3-butadiynamides—the ethynylogous variants of ynamides—receive considerable attention as precursors of complex molecular scaffolds for organic and heterocyclic chemistry. The synthetic potential of these C4-building blocks reveals itself in sophisticated transition-metal catalyzed annulation reactions and in metal-free or silver-mediated HDDA (Hexa-dehydro-Diels–Alder) cycloadditions. 1,3-Butadiynamides also gain significance as optoelectronic materials and in less explored views on their unique helical twisted frontier molecular orbitals (Hel-FMOs). The present account summarizes different methodologies for the synthesis of 1,3-butadiynamides followed by the description of their molecular structure and electronic properties. Finally, the surprisingly rich chemistry of 1,3-butadiynamides as versatile C4-building blocks in heterocyclic chemistry is reviewed by compiling their exciting reactivity, specificity and opportunities for organic synthesis. Besides chemical transformations and use in synthesis, a focus is set on the mechanistic understanding of the chemistry of 1,3-butadiynamides—suggesting that 1,3-butadiynamides are not just simple alkynes. These ethynylogous variants of ynamides have their own molecular character and chemical reactivity and reflect a new class of remarkably useful compounds. [ABSTRACT FROM AUTHOR]

ObjectiveTo describe a serious adverse event of gastrointestinal obstruction requiring surgery following routine administration of multiple doses of activated charcoal (AC) granules, which were prescribed for carprofen toxicosis.Case summaryA 2-year-old female neutered Airedale Terrier presented for ingestion of 207 mg/kg of carprofen. Decontamination was initiated with apomorphine to induce emesis. Along with additional supportive care, the dog received an initial dose of 75 mL of AC suspension containing sorbitol by mouth (15.6 g of AC, or 0.6 g/kg), followed by 50 g of AC granules every 8 hours for 4 additional doses. While hospitalized, the dog experienced clinical signs, including vomiting and black diarrhea, as well as bloodwork changes including mild to moderate elevations in kidney and liver enzymes. Given clinical improvement after 72 hours of hospitalization, the patient was discharged for monitoring and ongoing care at home. Two days later, the patient presented again for nausea, dark diarrhea with frank blood, and panting. Abdominal ultrasound showed findings suspicious for partially obstructive foreign material or atypical impacted fecal material partially occluding the distal ileum. Despite medical management overnight, recheck ultrasound the following day demonstrated persistent obstruction with ileal foreign material. Exploratory laparotomy and enterotomy revealed moderate distension and obstruction of the distal ileum with black granular foreign material consistent with charcoal granules. The patient remained in hospital for supportive care for 4 days following the procedure, and all clinical signs were resolved at the time of discharge.New or unique information providedThis report documents a serious adverse event of gastrointestinal obstruction associated with routine multidose AC administration, which has been occasionally reported in people but not in dogs. The potential for this complication should be taken into account when prescribing multiple doses of AC granules.

The free-living amebae Naegleria, Acanthamoeba, and Balamuthia cause rare but life-threatening infections. All three parasites can cause meningoencephalitis. Acanthamoeba can also cause chronic keratitis and both Balamuthia and Acanthamoeba can cause skin and systemic infections. There are minimal drug development pipelines for these pathogens despite a lack of available treatment regimens and high fatality rates. To identify anti-amebic drugs, we screened 159 compounds from a high-value repurposed library against trophozoites of the three amebae. Our efforts identified 38 compounds with activity against at least one ameba. Multiple drugs that bind the ATP-binding pocket of mTOR and PI3K are active, highlighting these compounds as important inhibitors of these parasites. Importantly, 24 active compounds have progressed at least to phase II clinical studies and overall 15 compounds were active against all three amebae. Based on central nervous system (CNS) penetration or exceptional potency against one amebic species, we identified sixteen priority compounds for the treatment of meningoencephalitis caused by these pathogens. The top five compounds are (i) plicamycin, active against all three free-living amebae and previously U.S. Food and Drug Administration (FDA) approved, (ii) TG02, active against all three amebae, (iii and iv) FDA-approved panobinostat and FDA orphan drug lestaurtinib, both highly potent against Naegleria, and (v) GDC-0084, a CNS penetrant mTOR inhibitor, active against at least two of the three amebae. These results set the stage for further investigation of these clinically advanced compounds for treatment of infections caused by the free-living amebae, including treatment of the highly fatal meningoencephalitis.

The preparation of multifunctionalized luminophores with full‐color emission based on an identical core skeleton is a significative but challenging research topic. In this work, eight donor‐donor‐acceptor (D‐D‐A)‐type luminogens based on a central carbazole core bearing a C6 hydrocarbon chain were designed by using different kinds of donor and acceptor units on the left and right, and synthesized in good yields. These D‐D‐A carbazole derivatives display deep‐blue, sky‐blue, cyan, green, yellow‐green, yellow, orange and red fluorescence in the solid state, achieving full‐color emission covering the whole visible light range under UV light illumination. Notably, the dicyano‐functionalized triphenylamine‐containing carbazole derivative exhibits rare aggregation‐induced near‐infrared emission and red‐to‐near‐infrared mechano‐fluorochromism with high contrast beyond 100 nm. Furthermore, the red‐emissive luminogen can serve as a potential candidate for cell imaging and photodynamic therapy (PDT). This work not only provides reference for the construction of full‐color emissive systems but also opens a new avenue to the preparation of multifunctionalized luminophores capable of simultaneous application in near‐Infrared mechanical‐force sensors and PDT fields. [ABSTRACT FROM AUTHOR]

The reductive cyclization of different organic nitro compounds by carbon monoxide, catalyzed by transition metal complexes, is a very efficient and clean strategy for the synthesis of many N-heterocycles. However, its use requires the use of autoclaves and pressurized CO lines. In this perspective, the authors will present the results obtained in their laboratories on the use of phenyl formate as a convenient CO surrogate, able to liberate carbon monoxide under the reaction conditions and allowing the use of a cheap glass pressure tube as a reaction vessel. In most cases, yields were better than those previously reported by the use of pressurized CO, proving that the use of CO surrogates can be a viable alternative to the gaseous reagent. [ABSTRACT FROM AUTHOR]

The Coronavirus disease 2019 (COVID-19) outbreak was declared by the World Health Organization (WHO) in March 2020 to be a pandemic and many drugs used at the beginning proved useless in fighting the infection. Lately, there has been approval of some new generation drugs for the clinical treatment of severe or critical COVID-19 infections. Nevertheless, more drugs are required to reduce the pandemic's impact. Several treatment approaches for COVID-19 were employed since the beginning of the pandemic, such as immunomodulatory, antiviral, anti-inflammatory, antimicrobial agents, and again corticosteroids, angiotensin II receptor blockers, and bradykinin B2 receptor antagonists, but many of them were proven ineffective in targeting the virus. So, the identification of drugs to be used effectively for treatment of COVID-19 is strongly needed. It is aimed in this review to collect the information so far known about the COVID-19 studies and treatments. Moreover, the observations reported in this review about carbazoles as a treatment can signify a potentially useful clinical application; various drugs that can be introduced into the therapeutic equipment to fight COVID-19 or their molecules can be used as the basis for designing new antivirals. [ABSTRACT FROM AUTHOR]

The expression of biosynthetic genes in bacterial hosts can enable access to high-value compounds, for which appropriate molecular genetic tools are essential. Therefore, we developed a toolbox of modular vectors, which facilitate chromosomal gene integration and expression in Pseudomonas putida KT2440. To this end, we designed an integrative sequence, allowing customisation regarding the modes of integration (random, at attTn7, or into the 16S rRNA gene), promoters, antibiotic resistance markers as well as fluorescent proteins and enzymes as transcription reporters. We thus established a toolbox of vectors carrying integrative sequences, designated as pYT series, of which we present 27 ready-to-use variants along with a set of strains equipped with unique 'landing pads' for directing a pYT interposon into one specific copy of the 16S rRNA gene. We used genes of the well-described violacein biosynthesis as reporter to showcase random Tn5-based chromosomal integration leading to constitutive expression and production of violacein and deoxyviolacein. Deoxyviolacein was likewise produced after gene integration into the 16S rRNA gene of rrn operons. Integration in the attTn7 site was used to characterise the suitability of different inducible promoters and successive strain development for the metabolically challenging production of mono-rhamnolipids. Finally, to establish arcyriaflavin A production in P. putida for the first time, we compared different integration and expression modes, revealing integration at attTn7 and expression with NagR/PnagAa to be most suitable. In summary, the new toolbox can be utilised for the rapid generation of various types of P. putida expression and production strains. [ABSTRACT FROM AUTHOR]

A strategy for the design of potential drugs for the treatment of neurodegenerative diseases is considered. This strategy is based on multipharmacophore compounds combining several characteristic structural moieties (scaffolds) of different neuroactive substances within the one molecule. Various synthetic approaches to such compounds are considered and exemplified by the synthesis of conjugates of phenothiazine, tetrahydro-γ-carboline, carbazole, and aminoadamantane moieties linked through a series of spacers. Data on the biological activity of compounds acquired within the framework of complex screening system are presented. In particular, effects of the novel compounds on cholinesterase enzyme systems, glutamate receptors, mitochondrial structures, formation of microtubule systems, as well as their antioxidant properties, were evaluated. For some multipharmacophore structures, the appearance of neurobiological properties that are not characteristic of the parent compounds was observed, thus providing new opportunities for the design of original highly efficient multitarget drugs. The acquired results allowed us to select several leading compounds that have successfully passed preclinical trials. [ABSTRACT FROM AUTHOR]

Our present study provides expedient methods for the synthesis of novel substituted indanes, pyrido[3,2,1-jk]carbazoles and pyrido[3,2,1-kl]phenothiazines utilizing intramolecular Friedel-Crafts cyclialkylations of synthesized heteroaryl alcohols. This methodology is realized by a three-step protocol involving first esterification of starting carboxylic acids to the corresponding esters, addition of Grignard reagents to give carbinol precursors and followed by Friedel-Crafts cyclizations of alcohols mediated by AlCl3/CH3NO2, PPA or P2O5-catalysts to furnish the desired polycycles in good to excellent yields of 65-85%. The designed protocol offers easy access to the pharmaceutically promising templates in good yields. The molecular structural elucidations of all newly obtained compounds have been proved by spectral and elemental analysis. [ABSTRACT FROM AUTHOR]

In this article, we demonstrate an atom economical, practical, mild and selective HBF4‐catalyzed 1,6‐conjugate addition of carbazoles to para‐Quinone Methides (p‐QMs) to access 3,6‐bis‐diarylmethyl‐ and mono‐diarylmethyl carbazoles. This metal and additive free protocol provides convenient access to the substituted carbazole derivatives in moderate to excellent yields with a good functional group tolerance. It was found that a couple of 3,6‐disubstituted carbazoles showed interesting photophysical properties and, therefore, might potentially find some applications as host materials in OLEDs. [ABSTRACT FROM AUTHOR]

The development of a Lewis acid-catalyzed, intramolecular ring-opening benzannulation of 5-(indolyl)2,3-dihydrofuran acetals is described. The resulting 1-hydroxycarbazole-2-carboxylates are formed in up to 90% yield in 1 h. The dihydrofuran acetals are readily accessed from the reactions of enol ethers and α-diazo-β-indolyl-β-ketoesters. To highlight the method's synthetic utility, a formal total synthesis of murrayafoline A, a bioactive carbazole-containing natural product, was undertaken. [ABSTRACT FROM AUTHOR]

• Petroleum separation into pyrolic, phenolic-ketonic, and carboxylic acid fractions. • The reliability of separation results strongly depends on the mass of the fraction. • The relative expanded uncertainty of concentration decreases with increasing mass. • A power function can describe the relative expanded uncertainty and mass relation. • Using plastic labware may negatively affect the fractionation results. This research outlines a fast and efficient technique for separating the pyrrolic, phenolic-ketonic, and carboxylic acid fractions from oils in a small-scale setting. This approach enables the separation and analysis of neutral nitrogen fractions that contain indoles, carbazoles, and benzocarbazoles, as well as ketonic-phenolic fractions that contain phenols and ketones. The study showcases the potential for accurately measuring petroleum composition. The reliability of the fractions' concentration results is determined by the mass of the separated fraction, with completely reliable results achievable for masses exceeding 1.4 mg. The fraction's mass can also be used to evaluate the relative expanded uncertainty of a single separation procedure. As the mass and concentration of the fraction increase, the relative expanded uncertainty of the concentration decreases, and this can be modelled using a power function. [ABSTRACT FROM AUTHOR]

There is a critical need for translating basic science discoveries into new therapeutics for patients suffering from difficult to treat neuropsychiatric and neurodegenerative conditions. Previously, a target-agnostic in vivo screen in mice identified P7C3 aminopropyl carbazole as capable of enhancing the net magnitude of postnatal neurogenesis by protecting young neurons from death. Subsequently, neuroprotective efficacy of P7C3 compounds in a broad spectrum of preclinical rodent models has also been observed. An important next step in translating this work to patients is to determine whether P7C3 compounds exhibit similar efficacy in primates. Adult male rhesus monkeys received daily oral P7C3-A20 or vehicle for 38 weeks. During weeks 2-11, monkeys received weekly injection of 5'-bromo-2-deoxyuridine (BrdU) to label newborn cells, the majority of which would normally die over the following 27 weeks. BrdU+ cells were quantified using unbiased stereology. Separately in mice, the proneurogenic efficacy of P7C3-A20 was compared to that of NSI-189, a proneurogenic drug currently in clinical trials for patients with major depression. Orally-administered P7C3-A20 provided sustained plasma exposure, was well-tolerated, and elevated the survival of hippocampal BrdU+ cells in nonhuman primates without adverse central or peripheral tissue effects. In mice, NSI-189 was shown to be pro-proliferative, and P7C3-A20 elevated the net magnitude of hippocampal neurogenesis to a greater degree than NSI-189 through its distinct mechanism of promoting neuronal survival. This pilot study provides evidence that P7C3-A20 safely protects neurons in nonhuman primates, suggesting that the neuroprotective efficacy of P7C3 compounds is likely to translate to humans as well.

FICZ and TCDD, two high-affinity AhR ligands, are reported to have opposite effects on T cell differentiation with TCDD inducing regulatory T cells and FICZ inducing Th17 cells. This dichotomy has been attributed to ligand-intrinsic differences in AhR activation, although differences in sensitivity to metabolism complicate the issue. TCDD is resistant to AhR-induced metabolism and produces sustained AhR activation following a single dose in the μg/kg range, whereas FICZ is rapidly metabolized and AhR activation is transient. Nonetheless, prior studies comparing FICZ with TCDD have generally used the same 10-50 μg/kg dose range, and thus the two ligands would not equivalently activate AhR. We hypothesized that high-affinity AhR ligands can promote CD4+ T cell differentiation into both Th17 cells and Tregs, with fate depending on the extent and duration of AhR activation. We compared the immunosuppressive effects of TCDD and FICZ, along with two other rapidly metabolized ligands (ITE and 11-Cl-BBQ) in an acute alloresponse mouse model. The dose and timing of administration of each ligand was optimized for TCDD-equivalent Cyp1a1 induction. When optimized, all of the ligands suppressed the alloresponse in conjunction with the induction of Foxp3- Tr1 cells on day 2 and the expansion of natural Foxp3+ Tregs on day 10. In contrast, a low dose of FICZ induced transient expression of Cyp1a1 and did not induce Tregs or suppress the alloresponse but enhanced IL-17 production. Interestingly, low doses of the other ligands, including TCDD, also increased IL-17 production on day 10. These findings support the conclusion that the dose and the duration of AhR activation by high-affinity AhR ligands are the primary factors driving the fate of T cell differentiation.

Anaplastic thyroid cancer (ATC) is a rare and lethal human malignancy with no known effective therapies in the majority of cases. Despite the use of conventional treatments such as chemotherapy, radiation and surgical resection, this disease remains almost universally fatal. In the present study, we identified the JAK2 inhibitor Lestaurtinib as a potent compound when testing against 13 ATC cell lines. Lestaurtinib demonstrated a potent antiproliferative effect in vitro at nanomolar concentrations. Furthermore, Lestaurtinib impeded cell migration and the ability to form colonies from single cells using scratch-wound and colony formation assays, respectively. Flow cytometry was used for cell cycle analysis following drug treatment and demonstrated arrest at the G2/M phase of the cell cycle, indicative of a cytostatic effect. In vivo studies using the chick chorioallantoic membrane xenograft models demonstrated that treatment with Lestaurtinib resulted in a significant decrease in endpoint tumor volume and vascularity using power Doppler ultrasound imaging. Overall, this study provides evidence that Lestaurtinib is a potent antiproliferative agent with potential antiangiogenic activity that warrants further investigation as a targeted therapy for ATC.

Herein, we report the structures of chiral‐at‐cage carborane derivatives bearing carbazole chromophores that emit circularly polarized luminescence (CPL) and aggregation‐induced electrochemiluminescence (AIECL). By adjusting the substituent positions on the carborane derivatives, two chiral luminescent molecules, Cb1 and Cb2, with different properties were obtained. The photoluminescence dissymmetry factors |gPL| of both (R/S)‐Cb1 and (R/S)‐Cb2 enantiomers in neat films were as high as 6.24×10−3 and 7.38×10−3, respectively. Cb1 showed a deep blue emission peak at 434 nm in n‐pentane. Interestingly, distinct fluorescence and CPL spectra were observed in solvents of different polarities due to the twisted intramolecular charge transfer effect, suggesting its potential use in solvent recognition. Meanwhile, Cb2 exhibited good AIECL property, excellent ECL stability and could be used for determining dopamine concentrations, suggesting its potential applications in biology and diagnosis. [ABSTRACT FROM AUTHOR]

Organic synthesis plays a pivotal role in the development of innovative organic functional materials for optoelectronic applications such as organic light emitting diodes (OLEDs), photovoltaics (OPVs), non‐linear optics (NLOs), field effect transistors (OFETs) and sensors. Chemical functionalization methods available for polyaromatic hydrocarbons (PAHs) are particularly attractive as they provide opportunities to fine‐tune the physicochemical, charge transporting and device parameters. Among the PAHs containing heteroatoms, carbazole is recognized as one of the most promising building blocks for assembling the functional materials for organic electronics, particularly for OLED and OPVs due to its unique features such as good hole transporting ability, excellent thermal and morphological stability, amorphous nature, low cost, high triplet energy and flexibility for functionalization. Until 2011, carbazole‐based functional materials were limited to use as a donor in donor–acceptor molecular configurations and as difunctionalized (C3,C6‐ or C2,C7‐ or N‐) derivatives capable of hole transporting/emitting characteristics. Recently, polyfunctionalization on carbazole at various positions has drawn significant attention as a result of their promising structure–function relationships. Although some reviews have focused on structure–property relationships within difunctionalized carbazoles, recent synthetic advances in the field of polyfunctionalized carbazoles and their resultant structure–property relationships remain unreviewed. To bridge this gap, in this article we review newly emerged synthetic approaches for polyfunctionalization of carbazole and discuss the effects of substitution pattern, chromophore nature and its density on the photophysical and device properties. [ABSTRACT FROM AUTHOR]

A coupling reaction of 2‐iodobiphenyl with benzoisoxazole under the cooperative catalysis of Pd(CH3CN)2Cl2 and P(4‐F−Ph)3 is disclosed. The reaction proceeds via intramolecular C−H activation/N−O cleavage/migratory insertion sequence to give an array of N‐arylcarbazoles with an aldehyde or a ketone. The employment of benzoisoxazoles as an amination agent obviates the need for stoichiometric amount of oxidants. [ABSTRACT FROM AUTHOR]

The modular synthesis of carbazole functionalized phthalimides (PIs) and their applicability as catalyst in selected photocatalytic transformations are reported. The developed synthetic approach provides high variability of phthalimide considering that the synthesis of the phthalimide core can be easily performed. Starting from fluorophthalic acid anhydrides, the corresponding fluorophthalimides were prepared with various amines, and the fluoro function ensured the introduction of carbazoles into the phthalimide framework through aromatic nucleophilic substitution. Besides the synthetic developments, some of the carbazolyl phthalimides were tested in four different photocatalytic transformations, which showed attractive and comparable activity to the known 4-CzIPN and noble metal complexes. [ABSTRACT FROM AUTHOR]

Donor–acceptor–donor (D–A–D)-type molecules are considered as a promising class of NIR fluorescence materials. In this communication, 4,7-di(9H-carbazol-9-yl)-[1,2,5]oxadiazolo[3,4-d]pyridazine was obtained by dehydrogenation of 4,7-bis(1,2,3,4,4a,9a-hexahydro-9H-carbazol-9-yl)-[1,2,5]oxadiazolo[3,4-d]pyridazine with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in toluene. The structure of the synthesized compound was established by elemental analysis; high-resolution mass spectrometry; 1H, 13C NMR, IR, and UV spectroscopy; and mass spectrometry. The photophysical properties of the title compound were studied and compared with spectral data of the [1,2,5]thiadiazolo[3,4-d]pyridazine analogue. [ABSTRACT FROM AUTHOR]

Microglia-mediated neuroinflammation is critical in the pathogenesis of sepsis-associated encephalopathy(SAE). Identifying the key factors that inhibit microglia-mediated neuroinflammation holds promise as a potential target for preventing and treating SAE. Esketamine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, has been proposed to possess protective and therapeutic properties against neuroinflammatory disorders. This study provides evidence that the administration of Esketamine in SAE mice improves cognitive impairments and alleviates neuronal damage by inhibiting the microglia-mediated neuroinflammation. The BDNF receptor antagonist K252a was employed in both vivo and in vitro experiments. The findings indicate that K252a successfully counteracted the beneficial effects of Esketamine on microglia and cognitive behavior in mice with SAE. Consequently, these results suggest that Esketamine inhibits microglia-mediated neuroinflammation by activating the BDNF pathway, and mitigating neuronal damage and cognitive dysfunction associated with SAE., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: A direct link between the tryptophan (Trp) metabolite kynurenine (Kyn) and the aryl hydrocarbon receptor (AhR) is not supported by metabolic considerations and by studies demonstrating the failure of Kyn concentrations of up to 100 μM to activate the receptor in cell culture systems using the proxy system of cytochrome P- 450-dependent metabolism. The Kyn metabolite kynurenic acid (KA) activates the AhR and may mediate the Kyn link. Recent studies demonstrated down regulation and antagonism of activation of the AhR by Trp. We have addressed the link between Kyn and the AhR by looking at their direct molecular interaction in silico ., Methods: Molecular docking of Kyn, KA, Trp and a range of Trp metabolites to the crystal structure of the human AhR was performed under appropriate docking conditions., Results: Trp and 30 of its metabolites docked to the AhR to various degrees, whereas Kyn and 3-hydroxykynurenine did not. The strongest docking was observed with the Trp metabolite and photooxidation product 6-Formylindolo[3,2-b]carbazole (FICZ), cinnabarinic acid, 5-hydroxytryptophan, N-acetyl serotonin and indol-3-yllactic acid. Strong docking was also observed with other 5-hydroxyindoles., Conclusions: We propose that the Kyn-AhR link is mediated by KA. The strong docking of Trp and its recently reported down regulation of the receptor suggest that Trp is an AhR antagonist and may thus play important roles in body homeostasis beyond known properties or simply being the precursor of biologically active metabolites. Differences in AhR activation reported in the literature are discussed., (© 2024 The Author(s). Published by IMR Press.)

The aim of this study was to explore the neuroprotective effects of the P2X7 receptor antagonist A740003 on retinal ganglion cells (RGCs) in chronic intraocular hypertension (COH) experimental glaucoma mouse model. Bioinformatics was used to analyze the glaucoma-related genes. Western blot, real-time fluorescence quantitative PCR, and immunofluorescence staining techniques were employed to explore the mechanisms underlying the neuroprotective effects of A740003 on RGCs in COH retinas. Bioinformatic analysis revealed that oxidative stress, neuroinflammation, and cell apoptosis were highly related to the pathogenesis of glaucoma. In COH retinas, intraocular pressure elevation significantly increased the levels of translocator protein, a marker of microglial activation, which could be reversed by intravitreal preinjection of A740003. A740003 also suppressed the increased mRNA levels of proinflammatory cytokines interleukin (IL) 1β and tumor necrosis factor α in COH retinas. In addition, although the mRNA levels of anti-inflammatory cytokine IL-4 and IL-10 were kept unchanged in COH retinas, administration of A740003 could increase their levels. The mRNA and protein levels of Bax and cleaved caspase-3 were increased in COH retinas, which could be partially reversed by A740003, while the levels of Bcl-2 kept unchanged in COH retinas with or without the injections of A740003. Furthermore, A740003 partially attenuated the reduction in the numbers of Brn-3a-positive RGCs in COH mice. A740003 could provide neuroprotective roles on RGCs by inhibiting the microglia activation, attenuating the retinal inflammatory response, reducing the apoptosis of RGCs, and enhancing the survival of RGCs in COH experimental glaucoma., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Tolerogenic dendritic cells (TolDCs) have been evidenced to trigger regulatory T cell's (Treg's) differentiation and be involved in the pathogenesis of Crohn's disease (CD). Aryl hydrocarbon receptor (AhR) plays a crucial role in the differentiation of TolDCs, although the mechanism remains vague. This study aimed to evaluate the role of AhR in TolDCs formation, which may affect Th17/Treg balance in CD., Methods: Colon biopsy specimens were obtained from healthy controls and patients with CD. Wild type (WT) and AhR-/- mice were induced colitis by drinking dextran sulphate sodium (DSS) with or without 6-formylindolo 3,2-b carbazole (FICZ) treatment. Wild type and AhR-/- bone marrow-derived cells (BMDCs) were cultured under TolDCs polarization condition. Ratios of DCs surface markers were determined by flow cytometry. Enzyme-linked immunosorbent assay (ELISA) was performed to quantify the levels of interleukin (IL)-1β, transforming growth factor (TGF)-β and IL-10. Tolerogenic dendritic cells differentiated from BMDCs of WT or AhR-/- mice were adoptively transferred to DSS-induced WT colitis mice., Results: Patients with CD showed less AhR expression and activation in their inflamed colon regions. Compared with WT mice, AhR-/- mice experienced more severe colitis. Tolerogenic dendritic cells and Tregs were both decreased in the colon of AhR-/- colitis mice, while Th17 cells were upregulated. In vitro, compared with WT DCs, AhR-deficient DCs led to less TolDC formation. Furthermore, intestinal inflammation in WT colitis mice, which transferred with AhR-/- TolDCs, showed no obvious improvement compared with those transferred with WT TolDCs, as evidenced by no rescues of Th17/Treg balance., Conclusions: Activation of AhR attenuates experimental colitis by modulating the balance of TolDCs and Th17/Treg. The AhR modulation of TolDCs may be a viable therapeutic approach for CD., (© The Author(s) 2024. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Introduction: With multiple targeted therapies approved for anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC), it is increasingly important to understand outcomes with various sequences of next-generation ALK tyrosine kinase inhibitors (TKIs). We describe contemporary sequencing patterns and treatment effectiveness of first-line (1L) and second-line (2L) treatments in patients who received second-generation ALK TKIs in the 1L treatment of ALK-positive NSCLC in the United States., Methods: A cohort of adults with ALK-positive advanced NSCLC who initiated treatment with 1L alectinib or brigatinib between June 2017 and April 2021 in the Flatiron Health electronic health record-derived de-identified database were followed through April 2023. Time to treatment discontinuation (TTD) in 1L and 2L, TTD on 1L plus 2L sequential therapy (TTD2), and total time on sequential ALK TKI therapy (including beyond 2L) were evaluated., Results: Patients (N=273) were followed up for a median duration of 28.9 months. Among patients who discontinued 1L therapy, 22% died after 1L discontinuation (median time from discontinuation to death, 4.0 months) without receiving 2L therapy. Median (95% confidence interval [CI]) TTD was 21.9 (15.2-25.8) and 7.3 (5.3-10.2) months in 1L and 2L, respectively. Median (95% CI) TTD2 was 29.4 (25.1-36.1) months and total time on sequential ALK TKI treatment was 28.0 (23.6-32.9) months., Conclusions: In this large real-world study, TTD2 and the total time on sequential ALK TKIs was approximately 2.5 years. The high attrition rate from 1L to 2L and the longest clinical benefit observed with 1L therapy support using the drug with the longest 1L effectiveness up front in patients with ALK-positive advanced NSCLC., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Bauman reports consulting fees from EMD Serono and participation on an advisory board for BeiGene, Blueprint Medicine, Janssen, Lilly, Merck, Mirati, Pfizer, and Turning Point Therapeutics. Dr. G. Liu reports grant support from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Canadian Cancer Society Research Institute, Canadian Institute of Health Research, EMD Serono, NCI (US), Pfizer, and Takeda; honoraria from AstraZeneca, EMD Serono, Pfizer, and Takeda; and participation on an advisory board for AbbVie, AstraZeneca, Bristol Myers Squibb, EMD Serono, Jazz Pharmaceuticals, Lilly, Merck, Novartis, Pfizer, and Roche. Dr. Preeshagul reports honoraria from AstraZeneca, Bristol Myers Squibb, Dava Oncology, G1 Therapeutics, Genentech, Jazz Pharmaceuticals, Novartis, OncLive, PER, Pfizer, and Takeda and a leadership role at LCRF and ASCO. Dr. S. Liu reports funding support from Pfizer; grant support from AbbVie, Alkermes, Elevation Oncology, Ellipses, Genentech, Gilead, Merck, Merus, Nuvalent, Puma Biotechnology, RAPT Therapeutics, and Turning Point Therapeutics; consulting fees and participation on advisory boards for AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Catalyst, Daiichi Sankyo, Eisai, Elevation Oncology, Genentech/Roche, Gilead, Guardant Health, Janssen, Jazz Pharmaceuticals, Merck, Merus, Mirati, Novartis, Pfizer, Regeneron, Sanofi, Takeda, and Turning Point Therapeutics; and participation on data safety and monitoring board for Candel Therapeutics. Dr. Melosky reports honoraria from AstraZeneca, Bristol Myers Squibb, EMD Serono, Janssen, Jazz Pharmaceuticals, Merck, Novartis, Pfizer, Roche, Sanofi, and Takeda; funding support for meetings and/or travel from Janssen, Pfizer, and Sanofi; and participation on advisory boards for AstraZeneca, Bristol Myers Squibb, EMD Serono, Janssen, Jazz Pharmaceuticals, Merck, Novartis, Pfizer, Roche, Sanofi, and Takeda. Dr. Abrahami, Dr. Li, Ms. Thomaidou, and Ms. Duncan are employed by and own stocks in Pfizer. Mr. Krulewicz is employed by Pfizer and owns stock in AbbVie, Amgen, GSK, Merck, Pfizer, United Health Group, Viatris, and XLV. Dr. Rupp was employed by and owned stock in Pfizer at the time of this study. Dr. Lin has received grant support from Bayer, Elevation Oncology, Hengrui Therapeutics, Linnaeus Therapeutics, Neon Therapeutics, Novartis, Nuvalent, Relay Therapeutics, Roche, and Turning Point Therapeutics and received consulting fees from AnHeart Therapeutics, AstraZeneca, Bayer, Blueprint Medicines, Bristol Myers Squibb, C4 Therapeutics, CLaiM Therapeutics, Daiichi Sankyo, Elevation Oncology, Ellipses, Genentech, Hyku Biosciences, Merus, Mirati Therapeutics, Novartis, Nuvalent, Pfizer, Regeneron, Takeda, Turning Point Therapeutics, and Yuhan., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

We describe the synthesis of seven C2‐alkylcarbazoles via a sequence of Buchwald–Hartwig coupling of arylamines with aryl halides followed by oxidative cyclization of the resulting diarylamines. Methyl groups at the positions 4 and 5 were introduced by taking advantage of the ortho‐directed palladation of meta‐pivaloyloxy‐substituted diarylamines and subsequent conversion of the pivaloyloxy to methyl groups through Stille coupling of intermediate triflates. The obtained ethyl‐ and dimethylcarbazoles served as analytical standards for their identification in petroleum samples and source rocks. [ABSTRACT FROM AUTHOR]

The present work describes the effect of structural modification of carbazole‐based photosensitizers carrying carboxylic acid as a common anchoring functionality, on the photovoltaic parameters of newly fabricated DSSCs. In this study, we have selected our previously reported three carbazole‐based derivatives, viz. S1‐3 having different structural designs, that is, D‐π‐A (S1), D‐D‐π‐A (S2), and A‐π‐D‐π‐A (S3) with different donor units and π‐spacers, but an identical cyanoacetic acid anchoring unit. We have evaluated their optical, electrochemical, and photovoltaic behaviors in order to explore their structure‐property relationships. Also, the theoretical investigations were performed to obtain a deeper understanding of their HOMO‐LUMO levels, charge distribution in FMOs, directional flow of electrons within the push‐pull type sensitizers, and optical behavior. Finally, the DSSCs were constructed by employing these dyes as sensitizers without any co‐absorbents and the performance of the devices was evaluated by using illuminated current‐voltage characteristics. Among the tested dyes, di‐anchoring S3 exhibited improved PCE of 3.77 % due to its strong adsorption on the TiO2 surface that resulted in superior VOC of the cell. While the S2 containing electron‐releasing anisole as an auxiliary donor exhibited better JSC value leading to the optimum PCE of 3.73 % which is comparable to that of S3. Obviously, these results validate the role of the π‐spacer and additional donor of the sensitizers on the overall performance of the DSSCs. [ABSTRACT FROM AUTHOR]

The reaction of isomeric 2/3-bromomethylindoles containing masked aldehydic function with heteroarenes in the presence of Zn(OTf)2 as a catalyst in 1,2-DCE at room temperature led to the formation of benzo[b]-hetero annulated carbazoles. [ABSTRACT FROM AUTHOR]

In previous studies, the β-blocker carvedilol inhibited EGF-induced epidermal cell transformation and chemical carcinogen-induced mouse skin hyperplasia. As exposure to ultraviolet (UV) radiation leads to skin cancer, the present study examined whether carvedilol can prevent UV-induced carcinogenesis. Carvedilol absorbs UV like a sunscreen; thus, to separate pharmacological from sunscreen effects, 4-hydroxycarbazole (4-OHC), which absorbs UV to the same degree as carvedilol, served as control. JB6 P+ cells, an established epidermal model for studying tumor promotion, were used for evaluating the effect of carvedilol on UV-induced neoplastic transformation. Both carvedilol and 4-OHC (1 mM) blocked transformation induced by chronic UV (15 mJ/cm(2)) exposure for eight weeks. However, EGF-mediated transformation was only inhibited by carvedilol but not by 4-OHC. Carvedilol (1 and 5 mM), but not 4-OHC, attenuated UV-induced AP-1 and NF-kB luciferase reporter activity, suggesting a potential anti-inflammatory activity. In a single dose UV (200 mJ/cm(2)) induced skin inflammation mouse model, carvedilol (10 mM), applied topically after UV exposure, reduced skin hyperplasia and the levels of cyclobutane pyrimidine dimers, IL-1β, IL-6, and COX-2 in skin. In SKH-1 mice exposed to gradually increasing levels of UV (50-150 mJ/cm(2)) three times a week for 25 weeks, topical administration of carvedilol (10 mM) after UV exposure increased tumor latency compared with control (week 18 vs. 15), decreased incidence and multiplicity of squamous cell carcinomas, while 4-OHC had no effect.  These data suggest that carvedilol has a novel chemopreventive activity and topical carvedilol following UV exposure may be repurposed for preventing skin inflammation and cancer.

Using compounded multidose vials (cMDV) is a common practice in the laboratory animal setting, where medications often are diluted to provide appropriate doses to rodents. However, bacterial contamination of MDV has been well established in both the human and veterinary medical literature. For this study, we created 14 cMDV by diluting carprofen into sterile water (dilution, 1:10) and stored 6 cMDV each at 5 and 24 °C. The stoppers of the cMDV were not cleaned with alcohol, and all were punctured twice daily for 28 d. The sterility of the diluted carprofen was evaluated by assessing bacterial growth on days 0, 7, 14, 21, and 28 and by testing for bacterial endotoxin on days 0 and 28. We used liquid chromatography-tandem mass spectrometry to assess the stability of 2 cMDV, with each cMDV being divided into the 2 storage-temperature subsets for days 0, 7, 14, 21, and 28. Neither bacterial contamination nor endotoxin was detected, and drug stability was stable over the 28 d. We suggest that with pragmatic techniques, such as secondary containment and consistent use of new needles, the contents of cMDV can remain sterile and stable for 28 d.

Currently, it is not well understood how ligands of the aryl hydrocarbon receptor (AhR) modify inflammatory responses triggered by Toll-like receptor (TLR) agonists in human dendritic cells (DCs). Here, we show that AhR ligands 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the tryptophan derivatives 6-formylindolo[3,2-b] carbazole (FICZ), kynurenine (kyn), and the natural dietary compound indole-3-carbinol (I3C) differentially modify cytokine expression in human monocyte-derived DCs (MoDCs). The results show that TLR-activated MoDCs express higher levels of AhR and are more sensitive toward the effects of AhR ligands. Depending on the cytokine, treatment with AhR ligands led to a synergistic or antagonistic effect of the TLR-triggered response in MoDCs. Thus, activation of AhR increased the expression of interleukin (IL)-1β, but decreased the expression of IL-12A in TLR-activated MoDCs. Furthermore, TCDD and FICZ may have opposite effects on the expression of cytochrome P4501A1 (CYP1A1) in TLR8-activated MoDCs indicating that the effect of the specific AhR ligand may depend on the presence of the specific TLR agonist. Gene silencing showed that synergistic effects of AhR ligands on TLR-induced expression of IL-1β require a functional AhR and the expression of NF-κB RelB. On the other hand, repression of IL-12A by TCDD and FICZ involved the induction of the caudal type homeobox 2 (CDX2) transcription factor. Additionally, the levels of DC surface markers were decreased in MoDCs by TCDD, FICZ and I3C, but not by kyn. Overall, these data demonstrate that AhR modulates TLR-induced expression of cytokines and DC-specific surface markers in MoDCs involving NFκB RelB and the immune regulatory factor CDX2.

BackgroundType 2 diabetes mellitus (DM) and obesity independently increase the risk of heart failure by incompletely understood mechanisms. We propose that hyperinsulinemia might promote adverse consequences in the hearts of subjects with type-2 DM and obesity.MethodsHigh-fat diet feeding was used to induce obesity and DM in wild-type mice or mice lacking β2-adrenergic receptor (β2AR) or β-arrestin2. Wild-type mice fed with high-fat diet were treated with a β-blocker carvedilol or a GRK2 (G-protein-coupled receptor kinase 2) inhibitor. We examined signaling and cardiac contractile function.ResultsHigh-fat diet feeding selectively increases the expression of phosphodiesterase 4D (PDE4D) in mouse hearts, in concert with reduced protein kinase A phosphorylation of phospholamban, which contributes to systolic and diastolic dysfunction. The expression of PDE4D is also elevated in human hearts with DM. The induction of PDE4D expression is mediated by an insulin receptor, insulin receptor substrate, and GRK2 and β-arrestin2-dependent transactivation of a β2AR-extracellular regulated protein kinase signaling cascade. Thus, pharmacological inhibition of β2AR or GRK2, or genetic deletion of β2AR or β-arrestin2, all significantly attenuate insulin-induced phosphorylation of extracellular regulated protein kinase and PDE4D induction to prevent DM-related contractile dysfunction.ConclusionsThese studies elucidate a novel mechanism by which hyperinsulinemia contributes to heart failure by increasing PDE4D expression and identify β2AR or GRK2 as plausible therapeutic targets for preventing or treating heart failure in subjects with type 2 DM.