Divergent Synthesis of 5,7-Diazaullazines Derivatives through a Combination of Cycloisomerization with Povarov or Alkyne-Carbonyl Metathesis.

Ullazines and their π-expanded derivatives have gained much attention as active components in various applications, such as in organic photovoltaic cells or as photosensitizers for CO2 photoreduction. Here, we report the divergent synthesis of functionalized diazaullazines by means of two different domino-reactions consisting of either a Povarov/cycloisomerization or alkyne-carbonyl metathesis/cycloisomerization protocol. The corresponding quinolino-diazaullazine and benzoyl-diazaullazine derivatives were obtained in moderate to good yields. Their optical and electronic properties were studied and compared to related, literature-known compounds to obtain insights into the impact of nitrogen doping and π-expansion.

Synthesis and properties of 6-alkynyl-5-aryluracils.

The development of a new and straightforward chemoselective method for the synthesis of uracil-based structures by combining Suzuki-Miyaura and Sonogashira-Hagihara cross-coupling is reported. The methodology was applied to synthesize a series of novel compounds. The tolerance of the combination of different functional groups was tested. The influence of different functional groups on the physical properties was studied by ultraviolet-visible (UV-vis) and fluorescence spectroscopy, providing new insights into the potential applications of uracil-based structures.

Daratumumab and antineoplastic therapy versus antineoplastic therapy only for adults with newly diagnosed multiple myeloma ineligible for transplant.

BACKGROUND: Multiple myeloma (MM) is a haematological malignancy that is characterised by proliferation of malignant plasma cells in the bone marrow. For adults ineligible to receive high-dose chemotherapy and autologous stem cell transplant, the recommended treatment combinations in first-line therapy generally consist of combinations of alkylating agents, immunomodulatory drugs, and proteasome inhibitors. Daratumumab is a CD38-targeting, human IgG1k monoclonal antibody recently developed and approved for the treatment of people diagnosed with MM. Multiple myeloma cells uniformly over-express CD-38, a 46-kDa type II transmembrane glycoprotein, making myeloma cells a specific target for daratumumab. OBJECTIVES: To determine the benefits and harms of daratumumab in addition to antineoplastic therapy compared to antineoplastic therapy only for adults with newly diagnosed MM who are ineligible for transplant. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, EU Clinical Trials Register, ClinicalTrials.gov, WHO ICTRP, and conference proceedings from 2010 to September 2023. SELECTION CRITERIA: We included randomised controlled trials that compared treatment with daratumumab added to antineoplastic therapy versus the same antineoplastic therapy alone in adult participants with a confirmed diagnosis of MM. We excluded quasi-randomised trials and trials with less than 80% adult participants, unless there were subgroup analyses of adults with MM. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the results of the search strategies for eligibility. We documented the process of study selection in a flowchart as recommended by the PRISMA statement. We evaluated the risk of bias in included studies with RoB 1 and assessed the certainty of the evidence using GRADE. We followed standard Cochrane methodological procedures. MAIN RESULTS: We included four open-label, two-armed randomised controlled trials (34 publications) involving a total of 1783 participants. The ALCYONE, MAIA, and OCTANS trials were multicentre trials conducted worldwide in middle- and high-income countries. The AMaRC 03-16 trial was conducted in one high-income country, Australia. The mean age of participants was 69 to 74 years, and the proportion of female participants was between 40% and 54%. All trials evaluated antineoplastic therapies with or without daratumumab. In the ALCYONE and OCTANS trials, daratumumab was combined with bortezomib and melphalan-prednisone. In the AMaRC 03-16 study, it was combined with bortezomib, cyclophosphamide, and dexamethasone, and in the MAIA study, it was combined with lenalidomide and dexamethasone. None of the included studies was blinded (high risk of performance and detection bias). One study was published as abstract only, therefore the risk of bias for most criteria was unclear. The other three studies were published as full texts. Apart from blinding, the risk of bias was low for these studies. Overall survival Treatment with daratumumab probably increases overall survival when compared to the same treatment without daratumumab (hazard ratio (HR) 0.64, 95% confidence interval (CI) 0.53 to 0.76, 2 studies, 1443 participants, moderate-certainty evidence). After a follow-up period of 36 months, 695 per 1000 participants survived in the control group, whereas 792 per 1000 participants survived in the daratumumab group (95% CI 758 to 825). Progression-free survival Treatment with daratumumab probably increases progression-free survival when compared to treatment without daratumumab (HR 0.48, 95% CI 0.39 to 0.58, 3 studies, 1663 participants, moderate-certainty evidence). After a follow-up period of 24 months, progression-free survival was reached in 494 per 1000 participants in the control group versus 713 per 1000 participants in the daratumumab group (95% CI 664 to 760). Quality of life Treatment with daratumumab may result in a very small increase in quality of life after 12 months, evaluated on the EORTC QLQ-C30 global health status scale (GHS), when compared to treatment without daratumumab (mean difference 2.19, 95% CI -0.13 to 4.51, 3 studies, 1096 participants, low-certainty evidence). The scale is from 0 to 100, with a higher value indicating a better quality of life. On-study mortality Treatment with daratumumab probably decreases on-study mortality when compared to treatment without daratumumab (risk ratio (RR) 0.72, 95% CI 0.62 to 0.83, 3 studies, 1644 participants, moderate-certainty evidence). After the longest follow-up available (12 to 72 months), 366 per 1000 participants in the control group and 264 per 1000 participants in the daratumumab group died (95% CI 227 to 304). Serious adverse events Treatment with daratumumab probably increases serious adverse events when compared to treatment without daratumumab (RR 1.18, 95% CI 1.02 to 1.37, 3 studies, 1644 participants, moderate-certainty evidence). After the longest follow-up available (12 to 72 months), 505 per 1000 participants in the control group versus 596 per 1000 participants in the daratumumab group experienced serious adverse events (95% CI 515 to 692). Adverse events (Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 3) Treatment with daratumumab probably results in little to no difference in adverse events (CTCAE grade ≥ 3) when compared to treatment without daratumumab (RR 1.01, 95% CI 0.99 to 1.02, 3 studies, 1644 participants, moderate-certainty evidence). After the longest follow-up available (12 to 72 months), 953 per 1000 participants in the control group versus 963 per 1000 participants in the daratumumab group experienced adverse events (CTCAE grade ≥ 3) (95% CI 943 to 972). Treatment with daratumumab probably increases the risk of infections (CTCAE grade ≥ 3) when compared to treatment without daratumumab (RR 1.52, 95% CI 1.30 to 1.78, 3 studies, 1644 participants, moderate-certainty evidence). After the longest follow-up available (12 to 72 months), 224 per 1000 participants in the control group versus 340 per 1000 participants in the daratumumab group experienced infections (CTCAE grade ≥ 3) (95% CI 291 to 399). AUTHORS' CONCLUSIONS: Overall analysis of four studies showed a potential benefit for daratumumab in terms of overall survival and progression-free survival and a slight potential benefit in quality of life. Participants treated with daratumumab probably experience increased serious adverse events. There were likely no differences between groups in adverse events (CTCAE grade ≥ 3); however, there are probably more infections (CTCAE grade ≥ 3) in participants treated with daratumumab. We identified six ongoing studies which might strengthen the certainty of evidence in a future update of this review.

π-Expanded azaullazines: synthesis of quinolino-azaullazines by Povarov reaction and cycloisomerisation.

Doping and extension of polycyclic aromatic hydrocarbons (PAHs) by simple and efficient synthetic methods is of increased demand for the development of novel and improved organic electronics. Diarylindolizino[6,5,4,3-ija]quinolino[2,3-c][1,6]naphthyridines (quinolino-azaullazines) were prepared by combination of Pd catalyzed cross-coupling with Povarov and cycloisomerisation reactions. The products contain an electron-rich ullazine and an electron-poor quinoline moiety and show intramolecular charge transfer properties that can be tuned by the substitution pattern. The optical properties were studied experimentally and further elaborated by (TD)DFT calculations.

Synthesis and Properties of 4- and 10-Benzoyl-1-azapyrenes.

A series of 4- and 10-benzoyl-1-azapyrenes were prepared by a combination of Pd-catalyzed cross-coupling reactions and Brønsted-acid-mediated alkyne-carbonyl-metathesis (ACM). The photophysical and electrochemical properties of the products were studied and compared to theoretical results.

Synthesis and Properties of 5,7-Diazaullazines.

Hitherto unknown 5,8-substituted-pyrimido[4,5,6-ij]pyrrolo[2,1,5-de]quinolizines (5,7-diazaullazines) were prepared by a three-step synthesis via Clauson-Kaas, Sonogashira, and cycloisomerization reactions with diverse functionalization. The properties, including cyclovoltammetry and UV-vis and fluorescence spectroscopy, as well as solvatochromism, were studied for selected derivatives and supported by density functional theory calculations. Results were compared in detail with previously reported 5- and 6-azaullazines, and the impact of introduced nitrogen atoms was analyzed.

Dibenzoindolo[1,8]naphthyridines: Synthesis and Characterization of X-Shaped Aza[4,6]helicenes.

This report describes a one-pot multi-step procedure to obtain double azahelicenes via nucleophilic fluorine substitution of 2,2-di(2-bromophenyl)-1,1-difluoroalkenes and palladium-catalysed ring closing reaction. The developed synthesis approach allows easy diversification of substituents at all four fragments of the obtained X-shaped aza[4,6]helicene entity. Yields range from 20 % to 60 % among 12 product examples. X-ray single crystal analysis reveals formation of (P,P) and (M,M) enantiomer mixture of products. Optical and electrochemical properties of selected products were studied by performing UV/Vis absorption, photoluminescence and cyclic voltammetry measurements. Experimental results are supported by (TD)-DFT, NICS and NICS2BC calculations.

Synergistic effect of cold gas plasma and experimental drug exposure exhibits skin cancer toxicity in vitro and in vivo.

INTRODUCTION: Skin cancer is often fatal, which motivates new therapy avenues. Recent advances in cancer treatment are indicative of the importance of combination treatments in oncology. Previous studies have identified small molecule-based therapies and redox-based technologies, including photodynamic therapy or medical gas plasma, as promising candidates to target skin cancer. OBJECTIVE: We aimed to identify effective combinations of experimental small molecules with cold gas plasma for therapy in dermato-oncology. METHODS: Promising drug candidates were identified after screening an in-house 155-compound library using 3D skin cancer spheroids and high content imaging. Combination effects of selected drugs and cold gas plasma were investigated with respect to oxidative stress, invasion, and viability. Drugs that had combined well with cold gas plasma were further investigated in vascularized tumor organoids in ovo and a xenograft mouse melanoma model in vivo. RESULTS: The two chromone derivatives Sm837 and IS112 enhanced cold gas plasma-induced oxidative stress, including histone 2A.X phosphorylation, and further reduced proliferation and skin cancer cell viability. Combination treatments of tumor organoids grown in ovo confirmed the principal anti-cancer effect of the selected drugs. While one of the two compounds exerted severe toxicity in vivo, the other (Sm837) resulted in a significant synergistic anti-tumor toxicity at good tolerability. Principal component analysis of protein phosphorylation profiles confirmed profound combination treatment effects in contrast to the monotherapies. CONCLUSION: We identified a novel compound that, combined with topical cold gas plasma-induced oxidative stress, represents a novel and promising treatment approach to target skin cancer.

Pyrene-bridged acenaphthenes: synthesis and properties of a diacenaphtho[1,2-e:1',2'-l]pyrene and its symmetrical nitrogen analogue.

The considerable need for novel polyaromatic hydrocarbons (PAHs) for applications in the area of organic electronics remains unchanged. Diacenaphthopyrene represents a new PAH consisting of two acenaphthylene units connected by a pyrene bridge. The system is built up by Pd-catalyzed cross-coupling, followed by acid catalyzed cyclosiomerization to generate the pyrene moiety. The new fused scaffold is formed in the last step in convincing yields by means of CH-activation. We additionally synthesized one aza-pyrene based analogue. The two hitherto unknown PAHs were investigated in detail by UV-Vis and PL spectroscopy, CV measurements and DFT calculations. Based on these results, the abilities of the novel structure as well as the effect of incorporation of nitrogen were evaluated.

Exploring Thiazolopyridine AV25R: Unraveling of Biological Activities, Selective Anti-Cancer Properties and In Silico Target and Binding Prediction in Hematological Neoplasms.

Thiazolopyridines are a highly relevant class of small molecules, which have previously shown a wide range of biological activities. Besides their anti-tubercular, anti-microbial and anti-viral activities, they also show anti-cancerogenic properties, and play a role as inhibitors of cancer-related proteins. Herein, the biological effects of the thiazolopyridine AV25R, a novel small molecule with unknown biological effects, were characterized. Screening of a set of lymphoma (SUP-T1, SU-DHL-4) and B- acute leukemia cell lines (RS4;11, SEM) revealed highly selective effects of AV25R. The selective anti-proliferative and metabolism-modulating effects were observed in vitro for the B-ALL cell line RS4;11. Further, we were able to detect severe morphological changes and the induction of apoptosis. Gene expression analysis identified a large number of differentially expressed genes after AV25R exposure and significant differentially regulated cancer-related signaling pathways, such as VEGFA-VEGFR2 signaling and the EGF/EGFR pathway. Structure-based pharmacophore screening approaches using in silico modeling identified potential biological AV25R targets. Our results indicate that AV25R binds with several proteins known to regulate cell proliferation and tumor progression, such as FECH, MAP11, EGFR, TGFBR1 and MDM2. The molecular docking analyses indicates that AV25R has a higher binding affinity compared to many of the experimentally validated small molecule inhibitors of these targets. Thus, here we present in vitro and in silico analyses which characterize, for the first time, the molecular acting mechanism of AV25R, including cellular and molecular biologic effects. Additionally, this predicted the target binding of the molecule, revealing a high affinity to cancer-related proteins and, thus, classified AVR25 for targeted intervention approaches.

[1, 8]-Naphthyridine derivatives as dual inhibitor of alkaline phosphatase and carbonic anhydrase.

[1,8]-Naphthyridine derivatives have been reported to possess important biological activities and may serve as attractive pharmacophores in the drug discovery process. [1,8]-Naphthyridine derivatives (1a-1l) were evaluated for inhibitory potential for isozymes of carbonic anhydrase (CA) and alkaline phosphatase (ALP). CAs have been reported to carry out reversible hydration of CO2 into HCO3-, secretion of electrolytes, acid-base regulation, bone resorption, calcification, and biosynthetic reactions. Whereas ALPs hydrolyze monophosphate esters with the release of inorganic phosphate and play an important role in bone mineralization. Both enzymes have been found to be over-expressed and raised functional activities in patients suffering from rheumatoid arthritis. The discovery of dual inhibitors of these enzymes may provide a synergistic effect to cure bone disorders such as rheumatoid arthritis and ankylosing spondylitis. Among the test compounds, the most potent inhibitors for CA-II, CA-IX, and CA-XII were 1e, 1g, and 1a with IC50 values of 0.44 ± 0.19, 0.11 ± 0.03 and 0.32 ± 0.07 µM, respectively. [1,8]-Naphthyridine derivatives (1a-1l) were approximately 4 folds more potent than standard CA inhibitor acetazolamide. While in the case of ALPs, the most potent compounds for b-TNAP and c-IAP were 1b and 1e with IC50 values of 0.122 ± 0.06 and 0.107 ± 0.02 µM, respectively. Thus, synthesized derivatives proved to be 100 to 800 times more potent as compared to standard inhibitors of b-TNAP and c-IAP (Levamisole and L-phenyl alanine, respectively). In addition, selectivity and dual inhibition of [1,8]-Naphthyridine derivatives confer precedence over known inhibitors. Molecular docking and molecular simulation studies were also conducted in the present studies to define the type of interactions between potential inhibitors and enzyme active sites.

A Thia-Analogous Indirubin N-Glycoside Disrupts Mitochondrial Function and Causes the Death of Human Melanoma and Cutaneous Squamous Cell Carcinoma Cells.

Skin cancer is the most common malignant disease worldwide and, therefore, also poses a challenge from a pharmacotherapeutic perspective. Derivatives of indirubin are an interesting option in this context. In the present study, the effects of 3-[3'-oxo-benzo[b]thiophen-2'-(Z)-ylidene]-1-(ß-d-glucopyranosyl)-oxindole (KD87), a thia-analogous indirubin N-glycoside, on the viability and mitochondrial properties of melanoma (A375) and squamous cell carcinoma cells (A431) of the skin were investigated. In both cell lines, KD87 caused decreased viability, the activation of caspases-3 and -7, and the inhibition of colony formation. At the mitochondrial level, a concentration-dependent decrease in both the basal and ATP-linked oxygen consumption rate and in the reserve capacity of oxidative respiration were registered in the presence of KD87. These changes were accompanied by morphological alterations in the mitochondria, a release of mitochondrial cytochrome c into the cytosol and significant reductions in succinate dehydrogenase complex subunit B (SDHB, subunit of complex II) in A375 and A431 cells and NADH:ubiquinone oxidoreductase subunit B8 (NDUFB8, subunit of complex I) in A375 cells. The effect of KD87 was accompanied by a significant upregulation of the enzyme heme oxygenase-1, whose inhibition led to a partial but significant reduction in the metabolic-activity-reducing effect of KD87. In summary, our data show a mitochondria-targeting effect of KD87 as part of the cytotoxic effect of this compound on skin cancer cells, which should be considered in future studies with this class of compounds.

Synthesis and Properties of Carbo- and Heterocyclic Benz[a]azulenes.

A new and convenient synthesis of aryl-substituted naphtho[2,1-a]azulenes by the combination of Suzuki-Miyaura, Sonogashira, and cycloisomerization reactions is reported. The methodology was applied to the synthesis of hitherto unknown azuleno[1,2-h]quinolines, cyclohepta[1,2]indeno[4,5-b]thiophenes, and cyclohepta[1,2]indeno[4,5-c]thiophenes. The impact of different fused-heterocyclic rings on the photophysical and electrochemical properties of these azulene derivatives was studied by experimental and theoretical methods and hence provides a rationale for the preparation of novel azulene derivatives with improved properties for application as organic materials.

Synthesis and Properties of 5-Azaullazines.

5-Azaullazines, indolizino[6,5,4,3-ija][1,5]naphthyridines, and their benzo-fused analogues were prepared in three steps by combination of Pd catalyzed cross-coupling reactions with Brønsted acid mediated cycloisomerisations. The reaction tolerates various substitution patterns and functional groups and proceeds in high yields. Optical and electrochemical properties of selected products were studied experimentally and by DFT calculations.

Synthesis and Properties of Thieno[2',3',4':4,5]naphtho[1,8-cd]pyridines.

Thieno[2',3',4':4,5]naphtho[1,8-cd]pyridines, S,N-doped pyrene analogs, were prepared by combination of Pd catalyzed cross-coupling reactions and acid-mediated cycloisomerization. The modular scope of the synthesis allowed for access to a variety of functionalized derivatives. The photophysical properties have been studied in detail by steady-state and femtosecond transient absorption accompanied by cyclic voltammetry and (TD)-DFT calculations. The introduction of a five-membered thiophene into the 2-azapyrene scaffold leads to redshifted emission and substantial effects on the excited state dynamics, e.g., quantum yield, lifetime, decay rates, and the ISC ability, which can be further tuned by the substitution pattern of the heterocyclic scaffold.

Synthesis, structure-activity relationships and biological evaluation of benzimidazole derived sulfonylurea analogues as a new class of antagonists of P2Y1 receptor.

The P2Y receptors are responsible for the regulation of various physiological processes including neurotransmission and inflammatory responses. These receptors are also considered as novel potential therapeutic targets for prevention and treatment of thrombosis, neurological disorders, pain, cardiac diseases and cancer. Previously, number of P2Y receptor antagonists has been investigated but they are less potent and non-selective with poor solubility profile. Herein, we present the synthesis of new class of benzimidazole derived sulfonylureas (1a-y) as potent antagonists of P2Y receptors, with the specific aim to explore selective antagonists of P2Y1 receptors. The efficacy and selectivity of the synthesized derivatives 1) against four P2Y receptors i.e., t-P2Y1, h-P2Y2, h-P2Y4, and r-P2Y6Rs was carried out by calcium mobilization assay. The results revealed that except 1b, 1d, 1l, 1m, 1o, 1u, 1v, 1w, and 1y, rest of the synthesized derivatives exhibited moderate to excellent inhibitory potential against P2Y1 receptors. Among the potent antagonists, derivative 1h depicted the maximum inhibition of P2Y1 receptor in calcium signalling assay, with an IC50 value of 0.19 ± 0.04 µM. The potential of inhibition was validated by computational investigations where bonding and non-bonding interactions between ligand and targeted receptor further strengthen the study. The best identified derivative 1h revealed the same binding mechanism as that of already reported selective antagonist of P2Y1 receptor i.e (1-(2- (2-tert-butyl-phenoxy) pyridin-3-yl)-3-4-(trifluoromethoxy) phenylurea but the newly synthesized derivative exhibited better solubility profile. Hence, this derivative can be used as lead candidate for the synthesis of more potential antagonist with much better solubility profile and medicinal importance.

Synthesis and Properties of Benzo[h]imidazo[1,2-a]quinolines and 1,2a-Diazadibenzo[cd,f]azulenes.

Benzo[h]imidazo[1,2-a]quinolines and 1,2a-diazadibenzo[cd,f]azulenes were prepared from a common intermediate by regioselective cycloisomerization reactions. The selectivity was controlled by the choice of Brønsted acid and solvent. The optical and electrochemical properties of the products were studied by UV/vis, fluorescence, and cyclovoltammetric measurements. The experimental results were complemented by density functional theory calculations.

Thienoindolizines and their Benzo-Fused Derivatives: Synthesis and Physical Properties.

A series of thienoindolizine structural isomers have been synthesized in a one-pot, two-step procedure starting from easily accessible gem-difluoroalkene functionalized bromothiophenes. The developed method gives easy access to a range of thienoindolizine products containing thieno[3,2-g]-, thieno[3,4-g]- and thieno[2,3-g]indolizine core structures. The described synthesis strategy consists of a base mediated, transition metal free nucleophilic substitution of fluorine atoms by nitrogen containing heterocycles followed by a Pd catalyzed intramolecular cyclization. A series of 22 final product examples has been obtained with yields ranging from 29 % to 95 %. UV/Vis absorption, fluorescence spectroscopy, fluorescence lifetime measurements and cyclic voltammetry were carried out with selected final products to evaluate structural effects on photophysical and electrochemical properties. (TD)DFT and NICS calculations were performed to provide insight into the electronic properties of the four core molecular structures.

Dibenzoacridines: synthesis by alkyne-carbonyl-metathesis and properties.

Dibenzo[a,j]acridines and regioisomeric dibenzo[c,h]acridines were synthesized from a common starting material, 2,3,5,6-tetrachloropyridine, by combination of site-selective cross-coupling reaction followed by ring-closing alkyne-carbonyl metathesis using simple Brønsted acids. The two regioisomeric series were accessed by change of the order of Sonogashira and Suzuki-Miyaura reactions. The optical properties of the products were studied by steady-state absorption spectroscopy and time-resolved emission measurements. The electronic properties of the products were further elucidated by DFT calculations.

Marine Bacteroidetes enzymatically digest xylans from terrestrial plants.

Marine Bacteroidetes that degrade polysaccharides contribute to carbon cycling in the ocean. Organic matter, including glycans from terrestrial plants, might enter the oceans through rivers. Whether marine bacteria degrade structurally related glycans from diverse sources including terrestrial plants and marine algae was previously unknown. We show that the marine bacterium Flavimarina sp. Hel_I_48 encodes two polysaccharide utilization loci (PULs) which degrade xylans from terrestrial plants and marine algae. Biochemical experiments revealed activity and specificity of the encoded xylanases and associated enzymes of these PULs. Proteomics indicated that these genomic regions respond to glucuronoxylans and arabinoxylans. Substrate specificities of key enzymes suggest dedicated metabolic pathways for xylan utilization. Some of the xylanases were active on different xylans with the conserved ß-1,4-linked xylose main chain. Enzyme activity was consistent with growth curves showing Flavimarina sp. Hel_I_48 uses structurally different xylans. The observed abundance of related xylan-degrading enzyme repertoires in genomes of other marine Bacteroidetes indicates similar activities are common in the ocean. The here presented data show that certain marine bacteria are genetically and biochemically variable enough to access parts of structurally diverse xylans from terrestrial plants as well as from marine algal sources.