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Chemical modifications of quinoline moiety have been recognized as a useful strategy to development of new drugs. Here, the cytotoxicity of a set of twenty-four 4-substituted ...quinolines (named HTI) was screened for their antitumor and antileishmanial potential in vitro, and the underlying mechanisms investigated. HTI 21 and HTI 22 exhibited the highest cytotoxicity, being selected to the subsequent studies. Both derivatives induced caspase-dependent apoptosis associated to the dissipation of the mitochondrial transmembrane potential (ΔΨ) and ROS generation. HTI-induced cell death was calcium dependent, associated to thiol oxidation and cysteine proteases activation. In isolated mitochondria, HTI derivatives promoted mitochondrial permeabilization by different mechanisms. The inhibition of BCL-2 by venetoclax enhanced the HTI-induced cytotoxicity. Regarding the inhibition of cysteine proteases type B of Leishmania mexicana, HTI 15 exhibited the most potent inhibitory activity through a linear non-competitive mechanism. These data highlight the therapeutic potential of 4-substituted quinolines as antitumor and antileishmanial drugs.
The synthesis of C‐glycosides is of great importance in the field of carbohydrate chemistry given its ubiquity in biologically active molecules. Herein, we describe a protocol for the Pd‐catalyzed ...carbonylative Heck reaction of activated olefins and 2‐iodoglycals. A variety of α,β‐unsaturated 2‐ketoglycosides were obtained in up to 89 % yield using d‐glucal, d‐galactal, d‐xylal, and l‐arabinal derivatives.
The synthesis of biologically relevant C‐ketoglycosides, found in many important natural products and medicinally active molecules is reported. This strategy allows to connect a series of glycal units to activated olefins via the Pd‐catalyzed carbonylative Heck cross‐coupling reaction.
Since the development of the Ullmann coupling in the early 20th Century, there has been intense and continuous research on the syntheses of biaryl compounds, which appears as an interesting branch of ...organic chemistry.
A myriad of methodologies for the synthesis of biaryl compounds have been studied and well established, including homocoupling methodologies, which in general are robust as well as consolidated strategies. Biaryl systems are quite relevant building blocks for the synthesis of more complex chemical structures. Besides the diversity of functional groups that can be used to promote a new aryl-aryl bond, there is a wide variety of transition metals that can act as catalyst in these processes.
In this review, we summarized numerous methodologies of homocoupling reactions for the synthesis of symmetrical biaryl compounds.
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The joint disease called pararamosis is an occupational disease caused by accidental contact with bristles of the caterpillar Premolis semirufa. The chronic inflammatory process narrows the joint ...space and causes alterations in bone structure and cartilage degeneration, leading to joint stiffness. Aiming to determine the bristle components that could be responsible for this peculiar envenomation, in this work we have examined the toxin composition of the caterpillar bristles extract and compared it with the differentially expressed genes (DEGs) in synovial biopsies of patients affected with rheumatoid arthritis (RA) and osteoarthritis (OA). Among the proteins identified, 129 presented an average of 63% homology with human proteins and shared important conserved domains. Among the human homologous proteins, we identified seven DEGs upregulated in synovial biopsies from RA or OA patients using meta-analysis. This approach allowed us to suggest possible toxins from the pararama bristles that could be responsible for starting the joint disease observed in pararamosis. Moreover, the study of pararamosis, in turn, may lead to the discovery of specific pharmacological targets related to the early stages of articular diseases.
The carbonylative cross‐coupling reactions of 2‐iodoglycals with thiols and selenols in the presence of molybdenum hexacarbonyl as a solid source of carbon monoxide is described. This methodology ...permitted the synthesis of 29 C2‐glycosides bearing thioester and selenoester functionalities in moderate to excellent yields and high functional group tolerance. Moreover, this communication describes the first catalytic carbonylative coupling reaction of selenols with a carbon electrophile.
Are you in a rush? Carbonylative cross‐coupling reactions of 2‐iodoglycals with thiols (RSH) and selenols (RSeH) in the presence of molybdenum hexacarbonyl as a solid source of carbon monoxide is described. A useful methodology for the synthesis of chalcogen‐containing C2‐glycosides with high functional group tolerance.
The iron(III)‐promoted synthesis of densely‐substituted 4H‐chalcogenchromene from organochalcogen propargylamines in the presence of diaryl dichalcogenides is reported. Subsequent ...C2‐functionalization with electrophiles and potassium trifluoroborate salts via Suzuki‐Miyaura coupling reaction are also presented. A plausible mechanism based on HRMS experiments is proposed and discussed.
COVID-19 has affected more than half a billion people worldwide, with more than 6.3 million deaths, but the pathophysiological mechanisms involved in lethal cases and the host determinants that ...determine the different clinical outcomes are still unclear. In this study, we assessed lung autopsies of 47 COVID-19 patients and examined the inflammatory profiles, viral loads, and inflammasome activation. Additionally, we correlated these factors with the patient’s clinical and histopathological conditions. Robust inflammasome activation was detected in the lungs of lethal cases of SARS-CoV-2. Experiments conducted on transgenic mice expressing hACE2 and infected with SARS-CoV-2 showed that Nlrp3 -/- mice were protected from disease development and lethality compared to Nlrp3 +/+ littermate mice, supporting the involvement of this inflammasome in disease exacerbation. An analysis of gene expression allowed for the classification of COVID-19 patients into two different clusters. Cluster 1 died with higher viral loads and exhibited a reduced inflammatory profile than Cluster 2. Illness time, mechanical ventilation time, pulmonary fibrosis, respiratory functions, histopathological status, thrombosis, viral loads, and inflammasome activation significantly differed between the two clusters. Our data demonstrated two distinct profiles in lethal cases of COVID-19, thus indicating that the balance of viral replication and inflammasome-mediated pulmonary inflammation led to different clinical outcomes. We provide important information to understand clinical variations in severe COVID-19, a process that is critical for decisions between immune-mediated or antiviral-mediated therapies for the treatment of critical cases of COVID-19.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
1,2,3-Triazole-, arylamino- and thio-substituted naphthoquinones (24, 8, and 2 representatives, respectively) were synthesized in moderate yields and evaluated against several human cancer cell lines ...(blood, ovarian, breast, central nervous system, colon, and prostate cancers and melanoma), showing, for some of them, IC50 values below 2μM. The cytotoxic potential of the tested naphthoquinones was also assayed on non-tumor cells such as human peripheral blood mononucluear cells (PBMC) and two murine fibroblast lines (L929 and V79 cells). α-Lapachone- and nor-α-lapachone-based 1,2,3-triazoles and arylamino-substituted naphthoquinones showed potent cytotoxicity against different cancer cell lines. The compounds may represent promising new lead derivatives for anticancer drug development. The electrochemical properties of selected compounds were evaluated in an attempt to correlate them with antitumor activity.
The synthesis of amidoglucals and glucal esters in good to high yields using 2-iodo-3,4,6-tri- O -acetyl- d -glucal as a substrate, Mo(CO) 6 as a carbon monoxide source and PdCl 2 as a catalyst is ...reported. This procedure shows advantages when compared to other published methodologies, as it is carried out in one pot relying on short reaction times at mild temperatures, under ligand-free conditions and with only one equivalent of Mo(CO) 6 .
A mild stereo‐ and regioselective Cu‐catalyzed hydroboration method for the synthesis of (Z)‐seleno‐alkenyl boronates and (Z)‐thio‐alkenylboronates from internal alkynes in the presence of ...commercially available B2pin2 is presented. This highly selective transformation relies on the use of N‐heterocyclic carbene (NHC) complex IPrCuCl as the active catalytic species. We also explore the functionalization of the alkenylboronates obtained via oxidation to give α‐chalcogeno ketones, useful building blocks for the synthesis of more complex chalcogen‐containing molecules.
Selective hydroboration: A mild stereo‐ and regioselective Cu‐catalyzed hydroboration method for the synthesis of (Z)‐seleno‐alkenyl boronates and (Z)‐thio‐alkenylboronates from internal alkynes in the presence of commercially available B2pin2 is presented. This highly selective transformation relies on the use of N‐heterocyclic carbene (NHC) complex IPrCuCl as the active catalytic species. We also explore the functionalization of the alkenylboronates obtained via oxidation to give α‐chalcogeno ketones, useful building blocks for the synthesis of more complex chalcogen‐containing molecules.
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