Search results for "molecular medicine"
showing 10 items of 3013 documents
Bistacrine derivatives as new potent antimalarials
2016
Linking two tacrine molecules results in a tremendous increase of activity against Plasmodia in comparison to the monomer. This finding prompted the synthesis of a library of monomeric and dimeric tacrine derivatives in order to derive structure-activity relationships. The most active compounds towards chloroquine sensitive Plasmodium strain 3D7 and chloroquine resistant strain Dd2 show IC50 values in the nanomolar range of concentration, low cytotoxicity and target the cysteine protease falcipain-2, which is essential for parasite growth.
Release of copper-amended particles from micronized copper-pressure-treated wood during mechanical abrasion
2016
Background We investigated the particles released due to abrasion of wood surfaces pressure-treated with micronized copper azole (MCA) wood preservative and we gathered preliminary data on its in vitro cytotoxicity for lung cells. The data were compared with particles released after abrasion of untreated, water (0% MCA)-pressure-treated, chromated copper (CC)-pressure-treated wood, and varnished wood. Size, morphology, and composition of the released particles were analyzed. Results Our results indicate that the abrasion of MCA-pressure-treated wood does not cause an additional release of nanoparticles from the unreacted copper (Cu) carbonate nanoparticles from of the MCA formulation. Howev…
Prospective Evaluation of Free Energy Calculations for the Prioritization of Cathepsin L Inhibitors.
2017
Improving the binding affinity of a chemical series by systematically probing one of its exit vectors is a medicinal chemistry activity that can benefit from molecular modeling input. Herein, we compare the effectiveness of four approaches in prioritizing building blocks with better potency: selection by a medicinal chemist, manual modeling, docking followed by manual filtering, and free energy calculations (FEP). Our study focused on identifying novel substituents for the apolar S2 pocket of cathepsin L and was conducted entirely in a prospective manner with synthesis and activity determination of 36 novel compounds. We found that FEP selected compounds with improved affinity for 8 out of …
Trio Clinical Exome Sequencing in a Patient With Multicentric Carpotarsal Osteolysis Syndrome: First Case Report in the Balkans
2018
Exome sequencing can interrogate thousands of genes simultaneously and it is becoming a first line diagnostic tool in genomic medicine. Herein, we applied trio clinical exome sequencing in a patient presenting with undiagnosed skeletal disorder, minor facial abnormalities, and kidney hypoplasia; her parents were asymptomatic. Testing the proband and her parents led to the identification of a de novo mutation c.188C>T (p.Pro63Leu) in the MAFB gene, which is known to cause multicentric carpotarsal osteolysis syndrome (MCTO). The c.188C>T mutation lies in a hotspot amino acid stretch within the transactivation domain of MAFB, which is a negative regulator of RANKL-induced osteoclastogenesis. M…
A naturally occuring triterpene saponin ardisiacrispin B displayed cytotoxic effects in multi-factorial drug resistant cancer cells via ferroptotic a…
2018
WOS: 000432722700010
Cytotoxicity of epunctanone and four other phytochemicals isolated from the medicinal plants Garcinia epunctata and Ptycholobium contortum towards mu…
2018
Abstract Introduction Resistance of cancer cells is a serious impediment to chemotherapy and several phytochemicals are active against multi-drug resistant (MDR) phenotypes. The cytotoxicity of five naturally occurring compounds: betulin (1), mundulea lactone (2), seputhecarpan A (3), seputheisoflavone (4) and epunctanone (5) was evaluated on a panel of 9 cancer cell lines including various sensitive and drug-resistant cell lines. The modes of action of compound 5 were further investigated. Methods The resazurin reduction assay was used to evaluate cytotoxicity of samples and ferroptotic cell death induced by compound 5; caspase-Glo assay was used to detect the activation of caspases in CCR…
Extracellular histones disarrange vasoactive mediators reléase through COX-NOS interaction in human endothelial cells
2017
Abstract Extracellular histones are mediators of inflammation, tissue injury and organ dysfunction. Interactions between circulating histones and vascular endothelial cells are key events in histone‐mediated pathologies. Our aim was to investigate the implication of extracellular histones in the production of the major vasoactive compounds released by human endothelial cells (HUVECs), prostanoids and nitric oxide (NO). HUVEC exposed to increasing concentrations of histones (0.001 to 100 μg/ml) for 4 hrs induced prostacyclin (PGI2) production in a dose‐dependent manner and decreased thromboxane A2 (TXA2) release at 100 μg/ml. Extracellular histones raised cyclooxygenase‐2 (COX‐2) and prostac…
Discovery and validation of 2-styryl substituted benzoxazin-4-ones as a novel scaffold for rhomboid protease inhibitors
2017
Abstract Rhomboids are intramembrane serine proteases with diverse physiological functions in organisms ranging from archaea to humans. Crystal structure analysis has provided a detailed understanding of the catalytic mechanism, and rhomboids have been implicated in various disease contexts. Unfortunately, the design of specific rhomboid inhibitors has lagged behind, and previously described small molecule inhibitors displayed insufficient potency and/or selectivity. Using a computer-aided approach, we focused on the discovery of novel scaffolds with reduced liabilities and the possibility for broad structural variations. Docking studies with the E. coli rhomboid GlpG indicated that 2-styry…
Warhead Reactivity Limits the Speed of Inhibition of the Cysteine Protease Rhodesain.
2021
Viral and parasitic pathogens rely critically on cysteine proteases for host invasion, replication, and infectivity. Their inhibition by synthetic inhibitors, such as vinyl sulfone compounds, has emerged as a promising treatment strategy. However, the individual reaction steps of protease inhibition are not fully understood. Using the trypanosomal cysteine protease rhodesain as a medically relevant target, we design photoinduced electron transfer (PET) fluorescence probes to detect kinetics of binding of reversible and irreversible vinyl sulfones directly in solution. Intriguingly, the irreversible inhibitor, apart from its unlimited residence time in the enzyme, reacts 5 times faster than …
Oxidative post‐translational modifications in histones
2019
Epigenetic regulation is attracting much attention because it explains many of the effects that the external environment induces in organisms. Changes in the cellular redox status and even more specifically in its nuclear redox compartment is one of these examples. Redox changes can induce modulation of the epigenetic regulation in cells. Here we present a few cases where reactive oxygen or nitrogen species induces epigenetic marks in histones. Posttranslational modification of these proteins like histone nitrosylation, carbonylation, or glutathionylation together with other mechanisms not reviewed here are the cornerstones of redox-related epigenetic regulation. We currently face a new fie…