Conformational and docking studies of acyl homoserine lactones as a robust method to investigate bioactive conformations

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Marine Natural Meroterpenes: Synthesis and Antiproliferative Activity

Meroterpenes are compounds of mixed biogenesis, isolated from plants, microorganisms and marine invertebrates. We have previously isolated and determined the structure for a series of meroterpenes extracted from the ascidian Aplidium aff. densum. Here, we demonstrate the chemical synthesis of three of them and their derivatives, and evaluate their biological activity on two bacterial strains, on sea urchin eggs, and on cancerous and healthy human cells

New 4-aryl-1,3,2-oxathiazolylium-5-olates: chemical synthesis and photochemical stability of a novel series of S-nitrosothiols

S-nitrosothiols (RSNOs) remain one of the most popular classes of NO-donating compounds due to their ability to release nitric oxide (NO) under non-enzymatic means whilst producing an inert disulphide byproduct. However, alligning these compounds to the different biological fields of NO research has proved to be problematic due to the inherent instability of such compounds under a variety of conditions including heat, light and the presence of copper ions. 1,3,2-Oxathiazolylium-5-olates (OZOs) represent an interesting subclass of S-nitrosothiols that lock the –SNO moiety into a five membered heterocyclic ring in an attempt to improve the compound’s overall stability. The synthesis of a novel series of halogen-containing OZOs was comprehensively studied resulting in a seven-step route and overall yields ranging between 21 and 37%. The photochemical stability of these compounds was assessed to determine if Snitrosothiols locked within these mesoionic ring systems can offer greater stability and thereby release NO in a more controllable fashion than their non-cyclic counterparts

Kunnskapsdeling i en hektisk arbeidshverdag : En kvalitativ studie av effekten av tidspress på kunnskapsdeling i en organisatorisk kontekst

Denne studien har undersøkt hvilken effekt tidspress har på formell og uformell arena for kunnskapsdeling i organisasjoner. Dette ble gjort med utgangspunkt i en portefølje med prosjekter i Statoil, kalt fast track. Studiens utgangspunkt var et samarbeid med Statoil ASA. Det er blitt benyttet en kvalitativ tilnærming til metoden, og empirien er hentet fra ansatte i porteføljeorganiseringen fast track. Det ble utført 8 dybdeintervjuer, og Grounded Theory ble anvendt som tilnærming til innsamling og analysen av dataene. Resultatene indikerer at tidspress i arbeidshverdagen påvirker den formelle og den uformelle arenaen for kunnskapsdeling ulikt, hvor den formelle er funnet å lide mest. Dette forklares ut fra tilstedeværelsen av sosial kapital på de to arenaene. Studien tyder på at faktorer ved sosial kapital, som tillit, normer, nettverksbånd og felles referanserammer, i større grad er til stede på den uformelle arenaen, enn på den formelle. Disse virker som en buffer og gjør at kunnskapsdelingen finner sted, på tross av stort tidspress. Organiseringen i porteføljene, hvor man sitter sammen med medlemmer av samme praksisfellesskap, gjør det mulig å opprettholde og videreutvikle den sosiale kapitalen. Mangelen på tilstedeværelse av sosial kapital på den formelle arenaen, gjør at kunnskapsdelingen blir dårligere som følge av tidspresset. Funnene kan gi viktige implikasjoner for organiseringen av fast track-prosjektene. På bakgrunn av at porteføljeorganiseringen gjør det mulig å opprettholde og videreutvikle den sosiale kapitalen, så blir det fremhevet at denne organiseringen bør opprettholdes. Dette kommer av at tilstedeværelsen av den sosiale kapitalen fungerer som en buffer mot tidspresset i arbeidshverdagen

Machine learning approaches for the identification of ligands of the autophagy marker LC3

The LC3 proteins play a crucial role in autophagy by participating to the formation of the autophagosome. Modulation of autophagy by molecular interference with LC3 proteins could help to understand this complex fundamental biological process and how it is involved in several pathologies. Identifying new LC3 ligands is a useful contribution to this aim. In the present study, we created a PubChem library of 749 compounds having a structure based on the central scaffold of novobiocin, a reported LC3A ligand. A robust, rapid and exhaustive algorithm was used for docking each compound of this database as ligands within the dihydronovobiocin binding site, providing a docking score. Remarkable reliability and consistency between docking scores and the reported binding efficiencies of known ligands was observed, validating the machine leaning protocol used in this study. Investigation of the binding mode of the ligands having the best docking score provides additional insights in possible mode of actions of the LC3 identified ligands

Rational design, solid phase synthesis and evaluation of cationic ferrocenoyl peptide bioconjugates as potential antioxidant enzyme mimics

International audienceSynthetic C-terminal amidated cationic ferrocenoyl peptide bioconjugates Fc-Orn-Orn-Orn (1) and Fc-Tyr-Orn-Orn-Orn (2) were rationally designed as superoxide dismutase (SOD) mimics based on the structure of the iron SOD from Escherichia coli. Ferrocenoyl peptide bioconjugates 1, 2 and ferrrocenecarboxylic acid (4) were subsequently evaluated as SOD mimics and as inhibitors of peroxynitrite-mediated tyrosine nitration. Due to their cationic character, ferrocenoyl peptide bioconjugates 1 and 2 exerted an acceptable SOD activity (EC50 = 575 μM and 310 μM, respectively) in comparison with 4 (EC50 = 1.4 mM). The C-terminal amidated cationic peptide Ac-Tyr-Orn-Orn-Orn (3), designed as marker of peroxynitrite, was used to evaluate the inhibitory activity of 1 and 4 towards peroxynitrite-mediated tyrosine nitration. Both compounds proved to inhibit the nitration especially the cationic ferrocenoyl peptide bioconjugates 1. The ferrocene moiety of conjugate 2 displayed a strong inhibitory activity of peroxynitrite-mediated nitration of the neighboring tyrosine

Exploring docking methods for virtual screening: application to the identification of neuraminidase and Ftsz potential inhibitors

Virtual screenings based on molecular docking play a major role in medicinal chemistry for the identification of new bioactive molecules. For this purpose, several docking methods can be used. Here, using Arguslab as software and a Gold Platinum subset library of commercially available compounds from Asinex, two docking methods associated to the scoring function Ascore were employed to investigate virtual screenings. One method is based on a genetic algorithm and the other based on a shape-based method. As case studies, both docking techniques were explored by targeting the PC190723 binding site of FtsZ protein from Staphylococcus aureus and the active site of N8 neuraminidase from Influenza virus. Following four docking sequences for each docking engine, the genetic algorithm led to multiple docking results, whereas the shape-based method gave reproducible results. The present study shows that the stochastic nature of the genetic algorithm will require the biological evaluation of more compounds than the shape-based method. This study showed that both methods are complementary and also led to the identification of neuraminidase and FtsZ potential inhibitors

Biological Evaluation and Docking Studies of New Carbamate, Thiocarbamate, and Hydrazide Analogues of Acyl Homoserine Lactones as Vibrio fischeri-Quorum Sensing Modulators

International audiencePhosphodiesters of glucose-2-phosphate (G2P) are found only in few natural compounds such as agrocinopine D and agrocin 84. Agrocinopine D is a G2P phosphodiester produced by plants infected by Agrobacterium fabrum C58 and recognized by the bacterial periplasmic binding protein AccA for being transported into the bacteria before cleavage by the phosphodiesterase AccF, releasing G2P, which promotes virulence by binding the repressor protein AccR. The G2P amide agrocin 84 is a natural antibiotic produced by the non-pathogenic Agrobacterium radiobacter K84 strain used as a biocontrol agent by competing with Agrobacterium fabrum C58. G2P esters are also found in irregular glycogen structures. The rare glucopyranosyl-2-phophoryl moiety found in agrocin 84 is the key structural signature enabling its action as a natural antibiotic. Likewise, G2P and G2P esters can also dupe the Agrobacterium agrocinopine catabolism cascade. Such observations illustrate the importance of G2P esters on which we have recently focused our interest. After a brief review of the reported phosphorylation coupling methods and the choice of carbohydrate building blocks used in G2P chemistry, a flexible access to glucose-2-phosphate esters using the phosphoramidite route is proposed