Mole (unité) | EPFL Graph Search

La mole (symbole : mol) est une des unités de base du Système international, adoptée en 1971, qui est principalement utilisée en physique et en chimie. La mole est la quantité de matière d'un système contenant exactement élémentaires (atomes, ions, molécules). Ce nombre, appelé « nombre d'Avogadro », correspond à la valeur numérique fixée de la constante d’Avogadro, N_\text{A}, lorsqu’elle est exprimée en . Pour donner un ordre de grandeur, le même nombre en grains de maïs permettrait de recouvrir la surface des États-Unis d'une couche uniforme d'une épaisseur d'environ . Le BIPM a adopté cette valeur dans les résolutions de la CGPM en , elle est applicable à partir du . Cette définition remplace celle posée en 1971 par la qui définissait la mole comme . Intérêt La mole est une unité de comptage, au même titre que la centaine, la vingtaine ou la douzaine, mais qui ne sert qu’à compter les atomes ou les molécules. Elle a la particularité d’être immense (

Heterogeneous kinetics of some atmospherically relevant reactions

A low pressure reactor (Knudsen cell) coupled to molecular beam modulated mass spectrometry was used to study the heterogeneous kinetics of the following three systems: (1) NO2 on amorphous carbon, (2) H2O vapor on ice and (3) gaseous HCl on ice. The first system was investigated at ambient temperature while the two last ones were investigated at temperatures typical of the stratosphere, that is roughly between 160 and 220K. The solid phase samples correspond to model surfaces whose physicochemical properties come very close to the ones of atmospheric particulates. Firstly, we studied the interaction of gaseous NO2 with three different commercial samples of amorphous carbon having widely differing physicochemical properties. Using in situ laser-induced fluorescence, the only major product was unambiguously determined to be NO with the oxidation product of carbon apparently remaining on the surface. Probing the gas phase with mass spectrometry (MS), both pulsed valve dosing and steady state experiments were performed and revealed a complex reaction mechanism for both the uptake as well as product formation. The initial uptake coefficient γo for NO2 was (6.4±2.0)·10-2 and proved to be identical within experimental uncertainty for all three types of amorphous carbon. The initial NO2 uptake rate was independent of the mass of the carbon sample and scaled with its external geometrical surface. Applying a simple chemical kinetic model to both pulsed dosing and steady state experiments resulted in an effective surface for uptake on amorphous carbon ranging between a factor of 2.8 to 8.4 larger than the geometrical surface area, but inversely proportional to the measured BET surface area of the three types of amorphous carbon. This means that the amorphous carbon with the highest BET surface (FW2) had the lowest external surface for NO2 adsorption. The chemical kinetic model included competing processes between Langmuir-type adsorption and inhibition controlling the adsorption kinetics of NO2 and revealed that the NO generation rate differed greatly between the three carbon samples examined. All samples showed saturation effects of differing degree that were partially reversible through prolonged pumping at 10-4 Torr and/or heating. Virgin amorphous carbon samples did not take up H2O vapor at 20 mTorr, and no HONO and/or HNO3 was detected in simultaneous NO2/H2O exposure experiments. CO and CO2 were detected when a sample previously exposed to NO2 was heated by an incandescent lamp. Moreover, upon heating such a sample, a MS signal m/e 62 originating from NO3 and/or N2O5 was detected. In addition to the experiments conducted on the three commercial carbon samples, we carried out uptake experiments of NO2 on acetylene soot. Originating from the flame of an acetylene burner, this soot was freshly deposited on glass dishes before each experiment. The initial uptake coefficient γo for NO2 was measured to be (3.0±1.1)·10-2 is smaller by a factor of two compared to γo observed in the uptake on commercial samples whose mass was a factor of 10 higher. In addition to NO, a net formation of HONO (m/e 47) was observed. This HONO formation is strongly dependent on the instantaneous water desorption from the sample as well as on the NO2 partial pressure in the reactor. On the other hand, it is not enhanced by an external water flow which did not show any interaction with the carbon sample. Upon heating the sample using an incandescent lamp, significant amounts of water desorbed, suggesting that the water vapor had condensed into the micropores of the soot during combustion. No quantitative results are presented yet. However, as no correlation between HONO formation and NO partial pressure has been observed so far, we suggest a reaction mechanism that only involves NO2 and H2O but no NO: 2 NO2 (g) + H2O HONO + HNO3 In a second study, the kinetics of condensation and evaporation of water on ice was determined in the temperature range of 170 to 220K. The rate of evaporation Fev corresponds to the evaporation of 70±10 monolayers of H2O per second at 200K. The condensation rate constant kc has a negative activation energy of -3.l±1.5kcal/mol which is significantly larger than the one recently measured by Haynes et al. We report the first real time kinetic measurements of water condensation on ice at stratospherically relevant temperatures. At temperatures above 160K, pulsed dosing experiments show a dose dependence of the condensation rate coefficient. For example, the condensation rate coefficient increases by a factor of five with a 1000 fold increase of the H2O dose from 1·1015 to 1·1018 molecules per pulse at 180K. This pressure dependence of the condensation rate constant may be explained by an autocatalytic mechanism involving the competition of two condensation channels. These two channels feed two different surface species, one of which leads to autocatalytic condensation. This mechanism gives insight into the manner in which a gas phase molecule is stepwise incorporated into tetrahedrally coordinated bulk ice. In a third and ongoing study, the uptake kinetics of HCl on ice has been investigated by pulsed valve experiments in the temperature range of 180 to 210K and are discussed as a function of the state of the surface. In fact, some of the pulsed valve experiments present a relaxation to a steady state level. It is shown that this level originates from the evaporation of a liquid solution corresponding to a temperature specific HCl concentration. The threshold of the injected dose leading to this solution layer is estimated to be 8·1014 molecules. This threshold corresponding to a fraction of a monolayer may be explained by the formation of small domains along grain boundaries or other lattice imperfections. Within detection limit, no difference in keff has been observed for pulses on the solution or on a previously exposed sample without formation of the solution. In the case of pulses forming a solution layer, a fraction of 20±20% of the injected molecules remains permanently adsorbed on the surface. In the temperature range from 210 to 180K, the pulsed valve experiments yield values of keff roughly between 5 and 25s-1 and an activation energy of -1.6±0.7kcal/mol which are consistent with the values observed by Flueckiger in steady state experiments using the 15mm escape aperture (kuni varying from 12 to 23s-1 and an activation energy of -1.9±0.25 kcal/mol).

EPFL1996

Generating macrocyclic inhibitors of protein-protein interactions

Gontran Sangouard

Protein-protein interactions (PPIs) play important roles in many diseases and their modulation is an attractive strategy for developing new therapeutics. However, the relatively large and often flat binding surfaces of PPIs makes the development of inhibitors based on classical small molecule drugs rather challenging. Macrocycles, a class of ring-shaped chemical structures, are able to bind to challenging targets such as PPIs, while having the potential to be cell-permeable or even orally available. The potential of targeting intracellular PPIs by macrocyclic compounds has triggered a great deal of interest in the pharmaceutical industry. A challenge with developing macrocycle-based drugs to new targets, however, is the identification of ligands, the reason for this mainly being the lack of large libraries of macrocyclic compounds that could be screened.The goal of my Ph.D. thesis project was to develop macrocyclic inhibitors for several protein-protein interactions. Towards this end, I contributed to establishing novel strategies for synthesizing and screening large macrocyclic compound libraries. Additionally, I established reported or developed new bioassays suited for the high-throughput screening of compound libraries, and I applied them for screening macrocycle libraries generated with the new methods.In my first project, I applied acoustic droplet ejection technology (ADE) for the synthesis and screening of large macrocyclic compound libraries at a picomole scale. Towards this aim, I used a synthetic strategy based on the combinatorial diversification of m bromoacetamide linear peptides with n primary amines followed by cyclization with o bis-electrophile linkers yielding m x n x o macrocycles. I used ADE to perform all liquid transfers, which proved efficient and yielded macrocycles at picomole scale. I performed the screening by directly adding assay reagents to the synthesis plates containing crude macrocycle products. As a proof-of-concept, I assembled a 2,700-member target-focused macrocycle library and screened it against the MDM2:p53 protein-protein interaction, and was able to identify macrocyclic inhibitors with micromolar to sub-micromolar affinity. Most importantly, this work validated the feasibility to synthesize combinatorial macrocycle libraries using ADE at the picomole scale, which was subsequently applied to several other approaches later developed in our lab.In my second project, I aimed at finding macrocyclic inhibitors of the PPI IL-23:IL-23R, which is an important target of several autoimmune disorders. To that end, I developed a high-throughput screening assay for identifying inhibitors of the interaction. I initially developed a screening assay based on fluorescence polarization, which turned out to be prone to artifacts. In a second attempt, I established an assay based on TR-FRET that proved reliable for the identification of IL-23:IL-23R inhibitors, and in particular also for the screening of crude products of macrocyclization reactions. I subsequently synthesized a pilot-scale library by combinatorially cyclizing 384 linear peptides with 8 cyclization linkers to generate 3,072 target-focused macrocyclic compounds. Screening the library using the TR-FRET-based assay identified single-digit micromolar inhibitors of the IL-23:IL-23R PPI, that however, were based on linear side-products of the macrocyclization reactions rather than macrocyclic structures. While no potent ma

EPFL2022

Synthesis and direct assay of large macrocycle diversities by combinatorial late-stage modification at picomole scale

Alessandro Angelini, Zsolt Bognár, Julien Bortoli Chapalay, Cristina Diaz Perlas, Sevan Mleh Habeshian, Christian Heinis, Manuel Leonardo Merz, Ganesh Kumar Mothukuri, Gontran Sangouard, Mischa Schüttel, Gerardo Turcatti, Jonathan Patrice Vesin

Macrocycles have excellent potential as therapeutics due to their ability to bind challenging targets. However, generating macrocycles against new targets is hindered by a lack of large macrocycle libraries for high-throughput screening. To overcome this, we herein established a combinatorial approach by tethering a myriad of chemical fragments to peripheral groups of structurally diverse macrocyclic scaffolds in a combinatorial fashion, all at a picomole scale in nanoliter volumes using acoustic droplet ejection technology. In a proof-of-concept, we generate a target-tailored library of 19,968 macrocycles by conjugating 104 carboxylic-acid fragments to 192 macrocyclic scaffolds. The high reaction efficiency and small number of side products of the acylation reactions allowed direct assay without purification and thus a large throughput. In screens, we identify nanomolar inhibitors against thrombin (Ki = 44 ± 1 nM) and the MDM2:p53 protein-protein interaction (Kd MDM2 = 43 ± 18 nM). The increased efficiency of macrocycle synthesis and screening and general applicability of this approach unlocks possibilities for generating leads against any protein target.

2022

Heterogeneous kinetics of some atmospherically relevant reactions

EPFL1996

Generating macrocyclic inhibitors of protein-protein interactions

Gontran Sangouard

EPFL2022