Small molecule antagonists of cell-surface heparan sulfate and heparin–protein interactions

Surfen, bis-2-methyl-4-amino-quinolyl-6-carbamide, was previously reported as a small molecule antagonist of heparan sulfate (HS), a key cell-surface glycosaminoglycan found on all mammalian cells. To generate structure–activity relationships, a series of rationally designed surfen analogs was synthesized, where its dimeric structure, exocyclic amines, and urea linker region were modified to probe the role of each moiety in recognizing HS. An in vitro assay monitoring inhibition of fibroblast growth factor 2 binding to wild-type CHO cells was utilized to quantify interactions with cell surface HS. The dimeric molecular structure of surfen and its aminoquinoline ring systems was essential for its interaction with HS, and certain dimeric analogs displayed higher inhibitory potency than surfen and were also shown to block downstream FGF signaling in mouse embryonic fibroblast cells. These molecules were also able to antagonize other HS–protein interactions including the binding of soluble RAGE to HS. Importantly, selected molecules were shown to neutralize heparin and other heparinoids, including the synthetic pentasaccharide fondaparinux, in a factor Xa chromogenic assay and in vivo in mice. These results suggest that small molecule antagonists of heparan sulfate and heparin can be of therapeutic potential for the treatment of disorders involving glycosaminoglycan–protein interactions.     

Expanding discriminative dimensions for analysis and imaging

Eliminating the contribution of interfering compounds is a key step in chemical analysis. In complex media, one possible approach is to perform a preliminary separation. However purification is often demanding, long, and costly; it may also considerably alter the properties of interacting components of the mixture (e.g. in a living cell). Hence there is a strong interest for developing separation-free non-invasive analytical protocols. Using photoswitchable probes as labelling and titration contrast agents, we demonstrate that the association of a modulated monochromatic light excitation with a kinetic filtering of the overall observable is much more attractive than constant excitation to read-out the contribution from a target probe under adverse conditions. An extensive theoretical framework enabled us to optimize the out-of-phase concentration first-order response of a photoswitchable probe to modulated illumination by appropriately matching the average light intensity and the radial frequency of the light modulation to the probe dynamics. Thus, we can selectively and quantitatively extract from an overall signal the contribution from a target photoswitchable probe within a mixture of species, photoswitchable or not. This simple titration strategy is more specifically developed in the context of fluorescence imaging, which offers promising perspectives.     

Biomimetic versus enzymatic high-potential electrocatalytic reduction of hydrogen peroxide on a functionalized carbon nanotube electrode

We report the non-covalent functionalization of a multi-walled carbon nanotube (MWCNT) electrode with a biomimetic model of the horseradish peroxidase (HRP) active site. By modifying the MWCNT electrode surface with imidazole-modified polypyrrole, a new biomimetic complex of HRP was synthesized on the MWCNT sidewalls via the coordination of imidazole (Im) to the metal centre of iron protoporphyrin IX, affording (Im)(PP)Fe^III. Compared to the pi-stacking of non-coordinated (PP)Fe^III on a MWCNT electrode, the (Im)(PP)Fe^III-modified MWCNT electrode exhibits higher electrocatalytic activity with an I _max = 0.52 mA cm^–2 for the reduction of H₂O₂, accompanied by a high onset potential of 0.43 V vs. Ag/AgCl. The performances of these novel surface-confined HRP mimics were compared to those of a MWCNT electrode modified by HRP. Although the enzyme electrode displays a higher electrocatalytic activity towards H₂O₂ reduction, the (Im)(PP)Fe^III-modified MWCNT electrode exhibits a markedly higher operational stability, retaining 63% of its initial activity after one month.     

Asymmetric Ring‐Opening of Cyclopropyl Ketones with Thiol,Alcohol, and Carboxylic Acid Nucleophiles Catalyzed by a Chiral N,N′‐Dioxide–Scandium(III) Complex

A highly efficient asymmetric ring‐opening reaction of cyclopropyl ketones with a broad range of thiols, alcohols and carboxylic acids has been first realized by using a chiral N,N′‐dioxide–scandium(III) complex as catalyst. The corresponding sulfides, ethers, and esters were obtained in up to 99 % yield and 95 % ee. This is also the first example of one catalytic system working for the ring‐opening reaction of donor–acceptor cyclopropanes with three different nucleophiles, let alone in an asymmetric version.     

Rhodium(III)‐Catalyzed [3+2]/[5+2] Annulation of 4‐Aryl 1,2,3‐Triazoles with Internal Alkynes through Dual C(sp2)?H Functionalization

A rhodium(III)‐catalyzed [3+2]/[5+2] annulation of 4‐aryl 1‐tosyl‐1,2,3‐triazoles with internal alkynes is presented. This transformation provides straightforward access to indeno[1,7‐cd]azepine architectures through a sequence involving the formation of a rhodium(III) azavinyl carbene, dual C(sp²) H functionalization, and [3+2]/[5+2] annulation.     

NaBF4催化合成二吲哚甲烷类化合物

在乙醇水溶液中,以Na BF4为催化剂,通过吲哚与芳香醛间的串联反应合成了二吲哚甲烷衍生物。考察了催化剂种类、反应介质、温度、反应时间等因素对反应的影响,在优化条件下以较高产率得到了一系列目标产物。     

Multi‐Species Multi‐Channel (MSMC): An Ab Initio‐based Parallel Thermodynamic and Kinetic Code for Complex Chemical Systems

Multi‐Species Multi‐Channel (MSMC) is an ab initio parallel program to calculate thermodynamic quantities (e.g., , , , and , time‐dependent species profiles, and rate coefficients as functions of temperature and pressure for complex chemical reaction systems, which consist of multiple stable species and multiple reaction channels interconnecting them. Thermodynamic properties of the species involved are calculated using statistical mechanics with molecular information from electronic structure calculations. Temperature‐ and pressure‐dependent behaviors are rigorously characterized within the eigenpair master equation/Rice–Ramsperger–Kassel–Marcus (ME/RRKM) framework. Corrections, e.g., for hindered internal rotation and tunneling treatment, are included. With the implementation of an ultra‐high precision package and rigorous matrix setup, MSMC is able to correctly mimic real behaviors of different types of chemical systems. Different eigenpair‐based approaches to extract phenomenological/macroscopic rate coefficients are implemented for different applications. Moreover, a friendly and platform‐independent graphical‐user‐interface (GUI) is provided to facilitate the use of MSMC and the pre‐/postcalculation data visualization/analysis on the fly. The program can be freely downloaded at https://sites.google.com/site/msmccode/ .