Photoregulation of Gene Expression with Ligand-Modified Caged siRNAs through Host/Guest Interaction

Small interfering RNA (siRNA) can effectively silence target genes through Argonate 2 (Ago2)-induced RNA interference (RNAi). It is very important to control siRNA activity in both spatial and temporal modes. Among different masking strategies, photocaging can be used to regulate gene expression through light irradiation with spatiotemporal and dose-dependent resolution. Many different caging strategies and caging groups have been reported for light-activated siRNA gene silencing. Herein, we describe a novel caging strategy that increases the blocking effect of RISC complex formation/process through host/guest (including ligand/receptor) interactions, thereby enhancing the inhibition of caged siRNA activity until light activation. This strategy can be used as a general approach to design caged siRNAs for the photomodulation of gene silencing of exogenous and endogenous genes.     

Enantioselective extraction of mandelic acid enantiomers based on chiral ligand exchange

Based on the chiral ligand exchange, the distribution behavior of mandelic acid enantiomers, and the partition of Cu^2 at different pH values were studied in a water/alcohol two-phase system containing Cu^2 and N-ndodecyl-L-proline(A). The influences of the solvent sort, the pH value, the concentrations of Cu^2 and chiral ligand on the partition coefficient(K) and separation factor(α) were discussed. The experimental results show that the A formed has more stable ternary complex with D-mandelic acid enantiomer than with L-mandelic acid enantiomer. There is an important influence of the pH value on K and a. When the pH values are less than 3.5, the formation of binary complexes is thermodynamically unfavourable. K and a become maximum when pH values are above 3.5 and the molar ratio of the chiral ligand to Cu^2 is 2:1.     

Synthesis,Characterization and Luminescent Properties of Complexes of Rare Earth Nitrates with Tris{2-[N-(pyridine-methanoyl)amino]ethyl} amine

Duringthelastdecade ,thedesignandsynthesisoftripodalligandsandtheirmetalcomplexeshaveattractedconsiderableattentionduetotheirpotentialusesaslumi nescentprobesinmedicineandbiochemistry[1～ 7] ,ascatalysts[8] andelectrochemicalmaterials[9] .However ,thecomplexesofrareearthmetalwithtripodalligandshavefewreported[10 ] .Asanextensionofourstudiesoncomplexesofmetalwithtripodalligands ,anewtripodalligand (tris { 2 [N (pyridine methanoyl)amino]ethyl}amine ,L)anditscomplexeswithrareearthnitratesweresyn…     

Rational Design of CYP3A4 Inhibitors: A One-Atom Linker Elongation in Ritonavir-Like Compounds Leads to a Marked Improvement in the Binding Strength

Inhibition of the major human drug-metabolizing cytochrome P450 3A4 (CYP3A4) by pharmaceuticals and other xenobiotics could lead to toxicity, drug–drug interactions and other adverse effects, as well as pharmacoenhancement. Despite serious clinical implications, the structural basis and attributes required for the potent inhibition of CYP3A4 remain to be established. We utilized a rational inhibitor design to investigate the structure–activity relationships in the analogues of ritonavir, the most potent CYP3A4 inhibitor in clinical use. This study elucidated the optimal length of the head-group spacer using eleven (series V) analogues with the R₁/R₂ side-groups as phenyls or R₁–phenyl/R₂–indole/naphthalene in various stereo configurations. Spectral, functional and structural characterization of the inhibitory complexes showed that a one-atom head-group linker elongation, from pyridyl–ethyl to pyridyl–propyl, was beneficial and markedly improved K_s, IC₅₀ and thermostability of CYP3A4. In contrast, a two-atom linker extension led to a multi-fold decrease in the binding and inhibitory strength, possibly due to spatial and/or conformational constraints. The lead compound, 3h, was among the best inhibitors designed so far and overall, the strongest binder (K_s and IC₅₀ of 0.007 and 0.090 µM, respectively). 3h was the fourth structurally simpler inhibitor superior to ritonavir, which further demonstrates the power of our approach.     

Accurate Receptor-Ligand Binding Free Energies from Fast QM Conformational Chemical Space Sampling

Small molecule receptor-binding is dominated by weak, non-covalent interactions such as van-der-Waals hydrogen bonding or electrostatics. Calculating these non-covalent ligand-receptor interactions is a challenge to computational means in terms of accuracy and efficacy since the ligand may bind in a number of thermally accessible conformations. The conformational rotamer ensemble sampling tool (CREST) uses an iterative scheme to efficiently sample the conformational space and calculates energies using the semi-empirical ‘Geometry, Frequency, Noncovalent, eXtended Tight Binding’ (GFN2-xTB) method. This combined approach is applied to blind predictions of the modes and free energies of binding for a set of 10 drug molecule ligands to the cucurbit[n]urils CB[8] receptor from the recent ‘Statistical Assessment of the Modeling of Proteins and Ligands’ (SAMPL) challenge including morphine, hydromorphine, cocaine, fentanyl, and ketamine. For each system, the conformational space was sufficiently sampled for the free ligand and the ligand-receptor complexes using the quantum chemical Hamiltonian. A multitude of structures makes up the final conformer-rotamer ensemble, for which then free energies of binding are calculated. For those large and complex molecules, the results are in good agreement with experimental values with a mean error of 3 kcal/mol. The GFN2-xTB energies of binding are validated by advanced density functional theory calculations and found to be in good agreement. The efficacy of the automated QM sampling workflow allows the extension towards other complex molecular interaction scenarios.     

次亚磷酸盐溶液电镀三价铬工艺的电化学

研究了次亚磷酸盐溶液电镀三价铬工艺的溶液化学性质，对镀液中三价铬离子与次亚磷酸根离子的配位化合物进行了探讨。用线性电势扫描法、循环伏安法研究了镀液的电化学特征及镀液中氟离子、次亚磷酸根离子、溶液ｐＨ值对阴极析氢反应的影响。讨论了获得最佳电流效率的条件     

甲烷单加氧酶模型化合物的合成及性能测试

设计、合成了一个新的甲烷单加氧酶(MMO)模型化合物[Fe2(Ⅲ,Ⅲ)L(μ-OAc)2]·PF6,其中L为2,6-二{[(2-羟基-5-叔丁基-苄基)(吡啶-2-甲基)-氨基]-甲基}-4-甲基苯酚。与以往的模型体系[Fe2(Ⅱ,Ⅲ)(bpmp)(μ-OAc)2]·(BPh4)2相比,新模型增加了2个酚配体、2个叔丁基。这些基团的引入提高了中心金属Fe的价态,并增加了配体的电子云密度从而调节了Fe的氧化还原电位。该模型进一步缩小了人工模型体系与甲烷单加氧活性中心(MMOH)的差异。通过红外(IR)、电喷雾电离质谱(ESI-MS)、核磁共振NMR(gCOSY、gHMBC、gHSQC)及电化学对新配体及络合物进行了表征和测试。     

高分子金属配合物发光材料的制备技术进展

高分子金属配合物发光材料是一类很有价值的功能材料,评述了有关它的各种合成方法。以金属离子与含配位基团的聚合物进行反应,容易在高聚物之间形成交联,难以获得发光强度高的高分子配合物;使金属离子与高分子配体和小分子配体同时作用,可以得到荧光强度比较理想的产物,但反应难以定量控制;以小分子金属配合物单体与某些单体之间进行共聚合反应,也可获得荧光强度较高的高分子配合物,但聚合反应的空间位阻较大;通过两端都含有配位基团的刚性链的有机小分子配体直接与金属离子配合形成高分子金属配合物;以小分子金属配合物单体进行均聚或者将小分子金属配合物接枝到高聚物上也可以形成高分子金属配合物。     

Interaction of metal ions with carboxylic and carboxamide groups in protein structures

An analysis of the geometry of metal binding by carboxylic andcarboxamide groups in proteins is presented. Most of the ligandsare from aspartic and glutamic acid side chains. Water moleculesbound to carboxylate anions are known to interact with oxygenlone-pairs. However, metal ions are also found to approach thecarboxylate group along the C - O direction. More metal ionsare found to be along the syn than the anti lone-pair direction.This seems to be the result of the stability of the five-memberedring that is formed by the carboxylate anion hydrogen bondedto a ligand water molecule and the metal ion in the syn position.Ligand residues are usually from the helix, turn or regionswith no regular secondary structure. Because of the steric interactionsassociated with bringing all the ligands around a metal center,a calcium ion can bind only near the ends of a helix; a metal,like zinc, with a low coordination number, can bind anywherein the helix. Based on the analysis of the positions of watermolecules in the metal coordination sphere, the sequence ofthe EF hand (a calcium-binding structure) is discussed.