发光铱(Ⅲ)配合物抗肿瘤活性研究及应用

铱(Ⅲ)配合物因其发光量子产率高且波长易调控、发光寿命长和光稳定性好的特点,在发光材料领域备受关注。铱(Ⅲ)配合物细胞渗透能力强,能靶向多种细胞组织并影响其结构和功能,表现出独特的抗肿瘤活性,是目前金属抗肿瘤药物特别是PDT光敏剂方向的研究热点。本文重点关注铱(Ⅲ)配合物的结构对其发光性能与抗肿瘤性能的影响,综述了近期铱(Ⅲ)配合物在生物成像、探针与传感、抗肿瘤诊疗等领域的研究进展,并对目前研究中存在的问题及其应用前景进行探讨和展望。     

Theoretical studies on the influence of metallic cations on ring opening of propylene oxide catalyzed by metal-salen complexes

We studied the ring opening of propylene oxide (PO) by salen-M coordinated OH⁻ group [M = Al(III), Sc(III), Cr(III), Mn(III), Fe(III), Co(II), Co(III), Ni(II), Cu(II), Zn(II), Ru(III) and Rh(III)]. The results show that the ring-opening energy barriers for M(II) complexes are much lower than those with M(III) complexes in the gas phase, and the barriers correlate linearly with the negative charges on the OH⁻ group and the Fukui function condensed on the OH⁻ group. The nucleophilicity ordering in the gas phase can be rationalized by the ratio of formal positive charges/radius of M cations. Solvent effect greatly increases the barriers of M(II) complexes but slightly changes the results of M(III) ones, making the barriers similar. Analysis indicates that the reaction heats are linearly proportional to the reverse reaction barriers. The relationships established here can be used to estimate the ring-opening barriers and to screen epoxide ring-opening catalysts.     

Insights into the electrochemical degradation of sulfamethoxazole and its metabolite by Ti/SnO2-Sb/Er-PbO2 anode

Electrochemical degradation of sulfamethoxazole (SMX) and its metabolite acetyl-sulfamethoxazole (Ac-SMX) by Ti/SnO₂-Sb/Er-PbO₂ were investigated. Results indicated that the electrochemical degradation of SMX and Ac-SMX followed pseudo-first-order kinetics. The rate constants of SMX and Ac-SMX were 0.268 and 0.072 min^-1 at optimal current density of 10 and 14 mA/cm², respectively. Transformation products of SMX and Ac-SMX were identified and the possible degradation pathways, including the cleavage of S-N bond, opening ring of isoxazole and nitration of amino group, were proposed. Total organic carbon removal of SMX was nearly 63.2% after 3 h electrochemical degradation. 22.4% nitrogen of SMX was transformed to NO₃^-, and 98.8% sulfur of SMX was released as SO₄^2-. According to quantitative structure-activity relationship model, toxicities of SMX and Ac-SMX to aquatic organisms significantly decreased after electrochemical degradation. Electric energy consumption for 90% SMX and Ac-SMX degradation was determined to be 0.58-8.97 and 6.88-44.19 Wh/L at different experimental conditions, respectively. Compared with parent compound SMX, the metabolite Ac-SMX is more refractory and toxic, which emphasizes the importance of taking its metabolites into account when investigating the disposal of pharmaceuticals from wastewater.     

Synthesis,Antiprotozoal Activity,and Cheminformatic Analysis of 2-Phenyl-2H-Indazole Derivatives

Indazole is an important scaffold in medicinal chemistry. At present, the progress on synthetic methodologies has allowed the preparation of several new indazole derivatives with interesting pharmacological properties. Particularly, the antiprotozoal activity of indazole derivatives have been recently reported. Herein, a series of 22 indazole derivatives was synthesized and studied as antiprotozoals. The 2-phenyl-2H-indazole scaffold was accessed by a one-pot procedure, which includes a combination of ultrasound synthesis under neat conditions as well as Cadogan’s cyclization. Moreover, some compounds were derivatized to have an appropriate set to provide structure-activity relationships (SAR) information. Whereas the antiprotozoal activity of six of these compounds against E. histolytica, G. intestinalis, and T. vaginalis had been previously reported, the activity of the additional 16 compounds was evaluated against these same protozoa. The biological assays revealed structural features that favor the antiprotozoal activity against the three protozoans tested, e.g., electron withdrawing groups at the 2-phenyl ring. It is important to mention that the indazole derivatives possess strong antiprotozoal activity and are also characterized by a continuous SAR.     

Tricyclic Pyrazole-Based Compounds as Useful Scaffolds for Cannabinoid CB1/CB2 Receptor Interaction

Cannabinoids comprise different classes of compounds, which aroused interest in recent years because of their several pharmacological properties. Such properties include analgesic activity, bodyweight reduction, the antiemetic effect, the reduction of intraocular pressure and many others, which appear correlated to the affinity of cannabinoids towards CB₁ and/or CB₂ receptors. Within the search aiming to identify novel chemical scaffolds for cannabinoid receptor interaction, the CB₁ antagonist/inverse agonist pyrazole-based derivative rimonabant has been modified, giving rise to several tricyclic pyrazole-based compounds, most of which endowed of high affinity and selectivity for CB₁ or CB₂ receptors. The aim of this review is to present the synthesis and summarize the SAR study of such tricyclic pyrazole-based compounds, evidencing, for some derivatives, their potential in the treatment of neuropathic pain, obesity or in the management of glaucoma.     

Total Synthesis and Bioactivity Mapping of Geodiamolide H

The first total synthesis of the actin-stabilizing marine natural product geodiamolide H was achieved. Solid-phase based peptide assembly paired with scalable stereoselective syntheses of polyketide building blocks and an optimized esterification set the stage for investigating the key ring-closing metathesis. Geodiamolide H and synthetic analogues were characterized for their toxicity and for antiproliferative effects in cellulo, by characterising actin polymerization induction in vitro, and by docking on the F-actin target and property computation in silico, for a better understanding of structure-activity relationships (SAR). A non-natural analogue of geodiamolide H was discovered to be most potent in the series, suggesting significant potential for tool compound design.     

新烟碱类杀虫剂生物活性的理论研究和结构修饰*

在B3LYP/6-311G基组水平下,运用密度泛函理论(DFT)的量子化学方法,对20种重氮乙烷新烟碱类杀虫剂分子的电子结构特征进行了研究,获得了它们的前线轨道能(EHOMO、ENHOMO、ELUMO、ENLUMO等)、原子电荷(Qi)、摩尔熵(Sm)、偶极矩(μ)等量化参数与物理性质。经最佳变量子集回归研究发现,重氮乙烷新烟碱类杀虫剂分子对果蝇n AChRs、哺乳动物α4β2亚型的亲和力常数(p KD、p KA)分别与ELUMO、QW、QF、QN等参数具有良好的线性关系。逐一或逐四剔除交互验证以及VIF、tα/2检验,所建2个QSAR模型具有良好的稳健性及预测能力。根据2个QSAR模型推断了重氮乙烷新烟碱类分子可能的杀虫机理。进一步研究发现,在重氮乙烷新烟碱类分子的吡啶环上的合适部位,选用不含复键的吸电子能力较强的取代基团对其进行结构修饰,有利于提高修饰后分子的生物活性。基于分子17,设计出4种经结构修饰后对果蝇n AChRs亲和力显著提高的重氮乙烷新烟碱类分子(分别是分子27,28,30和31),希望能得到实验的证实。     

Structure-Activity Relationship, Cytotoxicity and Mode of Action of 2-Ester-substituted 1,5-Benzothiazepines as Potent Antifungal Agents

Our studies examined the structural features responsible for the antifungal activity of 2-ethoxycarbonyl-1,5- benzothiazepine （7a）. Three series of 1,5-benzothiazepine derivatives were synthesized and screened for their antifungal activity. The results suggested that the ethoxycarbonyl group at the 2 position and the imine moiety on the seven-membered ring are essential for activity. The most potent of the synthesized analogues （7a, 7b） were further studied by evaluating their cytotoxicity and mode of action （for 7a）. The results showed that compounds 7a and 7b were relatively safe for BV2 cells, but compound 7a interfered with Cryptococcus neoformans cell wall integrity by increasing the chitinase activity. Therefore, compound 7a was considered safe as an antifungal agent for animal cells.     

二芳基三嗪类HIV-1逆转录酶抑制剂的分子对接及3D-QSAR研究

对40个二芳基三嗪类HIV-1逆转录酶抑制剂进行了分子对接研究,结果表明,2个疏水性芳香取代基团与结合口袋底部形成的疏水和范德华相互作用、三嗪环母核及其R4取代基与结合位点产生的氢键和静电作用以及R4取代基与袋口形成的空间位阻效应是影响该系列化合物活性的重要因素.根据对接优势构象进行分子叠合和比较分子相似性指数分析(C...     

分子表面随机采样分析法用于药物定量构效关系研究

考虑药物配基与蛋白质受体的3类非键作用模式,利用蒙特卡罗随机采样技术得到了一种分子结构性质表达方法:分子表面随机采样分析(RaSMS).同时,定义了蛋白质原子探针、虚拟受体可及表面、表面随机采样目标面积逼近法等多个相关概念,在理论和算法上对该法进行了可行性分析.在此基础上,对31个标准甾体化合物进行了定量构效关系(QS...