Acetylcholinesterase (AChE) is one of the key targets of drugs for treating Alzheimer's disease (AD). Tacrine is an approved drug with AChE-inhibitory activity. In this paper, 3D-QSAR, molecular docking, and molecular dynamics were carried out in order to study 60 tacrine derivatives and their AChE-inhibitory activities. 3D-QSAR modeling resulted in an optimal CoMFA model with q(2) = 0.552 and r(2) = 0.983 and an optimal CoMSIA model with q(2) = 0.581 and r(2) = 0.989. These QSAR models also showed that the steric and H-bond fields of these compounds are important influences on their activities. The interactions between these inhibitors and AChE were further explored through molecular docking and molecular dynamics simulation. A few key residues (Tyr70, Trp84, Tyr121, Trp279, and Phe330) at the binding site of AChE were identified. The results of this study improve our understanding of the mechanisms of AChE inhibitors and afford valuable information that should aid the design of novel potential AChE inhibitors. Graphical Abstract Superposition of backbone atoms of the lowest-energy structure obtained from MD simulation (magenta) onto those of the structure of the initial molecular docking model (green).

Objective. Sufentanil is the most common drug in clinical practice for the treatment of ischemic heart disease. This study is to investigate the protective mechanism of sufentanil on rat myocardial ischemia-reperfusion (I/R) injury. Methods. A rat I/R model was established by ligating the left anterior descending coronary artery. A total of 24 SD male rats were enrolled and divided randomly into the control group, I/R group, sufentanil group (SUF; 3 μg/kg), and diltiazem group (DLZ; 20 mg/kg; positive control). The rat hearts were subjected to 30 min of ischemia followed by 120 min of reperfusion. Subsequently, hemodynamics, pathological changes of myocardial tissue, serum biochemical parameters, oxidative stress factors, the level of serum inducible nitric oxide synthases (iNOS), interleukin-6 (IL-6), and other bioactive factors were analyzed in the rats. Result. Compared with the I/R group, sufentanil significantly improved cardiac action, myocardial fiber, and cardiomyocyte morphology and reduced inflammatory cell infiltration in rats in the SUF group. And the level of creatine kinase isoenzyme (CK-MB), troponin (cTn), lactate dehydrogenase (LDH), malondialdehyde (MDA), iNOS, and IL-6 was significantly declined in the serum of SUF group, while the activities of glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) were significantly activated in the myocardial tissues. In addition, sufentanil also significantly decreased the protein expression of GRP78, CHOP, Caspase 12, and ATF6 in the myocardial tissue of the SUF group. Conclusion. Sufentanil has a significant protective activity on myocardial I/R injury in rats, the mechanism of which may be associated with the inhibition of endoplasmic reticulum stress and oxidative stress.

According to the scaffold hopping, a series of N-aryl-salicylamide derivatives, which have fragments of tyrosine kinase inhibitors lapatinib and neratinib were designed and synthesized. Their structures were identified by IR, 1 H NMR, 13 C NMR and MS techniques. The target compounds were tested for cytotoxic activity against four cancer cell lines, including A549, MCF-7, SGC-7901, Bel-7402, by methyl thiazolyl tetrazolium (MTT) in vitro. All the compounds demonstrated certain antitumor abilities, and some of them were better than gefitinib. Keywords N-aryl-salicylamide; tyrosine kinase inhibitors; antitumor 长期以来, 肿瘤治疗一直是世界性的难题, 也是医 药研究面临的一项挑战. 近些年来, 随着分子生物学和 细胞生物学的快速发展, 人们逐渐认识到细胞癌变的本 质可能是细胞信号转导通路失调导致的细胞无限增殖, 抗肿瘤药物研发的理念也从传统细胞毒类药物的研究 (主要作用于 DNA, RNA 和微管蛋白)转向寻找针对细胞 内信号转导通路的新型抗肿瘤药物 [1,2] . 在此研究基础 上科学家们已发现了多种抗肿瘤的新药物靶标, 其中蛋 白酪氨酸激酶(protein tyrosine kinase, PTK)作为新型靶 标引起了人们的高度关注. PTK 是一类具有酪氨酸激酶 活性的蛋白质, 其与配体结合导致重要的构象变化, 暴 露受体中的二聚环结构, 引发自身磷酸化, 转导下游信 号, 调节细胞的增殖、凋亡、迁移、存活等一系列生理 生化过程, 而 PTK 的过度表达则会促进细胞的癌变, 导致肿瘤的发生. 因此许多科研工作者致力于发现、设 计与合成酪氨酸激酶抑制剂, 并取得了一定的成果, 如: 吉非替尼(Gefitinib)、拉帕替尼(Lapatinib)和厄洛替尼 (Erlotinib) (图 1)等 9 个小分子蛋白酪氨酸激酶抑制剂已 被美国食品药物管理局(FDA)批准上市, 诺拉替尼(图 1) 等 100 多个候选药物正处于临床试验阶段 [3～8] . 研究发现氯硝柳胺对肺癌、 前 列腺癌、口腔上皮癌、肾癌、结肠癌、急性髓细胞性白 血病等显示出良好的抗癌活性. 水杨酰胺类化合物结构 中的 2 位羟基与酰胺羰基通过分子内氢键形成一个六元 环构型, 该构型与酪氨酸激酶抑制剂替尼类抗肿瘤药物 的主要基本母核 4-芳氨基喹唑啉的空间构型具有相似 性(图 2), 因而产生类似酪氨酸激酶抑制剂的抗肿瘤活 性 [13] . 149.2～149.9 ℃(文献值 [14] : m.p. 149～150 ℃). 近年来, 水杨酰胺类化合物的抗肿瘤活性引起了人 们的高度关注, 文献报道, 4-(4-氨基苯基)-N-(3-氯苯基) 4-[(吡啶-2-基)甲氧基] -3-氯苯胺(4a)的合成 N-{4-[(吡啶-2-基)甲氧基]-3-氯苯基}-2-羟基-4-氯苯甲酰胺(5a)的合成在 250 mL 三颈瓶中, 依次加入 4a (3.0 g , 13 mmol), 4-氯水杨酸 (5) 156.2, 150.0, 149.0, 137.4, 137.1, 132.1, 130.6, 123.0, 122.6, 121.4, 121.1, 120.8, 119.2, 116.9, 116.8, 114.4, 71.1; IR (KBr) v: 3341.9, 3075.1, 1662.4, 1600.1, 1545.7, 1502.3, 1443.5, 1411.3, 1280.1, 1215.7, 1063 164.7, 157.3, 156.2, 150.0, 149.0, 137.1, 132.3, 132.2, 130.5, 125.3, 123.2, 123.0, 122.2, 121.4, 121.2, 120.5, 115.3, 114.4, 113.4, 71.1; IR (KBr) v: 3348.4, 3075.8, 1665.0, 1597.0, 1543.2, 1502.8, 1422.4, 1290.2, 1157.5, 1128.1, 1065.4, 1036 388.0381, found 388.0373. 161.7, 158.6, 149.0, 148.4, 141.0, 139.5, 136.4, 131.8.0, 131.6, 125.4, 124.5, 124.0, 122.1, 119.4, 116.8, 113.8, 112.3, 68.7; IR (KBr) v: 3083.4, 2931.6, 1673.9, 1584.0, 1519.8, 1486.5, 1358.2, 1279.0, 1215.0, 1124.3, 1009 171.9, 166.9, 161.2, 159.1, 149.9, 148.8, 146.4, 135.6, 132.2, 130.0, 128.5, 123.6, 122.7, 120.3, 117.1, 114.6, 113.8, 110.2, 68.1, 21.3; IR (KBr) v: 3442.1, 3309.6, 2922.0, 1650.1, 1618.9, 1538.3, 1503.6, 1450.3, 1407.1, 1369.7, 1291.1, 1247.8, 1219.8, 1159.8, 1065 8.58 (dd, J＝1.2, 4.8 Hz, 1H, PyH), 7.97 (d, J＝8.8 Hz, 1H, PhH), 7.91 (d, J＝8.0 Hz, 1H, PyH), 7.88 (d, J＝2.4 Hz, 1H, PhH), 7.60 (dd, J＝2.4, 8.8 Hz, 1H, PhH), 7.45～ 7.48 (m, 1H, PhH), 7.30 (d, J＝9.2 Hz, 1H, PhH), 6.57 (dd, J＝2.4, 4.4 Hz, 1H, PyH), 6.50 (d, J＝2.4 Hz, 1H, PhH), 5.26 (s, 2H, CH 2 ), 3.80 (s, 3H, OCH 3 ); 13 C NMR (DMSO-d 6 , 75 MHz) δ: 167.2, 163.8, 161.8, 149.9, 149.1, 148.8, 135.6, 132.3, 132.2, 129.9, 123.7, 122.9, 121....

A practical method to stereospecifically synthesize trans-stilbenes was developed via the one-pot benzylation-dehydration reaction of aromatic aldehydes with benzyltrimethylsilane (BTMS), which was driven by tetrabutylammonium fluoride (TBAF) in THF. At the same time a plausible description of the whole process was proposed and the effects of substituted groups on the reaction were investigated. Also this method was employed to synthesize three precursors of natural products with excellent yields, which demonstrated that this method is much efficient and practical in the synthesis of some natural products.

Two series of novel salicylanilide were synthesized as potential epidermal growth factor receptor (EGFR) inhibitors. The enzyme inhibitory activity against EGFR of all compounds was carried out, and their antiproliferative activities against the A549 and A431 cell lines were also evaluated. Of the compounds studied, majority of them exhibited high antiproliferative activities compared with gefitinib; especially, 12a and 12b exhibited stronger inhibitory activity against EGFR with IC50 values of 10.4 ± 2.25 and 15.4 ± 2.33 nm, respectively, which were comparable to the positive control of gefitinib (IC50 = 12.1 ± 2.21 nm). Compound 12b also showed outstanding inhibitory activity against A431 and A549 cell lines with the IC50 values of 0.42 ± 0.43 μm and 0.57 ± 0.43 μm, which was better than the positive controls. In the molecular modeling study, compound 12b was bound into the active pocket of EGFR with two hydrogen bond and with minimum binding free energy ▵Gb = -25.1125 kcal/mol. The result also suggested that compound 12b could bind the EGFR kinase well.