摘要：4,5-Dihydro-3-methylbenzo[1,2-b]furan-4,5-dione（4） was identified as a novel and potent inhibitor of caspase-3 through structural modification of an existing drug, sodium tanshinone IIA sulfonate（STS）. Compound 4 showed high potency against caspase-3 in vitro（ICso=0. 13μmol/L）. Molecular docking study further provided an insight into the interaction of compound 4 with activated caspase-3. Hence, this small-molecule caspase-3 inhibitor could be a oromising theraoeutic candidate against diseases caused by abnormally up-regulated apptosis.

摘要：目的:探明RAC1蛋白调控阿霉素(DOX)诱导肿瘤转移机制,设计靶向RAC1的小干扰RNA(siRNA)递释系统,抑制DOX治疗诱导的肿瘤皮质间质样(EMT)转化。创新点:探明了DOX通过RAC1蛋白诱导肿瘤细胞发生转移性变化的机制,构建了靶向沉默RAC1蛋白的siRNA递释系统,有效降低了DOX化疗后肿瘤组织转移的风险。方法:选用MCF-7细胞为模型细胞,体外考察DOX相关活性氧(ROS)对RAC1蛋白的调控作用。针对肿瘤细胞内高谷胱甘肽(GSH)浓度的氧化还原条件,选用二硫键为敏感桥链,壳聚糖为亲水性骨架,硬脂胺为疏水基团,构建氧化还原敏感型基因药物载体CSO-ss-SA。选择靶向沉默RAC1的siRNA为模型药物,构建基因药物递释系统CSO-ss-SA/siRNA。考察CSO-ss-SA/siRNA的理化性质、体外敏感释放及细胞摄取。通过免疫荧光染色法、蛋白免疫印迹法和细胞侵袭性实验考察基因药物递释系统的细胞药效。选用Balb/c裸鼠构建MCF-7乳腺肿瘤原位荷瘤动物模型,考察CSO-ss-SA/siRNA对DOX治疗诱导肿瘤组织EMT转化的抑制作用。结论:RAC1是DOX诱导细胞侵袭性的关键蛋白。靶向沉默RAC1的siRNA基因递释系统可在体内外有效抑制DOX治疗诱导的肿瘤组织EMT转化,降低化疗诱导转移的风险。

摘要：The present work deals with the development of controlled release tablets of salbutamol sulphate(SS)using graft copolymers of methyl methacrylate(St-g-PMMA and Ast-g-PMMA)on starch and acetylated *** were evaluated for physical characteristics like hardness,friability,drug release,drug content and weight variations,which fulfilled all the official requirements of tablet dosage *** release rates from formulated matrix tablets were studied at SGF(pH 1.2)followed by SIF(pH 6.8).Drug release from the graft copolymer based tablets was found to be sustained upto the 14 h with>75%drug *** in-vitro release study showed that the graft copolymer based matrix formulations(F3&F4)exhibited highest correlation value(r2)for higuchi kinetic model and Korsmeyer's model with n values between 0.61 and 0.67 proved that release mechanisms were governed by both diffusion and erosion *** was no significant difference in the pharmacokinetic parameters(tmax,Cmax,AUC,Ke,and t1/2)of the graft copolymers matrices and HPMC K100M matrix tablets,indicating their comparable sustained release *** potential of graft copolymers to sustain the drug release is well supported by in-vivo pharmacokinetic studies and their adequate physicochemical properties make them promising excipients for controlled drug delivery system.

摘要：目的磺胺、磺胺嘧啶和氨苯砜是第一批通过破坏叶酸生物合成过程来治疗疟疾的磺胺类药物,叶酸生物合成过程是寄生虫存活的关键。因此,我们旨在通过合理的药物设计方法合成新型N-(2-芳基氨基苯基)-2,3-二苯基喹喔啉-6-磺酰胺衍生物。方法按常规方法合成所有化合物,并用光谱分析(1H核磁共振和质谱)对产物进行表征。使用薄层色谱法(TLC)监测反应进程。分析了所有衍生物在疟原虫半胱氨酸蛋白酶falcipain-2变构位点的有效结合模式。采用肉汤稀释法测定抗菌和抗真菌活性。结果S6(N-(2-噻唑-4-基)-乙酰基-氨基苯基)-2,3-二苯基喹喔啉-6-磺酰胺与S9(N-(1H-苯并[d]咪唑-2-基)氨基苯基)-2,3-二苯基喹喔啉-6-磺酰胺形成5个氢键;S8(N-(2-1H-咪唑-2-基)氨基苯基)-2,3-二苯基喹喔啉-6-磺酰胺和S10(N-(1-苯并[d]咪唑-5-基)氨基苯基)-2,3-二苯基喹喔啉-6-磺酰胺与酶的变构位点形成四个氢键。考虑到与目标酶的对接分数和氢键的形成,新的衍生物被加工用于湿实验室合成。所有新合成的衍生物都具有体外抗疟疾、抗真菌和抗菌活性。与标准品相比,所有衍生物对恶性疟原虫株表现出足够的敏感性。此外,化合物S9和S10显示出最有效的双重抗微生物和抗疟疾活性。它们在分子对接研究中也显示出强大的分子相互作用。结论基于以上结果,我们认为N-(2-芳基氨基苯基)-2,3-二苯基喹喔啉-6-磺酰胺衍生物具有作为抗疟药、抗真菌药和抗菌剂的优异生物潜力。