抗癫痫药物是癫痫患者的首选治疗癫痫手段。全球癫痫发病率的不断提高,给国家、个人和家庭生活等带来较大经济负担。随着越来越多的癫痫患者得到规范化治疗,使得抗癫痫药物临床需求越来越大。突触囊泡蛋白2A(synaptic vesicle protein 2...抗癫痫药物是癫痫患者的首选治疗癫痫手段。全球癫痫发病率的不断提高,给国家、个人和家庭生活等带来较大经济负担。随着越来越多的癫痫患者得到规范化治疗,使得抗癫痫药物临床需求越来越大。突触囊泡蛋白2A(synaptic vesicle protein 2A,SV2A)通过调节神经递质的释放,来维持脑内兴奋性神经递质和抑制性神经递质的平衡。随着SV2A确证为新的抗癫痫靶点,左乙拉西坦和布瓦西坦的上市,抗癫痫靶点和抗癫痫新药进一步丰富。本文围绕抗癫痫药物靶点SV2A以及以SV2A为靶点的上市及在研药物做概述,并对其构效关系进行总结。展开更多
According to the principle of bioisosterism and the Evans′pharmacophore model of 5-HT3 receptor antagonists, twelve derivatives of tetramethylpyrazine were synthesized. The structures of the compounds were confirmed ...According to the principle of bioisosterism and the Evans′pharmacophore model of 5-HT3 receptor antagonists, twelve derivatives of tetramethylpyrazine were synthesized. The structures of the compounds were confirmed by MS, 1H NMR and HRMS. All the target compounds are unreported. The preliminary activity test showed that most of the compounds had fairly potent 5-HT3 receptor antagonistic activities, especially compound 3c. And the conformational analysis showed that the active conformation of the compounds was quite fitted to the Evans′pharmacophore model. This indicates that besides the three pharmacophoric elements, the aromatic ring and the substituents attached may affect the bioactivities of the compounds.展开更多
Gambogic acid （GA, 1）, the most prominent representative of Garcinia natural products, has been reported to be a promising anti-tumor agent. In order to further explore the structure-activity relationship of GA and ...Gambogic acid （GA, 1）, the most prominent representative of Garcinia natural products, has been reported to be a promising anti-tumor agent. In order to further explore the structure-activity relationship of GA and discover novel GA derivatives as anti-tumor agents, 17 novel C-37 modified derivatives of GA were synthesized and evaluated for their in vitro anti-tumor activities against A549, HCT-116, BGC-823, HepG2 and MCF-7 cancer cell lines. Among them, 11 compounds were found to be more potent than GA against some cancer cell lines. Notably, com- pound 8 was almost 5--10 folds more active than GA against A549 and BGC-823 cell lines with the IC50 values of 0.12 μmol·L^-1 and 0.57 μmol·L^-1, respectively. Chemical modification at C-37 position of GA by introducing of hydrophilic amines could lead to increased activity and improved drug-like properties. These findings will enhance our understanding of the structure-activity relationship （SAR） of GA and lead to the discovery of novel GA derivatives as potential anti-tumor agents.展开更多
1, 3, 4-Oxadiazole derivatives(4 a–5 f) were previously synthesized to investigate their anticancer properties.However, studies relating to their antioxidant potential and signal transducer and activator of transcrip...1, 3, 4-Oxadiazole derivatives(4 a–5 f) were previously synthesized to investigate their anticancer properties.However, studies relating to their antioxidant potential and signal transducer and activator of transcription(STAT) inhibition have not been performed. We investigated previously synthesized 1, 3, 4-oxadiazole derivatives(4 a–5 f) for various radical scavenging properties using several in vitro antioxidant assays and also for direct inhibition of STAT3 through molecular docking. The data obtained from various antioxidant assays such as 2, 2,-diphenyl-1-picrylhydrazyl radical(DPPH), nitric oxide, hydrogen peroxide, and superoxide anion radical revealed that among all the derivatives, compound 5 e displayed high antioxidant activities than the standard antioxidant L-ascorbic acid. Additionally, the total reduction assay and antioxidant capacity assay further confirmed the antioxidant potential of compound 5 e. Furthermore, the molecular docking studies performed for all derivatives along with the standard inhibitor STX-0119 showed that binding energy released in direct binding with the SH2 domain of STAT3 was the highest for compound 5 e(-9.91 kcal/mol).Through virtual screening, compound 5 e was found to exhibit optimum competency in inhibiting STAT3 activity. Compound 5 e decreased the activation of STAT3 as observed with Western blot. In brief, compound5 e was identified as a potent antioxidant agent and STAT3 inhibitor and effective agent for cancer treatment.展开更多
Gout is caused by the deposition of uric acid as monosodium urate（MSU）. Chronic hyperuricemia is the necessary condition for MSU deposition, which arises from over-production and/or under-excretion of uric acid. Ren...Gout is caused by the deposition of uric acid as monosodium urate（MSU）. Chronic hyperuricemia is the necessary condition for MSU deposition, which arises from over-production and/or under-excretion of uric acid. Renal under-excretion of uric acid accounts for greater than 90% of the patients with hyperuricemia, making URAT1 inhibitors, which act through uricosuric effect a promising class of urate-lowering therapy（ULT）. This review aims at the summary and discussion of the latest development of URAT1 inhibitors for the treatment of hyperuricemia and gout and providing an insight into their structure-activity relationship（SAR）, which will be helpful to the design of URAT1 inhibitors for both academic research and pharmaceutical industry. The current development pipeline of URAT1 inhibitors is promising and encouraging.展开更多
The support vector classification （SVC） was employed to make a model for classification of antifungal activities of 1-（1H-1,2,4-triazole-l-yl）-2-（2,4-difluorophenyl）-3-substituted-2-propanols triazole derivative...The support vector classification （SVC） was employed to make a model for classification of antifungal activities of 1-（1H-1,2,4-triazole-l-yl）-2-（2,4-difluorophenyl）-3-substituted-2-propanols triazole derivatives. The compounds with high antifungal activities and those with low antifungal activities were compared on the basis of the following molecular descriptors： net atomic charge on the atom N connecting with R, dipole moment and heat of formation, By using the SVC, a mathematical model was constructed, which can predict the antifungal activities of the triazole derivatives, with an accuracy of 91% on the basis of the leave-one-out cross-validation （LOOCV） test, The results indicate that the performance of the SVC model can exceed that of the principal component analysis （PCA） and K-Nearest Neighbor （KNN） models for this real world data set.展开更多
目的对抗肿瘤药物二乙基二氯化锡配合物（Et2SnCl2L）（L=phen，Pphen，DMphen and TMphen）1-4的电子结构和分子性质进行理论研究。方法在B3LYP／6—31G的水平上，采用量子化学密度泛函法进行计算。结果配合物Et2SnCl2（phen）通过两...目的对抗肿瘤药物二乙基二氯化锡配合物（Et2SnCl2L）（L=phen，Pphen，DMphen and TMphen）1-4的电子结构和分子性质进行理论研究。方法在B3LYP／6—31G的水平上，采用量子化学密度泛函法进行计算。结果配合物Et2SnCl2（phen）通过两种方式与DNA结合，一是静电结合，可用静电作用能（Ee）表示氯原子和金属锡原子间的静电作用强度；二是插入结合，配合物的LUMO轨道的能量（εL）、插入配体的电荷（QL）以及插入配体的配位键长（Sn-N）等对配合物与DNA的作用有显著影响。结论对配合物的抗肿瘤活性进行了合理解释并设计了具有较高活性的新配合物5。展开更多
文摘抗癫痫药物是癫痫患者的首选治疗癫痫手段。全球癫痫发病率的不断提高,给国家、个人和家庭生活等带来较大经济负担。随着越来越多的癫痫患者得到规范化治疗,使得抗癫痫药物临床需求越来越大。突触囊泡蛋白2A(synaptic vesicle protein 2A,SV2A)通过调节神经递质的释放,来维持脑内兴奋性神经递质和抑制性神经递质的平衡。随着SV2A确证为新的抗癫痫靶点,左乙拉西坦和布瓦西坦的上市,抗癫痫靶点和抗癫痫新药进一步丰富。本文围绕抗癫痫药物靶点SV2A以及以SV2A为靶点的上市及在研药物做概述,并对其构效关系进行总结。
文摘According to the principle of bioisosterism and the Evans′pharmacophore model of 5-HT3 receptor antagonists, twelve derivatives of tetramethylpyrazine were synthesized. The structures of the compounds were confirmed by MS, 1H NMR and HRMS. All the target compounds are unreported. The preliminary activity test showed that most of the compounds had fairly potent 5-HT3 receptor antagonistic activities, especially compound 3c. And the conformational analysis showed that the active conformation of the compounds was quite fitted to the Evans′pharmacophore model. This indicates that besides the three pharmacophoric elements, the aromatic ring and the substituents attached may affect the bioactivities of the compounds.
基金Acknowledgement This work was supported by the National Natural Science Foundation of China （Nos. 90713038, 21072231, 30873157） and National Major Science and Technology Project of China （Innovation and Development of New Drugs. Nos. 2008ZX09401-001, 2009ZX09501-003）.
文摘Gambogic acid （GA, 1）, the most prominent representative of Garcinia natural products, has been reported to be a promising anti-tumor agent. In order to further explore the structure-activity relationship of GA and discover novel GA derivatives as anti-tumor agents, 17 novel C-37 modified derivatives of GA were synthesized and evaluated for their in vitro anti-tumor activities against A549, HCT-116, BGC-823, HepG2 and MCF-7 cancer cell lines. Among them, 11 compounds were found to be more potent than GA against some cancer cell lines. Notably, com- pound 8 was almost 5--10 folds more active than GA against A549 and BGC-823 cell lines with the IC50 values of 0.12 μmol·L^-1 and 0.57 μmol·L^-1, respectively. Chemical modification at C-37 position of GA by introducing of hydrophilic amines could lead to increased activity and improved drug-like properties. These findings will enhance our understanding of the structure-activity relationship （SAR） of GA and lead to the discovery of novel GA derivatives as potential anti-tumor agents.
基金supported by UGC (University Grant Commission) (F no.- 43-172/2014 (SR))
文摘1, 3, 4-Oxadiazole derivatives(4 a–5 f) were previously synthesized to investigate their anticancer properties.However, studies relating to their antioxidant potential and signal transducer and activator of transcription(STAT) inhibition have not been performed. We investigated previously synthesized 1, 3, 4-oxadiazole derivatives(4 a–5 f) for various radical scavenging properties using several in vitro antioxidant assays and also for direct inhibition of STAT3 through molecular docking. The data obtained from various antioxidant assays such as 2, 2,-diphenyl-1-picrylhydrazyl radical(DPPH), nitric oxide, hydrogen peroxide, and superoxide anion radical revealed that among all the derivatives, compound 5 e displayed high antioxidant activities than the standard antioxidant L-ascorbic acid. Additionally, the total reduction assay and antioxidant capacity assay further confirmed the antioxidant potential of compound 5 e. Furthermore, the molecular docking studies performed for all derivatives along with the standard inhibitor STX-0119 showed that binding energy released in direct binding with the SH2 domain of STAT3 was the highest for compound 5 e(-9.91 kcal/mol).Through virtual screening, compound 5 e was found to exhibit optimum competency in inhibiting STAT3 activity. Compound 5 e decreased the activation of STAT3 as observed with Western blot. In brief, compound5 e was identified as a potent antioxidant agent and STAT3 inhibitor and effective agent for cancer treatment.
基金Supported by Key Projects of Tianjin Science and Technology Support Plan(16YFZCSY00910)Natural Science Foundation of Shandong Province(ZR2015BM028)
文摘Gout is caused by the deposition of uric acid as monosodium urate（MSU）. Chronic hyperuricemia is the necessary condition for MSU deposition, which arises from over-production and/or under-excretion of uric acid. Renal under-excretion of uric acid accounts for greater than 90% of the patients with hyperuricemia, making URAT1 inhibitors, which act through uricosuric effect a promising class of urate-lowering therapy（ULT）. This review aims at the summary and discussion of the latest development of URAT1 inhibitors for the treatment of hyperuricemia and gout and providing an insight into their structure-activity relationship（SAR）, which will be helpful to the design of URAT1 inhibitors for both academic research and pharmaceutical industry. The current development pipeline of URAT1 inhibitors is promising and encouraging.
基金Project supported by the National Natural Science Foundation of China （Grant Nos.20373040, 20503015）
文摘The support vector classification （SVC） was employed to make a model for classification of antifungal activities of 1-（1H-1,2,4-triazole-l-yl）-2-（2,4-difluorophenyl）-3-substituted-2-propanols triazole derivatives. The compounds with high antifungal activities and those with low antifungal activities were compared on the basis of the following molecular descriptors： net atomic charge on the atom N connecting with R, dipole moment and heat of formation, By using the SVC, a mathematical model was constructed, which can predict the antifungal activities of the triazole derivatives, with an accuracy of 91% on the basis of the leave-one-out cross-validation （LOOCV） test, The results indicate that the performance of the SVC model can exceed that of the principal component analysis （PCA） and K-Nearest Neighbor （KNN） models for this real world data set.
文摘目的对抗肿瘤药物二乙基二氯化锡配合物（Et2SnCl2L）（L=phen，Pphen，DMphen and TMphen）1-4的电子结构和分子性质进行理论研究。方法在B3LYP／6—31G的水平上，采用量子化学密度泛函法进行计算。结果配合物Et2SnCl2（phen）通过两种方式与DNA结合，一是静电结合，可用静电作用能（Ee）表示氯原子和金属锡原子间的静电作用强度；二是插入结合，配合物的LUMO轨道的能量（εL）、插入配体的电荷（QL）以及插入配体的配位键长（Sn-N）等对配合物与DNA的作用有显著影响。结论对配合物的抗肿瘤活性进行了合理解释并设计了具有较高活性的新配合物5。
