摘要：In order to investigate the effect of different C4 linkage moieties on the cytotoxicity of podophyllotoxin derivatives, novel 4-N- and 4-C-substituted 4＇-O-demethylepipodophyllotoxin derivatives were designed and synthesized. All the compounds were tested against A549 and MCF-7 tumor cells in vitro, and six compounds showed significant cytotoxicity. The most active compound 9f was superior to GL-331, and exhibited potent cytotoxicity with IC50 value at 10^-7 mol/L level.

摘要：Purpose Skin pigmentation disorders,such as vitiligo and melasma,are difficult to diagnose in the early stages,but abnor-mal tyrosinase levels and tyrosinase activity are potential *** resorufin-based fluorescence probes(RBFPs)have been designed to detect tyrosinase in tumors,but they have not been used in skin pigmentation *** this study,one of these RBFPs(synthesized by resorufin salt coupled with 3-(bromomethyl)phenol)was evaluated *** The RBFP was tested in different kinds of mouse and human skin cells,as well as in in vivo models,including zebrafish,guinea pigs,and Sprague-Dawley *** addition,small interfering RNAs(siRNAs),kojic acid,and 1-phenyl-2-thiourea(PTU)were used to inhibit tyrosinase levels or tyrosinase *** This probe successfully detected tyrosinase and emitted red fluorescence in melanoma cells and *** was also observable in zebrafish and on the skin of guinea pigs when using the *** mouse and human cells,the RBFP showed good selectivity to ***,in the case of decreased tyrosinase levels or activity caused by siRNAs,kojic acid,or PTU,the probe was sensitive to these ***,the RBFP showed no toxic effects at concentrations of<20μmol/L,both in vitro and in *** Our findings indicate the value and limitations of the RBFP in tyrosinase detection,but suggest the need for further improvement of fluorescent probes in the diagnosis of skin pigmentation disorders.

摘要：Proprotein convertase subtilisin/kexin type 9(PCSK9)modulators may attenuate PCSK9-induced low-density lipoprotein receptor(LDLR)degradation in lysosome and promote the clearance of circulating low-density lipoprotein cholesterol(LDL-C).A novel series of tetrahydroprotoberberine derivatives(THPBs)were designed,synthesized,and evaluated as PCSK9 modulators for the treatment of *** them,eight compounds exhibited excellent activities in downregulatinghepatic PCSK9 expression better than berberine in HepG2 *** addition,five compounds 15,18,22,(R)-22,and(S)-22 showed better performance in the low-density lipoprotein,labeled with 1,1’-dioctadecyl-3,3,3’,3’-tetramethyl-indocarbocyanine perchlorate(Dil-LDL)uptake assay,compared with berberine at the same *** 22,selected for in vivo evaluation,demonstrated significant reductions of total cholesterol(TC)and LDL-C in hyperlipidemic hamsters with a good pharmacokinetic *** exploring of the lipid-lowering mechanism showed that compound 22 promoted hepatic LDLR expression in a dose-dependent manner in HepG2 *** results of human ether-ago-go related gene(hERG)inhibition assay indicated the potential druggability for compound 22,which is a promising lead compound for the development of PCSK9 modulator for the treatment of hyperlipidemia.

摘要：Dear Editor,Since the declaration of COVID-19 as a global pandemic on March 11,2020,this pandemic has been circulating for 17 months throughout the world,leading to more than 200 million infections and nearly 4A million deaths as of August 15,*** pathogen of COVID-19 is a novel coronavirus named SARS-CoV-2,which shares ～79％ genome sequence identity with SARS-CoV.1 At the early stage of the COVID-19 outbreak,SARS-CoV-2 caused great panic in the hardest-hit areas due to its high transmissibility and *** fight the COVID-19 crisis,drug repurposing was immediately pursued in order to find potential *** now,though some treatment options are available,there still lack effective antiviral *** is considered as the best way to control this global pandemic,but the emerging SARS-CoV-2 variants pose a great challenge to the protective efficacy of the existing ***,in the long run,finding an effective antiviral medication against the SARS-CoV-2 infection is a pressing need.

摘要：Thanks to the fast improvement of the computing power and the rapid development of the computational chemistry and biology,the computer-aided drug design techniques have been successfully applied in almost every stage of the drug discovery and development pipeline to speed up the process of research and reduce the cost and risk related to preclinical and clinical *** to the development of machine learning theory and the accumulation of pharmacological data, the artificial intelligence(AI) technology, as a powerful data mining tool, has cut a figure in various fields of the drug design, such as virtual screening,activity scoring, quantitative structure-activity relationship(QSAR) analysis, de novo drug design, and in silico evaluation of absorption, distribution, metabolism, excretion and toxicity(ADME/T) properties. Although it is still challenging to provide a physical explanation of the AI-based models, it indeed has been acting as a great power to help manipulating the drug discovery through the versatile frameworks. Recently, due to the strong generalization ability and powerful feature extraction capability,deep learning methods have been employed in predicting the molecular properties as well as generating the desired molecules,which will further promote the application of AI technologies in the field of drug design.

摘要：A series of novel L-amino acid esters prodrugs of acyclic nucleoside phosphonates was synthesized and their anti-HBV activity was evaluated in HepG2 2.2.15 cells. Compound 1d exhibited more potent anti-HBV activity and lower cytotoxicity than those of adefovir dipivoxil with EC50 and CC50 values of 0.207 μmol/L and 2530 μmol/L, respectively.

摘要：To discover novel strobilurins analogues with good and broad spectrum activity,a series of nove 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides-based strobilurins was designed,synthesized,and tested agains various phytopathogenic *** *** 7k exhibited substantial and broad spectrum antifungal activities against the tested phytopathogenic fungi,especially compound 7b,which showed 100%,80%,90%,and 90%antifungal activity(in virto)against Erysiphe graminis(***),Puccinia sorghi Schw:(P sorghi Schw.)Colletotrichum lagenarium(***),and Pseudoperonospora cubensis(P cubensis)at 300 ug/mL,*** or comparable to the positive control ***,compound 7b exhibited 85%greenhouse *** activity(in vivo)against *** even at 0.2μg/mL,equal to azoxystrobin(90%)and trifloxystrobin(90%)Meanwhile,compound 7b against P cubensis displayed 70%and 55%greenhouse inhibition activity(in vivo)at 1.56 and 0.2μg/mL,respectively,much better than those of azoxystrobin and trifloxystrobin(both 0%at 1.56 and 0.2 ug/mL).Therefore,compound 7b could be considered as the most promising fungicidal candidate for furthe ***,based on the effective concentration(ECso)against ***,the built CoMSIA model provided the useful reference for the further structural optimization design.

摘要：Dipeptidyl peptidase 4(DPP-4)is a clinically validated target for the treatment of type 2 diabetes mellitus(T2DM).To discover novel and potent DPP-4 inhibitors,three series of compounds were designed and synthesized in this study based on our previously identified novel scaffold of 2-phenyl-3,4-dihydro-2H-benzo[f]*** the designed compounds,41d-1 was the most po tent one with an IC_(50) value of 16.00 nM.

摘要：多模态疗法是结合多种疗法治疗通常复杂而隐蔽的肿瘤组织的最有希望的策略之一.尽管多功能纳米材料已被设计用于构建多模态疗法,但普遍存在的各组成部分之间的不充分协调可能导致协同治疗效果不佳,并妨碍其充分实现临床潜力.在此,受可控“集束炸弹”模型的启发,我们设计了一种智能、生物相容、多功能的纳米工厂系统(PDA@GOx@MnO_(2)-PEG),它封装了多种纳米试剂,以达到对肿瘤组织的高破坏效率.刺激反应性的外层二氧化锰作为“炸弹”的外壳可触发级联催化反应,并与GOx形成一个自给自足的环形催化链.PDA作为一种具有良好蛋白质携带能力的基质,实现了高的GOx负载.同时,其高效的光热转换效率显示了低温(~45℃)进一步提高GOx酶活性的潜力.值得注意的是,内部的GOx就像一个“子炸弹”,通过控制释放来增加肿瘤缺氧部位的积累,并在充足的氧气和低热度的帮助下充分发挥其葡萄糖消耗能力进行饥饿治疗.在这个体系中,各种纳米试剂相互配合,层层推进,充分发挥其威力,形成了一个自给自足的纳米工厂模型,通过协同策略实现了良好的低温光热-饥饿协同治疗.此外,该纳米复合材料表现出三态成像能力,可用于敏感诊断和实时监控治疗.这项研究为设计生物相容性和智能治疗纳米平台提供了新的见解,使精准医疗中的多模式治疗效果最大化.

摘要：目的为了解决传统fMRI快速成像脉冲序列存在的空间分辨率相对低和时间分辨率低的固有问题,提出使用高时间分辨率脑皮层血氧动态光传感反馈技术,实现高空间分辨率MR成像。方法多周期事件刺激实验产生的脑皮层血氧动态响应,由MRI线圈时分式频域数据采集,成像序列磁脉冲发射由光传感反馈控制;设计了光子在3D MRI数字化脑皮层多光学性质介质中迁移的蒙特卡罗程序。结果脑皮层血氧响应状态及其重现状态能够精确光学监测,时分式k空间覆盖策略(TDC)成功采集高频数据。结论该理论和算法具有高时空分辨率的成像性能优点,为MRI时空成像提供了新的有效手段。