A review on flavones targeting serine/threonine protein kinases for potential anticancer drugs

Protein kinases have been important targets for antitumor targets due to their key roles in regulating multiple cell signaling pathways. Numerous compounds containing flavonoid scaffold as an indispensable anchor have been found to be potent inhibitors of protein kinases. Some of these flavonoids have been in clinical research as protein kinases inhibitors. Thus, the present review mainly focuses on the structural requirement for anticancer potential of flavone derivatives targeting several key serine/threonine protein kinases. This information may provide an opportunity to scientists of medicinal chemistry to design multi-functional flavone derivatives for the treatment of cancer.     

Development of an anti-hepatitis B virus (HBV) agent through the structure-activity relationship of the interferon-like small compound CDM-3008

Hepatitis B, a viral infectious disease caused by hepatitis B virus (HBV), is a life-threatening disease that leads liver cirrhosis and liver cancer. Because the current treatments for HBV, such as an interferon (IFN) formulation or nucleoside/nucleotide analogues, are not sufficient, the development of a more effective agent for HBV is urgent required.CDM-3008 (1, 2-(2,4-bis(trifluoromethyl)imidazo[1,2-a][1,8]naphthyridin-8-yl)-1,3,4-oxadiazole) (RO8191)) is a small molecule with an imidazo[1,2-a][1,8]naphthyridine scaffold that shows anti-HCV activity with an IFN-like effect. Here, we report that 1 was also effective for HBV, although the solubility and metabolic stability were insufficient for clinical use. Through the structure-activity relationship (SAR), we discovered that CDM-3032 (11, N-(piperidine-4-yl)-2,4-bis(trifluoromethyl)imidazo[1,2-a][1,8]naphthyridine-8-carboxamide hydrochloride) was more soluble than 1 (>30?mg/mL for 11 versus 0.92?mg/mL for 1). In addition, the half-life period of 11 was dramatically improved in both mouse and human hepatic microsomes (T1/2, >120?min versus 58.2?min in mouse, and >120?min versus 34.1?min in human, for 11 and 1, respectively).     

Dual inhibitors of RAF-MEK-ERK and PI3K-PDK1-AKT pathways: Design,synthesis and preliminary anticancer activity studies of 3-substituted-5-(phenylamino) indolone derivatives

The dysfunction and mutual compensatory activation of RAF-MEK-ERK and PI3K-PDK1-AKT pathways have been demonstrated as the hallmarks in several primary and recurrent cancers. The strategy of concurrent blocking of these two pathways shows clinical merits on effective cancer therapy, such as combinatory treatments and dual-pathway inhibitors. Herein, we report a novel prototype of dual-pathway inhibitors by means of merging the core structural scaffolds of a MEK1 inhibitor and a PDK1 inhibitor. A library of 43 compounds that categorized into three series (Series I–III) was synthesized and tested for antitumor activity in lung cancer cells. The results from structure-activity relationship (SAR) analysis showed the following order of antitumor activity that 3-hydroxy-5-(phenylamino) indolone (Series III)?>?3-alkenyl-5-(phenylamino) indolone (Series I)?>?3-alkyl-5-(phenylamino) indolone (Series II). A lead compound 9za in Series III showed most potent antitumor activity with IC₅₀ value of 1.8?±?0.8?µM in A549 cells. Moreover, antitumor mechanism study demonstrated that 9za exerted significant apoptotic effect, and cellular signal pathway analysis revealed the potent blockage of phosphorylation levels of ERK and AKT in RAF-MEK-ERK and PI3K-PDK1-AKT pathways, respectively. The results reported here provide robust experimental basis for the discovery and optimization of dual pathway agents for anti-lung cancer therapy.     

Substrate specificity of tuliposide-converting enzyme,a unique non-ester-hydrolyzing carboxylesterase in tulip: Effects of the alcohol moiety of substrate on the enzyme activity

6-Tuliposides A (PosA) and B (PosB) are glucose esters accumulated in tulip (Tulipa gesneriana) as major defensive secondary metabolites. Pos-converting enzymes (TgTCEs), which we discovered previously from tulip, catalyze the conversion reactions of PosA and PosB to antimicrobial tulipalins A (PaA) and B (PaB), respectively. The TgTCEs, belonging to the carboxylesterase family, specifically catalyze intramolecular transesterification, but not hydrolysis. In this report, we synthesized analogues of Pos with various alcohol moieties, and measured the TgTCE activity together with a determination of the kinetic parameters for these analogues with a view to probe the substrate recognition mechanism of the unique non-ester-hydrolyzing TgTCEs. It was found that d-glucose-like structure and number of the hydroxyl group in alcohol moiety are important for substrate recognition by TgTCEs. Among the analogues examined, 1,2-dideoxy analogues of PosA and PosB were found to be recognized by the TgTCEs more specifically than the authentic substrates by lowering K_m values. The present results will provide a basis for designing simple, stable synthetic substrate analogues for crystallographic analysis of TgTCEs.     

工业蛋白质构效关系的计算生物学解析

工业催化用酶已经成为现代生物制造技术的核心"芯片"。不断设计和研发新型高效的酶催化剂是发展工业生物技术的关键。工业催化剂创新设计的科学基础是对酶与底物的相互作用、结构与功能关系及其调控机制的深入剖析。随着生物信息学和智能计算技术的发展,可以通过计算的方法解析酶的催化反应机理,进而对其结构的特定区域进行理性重构,实现酶催化性能的定向设计与改造,促进其工业应用。聚焦工业酶结构-功能关系解析的计算模拟和理性设计,已成为工业酶高效创制改造不可或缺的关键技术。本文就各种计算方法和设计策略以及未来发展趋势进行简要介绍和讨论。     

拉萨河流域植物群落的数量分类与排序

青藏高原植物群落空间分异格局是异质生境条件下物种性状、种间相互作用等生态学过程共同作用的结果,对其分析有助于深入理解群落形成与环境因子之间的关系。基于拉萨河流域自然植被样带调查,采用双向指示种分析(TWINSPAN)和典范对应分析(CCA)等方法,探讨了群落的结构组成及影响其结构分异的主导环境因子。结果表明:(1) TWINSPAN数量分类将拉萨河流域草地系统划分成12个群系类型,即圆叶合头菊+唐古拉翠雀花群系;紫花针茅群系;青藏臺草群系;雪层杜鹃+鲜卑花-西藏嵩草群系;高山嵩草群系;小叶金露梅群系;硬叶柳+杯腺柳群系;水栒子+拱枝绣线菊-高山嵩草群系;绢毛蔷薇-冷蒿+白草群系;大果圆柏-垂穗披碱草群系;铺地柏-藏橐吾+高原荨麻群系;醉鱼草+砂生槐群系。12种群系类型包含了较多的植被类型,包括高寒灌丛草甸、高寒灌丛草原、稀树草原、高寒草甸和高寒草原等。(2) CCA排序表明:影响拉萨河流域植物群系分布的主要环境因子是年均温度、海拔和经度和纬度,其次是年均降雨量。(3) TWINSPAN分类与CCA排序结合反映了群系分布格局变异与环境因子之间的关系,可为拉萨河流域草地的保护和可持续利用,以及相关的植被群落研究提供参考。     

生态系统服务权衡与协同关系及驱动力——以江苏省太湖流域为例

生态系统服务权衡与协同关系研究是生态系统综合管理的前提。以太湖流域江苏省为例,通过空间显示的生物物理模型计算氮、磷净化、水量供给及土壤保持4种服务指标,借助GIS空间分析表征氮、磷指标与其他指标之间关系,并利用多元Logistic模型定量识别主导驱动力。结果表明:2000到2010年间,各指标的单位面积年均值呈现不同程度的变化,氮输出指标先增加后略下降,磷输出指标逐渐增加,水量供给先下降后上升,土壤保持逐渐下降,并且服务指标的空间格局显著差异。氮、磷净化与水量供给关系在空间上表现为广泛分布的权衡及协同变化区,但与土壤保持的关系不明显,氮、磷之间主要为协同变化关系。氮净化与水量供给的正向主导驱动力为城镇建设用地和农村居民点密度,而植被覆盖度和水网密度具有显著负作用。氮、磷关系的主要影响因素为植被覆盖度,其次是耕地及林地比例,且均起到正向促进作用。主导驱动力识别有助于明确生态系统服务间关系的作用机制,为区域环境管理及生态保护规划提供科学依据。     

VU6005806/AZN-00016130, an advanced M4 positive allosteric modulator (PAM) profiled as a potential preclinical development candidate

This letter describes progress towards an M₄ PAM preclinical candidate that resulted in the discovery of VU6005806/AZN-00016130. While the thieno[2,3-c]pyridazine core has been a consistent feature of key M₄ PAMs, no work had previously been reported with respect to alternate functionality at the C3 position of the pyridazine ring. Here, we detail new chemistry and analogs that explored this region, and quickly led to VU6005806/AZN-00016130, which was profiled as a putative candidate. While, the β-amino carboxamide moiety engendered solubility limited absorption in higher species precluding advancement (or requiring extensive pharmaceutical sciences formulation), VU6005806/AZN-00016130 represents a new, high quality preclinical in vivo probe.     

Design,synthesis and evaluation of biphenyl imidazole analogues as potent antifungal agents

To further explore the structure activity relationships (SARs) of our previously discovered antifungal lead compound (1), a series of biphenyl imidazole analogues were designed, synthesized and evaluated for their in vitro antifungal activity. Many of the synthesized compounds showed excellent activity against Candida albicans and Candida tropicalis. Among these compounds, 2-F substituted analogue 12m displayed the most remarkable in vitro activity against C. albicans, C. neoformans, A. fumigatus and fluconazole-resistant C. alb. strains, which is superior or comparable to the activity of the reference drugs fluconazole and itraconazole. Notably, the compound 12m exhibited low inhibition profiles for various human cytochrome P450 isoforms and showed low toxicity to mammalian A549 cells and U87 cells. The SARs and binding mode established in this study will be useful for further lead optimization.     

Ketamine esters and amides as short-acting anaesthetics: Structure-activity relationships for the side-chain

N-Aliphatic ester analogues of the non-opioid ketamine (1) retain effective anaesthetic/analgesic properties while minimising ketamine’s psychomimetic side-effects. We show that the anaesthetic/analgesic properties of these ester analogues depend critically on the length (from 2 to 4 carbons), polarity and steric cross-section of the aliphatic linker chain. More stable amide and ethylsulfone analogues generally showed weaker anaesthetic/analgesic activity. There was no correlation between the anaesthetic/analgesic properties of the compounds and their binding affinities for the N-methyl-d-aspartate (NMDA) receptor.