Discovery of novel 4-aryl-thieno[1,4]diazepin-2-one derivatives targeting multiple protein kinases as anticancer agents

A series of 4-aryl-thieno[1,4]diazepin-2-one were synthesized and evaluated for their antiproliferative activities against the A375P melanoma and U937 hematopoietic cell lines. Several compounds showed very potent antiproliferative activities toward both cell lines and the activities were better than that of sorafenib, the reference standard. Derivatives were made as amide (8a–8i, 9a–9m) and urea (10a–10d, 11a–11d) with diverse hydrophobic moieties. One of the most potent inhibitor 10d, 1-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(4-(2-oxo-2,3-dihydro-1H-thieno [3,4-b][1,4]diazepin-4-yl)phenyl)urea was found to be very potent inhibitor of multi-protein kinases including FMS kinase (IC₅₀?=?3.73?nM) and is a promising candidate for further development in therapeutics for cancer.     

Optimized synthesis and antiproliferative activity of desTHPdactylolides

Dactylolide and certain analogues are attractive targets for study due to their structural resemblance to zampanolide, a very promising anticancer lead compound and a unique covalent-binding microtubule stabilizing agent. The primary goal of this project is identification and synthesis of simplified analogues of dactylolide that would be easier to prepare and could be investigated for antiproliferative activity in comparison with zampanolide. Extension of Almann’s concept of a simplified zampanolide analogue to dactylolide in the form of desTHPdactylolide was attractive not only for reasons of synthetic simplification but also for the prospect that analogues of dactylolide could be prepared in both (17S) and (17R) configurations. Since Altmann’s overall yield for the six-step procedure leading to the C9–C18 fragment of desTHPdactylolide was only 8.7%, a study focused on optimized synthesis and antiproliferative evaluation of each enantiomer of desTHPdactylolide was initiated using Altmann’s route as a framework. To this end, two optimized approaches to this fragment C9–C18 were successfully developed by us using allyl iodide or allyl tosylate as the starting material for a critical Williamson ether synthesis. Both (17S) and (17R) desTHPdactylolides were readily synthesized in our laboratory using optimized methods in yields of 37–43%. Antiproliferative activity of the pair of enantiomeric desTHPdactylolides, together with their analogues, was evaluated in three docetaxel-sensitive and two docetaxel-resistant prostate cancer cell models using a WST-1 cell proliferation assay. Surprisingly, (17R) desTHPdactylolide was identified as the eutomer in the prostate cancer cell models. It was found that (17S) and (17R) desTHPdactylolide exhibit equivalent antiproliferative potency towards both docetaxel-sensitive (PC-3 and DU145) and docetaxel-resistant prostate cancer cell lines (PC-3/DTX and DU145/DTX).     

外来入侵植物意大利苍耳的传粉生态学特性

从开花物候、花粉活力、柱头可受性、传粉媒介、花粉散布距离、雄性、雌性功能以及繁育系统等方面系统地研究了意大利苍耳的传粉生态学特性,旨在为揭示该物种成功入侵的机理提供科学依据。研究结果显示:意大利苍耳种群的花期较长,雌花花期可达40d,雄花花期可达30d。其雄性和雌性功能都很强,意大利苍耳单株雄花序和花粉量分别高达3847个/株和37903037粒/株,单株雌花序和单株胚珠数高达3847个/株和7694枚/株,种群平均结实率高达80.59%,即平均每株个体能形成6200枚成熟的果实。花粉活力的日变化呈单峰型曲线,早晨和傍晚的花粉活力最低,14:00时的活力高达99%。雌蕊柱头一经伸出总苞即具有可受性,可受期长达7d,开花后的3—4d柱头的可受性最强。意大利苍耳为风媒传粉植物,在4.5km/h的微风条件下,其花粉的散布距离可达45m,大量的花粉集中分布在距花粉源0—20m的范围内,这对于往往高密度连片分布的意大利苍耳种群来说无疑是一种高效的传粉策略。意大利苍耳的交配系统灵活多样,盛花期自然结实率达到100%,套袋试验结果表明该植物自交亲和,自株自然授粉的结实率高达93%。表明较长的花期、大量的雌雄花序及花粉数量、较高的花粉活力、较长的柱头可授期、较远的花粉风媒散布距离、混合交配系统、以及较高的结实率是意大利苍耳繁殖成功的重要保障,也是其成功入侵的重要原因。     

Neurotoxic,cytotoxic, apoptotic and antiproliferative effects of some marine algae extracts on the NA2B cell line

Oxidative stress contributes to cancer pathologies and to apoptosis. Marine algae exhibit cytotoxic, antiproliferative and apoptotic effects; their metabolites have been used to treat many types of cancer. We investigated in culture extracts of Petalonia fascia, Jania longifurca and Halimeda tuna to determine their effects on mouse neuroblastoma cell line, NA2B. NA2B cells were treated with algae extracts, and the survival and proliferation of NA2B cells were assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The effects of algae extracts on oxidative stress in NA2B cells also were investigated using nitric oxide synthase (NOS) immunocytochemistry and apoptosis was assessed using terminal deoxynucleotidyl transferase dUTP nick end labeling. We observed significant neurite inhibition with moderate damage by the neurotoxicity-screening test (NST) at IC₅₀ dilutions of the extracts. MTT demonstrated that J. longifurca extracts were more toxic than P. fascia and H. tuna extracts. We found an increase of endothelial and inducible NOS immunostaining for oxidative stress and TUNEL analysis revealed increased apoptosis after application of extract. Our findings suggest that the algae we tested may have potential use for treatment of cancer.     

警惕杰克贝尔氏粉蚧Pseudococcus jackbeardsleyi Gimpel & Miller在中国大陆扩散

杰克贝尔氏粉蚧原产于新热带区,是新近传入中国大陆的一种外来生物,主要危害水果、蔬菜、园林植物和粮食作物。该虫于2012年首次在我国海南乐东被发现,寄主植物为丝瓜;之后又在新疆乌鲁木齐的花卉市场被发现,寄主植物为来自广东或福建的盆景人参榕。杰克贝尔氏粉蚧寄主范围广泛,涉及50科200多种,且极易随农产品的贸易活动进行远距离传播扩散,对我国农林产业的安全生产构成了潜在巨大威胁。概述了杰克贝尔氏粉蚧的地理分布和生物学特征,浅析了其在我国的传播扩散趋势,并从物种鉴定、生物防治和检验检疫处理等方面提出了防控建议,以期为有效预防和控制该种粉蚧在我国的进一步传播扩散提供参考。     

Habitat properties and plant traits interact as drivers of non‐native plant species’ seed production at the local scale

To answer the long‐standing question if we can predict plant invader success based on characteristics of the environment (invasibility) or the invasive species (invasiveness), or the combination of both, there is a need for detailed observational studies in which habitat properties, non‐native plant traits, and the resulting invader success are locally measured. In this study, we assess the interaction of gradients in the environmental and trait space on non‐native species fitness, expressed as seed production, for a set of 10 invasive and noninvasive non‐native species along a wide range of invaded sites in Flanders. In our multidimensional approach, most of the single environmental gradients (temperature, light availability, native plant species diversity, and soil fertility) and sets of non‐native plant traits (plant size, photosynthesis, and foliar chemical attributes) related positively with invader seed production. Yet correlation with seed production was much stronger when several environmental gradients were assessed in interaction, and even more so when we combined plant traits and habitat properties. The latter increased explanatory power of the models on average by 25% for invasive and by 7% for noninvasive species. Additionally, we report a 70‐fold higher seed production in invasive than in noninvasive species and fundamentally different correlations of seed production with plant traits and habitat properties in noninvasive versus invasive species. We conclude that locally measured traits and properties deserve much more attention than they currently get in invasion literature and thus encourage further studies combining this level of detail with the generality of a multiregion and multispecies approach across different stages of invasion.     

Functional expression of the plant K channel KAT1 in insect cells

Following the biophysical analysis of plant K⁺ channels in their natural environment, three members from the green branch of the evolutionary tree of life KAT1, AKT1 and KST1 have recently been identified on the molecular level. Among them, we focused on the expression and characterization of the Arabidopsis thaliana K⁺ channel KAT1 in the insect cell line Sf9. The infection of Sf9 cells with KAT1-recombinant baculovirus resulted in functional expression of KAT1 channels, which was monitored by inward-rectifying, K⁺-selective (impermeable to Na⁺ and even NH₄⁺) ionic conductance in whole-cell patch-clamp recordings. A voltage threshold as low as −60 to −80 mV for voltage activation compared to other plant inward rectifiers in vivo, and to in vitro expression of KAT1 in Xenopus oocytes or yeast, may be indicative for channel modulation by the expression system. A rise in cytoplasmic Ca²⁺ concentration (up to 1 mM), a regulator of the inward rectifier in Vicia faba guard cells, did not modify the voltage dependence of KAT1 in Sf9 cells. The access to channel function on one side and channel protein on the other make Sf9 cells a suitable heterologous system for studies on the biophysical properties, post-translational modification and assembly of a green inward rectifier.