Synthesis and docking study of 2-phenylaminopyrimidine Abl tyrosine kinase inhibitors

Six analogs of imatinib, an Abl kinase inhibitor clinically used as a first-line therapeutic agent for chronic myeloid leukaemia (CML), have been synthesized and characterized. And their potency as Abl kinase inhibitors have been screened by a robust virtual screening method developed based on the crystal structure (PDB code 2hyy) of Abl-imatinib complex using Surflex-Docking. The docking results are consistent with the inhibitory potency of the compounds characterized by MS method. And the H-bonds between imatinib analogs and Thr315 and Met318 residues in Abl kinase are shown to be crucial for achieving accurate poses and high binding affinities for the ATP-competitive kinase inhibitors.     

A novel series of IKKβ inhibitors part II: description of a potent and pharmacologically active series of analogs

A novel series of (E)-1-((2-(1-methyl-1H-imidazol-5-yl) quinolin-4-yl) methylene) thiosemicarbazides was discovered as potent inhibitors of IKKβ. In this Letter we document our efforts at further optimization of this series, culminating in 2 with submicromolar potency in a HWB assay and efficacy in a CIA mouse model.     

Substrate-controlled chemoselective synthesis and potent cytotoxic activity of novel 5,6,7-triarylpyrido[2,3-d]pyrimidin-4-one derivatives

The substrate-controlled chemoselective synthesis of novel 5,6,7-triarylpyrido[2,3-d]pyrimidin-4-one derivatives has been successfully achieved via microwave-assisted three-component reactions of 2,6-diaminopyrimidin-4(3H)-one, aromatic aldehydes and 1,2-diphenylethanone. This approach has the prominent features of chemoselectivity, diasteroselectivity, atom economy, short reaction time, high yield as well as operational simplicity. Moreover, these novel compounds were subject to the test of in vitro cytotoxicity to carcinoma SW1116 and SGC7901 cells. Most of the tested compounds showed significant cytotoxicity to SW1116 cells and compound 4b exhibited more potent and efficacious cytotoxicity to SGC7901 cells than doxorubicin hydrochloride as positive control.     

Efficient synthesis and biological evaluation of 1,3-benzenedicarbonyl dithioureas

The synthesis and biological activity of 1,3-benzenedicarbonyl dithioureas are described. Bioassay results indicated that these compounds exhibited cytotoxicity against various cancer cells. For example, compounds 4a showed the best inhibition activities against KB and CNE2 with IC₅₀ 10.72 and 9.91 μM, respectively.     

Discovery of INCB10820/PF-4178903, a potent, selective, and orally bioavailable dual CCR2 and CCR5 antagonist

We report the discovery of a potent, selective, and orally bioavailable dual CCR2 and CCR5 antagonist (3S,4S)-N-[(1R,3S)-3-isopropyl-3-({4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)cyclopentyl]-3-methoxytetrahydro-2H-pyran-4-amine (19). After evaluation in 28-day toxicology studies, compound 19 (INCB10820/PF-4178903) was selected as a clinical candidate.     

Discovery of a stable macrocyclic o-aminobenzamide Hsp90 inhibitor which significantly decreases tumor volume in a mouse xenograft model

An extension of our previously reported series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. Addition of a second methyl group to the tether provided analogs that show increased potency in binding as well as cell-proliferation assays and, more importantly, are stable toward microsomes. We wish to disclose the discovery of a macrocycle which showed impressive biomarker activity 24-h post dosing and which demonstrated prolonged exposure in tumors. When studied in a lung cancer xenograft model, the compound demonstrated significant tumor size reduction.     

小型生物反应器内人参不定根的人参皂苷累积

对小型生物反应器(3~10 L)培养人参不定根的生长和人参皂苷(Rg1、Re、Rb1)的累积规律,以及蔗糖浓度、初始接种量对其生长和人参皂苷累积的影响进行研究。结果表明:小型生物反应器内人参不定根的最佳收获周期为7周。初始接种量和蔗糖浓度影响生物反应器内人参不定根的生长和人参皂苷的累积,20或40 g/L蔗糖对人参不定根的生长和人参皂苷的累积优于60 g/L蔗糖;5和10 L生物反应器内最佳初始接种量分别为15和30g,其不定根的生长量分别为9.29和19.17 g,人参皂苷含量分别为5.16和4.58 mg/g。生物反应器内培养7周的人参与栽培4年的人参相比,人参皂苷Rg1和Re含量相差不大,但栽培人参中Rb1的含量远高于生物反应器中所培养的人参不定根。     

云雾山铁杆蒿茎叶浸提液对封育草地四种优势植物的化感效应

为了揭示铁杆蒿群落在植被演替中的作用,通过研究铁杆蒿茎叶浸提液对铁杆蒿草地4种优势植物(百里香、大针茅、本氏针茅和赖草)的种子萌发及幼苗生长的干扰,结果表明:高浓度的铁杆蒿浸提液(甲醇浸提液和水浸提液)使得百里香、大针茅、本氏针茅和赖草的种子发芽指数降低,发芽率、芽长和根长低于对照,种子平均发芽时间延长达1.13-2.16 d。而低浓度浸提液(0.005 g/mL)使得百里香的发芽要高于对照11.63%(水浸提液)、15.12%(甲醇浸提液)。在幼苗生长期,铁杆蒿浸提液对4种受试植物幼苗芽和根的生长受到不同程度的抑制,不同浓度的浸提液对植物的化感作用强度不同,随浓度的增加,抑制作用越强,0.1 g/mL相对其他浓度有显著性差异;其中0.005 g/mL浸提液对本氏针茅和赖草的幼苗生长有促进作用,幼根生长高出对照19.00%、16.06%,水浸提液对幼芽促进了2.33%、9.06%,在0.1 g/mL浓度下,本氏针茅或大针茅的生长完全受到抑制,芽长和根长抑制率为100%;同一浓度下的不同浸提液对植物的抑制作用也不同,其中百里香对铁杆蒿浸提液的敏感度是最低的;甲醇浸提液的化感作用要强于水浸提液。在封育过程中,百里香群落向铁杆蒿群落的过渡,铁杆蒿的化感作用是该草地演替的一个重要影响因子。     

渭北旱塬苹果园地产量和深层土壤水分效应模拟

为了研究实时气象条件下渭北旱塬不同生长年限苹果园地产量变化趋势和深层土壤水分变化规律,在模型适用性与模拟精度验证基础上,应用WinEPIC模型模拟研究了1962—2001年期间洛川旱塬苹果园地产量演变动态和深层土壤水分效应。结果表明：(1) 在模拟研究期间,洛川旱塬4—40年生苹果园产量整体上呈波动性下降趋势,初期产量逐渐增加,11—23年生达到最大值(平均为28.8 t/hm2),之后随降水量年际波动呈现出明显的波动性降低趋势。(2) 40年间苹果园地遭受的干旱胁迫日数呈波动性上升趋势,与年降水量波动趋势相反。(3) 1—15年生期间苹果园地平均年耗水量高于同期年降水量,导致苹果园地0—10 m土层土壤强烈干燥化,逐月土壤有效含水量波动性降低,1—10年生、11—20年生和21—40年生期间发生土壤干燥化并且程度逐渐加剧,但干燥化速率逐渐减缓,土壤干燥化速率分别为95.4 mm/a、12 mm/a和1.5 mm/a。(4) 随生长年限的延长,苹果园地0—10 m土层土壤湿度逐渐降低、土壤干层分布深度逐渐加大,在14年生时超过了10 m,20年生以后2—10 m 土层形成稳定的土壤干层。因此,基于土壤水分利用的苹果生长与果园利用的合理年限为20 a,最长不宜超过23 a。     

胡杨异形叶叶绿素荧光特性对高温的响应

胡杨(Populus euphratica Oliv)是塔里木极端干旱荒漠区优势乔木树种,由于其生长在荒漠环境中,极端高温远高于其它地区,因此研究胡杨对高温胁迫的响应特征对于解释胡杨的抗逆机理与生态适应策略具有极为重要的意义。以胡杨3种典型的异形叶为材料,研究不同温度对其叶绿素荧光特性和能量分配的影响。结果表明,25-45 ℃温度下胡杨异形叶的F₀、F_m、F_v/F_m与F_v/F₀变化不大,尤其F_v/F_m仍能保持在0.78左右,光合反应正常;高温胁迫下(＞45 ℃)F_m、F_v/F₀、F_v/F_m、F'_v/F'_m、qP、ΦPSⅡ、P和ETR均大幅降低;F₀、qN、E显著上升,而D先上升后下降,说明高温抑制了PSⅡ的功能,使PSⅡ反应中心活性下降,QA^-的还原速率加快,光化学电子传递速率降低,某些能量耗散途径受阻,影响了PSⅠ和PSⅡ激发能的平衡分配,最终导致光合机构受损、光合速率降低。胡杨3种异形叶的叶绿素荧光参数随温度升高变幅不同,高温处理下锯齿阔卵形叶各参数均高于卵形叶与条形叶,表明锯齿阔卵形叶比卵形叶和条形叶具有更强的高温耐受能力。用模糊数学的隶属度函数对胡杨3种异形叶的耐热性进行综合评价,锯齿阔卵形叶的耐热性最强。