Conjugation of Palbociclib with MHI-148 Has an Increased Cytotoxic Effect for Breast Cancer Cells and an Altered Mechanism of Action

The CDK4/6 inhibitor palbociclib, combined with endocrine therapy, has been shown to be effective in postmenopausal women with estrogen receptor-positive, HER2-negative advanced or metastatic breast cancer. However, palbociclib is not as effective in the highly aggressive, triple-negative breast cancer that lacks sensitivity to chemotherapy or endocrine therapy. We hypothesized that conjugation of the near-infrared dye MHI-148 with palbociclib can produce a potential theranostic in triple-negative, as well as estrogen receptor-positive, breast cancer cells. In our study, the conjugate was found to have enhanced activity in all mammalian cell lines tested in vitro. However, the conjugate was cytotoxic and did not induce G1 cell cycle arrest in breast cancer cells, suggesting its mechanism of action differs from the parent compound palbociclib. The study highlights the importance of investigating the mechanism of conjugates of near-infrared dyes to therapeutic compounds, as conjugation can potentially result in a change of mechanism or target, with an enhanced cytotoxic effect in this case.     

Recent Advances in Synergistic Antitumor Effects Exploited from the Inhibition of Ataxia Telangiectasia and RAD3-Related Protein Kinase (ATR)

As one of the key phosphatidylinositol 3-kinase-related kinases (PIKKs) family members, ataxia telangiectasia and RAD3-related protein kinase (ATR) is crucial in maintaining mammalian cell genomic integrity in DNA damage response (DDR) and repair pathways. Dysregulation of ATR has been found across different cancer types. In recent years, the inhibition of ATR has been proven to be effective in cancer therapy in preclinical and clinical studies. Importantly, tumor-specific alterations such as ATM loss and Cyclin E1 (CCNE1) amplification are more sensitive to ATR inhibition and are being exploited in synthetic lethality (SL) strategy. Besides SL, synergistic anticancer effects involving ATRi have been reported in an increasing number in recent years. This review focuses on the recent advances in different forms of synergistic antitumor effects, summarizes the pharmacological benefits and ongoing clinical trials behind the biological mechanism, and provides perspectives for future challenges and opportunities. The hope is to draw awareness to the community that targeting ATR should have great potential in developing effective anticancer medicines.     

伐地那非衍生物的合成和体内活性评价

首次完成了伐地那非衍生物—2-[2-乙氧基-5-(4-乙基-哌嗪-1-磺酰基)-吡啶]-5-甲基-7-丙基-3H-咪唑[5,1-f]-三 嗪-4-酮(1)的合成, 并且对其进行了家兔阴茎勃起的体内实验, 结果表明该化合物无壮阳作用.     

以gp41为靶标的小分子-多肽缀合物作为HIV-1融合抑制剂的设计、合成及活性初筛

芳基吡咯类小分子化合物NB-2衍生物(Noc或Npc)与衍生于C34中的靶标特异性多肽P26所形成的缀合物具有低纳摩尔水平的融合抑制活性.本文通过不同长度或不同柔性的连接臂将Noc或Npc与衍生于C34的靶标特异性多肽P27缀合,探讨了C34中a位残基I635和连接臂对缀合物活性的影响.人体免疫缺陷病毒1型(HIV-1)Env介导的细胞-细胞融合实验结果表明,多肽与小分子之间产生了强的协同作用.     

基于支持向量机方法的HERG钾离子通道抑制剂分类模型

对human ether-a-gō-gō related genes(HERG)钾离子通道(钾通道)抑制剂,计算了表征分子组成、电荷分布、拓扑、几何结构及物理化学性质等特征的1559个分子描述符.采用Fischer Score(F-Score)排序过滤和Monte Carlo模拟退火法相结合从中筛选与HERG钾通道抑制剂分类相关的分子描述符.采用支持向量机(SVM)方法,分别以IC50=1.0、10.0μmol·L-1为分类标准,建立了三个分类预测模型.对367个训练集分子,用五重交叉验证.得到正、负样本的平均预测精度分别为84.8%-96.6%、80.7%-97.7%,其总的平均预测精度为87.1%-97.2%,优于其它文献报道结果.对97个外部测试集分子,所建三个模型的总样本预测精度在67.0%-90.1%之间,接近或优于其它文献报道结果.     

氯化2,3,5-三苯基-2 氢-四唑(TTC)及2,4,6-三(2-吡啶基)-s -三嗪(TPT)在1mol/L HCl 中对Q235碳钢的缓蚀作用及机理的研究(Ⅱ)

通过X射线光电子能谱(XPS)、椭圆偏振原位测试考察了氯化2,3,5-三苯基-2H-四唑(TTC), 2,4,6-三(2-吡啶基)-s-三嗪(TPT)分子在1 mol/L HCl中对碳钢表面的缓蚀作用, 并从微观上对二者的缓蚀机理进行探讨. XPS测试结果显示, 由C, N元素的1s特征峰产生的化学位移及其积分峰面积表明TTC, TPT分子在金属表面产生了有效抑制腐蚀的保护层; 由椭圆偏振原位测试并结合动电位极化曲线测试,考察了TTC, TPT分子对金属表面腐蚀反应的抑制程度, 并得到了相位差等参量, 结果表明二者在金属表面形成了具有缓蚀作用的覆盖层.     

基于药效团模型的DHODH抑制剂构效关系研究

利用药效团模型研究二氢乳清酸脱氢酶(Dihydroorotate dehydrogenase,DHODH)抑制剂的构效关系,为DHODH抑制剂的虚拟筛选提供新的方法.以31个具有DHODH抑制活性的化合物为训练集化合物,半数抑制浓度(IC50)范围为7~63000 nmol/L,利用Catalyst/HypoGen算法构建DHODH抑制剂药效团模型,通过对训练集化合物多个构象进行叠合,提取药效团特征及三维空间限制构建药效团模型.利用基于CatScramble的交叉验证方法及评价模型对已知活性化合物的活性预测能力,确定较优药效团模型.模型包含1个氢键受体、3个疏水中心,表征了受体配体相互作用时可能发生的氢键相互作用、疏水相互作用和π-π相互作用,4个药效特征在三维空间的排列概括了DHODH抑制剂产生活性的结构特点.所得较优模型对训练集化合物及测试集化合物的计算活性值与实验活性值的相关系数分别为0.8405和0.8788.利用药效团模型对来源于微生物的系列化合物进行虚拟筛选,筛选出59个预测活性较好的化合物,可作为进一步药物研发的候选化合物.     

钙调蛋白抑制剂预测模型研究

选用30个结构多样的caM抑制剂分子作为数据集,采用多元线性回归(MLR)方法及主成分回归分析(PCA)方法对每个化合物的194个分子参数进行回归分析,分别建立了各自的最优预测模型.结果表明:多元线性回归分析方法所建模型与主成分回归所建模型相对比,发现逐步筛选法为最优建模方法?该方法所建模型统计结果良好(R2=0.952,SEE为0.289),应用于检验集时结果也比较令人满意(R2=0.941,SEP为0.295),模型表现出较强的可靠性和预测性.     

2-溴-4-[1-(E)-亚乙基-2-对甲氧基苯基-丁基]-1-甲氧基苯脱甲基及双键转位反应的研究

2-溴-4-[1-(E)-亚乙基-2-对甲氧基苯基-丁基]-1-甲氧基苯(3)是在合成3’-甲氧基己烯雌酚(2)过程中获得的意外羟基消除产物. 报道了2-溴-4-[1-(E)-亚乙基-2-对甲氧基苯基-丁基]-1-甲氧基苯在不同条件下的脱甲基反应产物以及双键转位反应的情况. 部分重要中间体的人脐静脉内皮细胞(HUVEC)抑制活性结果显示, 己烯雌酚骨架上的基团对该类化合物的抑制新生血管生成活性具有显著的影响, 甲氧基为活性有利基团, 而酚羟基全部游离时化合物没有活性.     

油溶性缓蚀剂ω,ω’-双(1-辛基苯并咪唑-2-基)烷烃的合成及缓蚀性能研究

合成了系列ω,ω’-双(1-辛基苯并咪唑-2-基)烷烃油溶性缓蚀剂,并通过红外、质谱等进行结构表征。通过恒电位极化曲线,考察了此类缓蚀剂在2×10-4mol/L H2S-乙醇溶液中对铜电极极化曲线的影响。结果表明,此系列油溶性缓蚀剂对铜电极具有明显的缓蚀作用,且对金属铜的缓蚀效率高,作为润滑油添加剂具有很好的应用前景。