Total Synthesis and Structure Correction of the Cyclic Lipodepsipeptide Orfamide A

A total synthesis of the cyclic lipodepsipeptide natural product orfamide A was achieved. By developing a synthesis format using an aminoacid ester building block and SPPS protocol adaptation, a focused library of target compounds was obtained, in high yield and purity. Spectral and LC-HRMS data of all library members with the isolated natural product identified the ⁵Leu residue to be d - and the 3’-OH group to be R-configured. The structural correction of orfamide A by chemical synthesis and analysis was confirmed by biological activity comparison in Chlamydomonas reinhardtii, which indicated compound configuration to be important for bioactivity. Acute toxicity was also found against Trypanosoma brucei, the parasite causing African sleeping sickness.     

Strong Antibiotic Activity of the Myxocoumarin Scaffold in vitro and in vivo

The increasing emergence of resistances against established antibiotics is a substantial threat to human health. The discovery of new compounds with potent antibiotic activity is thus of utmost importance. Within this work, we identify strong antibiotic activity of the natural product myxocoumarin B from Stigmatella aurantiaca MYX-030 against a range of clinically relevant bacterial pathogens, including clinical isolates of MRSA. A focused library of structural analogs was synthesized to explore initial structure-activity relationships and to identify equipotent myxocoumarin derivatives devoid of the natural nitro substituent to significantly streamline synthetic access. The cytotoxicity of the myxocoumarins as well as their potential to cure bacterial infections in vivo was established using a zebrafish model system. Our results reveal the exceptional antibiotic activity of the myxocoumarin scaffold and hence its potential for the development of novel antibiotics.     

Comparative QSAR studies on PAMPA/modified PAMPA for high throughput profiling of drug absorption potential with respect to Caco-2 cells and human intestinal absorption

Despite the dramatic increase in speed of synthesis and biological evaluation of new chemical entities, the number of compounds that survive the rigorous processes associated with drug development is low. Thus, an increased emphasis on thorough ADMET (absorption, distribution, metabolism, excretion and toxicity) studies based on in vitro and in silico approaches allows for early evaluation of new drugs in the development phase. Artificial membrane permeability measurements afford a high throughput, relatively low cost but labor intensive alternative for in vitro determination of drug absorption potential; parallel artificial membrane permeability assays have been extensively utilized to determine drug absorption potentials. The present study provides comparative QSAR analysis on PAMPA/modified PAMPA for high throughput profiling of drugs with respect to Caco-2 cells and human intestinal absorption.     

环境致癌物的计算机预测研究

环境致癌物可诱发人类或哺乳动物体内的肿瘤,建立环境致癌物的计算机预测模型对环境风险评价和生态安全具有重要的意义．通过构建了3780个化合物的数据集,随机选取其中3024个作为训练集,其余756个作为外部验证集;基于定量构-效关系（QSAR）方法,采用逐步判别分析和主成分分析建立数学模型．结果表明训练集非致癌物预测正确率为86．0％,可能致癌物的预测正确率为88．O％,而采用主成分建模时,非致癌物和可能致癌物的预测正确率分别为74．2％和73．1％．说明逐步判别分析法的结果优于主成分判别分析．同时确定了可能致癌物和非致癌物的分子结构参数,阐明了两者结构差异．以上结果为预测和评估环境致癌物提供参考依据．     

一种新的氨基酸描述符及其在肽QSAR中的应用

从20种天然氨基酸的41个randic molecular profiles非零描述符、44个eigenvalue based indices非零描述符和47个walk and path counts非零描述符分别进行主成分分析,得出一种新的氨基酸描述符-SVREW。将其应用于血管紧张素转化酶(ACE)抑制二肽和ACE抑制三肽、苦味二肽和苦味四肽、后叶催产素类似物、HLA-A*0201限制性CTL表位肽的结构表征,应用多元线性回归(MLR)建立定量构效关系模型,同时采用内部与外部双重验证的方法验证模型的稳定性。所建ACE抑制二肽、ACE抑制三肽、苦味二肽、苦味四肽、后叶催产素类似物、HLA-A*0201限制性CTL表位肽的模型复相关系数(R2cum)分别为0.994,0.797,0.948,0.878,0.686,0.720;留一法交互校验复相关系数(R2cv)分别为0.955,0.859,0.879,0.958,0.796,0.843;外部样本校验相关系数(Q2ext)分别为0.990,0.954,0.890,0.950,0.748,0.773。经研究表明SVREW描述符用于肽分子结构表征所建模型的稳定性与预测能力均较好,有望成为多肽定量构效关系研究中一种有效的结构表征方法,可对新药物的发现和研究提供指导。     

6-异位-5,8-O-二甲基乙酰紫草素衍生物的2D/3D-QSAR研究

本文综合运用密度泛函理论(DFT)、分子力学(MM2)和统计学等方法对22个具有抗人体乳腺癌(MDA-MB-231)活性的6-异位-5,8-O-二甲基乙酰紫草素类衍生物进行二维(2D)定量构效关系(QSAR)研究,同时运用比较分子相似性指数分析(Co MSIA)方法进行三维(3D)QSAR研究。所建最优2D-QSAR方程的留一法交叉验证系数(q2)和拟合相关系数(R2)分别为0.833和0.900;Co MSIA(SEHA)模型的q2和非交叉验证系数(r2)分别为0.624和0.999,预测相关系数R2pred为0.838,表明所建立的2D/3D-QSAR模型都具有良好的统计学意义及合理、可信的预报能力,可以预测未知化合物的活性。研究结果为理解该类化合物的作用机理和设计合成更高活性的新化合物提供理论参考。     

苯甲酰胺衍生物对Hh信号通路抑制的理论研究

基于拓扑方法计算了16种嘧啶吗啉苯甲酰胺衍生物的电性距离矢量(Mt)。通过最佳变量子集回归建立其对Hedgehog信号通路抑制活性(IC50)与Mt的最佳三元数学模型(QSAR),其判定系数(R2)及逐一剔除法的交叉验证相关系数(Rcv2)分别为0.832、0.600。经Rcv2、VIF、FIT、AIC等检验,该模型具有良好的稳健性及预测能力。根据进入此模型的M66,M18,M2可知,影响嘧啶吗啉苯甲酰胺衍生物对Hedgehog信号通路抑制活性的主要因素是分子的二维结构特征CH3-、-CHf-、-NHg-、N-和HO-等结构碎片。     

Theoretical elucidation of structure-activity relationship of flavonoid antioxidants

AM1 method was employed to calculate flavonoid antioxidants, and the results obtained are as follows. Firstly, flavonoid hydroxyls at ortho position were more active than the hydroxyls at meta position in scavenging oxygen-free radicals, which resulted from the facts that (ⅰ) the former were stabilized by forming intramolecular hydrogen bond and (ⅱ) ortho benzoquinone formed in the former structures through resonance, which resulted in large percentage of distribution of spin density on ortho oxygen and low internal energy. Secondly, electron-attracting effect of ring C of chromone-flavonoids showed some passive effects on hydroxyls of ring A, making the OH less active. As ring C had little effect on ring B and hydroxyls of ring B in most flavonoids were at ortho position, the rule summarized from experiments showing that hydroxyls of ring B were more active in scavenging oxygen-free radicals was elucidated.     

应用分子子图指数估计与预测烷烃核磁共振碳谱位移和

系统地研究了核磁共振碳谱(¹³C NMR)与化学位移规律及其定量构谱关系(QSSR).本文研究了一组多元素分子子图指数矢量(VMSG),并发现它与烷烃化学位移和(CCSA)有很好线性相关性.采用多元线性回归(MVLR)进行准确估计与预测,结果良好.