空心酞菁光物理性质的取代基效应

合成了一系列可溶性的2，9，16，23-四取代的空心酞菁，并研究了其光物理性质，实验表明，烷基、烷氧基、芳氧基取代空心酞菁的最低电子跃迁能和最低激发单重态能量与Hammett间位取代基常数线性相关．而强吸电子基如硝基和强给电子基如氨基取代则会诱导分子内电荷转移和使酞菁聚集，导致吸收光谱畸变和激发态量子产率下降．但取代基对酞菁的振动能级没有影响．     

4-取代Fentanyl类化合物电子结构及构效关系研究

本文对十一个4-取代Fentanyl类化合物进行了量子化学(INDO)计算, 研究了它们的电子结构及构效关系. 结果表明, 这些化合物同其他Fentanyl类化合物在主要活性部位和电子结构趋势上基本相同. 酰胺氧原子是最重要的负电中心, 哌啶氮原子在季铵化后发挥正电中心作用. 4-取代基的极性基团可能以电荷转移作用或氢键接受体形式与受体极性部位结合, 并能影响其他活性部位电子密度. 另外, 4-取代基的立体因素与疏水因素同生物活性相关.     

3-烷氧基-6-取代苯氧基哒嗪的合成及其除草活性的构效关系

用3,6-二取代苯氧基哒嗪与醇钠进行亲核取代反应的新方法合成19个3-烷基-6-取代苯氧基哒嗪.对目标化合物进行了pI₅₀和盆栽除草活性的测试,部分化合物的活性高于对照药品马来酰肼.初步定量构效关系的结果表明:苯环3,4位上带有吸电子取代基以及增加分子的脂溶性对提高除草活性有利     

含蒽醌基单偶氮染料光电导性质构效研究

由1-氨基蒽醌和不同偶合基合成了九个含蒽醌基的单偶氮染料，并对其进行了 元素分析、红外光谱和紫外光谱表征。紫外光谱研究结果表明，偶合基酰胺芳环上 取代基对偶氮染料的吸收光谱影响不大。当偶合基由2-羟基-3-氨替酰胺萘酚（ Azol～8)变为2-羟基-11氢-苯并咔唑-3-氨替酰胺萘酚（Azo9)时，偶氮染料的吸收 红移了130 nm，最大吸收出现在662 nm处，成为近红外染料。偶氮染料光电导性质 的研究表，偶合基酰胺芳环上取代基吸电子效应越强，光敏性越好，且与Hammett 常数σ有良好的相关性。值得注意的是萘环上扩大一个咔唑环（Azo9)，使偶氮染 料的光敏性提高了几十倍，表明在萘环上扩大共轭环是提高偶氮染料光敏性的一个 良好途径。     

1-环丙基-6-氟-7-取代喹诺酮抗HIV活性的定量构效关系

用量子化学AM1法对一系列1-环丙基-6-氟-7-取代-1,4-二氢-4-氧-喹啉-3-羧酸的定量构效关系进行了研究,结果表明该类化合物在对HIV的抑制过程中是一很好的电子给予体,给电子的部位主要是7-位哌嗪基末端氮原子,并进一步提出从抗C^+和G^-菌活性差的喹诺酮中有望筛选出好的抗HIV化合物。     

有机过氧化物-芳叔胺体系引发甲基丙烯酸甲酯聚合的研究

以过氧化二酰(BPO、LPO)或有机过氧化氢物(TBH、CHP)和芳叔胺如DMA或对位具有不同取代基的衍生物组成的引发体系进行MMA聚合,研究过氧化物与胺的结构对聚合的影响。结果表明,过氧化二酰的活性要比有机过氧化氢物大,其顺序为BPO>LPO>CHP>TBH。对于BPO-芳叔胺或LPO-芳叔胺体系,芳叔胺中给电子取代基能提高聚合速度,而吸电子取代基能降低聚合速度。测定了MMA聚合的总活化能E_α,BPO-芳叔胺体系时E_α=36-54kJ/mole,LPO-芳叔胺体系时E_α=56-71kJ/mole;还研究聚合动力学。     

1-芳基-1，4二氢-3芳酰肼基甲酰基-6甲基-4-哒嗪酮的合成及对黄瓜子叶生根作用的构效关系研究

合成了一系列的1-芳基-1，4-二氢-3-芳酰肼基甲酰基-各甲基斗哒嗪酮类化合 物，并用离体黄瓜子叶生根法测试其生物活性，生测结果表明，所有的化合物均显 示出一定的生物活性，并且芳环上的取代基对活性有重要影响．采用化合物的物理 化学参数及化合物促进黄瓜子叶生根的活性，进行了结构与活性定量关系研究，建 立了较好的结构与活性的相关式，化合物的亲脂性和取代基的电性对化合物的生物 活性具有重要的影响．研究结果对3-芳酰肼基甲酰基斗哒嗪酮类化合物的改性或新 类似物的合成具有指导意义．     

区域选择性合成2-硝基-5, 10, 15, 20-四芳基金属卟啉

研究了以硝酸盐为硝化剂与中位四芳基金属卟啉反应、选择性合成2-硝基-5,10,15,20-四芳基卟啉的方法,发现配位金属离子、中位苯环上的取代基对反应产率和时间有明显的影响,当金属离子为铜、镍时,可得定量的2-硝基卟啉,为锌时,完成反应的时间延长,反应产率迅速下降。推电子的甲氧基能加快反应的进行,吸电子的氯原子则延缓反应的进行。讨论了金属离子和取代基团对反应影响的原因。     

nbs与取代苯的亲电反应及其应用

选取含不同取代基的甲苯在不同条件下与NBS反应,考察了溶剂极性、取代基的电子效应和温度等因素对反应结果的影响,结果表明,取代反应的区域选择性强烈地依赖于反应溶剂和取代基的电子效应及其数量。随反应溶剂极性的增强,芳环上亲电取代产物的比例增加;随芳环上取代基的推电子能力的增大,亲电取代反应的优势愈加明显;相反,则有利于α-位上的游离基取代。在此基础上,研究了溴化Q0的合成方法,形成了一条新的、简便的溴化Q0的合成路线,收率达86％以上。     

手性磷酸催化亚甲胺叶立德与吲哚-3-甲醇不对称[3+3]环加成反应:一步构建多取代四氢-β-咔啉

研究了手性磷酸催化醛、氨基丙二酸酯与3-吲哚基苯基取代甲醇的三组分不对称[3+3]环加成反应,立体选择性地一步构建多取代四氢-β-咔啉骨架.考察了不同取代的手性磷酸催化剂、溶剂等因素对反应的影响,对芳环上不同位置具有不同性质取代基的底物进行了扩展,获得中等到优秀的产率(70%～91%),对映选择性良好到优秀(80%～93%ee),反应对底物芳环上的吸电子基和给电子基都具有良好的容忍性.     

Synthesis and screening of aromatase inhibitory activity of substituted C19 steroidal 17-oxime analogs

The synthesis and aromatase inhibitory activity of androst-4-en-, androst-5-en-, 1β,2β-epoxy- and/or androsta-4,6-dien-, 4β,5β-epoxyandrostane-, and 4-substituted androst-4-en-17-oxime derivatives are described. Inhibition activity of synthesized compounds was assessed using aromatase enzyme and [1β-3H]androstenedione as substrate. Most of the compounds displayed similar to or more aromatase inhibitory activity than formestane (74.2%). 4-Chloro-3β-hydroxy-4-androsten-17-one oxime (14, 93.8%) showed the highest activity, while 4-azido-3β-hydroxy-4-androsten-17-one oxime (17, 32.8%) showed the lowest inhibitory activity for aromatase.     

新型酪氨酸激酶小分子抑制的三维药效团研究

通过CATALYST软件包得到了两类HER2抑制的三维药效团模型。尽管亚苄基丙二腈化合物和3-取代吲哚啉-2-酮系列化合物具有完全不同的骨架结构,但得到的药效团却具有共同的特性,这表明当这两类抑制剂和受体发生相互作用时,采用了相似的结合模式。共同的药效团模型包括一个氢键受体,一个氢键给体,一个脂肪类疏水团以及一个芳香类疏水团。根据药效团模型,我们还进行了三维构效关系的研究,结果表明得到的药效团模型具有很好的预测能力(线性回归系数R≈0.96)。药效团模型对于研究酪氨酸激酶小分子抑制剂的结构与活性关系,以及评估和预测此类未知化合物活性具人重要的意义。     

4H-甲基咪唑苯二氮(艹卓)酮类抗HIV-1药物的量子化学研究

用分子力学MM3方法、量子化学MNDO法和从头算STO-3G基组计算了20个4H-甲基咪唑苯二氮(廿卓)酮HIV-1逆转录酶抑制剂的优势构型和电子结构,用逐步回归方法和BP神经网络方法得到其抗HIV-1活性与电子结构的定量构效关系.结果表明:(1)TIBO类衍生物的体积越大,极性越小,即流水性越大对抑制HIV-1活性越有利.(2)C环N上H原子可能是化合物的正电活性部位.(3)R′原子与受体作用时可能作为电子给予体,前线轨道中S的贡献比O大得多,故含S的TIBO化合物比含O化合物的活性高.(4)苯环上连接吸电子基团对活性有利,由于分子的正负电荷中心距离较近,极性较小,疏水性较大,故3位取代比2位取代活性更高.     

Electrochemical and Theoretical Studies of 1-Alkyl-2-substituted Benzimidazoles as Corrosion Inhibitors for Carbon Steel Surface in HCl Medium

The inhibition efficiencies of newly synthesized four 1-alkyl-2-substituted benzimidazole compounds(a~d) have been studied for the corrosion of carbon steel in 1.0 M HCl by using potentiodynamic polarization measurement. The four inhibitors act as mixed-type inhibitors,which mainly inhibit cathodes. The inhibition efficiency of these compounds enhanced when the concentration of the inhibitors increased. A theoretical study of the corrosion inhibition efficiency of these compounds was carried out by using the B3 LYP level with the 6-31+G* basis set. Considering the solvent effect,the IEFPCM model was selected. Furthermore,the adsorption energies of the inhibitors with the iron(001) surface were studied by using molecular dynamic(MD) simulations. The theoretical results show that these inhibitors all exhibit several adsorption active-centers. Meanwhile,the MD simulations indicate that the adsorption occurs mostly through benzene ring and the lone pair electrons of the nitro atoms. These results demonstrated that the theoretical studies and MD simulations are reliable and promising methods for analyzing the inhibition efficiency of organic inhibitors.     

Synthesis of diaryl-substituted imidazo[l,2-a]pyridines designed as potential aromatase inhibitors

From a pharmacophore model of bicyclic heterocycles as aromatase inhibitors we have designed three series of imidazo[1,2-a]pyridine derivatives. The synthesis and the spectroscopy determination of various compounds are reported. The crystal data of one of these compounds (10b) was obtained. The aromatase inhibition potency was evaluated in vitro and no activity was found.     

Pharmacophore modeling and in silico screening for new P450 19 (aromatase) inhibitors

Cytochrome P450 19 (P450 19, aromatase) constitutes a successful target for the treatment of breast cancer. This study analyzes chemical features common to P450 19 inhibitors to develop ligand-based, selective pharmacophore models for this enzyme. The HipHop and HypoRefine algorithms implemented in the Catalyst software package were employed to create both common feature and quantitative models. The common feature model for P450 19 includes two ring aromatic features in its core and two hydrogen bond acceptors at the ends. The models were used as database search queries to identify active compounds from the NCI database.     

6‐[(4‐Fluorophenyl)(1H‐imidazol‐1‐yl)methyl]‐1,3‐benzodioxol‐5‐ol and 6‐[(4‐methoxyphenyl)(1H‐imidazol‐1‐yl)methyl]‐1,3‐benzodioxol‐5‐ol

The title compounds, C₁₇H₁₃FN₂O₃ and C₁₈H₁₆N₂O₄, are new potent aromatase inhibitors combining the common features of second‐ and third‐generation nonsteroid anti‐aromatase compounds. The molecules have a propeller shape, with dihedral angles between adjacent planes in the range 49–86°. A quantum mechanical ab initio Roothaan–Hartree–Fock calculation for the isolated molecules shows values for these angles close to the ideal value of 90°. Docking studies of the molecules in the aromatase substrate show that their strong inhibitor potency can be attributed to molecular flexibility, hydrophobic interactions, heme Fe coordination and hydrogen bonding.     

Three-dimensional quantitative structure-activity relationships of steroid aromatase inhibitors

Summary Inhibition of aromatase, a cytochrome P450 that converts androgens to estrogens, is relevant in the therapeutic control of breast cancer. We investigate this inhibition using a three-dimensional quantitative structure-activity relationship (3D QSAR) method known as Comparative Molecular Field Analysis, CoMFA [Cramer III, R.D. et al., J. Am. Chem. Soc., 110 (1988) 5959]. We analyzed the data for 50 steroid inhibitors [Numazawa, M. et al., J. Med. Chem., 37 (1994) 2198, and references cited therein] assayed against androstenedione on human placental microsomes. An initial CoMFA resulted in a three-component model for log(1/K_i), with an explained variance r² of 0.885, and a cross-validated q² of 0.673. Chemometric studies were performed using GOLPE [Baroni, M. et al., Quant. Struct.-Act. Relatsh., 12 (1993) 9]. The CoMFA/GOLPE model is discussed in terms of robustness, predictivity, explanatory power and simplicity. After randomized exclusion of 25 or 10 compounds (repeated 25 times), the q² for one component was 0.62 and 0.61, respectively, while r² was 0.674. We demonstrate that the predictive r² based on the mean activity (Y_m) of the training set is misleading, while the test set Y_m-based predictive r² index gives a more accurate estimate of external predictivity. Using CoMFA, the observed differences in aromatase inhibition among C6-substituted steroids are rationalized at the atomic level. The CoMFA fields are consistent with known, potent inhibitors of aromatase, not included in the model. When positioned in the same alignment, these compounds have distinct features that overlap with the steric and electrostatic fields obtained in the CoMFA model. The presence of two hydrophobic binding pockets near the aromatase active site is discussed: a steric bulk tolerant one, common for C4, C6-alpha and C7-alpha substitutents, and a smaller one at the C6-beta region.     

Structure-activity relationships of estrogen derivatives as aromatase inhibitors. Effects of heterocyclic substituents

Aromatase, which is responsible for the conversion of androgens to estrogens, is a potential therapeutic target for the selective lowering estrogen level in patients with estrogen-dependent breast cancer. We prepared and tested series of the pyridine- and other heterocyclic ring-containing derivatives of 2- and 4-aminoestrones, estrone, and estradiol, compounds 5, 10, 12 and 15. The isonicotinyl derivatives of 2- and 4-aminoestrone, compounds 5c and 10c, were fairly potent competitive inhibitors of aromatase (K(i), 2.1+/-0.14 and 1.53+/-0.08 microM for 5c and 10c, respectively) and other compounds did not show, to a significant extent, the aromatase inhibitory activity. This result suggests that the isonicotinyl-substituted derivatives 5c and 10c would be accessible to the active site of aromatase.     

Facile synthesis of chrysin-derivatives with promising activities as aromatase inhibitors

Flavones such as chrysin show structural similarities to androgens, the substrates of human aromatase, which converts androgens to estrogens. Aromatase is a key target in the treatment of hormone-dependent tumors, including breast cancer. Flavone-based aromatase inhibitors are of growing interest, and chrysin in particular provides a (natural) lead structure. This paper reports multicomponent synthesis as a means for facile modification of the chrysin core structure in order to add functional elements. A Mannich-type reaction was used to synthesize a range of mono- and disubstituted chrysin derivatives, some of which are more effective aromatase inhibitors than the benchmark compound, aminoglutethimide. Similarly, the reaction of chrysin with various isonitriles and acetylene dicarboxylates results in a new class of flavone derivatives, tricyclic pyrano-flavones which also inhibit human aromatase. Multicomponent reactions involving flavones therefore enable the synthesis of a variety of derivatives, some of which may be useful as anticancer agents.