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.     

西加毒素(CTX)的电子结构及构效关系研究

应用MNDO方法对CTX衍生物进行了量子化学计算 ,得到了它们的电子结构信息.根据构象分析研究了它们的空间结构.推测出它们的活性部位 ,探讨了与受体结合时的作用方式 ,讨论了结构 -活性关系 ,解释了活性差异的原因.研究结果表明该类化合物的D、E、F环和A环及其支链等部位的不饱和键对活性有重要影响     

4H-甲基咪唑苯二氮Chuo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-甲基眯唑苯二氮革酮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，即疏水性越大对抑制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．     

13位取代苦参碱衍生物抗癌活性的定量构效关系研究

采用密度泛函理论B3LYP方法计算了13个13位取代苦参碱衍生物的电子结构,研究了化合物结构与抑制人肝癌细胞HepG2抗癌活性的定量构效关系(QSAR).结果表明:(1)13位取代的苦参碱类衍生物的最低空轨道能ELUMO越低,最低空轨道与最高占据轨道的能隙ΔE越小,化合物抗癌活性越高;(2)分子的能量Etotal、面积S以及体积V越大,其极化度P越大,活性越大;(3)分子的油水分配系数logP越大,活性越大,即分子的疏水性增大活性增强.综合得到了显著性较好的QSAR方程:-lgIC50=97.008-11.759ΔE+818.602QC2-2.132×10-4Etotal,可用于预测该类衍生物抑制人肝癌细胞HepG2的活性并进行分子设计.     

短裸甲藻毒素(Brevetoxins)的电子结构与构效关系研究

对短裸甲藻毒素衍生物进行了电子结构研究和构象分析,确定了它们的活性部位,探讨了作用方式,讨论了它们的结构-活性关系及受体的相互作用,解释了衍生物之间活性差异的原因。研究结果表明,分子骨架中段环上的烯键,A环及R烯键对活性有重要影响,分子骨架的折曲程度对活性也有较大影响。     

新型黄烷酮类衍生物的合成、杀菌活性及定量构效关系研究

设计合成了14个含不同性质取代基的黄烷酮类化合物,并采用核磁共振氢波谱、质谱和元素分析对所有化合物的结构进行了表征.在系统测定化合物对水稻稻瘟病抑制活性的IC₅₀值的基础上,采用Hansch-Fujita方法和CoMFA方法对其定量结构活性关系进行了系统研究,结果发现,化合物的疏水性质、极化效应以及最高空轨道能级对杀菌活性有重要影响,化合物的疏水参数越小,分子越容易极化,则化合物的杀菌活性越高.此外,最高空轨道能级越低,化合物越容易接受电子,其杀菌活性也相应提高.通过考察∑π、clgP以及lgK与化合物杀菌活性的相关性,发现lgK能较好地反映该类化合物的疏水效应.三维定量构效关系研究表明,B环2,3,4位上含有较大体积的取代基,而6位含较小体积的取代基,有利于提高其杀菌活性.     

4, 6-二芳基-2-氨基嘧啶类衍生物的合成与生物活性

合成并表征了5种4,6-二芳基-2-氨基嘧啶类化合物。 测试了它们对大肠肝菌甲硫酰胺肽酶(EcMetAP)的抑制作用及对CXCR4受体的拮抗作用。 发现5种化合物均对EcMetAP酶活有抑制作用,除化合物2外均对CXCR4受体有拮抗作用。 利用FieldTemplater和FieldAlign软件对化合物1～5的上述活性构效关系进行了分析,初步认为化合物的嘧啶环3位N原子及4位取代苯环上若引入给电子基团,可增强这类化合物的EcMetAP酶抑制活性;在嘧啶环2位引入负电性较强的基团取代,改造2个苯环和嘧啶环的4、5、6位Ｃ原子的结构可增强其CXCR4受体拮抗活性。     

西加毒素(CTX)的电子结构及构效关系研究

应用ＭＮＤＯ方法对ＣＴＸ衍生物进行了量子化学计算,得到了它们的电子结构信息,根据构象分析研究了它们的空间结构,推测出它们的活性部位,探讨了与受体结合时的作用方式,讨论了结构－活性关系,解释了活性差异的原因,研究结果表明该类化合物的Ｄ、Ｅ、Ｆ环和Ａ环及其支链等部位的不饱和键对活性有重要影响。     

以ALS为靶标的新型除草剂的分子设计、合成及生物活性研究Ⅳ: 1, 2, 4-三唑并[1, 5-a]嘧啶-2-磺酰胺的晶体结构、量子化学及构效关系研究

在测定了具有不同活性1, 2, 4-三唑并[1, 5-a]嘧啶-2-磺酰胺类除草剂的晶体结构基础上, 采用半经验AM1方法对十种标题化合物进行了量子化学计算, 从空间构象及电子结构的角度探讨了该类除草剂的构效关系。发现三唑并嘧啶环可能是这类除草剂主要的活性部位, 其空间取向及供电子能力直接影响化合物的除草活性。     

以ALS为靶标的新型除草剂的分子设计、合成及生物活性研究Ⅳ: 1, 2, 4-三唑并[1, 5-a]嘧啶-2-磺酰胺的晶体结构、量子化学及构效关系研究

在测定了具有不同活性1, 2, 4-三唑并[1, 5-a]嘧啶-2-磺酰胺类除草剂的晶体结构基础上, 采用半经验AM1方法对十种标题化合物进行了量子化学计算, 从空间构象及电子结构的角度探讨了该类除草剂的构效关系。发现三唑并嘧啶环可能是这类除草剂主要的活性部位, 其空间取向及供电子能力直接影响化合物的除草活性。     

Synthetic studies toward melotenine A

Attempts to the construction of B/C ring and E ring in melotenine A are described. Based on para-dienone chemistry, a tactical application of tandem aminolysis/aza-Michael addition reaction was made to access highly functionalized building blocks with the pyrrolo[2,3-d]carbazole tetracyclic unit (A/B/C/D ring). Albeit negative results for assembling the dihydroazepine unit (E ring) by using the proposed fragmentation reaction of gem-dihalocyclopropanes, an alternative strategy based on ring closing metathesis was evolved to forge the E ring possessing a twisted 1,3-diene unit embedded in the rigid skeleton of melotenine A.     

The Conformation of Cycloartenol Investigated by NMR and Molecular Mechanics

Cycloartenol ( 4 ), a natural plant sterol, was shown to be an effective membrane reinforcer; this was attributed to its conformation. We now present a conformational analysis of 4 by molecular modeling and NMR. Molecular modeling suggests that two conformations I and II coexist, differing mainly at the level of ring C, and of nearly equal energy, I and II each having ring A and B in a chair and half-chair conformation, respectively, with ring C 1,3-diplanar in I (solid-state structure as determined by X-ray crystallography) and in chair conformation in II . A complete assignment of the ¹H- and ¹³C-NMR spectra of 4 and the entire coupling network in rings A and B is determined by various modern NMR techniques. The conformation of rings A and B thus determined is in agreement with conformations I and II . Low-temperature NMR experiments show a fast equilibrium between two conformations, presumably I and II . It is concluded, therefore, that the cyclopropane ring of 4 produces a flexibility at the level of ring C which may be important for the membrane properties.     

Synthesis of ACE tricyclic systems of daphnicyclidin A and dehy-droxymacropodumine A

The synthesis of the ACE tricyclic system of daphnicyclidin A and dehydroxymacropodumine A are developed. The key reactions include an efficient aldol reaction to introduce chiral fragment 33 for further construction of piperidine ring B and seven-membered ring C, a nucleophilic addition of lithium pentene to aldehyde for installation of ring E, and a photocatalytic decarboxylation conjugate addition to construct ring C.     

Unsaturated didehydrodeoxycytidine drugs. 1. Impact of C=C positions in the sugar ring

The chemical names of a pair of recently synthesized antitumor drugs are given in the present study as 1',2'-didehydro-3',4'-deoxycytidine and 3',4'-didehydro-2',4'-deoxycytidine. The order of stabilities, geometries, and ionization potentials of the unsaturated sugar-modified cytidine derivatives is investigated quantum mechanically. Our density functional theory calculations based on the B3LYP/6-311++G** model reveal that 3',4'-didehydro-2',4'-deoxycytidine (SD-C2) is slightly more stable than its isomer, 1',2'-didehydro-3',4'-deoxycytidine, by an energy of 5.28 kJ x mol(-1) in isolation. The isomers structurally differ by only the C=C location in the sugar ring. However, the compounds exhibit an unusual orientation with a less puckered sugar ring; that is, 3',4'-didehydro-2',4'-deoxycytidine is determined to be a beta-nucleoside, which is a C1'-endo, north conformer with an anticlinal sugar ring, whereas 1',2'-didehydro-3',4'-deoxycytidine is neither an alpha-nucleoside nor a beta-nucleoside but is a C4'-endo, south conformer with an antiperiplanar sugar ring. The present study further indicates that the C=C double bond location imposes significant effects on their ionization potentials (IPs) and other important molecular properties such as molecular electrostatic potential (MEP). In addition, inner shell binding energy spectral variations with respect to the C=C bond exhibit more site dependence. The valence shell binding energy spectral changes are, on the other hand, significant and delocalized. The latter indicates that such changes in valence space are not isolated effects but are within the entire nucleoside. Finally, the present study suggests that the nearly 0.6 eV difference in the first ionization potentials (highest occupied molecular orbital) of the isomers is sufficiently large to identify them by further spectroscopic measures.     

Mechanism for the cyclotrimerization of alkynes and related reactions catalyzed by CpRuCl

A complete catalytic cycle for the cyclotrimerization of acetylene with the CpRuCl fragment has been proposed and discussed based on DFT/B3LYP calculations, which revealed a couple of uncommon intermediates. The first is a metallacyclopentatriene complex RuCp(Cl)(C(4)H(4)) (B), generated through oxidative coupling of two alkyne ligands. It adds another alkyne in eta(2) fashion to give an alkyne complex (C). No less than three successive intermediates could be located for the subsequent arene formation. The first, an unusual five- and four-membered bicyclic ring system (D), rearranges to a very unsymmetrical metallaheptatetraene complex (E), which in turn provides CpRuCl(eta(2)-C(6)H(6)) (F) via a reductive elimination step. The asymmetry of E, including Cp ring slippage, removes the symmetry-forbidden character from this final step. Completion of the cycle is achieved by an exothermic displacement (21.4 kcal mol(-)(1)) of the arene by two acetylene molecules regenerating A. In addition to acetylene, the reaction of B with ethylene and carbon disulfide, the latter taken as a model for a molecule lacking hydrogen atoms, has also been investigated, and several parallels noted. In the case of the coordinated alkene, facile C-C coupling to the alpha carbon of the metallacycle is feasible due to an agostic assistance, which tends to counterbalance the reduced degree of unsaturation. Carbon disulfide, on the other hand, does not coordinate to ruthenium, but a C=S bond adds instead directly to the Ru=C bond. The final products of the reactions of B with acetylene, ethylene, and carbon disulfide are, respectively, benzene, cyclohexadiene, and thiopyrane-2-thione, the activation energies being lower for acetylene.     

The conversion among various B4C clusters: a density functional theoretical study

Geometry optimizations and vibration frequencies of B4C clusters were performed with Becke-3LYP method using 6-31G(d) basis set. We have found 14 stable isomers, and the most stable structure among them is the five-member ring containing two three-member boron rings. We also analyzed these stable isomers in detail, and the results show that the structures containing three-member boron rings are predominant in energy for B4C clusters. In terms of MO and NBO analysis, the three-centered bond and the pi-electron delocalization play an important role in stabilizing the planar five-member rings of these B4C clusters. Our calculations suggest that isomer4 can be converted into isomer7 with only an energy barrier of 0.31 kJ mol(-1) at the B3LYP/6-311G+(3df) level. Although the planar structures of the five-member rings (isomers12-14) can be converted with each other, the conversions of isomer14 to isomer13 and isomer13 to isomer12 have high-energy barriers of 70.99 and 68.51 kJ mol(-1) at the B3LYP/6-31G(d) level, respectively.     

Mechanistic Study on the Cleavage and Reorganization of C(sp3)?H and CN Bonds in Carbodiimides: Synthesis of 1,2‐Dihydrothiopyrimidines and 2,3‐Dihydropyrimidinthiones through Four‐Component Coupling

This study sheds light on the cleavage and reorganization of C(sp³)? H and C?N bonds of carbodiimides in a three‐component reaction of terminal alkynes, sulfur, and carbodiimides by a combination of methods including 1) isolation and X‐ray analysis of six‐membered‐ring lithium species 2‐S , 2) trapping of the oxygen‐analogues ( B‐O and D‐O ) of both four‐membered‐ring intermediate B‐S and ring‐opening intermediate D‐S , 3) deuterium labeling studies, and 4) theoretical studies. These results show that 1) the reaction rate‐determining step is [2+2] cycloaddition, 2) the C?N bond cleavage takes place before C(sp³)? H bond cleavage, 3) the hydrogen attached to C6 in 2‐S originates from the carbodiimide, and 4) three types of new aza‐heterocycles, such as 1,2‐dihydrothiopyrimidines, N‐acyl 2,3‐dihydropyrimidinthiones, and 1,2‐dihydropyrimidinamino acids are constructed efficiently based on 2‐S . All results strongly support the idea that the reaction proceeds through [2+2] cycloaddition/4π electrocyclic ring‐opening/1,5‐H shift/6π electrocyclic ring‐closing as key steps. The research strategy on the synthesis, isolation, and reactivity investigation of important intermediates in metal‐mediated reactions not only helps achieve an in‐depth understanding of reaction mechanisms but also leads to the discovery of new synthetically useful reactions based on the important intermediates.     

Identification of the related substances of tilmicosin by liquid chromatography/ion trap mass spectrometry

Structures of seven impurities of the veterinary drug tilmicosin have been elucidated by multiple fragmentation with ion trap tandem mass spectrometry. All related compounds possess the main lactone ring of tilmicosin. The differences in their structures are due to the hydroxyl, mycaminose, 3,5-dimethylpiperidine and mycinose groups connected to C(3), C(5), C(6), C(14) of the lactone ring, respectively. The following compounds of the impurity profile of tilmicosin were identified: B - tilmicosin with a hydroxyl group at C(3); C - tilmicosin without a methyl group at the N-atom connected to C(3) of the mycaminose ring; D - tilmicosin with a hydroxyl group at C(6) of the mycaminose ring; E - tilmicosin with a methoxy group at C(3), F - desmicosin; G - 20-dihydrodesmicosin; and H - tilmicosin without a mycaminose ring. Isomers of the compounds B, C, D, E and H were identified by their mass chromatograms and retention times. The concentrations of the impurities varied in the range of 0.1% to 2.9%.     

Kinetically controlled one-pot formation of DEFGH-rings of type B physalins through domino-type transformations

The characteristic DEFGH-ring system of type B physalins has been synthesized by means of a one-pot procedure incorporating domino-type ring transformations. Unexpectedly, we found that introduction of an α-hydroxyester functionality at C17 in ring E allowed the key 7-endo oxy-Michael reaction to proceed. Originally this was thought to be an unfavored process. This afforded the desired caged ring system to be formed in a kinetically controlled manner. Consecutive treatment with AcOH at 100 °C furnished the DEFGH-ring system in one pot.     

Pseudo Jahn-Teller origin of nonplanarity and rectangular-ring structure of tetrafluorocyclobutadiene

It is shown that the pseudo Jahn-Teller effect (PJTE) in combination with ab initio calculations explains the origin of instability of the planar configuration of tetrafluorocyclobutadiene, C(4)F(4), with respect to a puckered structure and square-to-rectangle distortion of the carbon ring, and rationalizes its difference from the planar-rectangular geometry of C(4)H(4) and nonplanar (puckered) structure of Si(4)H(4). The two types of instability and distortion of the high-symmetry D(4h) configuration in these systems emerge from the PJT coupling of the ground B(2g) state with the excited A(1g) term producing instability along the b(2g) coordinate (elongation of the carbon or silicon square ring), and with the excited E(g) term resulting in e(g) (puckering) distortion. A rhombic distortion b(1g) of the ring is also possible due to the coupling between excited A(1g) and B(1g) terms. For C(4)F(4), ab initio calculations of the energy profiles allowed us to evaluate the PJTE constants and to show that the two instabilities, square-to-tetragonal b(2g) and puckering e(g) coexist, thus explaining the origin of the observed geometry of this system in the ground state. The preferred cis-trans (e(g) type) puckering in C(4)F(4) versus trans-trans puckering (b(2u) distortion) in Si(4)H(4) follows from the differences in the energy gaps to their excited electronic E(g) and A(1u) terms causing different PJTE in these two cases.