FRu（phen）2（3，8—2R—phen）-]^2＋（R=OH，H，F）电子结构与抗癌活性研究

用密度泛函(DFT)法，对配合物[Ru(phen)2(3，8-2R—phen)^2 (R=OH，H，F)进行了理论计算研究。探讨了配合物的电子结构与其抗癌活性的关系：主配体上3，8位上F原子的取代有利于配合物与DNA的作用，增加配合物的抗癌活性。计算结果能较好地预测配合物与DNA的作用强度、抗癌活性及指导具有较高抗癌活性配合物的合成。     

铜(Ⅱ)配合物抗癌活性研究进展

金属配合物抗癌药物的研究已经成为抗肿瘤药物研究的热点之一。越来越多的研究表明铜(Ⅱ)配合物具有较好的抗癌活性。本文在参阅大量文献的基础上,对铜(Ⅱ)配合物的结构特征﹑和铂(Ⅱ)配合物的活性对比、与DNA的作用﹑与氨基酸的共价作用及对癌细胞的诱导凋亡作用等方面作了介绍。     

多吡啶钌配合物[(Phen)_2Ru(dppz)](PF_6)_2的抗菌活性及机制研究

目的研究多吡啶钌配合物[(Phen)_2Ru(dppz)](PF_6)_2的抗菌活性,并进一步探讨其作用机制。方法采用最小抑菌浓度(MIC)以及最小杀菌浓度(MBC),测定无机配合物[(Phen)_2Ru(dppz)](PF_6)_2的抗菌活性。为了阐明其抗菌机制,首先利用配合物自身荧光特性和核酸染料对DNA的竞争性结合所导致的荧光强度变化,以确定配合物与DNA的结合能力;然后通过DNA凝胶电泳,检测配合物与细菌基因组DNA结合后产生的效果以检测抗菌活性的机制。结果多吡啶钌配合物[(Phen)_2Ru(dppz)](PF_6)_2对大肠杆菌以及金黄色葡萄球菌具有较强的抗菌活性,最小抑菌浓度达0.2~0.4 g·L~(-1)。荧光检测显示,配合物能够与细菌DNA发生结合,以此为基础,配合物能够干扰细菌的转录过程,抑制细菌生长。结论本研究证明了多吡啶钌配合物[(Phen)_2Ru(dppz)](PF_6)_2的抗菌活性及作用机制,为其进一步开发奠定了基础。     

铂(Ⅳ)类配合物的合成及其抗肿瘤活性

目的寻求高效低毒的新一代铂类抗肿瘤药物。方法以六氯合铂 (Ⅳ )酸钾 (K2 PtCl6)为原料 ,设计合成了一系列顺铂 (cisplatin)类似物 ,将其依次氧化、酰化 ,合成了 11个新型铂 (Ⅳ )类配合物 ,结构通式为 :PtCl2 (OR1) 2 (NH2 R) 2 。并以溴化乙锭 (Etd)为荧光探针 ,通过配合物与DNA相互作用而引起体系的荧光变化 ,测定最大荧光淬灭百分率 (Rm) ,计算结合常数Km ,由此推测配合物抗癌活性。结果所合成铂 (Ⅳ )配合物的化学结构由元素分析和光谱分析所证实 ,其中 7个化合物 (6c～ 6e ,7c～7f)尚未见文献报道。试验测得受试配合物Rm值和Km计算值均较顺铂低 ,其活性顺序为 :顺铂 >6a >6c>6d。结论铂 (Ⅳ )配合物是一类具有重要研究价值和开发前景的抗肿瘤剂。     

具有抗肿瘤活性的6,7-二氰基-二吡啶基[2,2-d:2′,3′-f]喹喔啉合钴 (II)配合物的合成、晶体结构及与DNA结合的研究(英文)

合成了 6 ,7 二氰基 二吡啶 [2 ,2 d :2′ ,3′ f]喹喔啉 (L)与钴 (II)形成的配合物 [CoL(NO3 ) 2 (CH3 CN) ](1)。通过元素分析、IR对其组成和性质进行了表征 ,并测定了它的晶体结构。结果表明 ,钴原子与 3个N原子和四个O氧原子形成变形五角双锥配位构型。体外抗肿瘤活性筛选试验结果表明 :该配合物具有强的抗肿瘤活性 ,且配合物活性明显优于配体。通过紫外滴定、粘度滴定、解链温度测定等方法研究了化合物及配体与CT DNA的作用模式及结合常数 ,结果表明配合物与CT DNA的作用模式为典型的嵌插作用 ,配合物和配体与CT DNA的结合常数分别为 4 .4 3× 10 5mol·L-1和 1.6 5× 10 5mol·L-1。     

3,5-二硝基水杨醛缩甘氨酸铜(Ⅱ)配合物的合成、表征及其抗O-.2活性

在水杨醛苯环上引入吸电子基并与甘氨酸缩合,设计合成了3,5-二硝基水杨醛缩甘氨酸席夫碱及其铜(Ⅱ)配合物,对配合物进行了元素分析、摩尔电导、红外光谱、紫外光谱等系列表征,讨论了配合物中金属配体键合作用以及配合物的结构,并用黄嘌呤-黄嘌呤氧化酶-鲁米诺化学发光法测定了其歧化超氧阴离子的活性,与超氧化物歧化酶(SOD)作了对照,发现该配合物有较强的清除O-.2作用,显示较强的SOD样活性,在一定程度上具有模拟SOD酶的作用.     

新型Cu(Ⅱ)配合物的合成与生物活性比较

<正> Schiff碱衍生物与许多金属配合物合成、应用的 研究近年来是人们研究的热点之一。研究表明,某 些Schiff碱衍生物具有抗癌、抗病毒、抑制细菌生长 等生物活性,配合物的生物活性常随配体组成的微 小变化而有明显的差异。因此,我们首先合成了以 水杨醛亚胺Schiff碱为配体的Cu(Ⅱ)配合物,为了 寻找活性最高,抗菌谱更广的抗癌抑菌药物,我们对 配体进行了结构修饰,合成了理化性及抑菌活性均 优于前者的4种Cu(Ⅱ)配合物。配体A(B)分别是 3——硝基(5—硝基)—N(2—羟基乙基)水杨醛亚胺 Schiff碱。     

大黄酸金属配合物的结构及对人肝癌HepG2细胞增殖的抑制作用

目的:以大黄酸和相应金属盐为原料,合成3种金属配合物,并对其结构进行表征,比较其抗癌活性大小。方法:采用核磁共振氢谱法、红外光谱法、紫外光谱法、滴定法、原子吸收光谱法进行结构表征;采用MTT法测试三种配合物对于人肝癌Hep G2细胞的抑制作用。结果:通过光谱法证实有配合物生成,并推测出其可能结构。MTT测试显示配合物和配体均具有一定的抗癌活性,其中大黄酸-Fe(Ⅲ)抗癌活性最强,其IC50值达17.44μg.m L-1,优于配体大黄酸(IC50=116.741μg.m L-1),大黄酸-Cu(Ⅱ)(IC50=54.427μg.m L-1),大黄酸-Cr(Ⅲ)(IC50=63.584μg.m L-1)。结论:大黄酸金属配合物抗癌活性相比配体增强。     

具有抗肿瘤活性的6,7-二氰基-二吡啶基[2,2-d:2',3'-f]喹喔啉合钴(Ⅱ)配合物的合成、晶体结构及与DNA结合的研究

合成了6,7-二氰基-二吡啶[2,2-d:2′,3′-f]喹喔啉(L)与钴(Ⅱ)形成的配合物[CoL(NO3)2(CH3CN)](1).通过元素分析、IR对其组成和性质进行了表征,并测定了它的晶体结构.结果表明,钴原子与3个N原子和四个O氧原子形成变形五角双锥配位构型.体外抗肿瘤活性筛选试验结果表明:该配合物具有强的抗肿瘤活性,且配合物活性明显优于配体.通过紫外滴定、粘度滴定、解链温度测定等方法研究了化合物及配体与CT-DNA的作用模式及结合常数,结果表明配合物与CT-DNA的作用模式为典型的嵌插作用,配合物和配体与CT-DNA的结合常数分别为4.43×105mol·L-1和1.65×105mol·L-1.     

糠酰异羟肟酸类有机锡配合物的合成及其抗癌活性

目的 设计合成糠酰异羟肟酸类有机锡配合物,并进行抗癌活性测定.方法 首先合成糠酰异羟肟酸(FuHA),并以之为配体合成一系列二烃基锡配合物;运用MTT法进行糠酰异羟肟酸类有机锡配合物对血癌K562细胞和骨髓瘤细胞EP-20的体外抗癌活性筛选.结果合成了1个配体和5个配合物,用熔点、元素分析、FT-IR、1H-NMR和13C-NMR等方法进行了结构表征,R2Sn(L)2型化合物为六配位畸变八面体,而[R2Sn(L)]2O型化合物为五配位双核三角双锥结构.结论正丁基锡和苯基锡配合物具有明显的抗癌活性.     

2,2’-二氟-6,6’-双(二苯基膦)联苯的合成

２，２’－二氟－６，６’－双（二苯基膦）联苯是一种极具吸引力的、缺电子的过渡金属催化剂的配体。本文用三步反应合成了这个配体（总收率为５３％）。比原文献报道的四步反应及４９％总收率的方法有了改进。其结构为ＩＲ，ＭＳ及ＮＭＲＩ所证实。     

4,5-Epoxy-2(E)-decenal-induced formation of 1,N(6)-etheno-2'-deoxyadenosine and 1,N(2)-etheno-2'-deoxyguanosine adducts

trans-4,5-Epoxy-2(E)-decenal reacted with 2'-deoxyadenosine to give 1,N(6)-etheno-2'-deoxyadenosine as well as other 2'-deoxyadenosine adducts. It also reacted with 2'-deoxyguanosine to give 1,N(2)-etheno-2'-deoxyguanosine and other 2'-deoxyguanosine adducts. Synthetic trans-4,5-epoxy-2(E)-decenal was quite stable under the reaction conditions that were used. It was not contaminated with 2,3-epoxyoctanal, a potential precursor to the formation of unsubstituted etheno adducts. Furthermore, using a sensitive LC/MS assay, it was possible to show that no 2,3-epoxyoctanal was formed during prolonged incubations of trans-4,5-epoxy-2(E)-decenal. Therefore, trans-4,5-epoxy-2(E)-decenal, a primary product of lipid peroxidation, is a precursor to the formation of 1,N(6)-etheno-2'-deoxyadenosine and 1,N(2)-etheno-2'-deoxyguanosine. There is no need for an additional oxidation step such as would be required if trans,trans-2,4-decadienal or 4-hydroxy-2-nonenal were the lipid hydroperoxide decomposition products that initiated the formation of unsubstituted etheno adducts. These findings provide an important link between a primary product of lipid peroxidation and a mutagenic DNA lesion that has been detected in human tissues.     

bis(2-(Acylamino)phenyl) disulfides, 2-(acylamino)benzenethiols, and S-(2-(acylamino)phenyl) alkanethioates as novel inhibitors of cholesteryl ester transfer protein

A series of bis(2-(acylamino)phenyl) disulfides, 2-(acylamino)benzenethiols, S-(2-(acylamino)phenyl) alkanethioates, and related compounds were synthesized, and their inhibitory effect on cholesteryl ester transfer protein activity in human plasma was evaluated. This study elucidated the structural requirements for inhibitory activity and determined that the optimum compound was S-(2-((1-(2-ethylbutyl)cyclohexane)carbonylamino)phenyl) 2-methylpropanethioate (27) (JTT-705). This compound achieved 50% inhibition of CETP activity in human plasma at a concentration of 9 microM and 95% inhibition of CETP activity in male Japanese white rabbits at an oral dose of 30 mg/kg. It increased the plasma HDL cholesterol level by 27% and 54%, respectively, when given at oral doses of 30 or 100 mg/kg once a day for 3 days to male Japanese white rabbits.     

Multiple column peptide synthesis,Part 2 (1, 2)

A manually operated apparatus for parallel multiple column soli-phase peptide synthesis is described. It employs Fmoc-amino acid-O-Dhbt or -Pfp esters in the continuous flow version of the polyamide method on small packed columns of kieselguhr supported resin in a reaction block of Teflon. The solvents and deprotecting reagents are dispensed from two washers in a parallel fashion and reagent consumption is low. Activated and protected amino acids are transferred from a dispenser tray as solutions, eight at a time. The use of the method is demonstrated by the synthesis of overlapping peptides from a protein structure and of analogous protease substrates. The products have been characterized by HPLC, FAB mass spectroscopy and amino acid analysis.     

Reactions of N,N-bis(2-chloroethyl)-p-aminophenylbutyric acid (chlorambucil) with 2'-deoxycytidine, 2'-deoxy-5-methylcytidine, and thymidine

N,N-Bis(2-chloroethyl)-p-aminophenylbutyric acid (chlorambucil, 1; 2.5 mM) was allowed to react with 2'-deoxycytidine, 2'-deoxy-5-methylcytidine, and thymidine (16.1 mM) at physiological pH (cacodylic acid, 50% base), and the reactions were followed by HPLC and HPLC-MS technique. Although the predominant reaction observed was chlorambucil hydrolysis, 1 reacted with various heteroatoms of the nucleosides. The principal site of alkylation with all pyrimidine nucleosides was N3, as judged by 1H NMR and HPLC-MS analyses. Also, several other adducts were detected, which could be tentatively characterized by means of HPLC-MS and MS/MS. As expected, thymidine was the least reactive pyrimidine nucleoside studied, and in addition of the N3 derivative, it reacted only at the carbohydrate moiety. Overall reactivity of cytosine nucleosides with 1 was considerably higher. The N3 adducts of dCyd and 5-Me-dCyd partially deaminated under the reaction conditions employed, but the reaction was not catalyzed by the participation of the omega-hydroxy function of the alkyl substituent but presumably by the nitrogen atom of the chlorambucil moiety. In the case of cytosine nucleosides, the O2 derivatives were the second most abundant species. 5-Me-dCyd reacted more readily at O2 than dCyd. These O2 adducts were labile under acidic, neutral, and basic conditions. No N4 derivatives or cross-links were detected, but dCyd reacted also at C5, although the yield of this derivative was very low. The role of chlorambucil-pyrimidine 2'-deoxyribonucleoside adducts on the cytotoxicity and mutagenity of 1 is also discussed.     

N,N'-bis(2-thiazolyl)-formamidines

N,N′-Bis(2-thiazolyl)-formamidines As the result of the interaction between 2-aminothiazoles (II) with s-triazine (I), N,N′-bis(2-thiazolyl)-formamidines (IV) are formed. Analogously, 2-aminobenzothiazole (VI) reacts with s-triazine (I) to form N,N′-bis(2-benzothiazolyl)-formamidine (VII). The intermediate stage III postulated for this reaction type could be identified in an interception reaction by means of secondary amines. As prototype, the reaction of piperidine with the intermediate product IIId, the latter resulting from the interaction of 2-amino-4-phenylthiazole (IId) with s-triazine (I), to form 4-phenyl-2-piperidinoformimidoyl-thiazole (V), has been cited.     

Reactions of N,N-bis(2-chloroethyl)-p-aminophenylbutyric acid (chlorambucil) with 2'-deoxyadenosine

N,N-bis(2-chloroethyl)-p-aminophenylbutyric acid (chlorambucil, 1; 0.6 mM) was allowed to react with 2'-deoxyadenosine (16.1 mM) at physiological pH (cacodylic acid, 50% base), and the reactions were followed by HPLC-MS and HPLC-MS/MS techniques. Although the predominant reaction observed was chlorambucil hydrolysis, ca. 7% of 1 reacted with various heteroatoms of the nucleoside. The principal site of alkylation was N1. Several other adducts were also detected. The N1, N6, N3, and N7 derivatives were characterized by means of MS/MS, UV, and (1)H NMR. The N6 adduct is derived directly from alkylation of N6 of 2'-dAdo. Dimroth rearrangement of the N1 adduct to the N6 adduct was very slow under the reaction conditions employed. Minor adducts such as a carbohydrate derivative were tentatively characterized by MS/MS. No cross-links were detected. The role of chlorambucil-2'-deoxyadenosine adducts in the cytotoxicity and mutagenicity of 1 is also discussed.