7-氮杂吲哚及其类似物的合成与抗肿瘤和抗菌活性研究

7-氮杂吲哚是一类重要的杂环化合物,因与吲哚、嘌呤等在结构上的类似性,成为后两类化合物的生物电子等排体,因而引起研究者关注。许多7-氮杂吲哚衍生物具有抑制多种蛋白酶的活性,在抗组胺和抗多巴胺等方面都体现潜在的生物活性及药用价值。本文根据不同的合成策略,对近年来合成7-氮杂吲哚母核的方法以及该类化合物的抗肿瘤与抗菌等活性研究进行综述,旨在能为以7-氮杂吲哚先导化合物的结构改造及其靶点的构效关系分析提供更多的信息。     

1,2,3-三氮唑并[4,5-d]嘧啶酮三环类衍生物的合成及抗肿瘤活性研究

目的 设计合成天然产物deoxyvasicinone和mackinazolinone类似物1,2,3-三氮唑并[4,5-d]嘧啶酮三环系列化合物,以期发现具有抗肿瘤活性的化合物.方法 采用商业易得的苯胺为起始原料,通过重氮化、[3+2]环加成、催化环化等步骤合成了27个结构新颖的三环类化合物;采用MTT法(以阿霉素作为...     

苯并三氮唑衍生物的抗肿瘤活性研究进展

癌症是仅次于心血管疾病的第二大杀手,且每年的发病率和死亡率仍呈不断上升之势。抗肿瘤药物对于癌症的防治至关重要,目前临床上使用的抗肿瘤药物超过100种。癌症经药物治疗缓解后,由于某些肿瘤细胞基因产生变异,会导致耐药性的产生。多重耐药性已成为癌症治疗失败的罪魁祸首,严重威胁人类健康。苯并三氮唑类化合物可通过多种非共价键作用与肿瘤细胞结合,具有潜在的抗肿瘤活性。本文归纳了自2012年以来所发展的具有抗肿瘤活性的苯并三氮唑衍生物的最新研究进展,以期为今后研究提供候选物。     

氧化阿朴菲生物碱衍生物与DNA的相互作用及抗肿瘤活性研究

目的研究氧化阿朴菲生物碱衍生物4位胺烷基甲酰胺取代的7 H-二苯并[de,g]喹啉-7-酮与小牛胸腺DNA的相互作用以及抗肿瘤活性。方法用紫外吸收光谱、荧光光谱和诱导CD光谱研究衍生物与小牛胸腺DNA的相互作用;用MTT法评价衍生物对NCI-H460,GLC-82和MCF 3种细胞株的细胞毒性。结果光谱研究结果表明,衍生物能与小牛胸腺DNA发生嵌入结合作用;细胞毒性测试表明,衍生物具有中等强度的抗肿瘤活性。结论衍生物的抗肿瘤活性很可能是因为衍生物能与DNA作用而产生的。     

3-去氮腺苷类似物的合成及抗肿瘤活性

目的探讨3-去氮腺苷类似物的抗肿瘤细胞增殖活性及初步的构效关系和作用机制。方法以2-氯甲基-4-甲氧基-3,5-二甲基吡啶为起始原料设计合成新型3-去氮腺苷类似物,考察化合物的体外肿瘤细胞增殖抑制作用。结果与结论合成了12个目标化合物及中间体,其结构经~1H-NMR,~(13)C-NMR和ESI-MS表征。体外抗肿瘤活性研究显示,活性最好的化合物7a和10a对A549细胞的体外抗肿瘤活性IC_(50)分别是9.23μmol·L~(-1)以及11.44μmol·L~(-1),说明了这两个3-去氮腺苷类似物与阳性对照相比具有更好的抗肿瘤细胞增殖活性。     

氧杂蒽-2-羧酸及氧杂蒽酮-2-羧酸类衍生物的合成

本文合成了一系列7位拉电子基团取代的氧杂蒽-2-羧酸及氧杂蒽酮-2-羧酸化合物。经大鼠被动皮肤过敏试验(PCA),显示化合物(Ⅷ),(Ⅻ_b)和(Ⅻ_e)有50～60%的抑制率(PO,200mg/kg),(Ⅻ_d)有54%的抑制率(ⅳ,10mg/kg)。氧杂蒽酮-2-羧酸(Ⅷ)经黄鸣龙还原反应生成(Ⅸ),但收率低,推测副产物2,2′-二羟基二苯基-甲烷(Ⅹ)的生成机理,改变反应条件,从而提高了(Ⅸ)的收率。化合物(Ⅻ_d)的元素分析和质谱均证明其结构为(Ⅻ_d),但核磁共振谱(溶剂为三氟醋酸)出现异常,而与(Ⅻ_d)在醋酐中回流所得产物(Ⅻ_d)的图谱相同。表明(Ⅻ_d)在三氟醋酸中环合、脱水产生了(Ⅻ_d)。     

1-取代苄氧基-3,6,7-三羟基-氧杂蒽酮的合成及NCI-H460细胞抑制活性研究

目的研究苄基上不同的取代基对1-取代苄氧基-3,6,7-三羟基-氧杂蒽酮类化合物细胞毒性的影响。方法设计合成氧杂蒽酮类化合物8个,所有化合物均经过核磁确证,并进行了初步的细胞毒活性筛选。结果和结论所合成8个化合物属首次报道,其中6个化合物对NCI-H460肿瘤细胞产生抑制作用,目标产物1b、1d、1e和1f作用较强。     

DNA-directed alkylating agents: synthesis, antitumor activity and DNA affinity of bis-N,N'-trisubstituted 1,2,4-triazolo-piperazines

A series of 1,4-bis-(1,5-dialkyl-1H-1,2,4-triazol-ylmethyl)piperazines and N-methyl-piperazine analogs were prepared spontaneously from the cycloaddition of various reactive cumulenes with the piperazino-1,4-(bis-ethanenitrile) and 1-cyanomethyl-4-methyl-piperazine, respectively. The new compounds were evaluated for their DNA affinity and antitumor activity.     

Potential antitumor agents. 39. Anilino ring geometry of amsacrine and derivatives: relationship to DNA binding and antitumor activity

The clinical antileukemic drug amsacrine and analogues are thought to exert their biological activity by binding tightly but reversibly to DNA, with the acridine chromophore intercalated and the anilino group making additional binding contact in the minor groove of the double helix. In this binding model the steric environment around the 3'- and 5'-positions of the anilino ring is crucial. Two 3',5'-disubstituted analogues of amsacrine have been prepared, and their conformation, DNA binding properties, and antitumor activity were determined and compared with corresponding unsubstituted and 3'-substituted compounds. Addition of 3'- and 3',5'-substituents have little effect on minimum-energy conformations of the anilino side chain but have significant effects on DNA binding and biological activity. Monosubstitution lowers binding constants several-fold, but intercalative binding with extensive drug-base pair overlap is retained. Disubstitution lowers binding further, and although the binding is still intercalative as assessed by unwinding angles, it appears to occur with little drug-base pair overlap, as determined by high-field NMR studies of DNA imino proton shifts. These changes in DNA binding are accompanied by an abrupt change in biological activity, with the 3',5'-disubstituted analogues proving inactive and nontoxic even though other physicochemical properties, such as lipophilicity and stability, remain within acceptable limits. This study provides further evidence that the binding of drugs to DNA has a critical influence on their biological activity.     

DNA binding by antitumor anthracene derivatives

The relative DNA binding strengths of bisantrene and nine new analogues were measured by spectrophotometric titration and melt transition temperature (Tm) techniques. Data from the spectrophotometric titrations could not be fit by simple Scatchard plots. However, they were fit by a McGhee-von Hippel equation over part of the binding range. The entire range of data was fit by a smoothing cubic spline function. The first derivative of this function gave, for each compound, a curve whose intercept provided a measure of relative binding strength. The delta Tm values agreed qualitatively with the spectrophotometric titration results, although there was not a precise linear relationship. Determinations of macroscopic pKas revealed that most of the compounds were dications at pH 7.0, but a few were mixtures of monocations and dications. No correlation was found between these binding studies and antitumor potencies in a clonogenic assay, which suggests that factors other than DNA binding can determine cytotoxicity for some of the analogues.     

Potential antitumor agents. 44. Synthesis and antitumor activity of new classes of diacridines: importance of linker chain rigidity for DNA binding kinetics and biological activity

Four classes of diacridines, joined at the 9-position by linker chains of varying length, rigidity, and polarity, were evaluated for DNA-binding properties and antitumor activity. Diacridines linked by flexible chains of varying polarity show relatively fast chromophore exchange kinetics among DNA binding sites but slower dissociation rates, suggesting the potential for considerable "creeping" of the drug along the helix, and are inactive in vivo. The exchange kinetics can be slowed dramatically by inclusion of positive charges in the side chain, but the resulting polycationic drugs are inactive in vivo, possibly due to poor distribution. Diacridines linked by a rigid, polar but neutral dicarbamoylpyrazole chain retain slow exchange kinetics, have a greatly reduced potential "creep rate", and possess good in vitro potency and significant in vivo antileukemic activity.     

Synthesis of congeners and prodrugs. 3. Water-soluble prodrugs of taxol with potent antitumor activity

Taxol has shown good in vivo antitumor activity in a number of test systems. The formulation of taxol for antitumor testing has been difficult. Esterification at either C-2' or C-7 resulted in loss of in vitro tubulin assembly activity but not cytotoxicity. These observations suggested that esters at C-2' and/or C-7, which would tend to promote water solubility, might serve as useful prodrugs of taxol. The reaction of taxol with either succinic anhydride or glutaric anhydride in pyridine solution at room temperature gave the crystalline mono 2'-adducts 1b and 1f, respectively. Salts of these acids (1b, 1f, 1i) were formed by the addition of 1 equiv of the corresponding base, followed by evaporation and/or freeze-drying of the solvent(s). The salts had improved antitumor activity as compared to the free acids. The triethanolamine and N-methylglucamine salts showed greatly improved aqueous solubility and were more active than the sodium salts. The glutarate series was preferred because of the higher activity and the higher yields obtained. 2'-Glutaryltaxol (1f) was coupled with 3-(dimethylamino)-1-propylamine, using CDI, to form in excellent yield the amino amide 1o. The hydrochloride salt (1p) showed good solubility and was extremely potent and active. At 10 mg/kg, in the B16 screen, 1p gave a T/C of 352 with 5 out of 10 cures. In the MX-1 breast xenograft assay, this prodrug gave values of -100 at doses of 40 and 20 mg/kg, with all live animals being tumor free.     

DNA binding affinity of bisguanidine and bis(2-aminoimidazoline) derivatives with in vivo antitrypanosomal activity

A new antitrypanosomal hit compound that cures an acute (STIB 900) mouse model of Trypanosoma brucei rhodesiense trypanosomiasis is described. This bis(2-aminoimidazolinium) dicationic compound proved to be an excellent DNA minor groove binder, suggesting a possible mechanism for its trypanocidal activity. From these studies, the 4,4'-diaminodiphenylamine skeleton emerged as a good scaffold for antitrypanosomal drugs.     

Functionalized congeners of adenosine: preparation of analogues with high affinity for A1-adenosine receptors

A series of functionalized congeners of adenosine based on N6-phenyladenosine, a potent A1-adenosine receptor against, was synthesized. Derivatives of the various congeners should be useful as receptor and histochemical probes and for the preparation of radioligands and affinity columns or as targeted drugs. N6-[4-(Carboxymethyl)phenyl]adenosine served as the starting point for synthesis of the methyl ester, the methyl amide, the ethyl glycinate, and various substituted anilides. One of the latter, N6-[4-[[[4-(carbomethoxymethyl)anilino]carbonyl]methyl]phenyl] adenosine, served as the starting point for the synthesis of another series of congeners including the methyl amide, the hydrazide, and the aminoethyl amide. The terminal amino function of the last congener was acylated to provide further analogues. The various congeners were potent competitive antagonists of binding of N6-[3H]cyclohexyladenosine to A1-adenosine receptors in rat cerebral cortical membranes. The affinity of the congener for the A1 receptor was highly dependent on the nature of the spacer group and the terminal moiety with Ki values ranging 1-100 nM. A biotinylated analogue had a Ki value of 11 nM. A conjugate derived from the Bolton-Hunter reagent had a Ki value of 4.5 nM. The most potent congener contained a terminal [(aminoethyl)amino]carbonyl function and had a Ki value of less than 1 nM.     

Synthesis and structure-activity studies of some antitumor congeners of L-canavanine

A number of structural analogs of the antitumor compound, L-canavanine, [L-2-amino-4-(guanidinooxy)butyric acid], a δ-oxa analog of L-arginine, have been synthesized and their growth-inhibitory effects evaluated in cultured MIA-PaCa-2 pancreatic carcinoma cells by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The results indicate that L-canavanine analogs in which the carbon chain-length and/or terminal guanidinooxy functional group has been modified elicit less growth inhibitory activity against these pancreatic cell lines than L-canavanine. On the other hand, several ester derivatives of L-canavanine have markedly enhanced growth inhibitory activity compared to L-canavanine. Thus, esterification of the carboxylic acid group constitutes an effective structural modification, which significantly amplifies the growth inhibitory properties of the parent compound against MIA-PaCa-2 cells. Drug Dev. Res. 40:325–332, 1997. © 1997 Wiley-Liss, Inc.     

Synthesis,antitumor activity,molecular modeling,and DNA binding properties of a new series of imidazonaphthalimides

A series of mono and bisintercalators based on the 5,8-dihydrobenz[de]imidazo[4,5-g]isoquinoline-4,6-dione system were synthesized and evaluated for growth inhibitory properties in several human cell lines. All target compounds showed activity in the micromolar range. Representative compounds were evaluated using UV--vis spectroscopy and viscosimetric determinations, showing that they behave as DNA intercalators. Molecular modeling techniques were used in order to rationalize the moderate activity observed for bisnaphthalimides.