4'-去甲基表鬼臼毒素芳香酰胺类衍生物的设计、合成及其抗肿瘤活性

目的为寻找高效低毒且作用谱广的鬼臼脂素类抗肿瘤药物,合成了20个4'-去甲基表鬼臼毒素芳香酰胺类化合物。方法以4'-去甲基表鬼臼毒素为原料,首先与氯乙腈进行取代反应,再与硫脲反应,最后与不同的取代芳香羧酸成酰胺制得目标化合物。采用MTT法测定目标化合物体外对人肺腺癌细胞A549、人肝肿瘤细胞株HepG2、人口腔癌KB细胞、L1210白血病细胞的抑制活性。结果与结论合成了20个未见文献报道的新化合物,目标化合物的结构均经~1H-NMR和MS谱确证,活性测试结果表明,大部分目标化合物均具有一定的肿瘤细胞增殖抑制活性。     

Elucidation of structure-activity relationship of 2-quinolone derivatives and exploration of their antitumor potential through Bax-induced apoptotic pathway

3-Aryl-2-quinolone derivates were extensively investigated for their inhibition of farnesyl transferase. Taking this as a cue, we studied the other possible mechanism of antitumor activity of 2-quinolone derivates. A series of new 2-quinolone derivatives have been synthesized and screened for their cytotoxicity by trypan blue assay on Ehrlich ascites carcinoma cells and MTT assay on MCF-7 cells. Compound 1a (nJST) was found to be more effective in both studies with the lowest CTC(50) value among all nine synthesized compounds. This compound was further screened on four different cell lines, viz. human breast adenocarcinoma (MCF-7, MDA-MB-231), colon cancer (HCT-15), murine melanoma (B16F10) cell lines for 24 and 48 h. The CTC(50) value of the compound was found to be <10 μm. Compound 1a induced DNA damage which was revealed by DNA fragmentation studies and further confirmed by nuclear staining. The compound also showed significant elevation in Bax and reduction Bcl-2 gene expression levels. Acute toxicity study in mice indicated that the compound is safe till 2000 mg/kg. Two different doses 50 and 100 mg/kg were selected and studied in Ehrlich ascites carcinoma model of cancer and have shown significant improvement in survival time and hematological parameters.     

Epileptogenic activity of some beta-lactam derivatives: structure-activity relationship

The epileptogenic activity of several derivatives of beta-lactam was compared following their intracerebroventricular administration in rats. At a dose of 0.033 mumol/kg cefazolin was the most powerful epileptogenic compound among the drugs tested; dramatic seizure signs (nodding, clonic convulsions and sometimes escape responses) were observed repeatedly. It was approximately three times more potent than benzylpenicillin and other similar compounds, such as ceftriaxone, cefoperazone and cefamandole. No epileptogenic signs were observed with equimolar doses of cefotaxime, cefonicid and ceftizoxime. All these derivatives differ from the substitution at position 3 and at position 7 of 7-aminocephalosporanic acid. The more convulsant compounds (i.e. cefazolin and ceftezole) are both derivatives of tetrazol and show a marked similarity with pentylentetrazol. In addition, aztreonam, a compound having only the beta-lactam ring substituted with a heterocyclic ring at the 4 position, possessed convulsant properties like those of cefoperazone and cefamandole. This suggests that the beta-lactam ring is able to produce epileptogenic activity and it seems likely that substitutions at the 7-aminocephalosporanic or 6-aminopenicillanic acid may increase or reduce the epileptogenic properties of beta-lactam derivatives.     

Imidazole derivatives and their antitumor activity (review)

Bis(2-chloroethyl)amino derivatives of imidazole, 4(5)-aminoimidazol-5(4)-carboxamide, 4-nitro-5-thioimidazole, benzimidazole, and imidazolylpeptides are reviewed. Data are presented for active compounds, some of which have passed the preclinical testing stage. Structures under consideration are interesting with respect to both the search for new antitumor drugs and the synthesis of compounds with different biological properties.     

白杨素抗肿瘤衍生物的合成及其构效关系

目的合成一系列白杨素衍生物并结合体外实验探讨白杨素衍生物抗肿瘤作用的构效关系。方法以5,7-二羟基黄酮为原料,通过取代、水解、酰胺缩合等化学反应引入一些极性不同的小分子化合物,合成一系列白杨素的衍生物,然后采用MTT比色法检测白杨素及其衍生物对食管癌EC109细胞、肝癌HepG2细胞、宫颈癌Hela细胞的增殖抑制作用。结果化合物Ⅲa、Ⅲb、Ⅲc、Ⅲd、Ⅲf对抑制EC109增殖表现出的抗癌活性较白杨素有明显的提高,化合物Ⅲa、Ⅲd、Ⅲe、Ⅲf对抑制HepG2增殖表现出的抗癌活性较白杨素有明显的提高,其中Ⅲd和Ⅲf的抗肿瘤作用显著;白杨素及其衍生物对抑制Hela细胞的增殖均较高,但其衍生物抗肿瘤作用与白杨素相比没有提高。结论引入极性基团对白杨素的抗肿瘤活性有明显的提高,经过极性基团修饰后的白杨素衍生物能明显提高对EC109、HepG2细胞增殖抑制作用。     

Synthesis and antitumor activity of tropolone derivatives. 4

Modifications of monotropolone 2 having poor potency against P388 in mice were studied. The alpha-ethoxy group of 2, prepared from hinokitiol and benzaldehyde diethyl acetal, was replaced with a phenolic or heteroaromatic compound by heating 2 with the appropriate nucleophile. Structure-activity relationships indicated that an acidic hydroxyl and a proton-accepting group situated in the neighboring position, which permits the formation of a chelate with a metal ion, contributed to enhanced activity. Among the compounds studied, the 8-hydroxyquinoline analogue 10f was the most favorable compound.     

鬼臼毒素衍生物的合成及其体外抗肿瘤活性

目的 获得更高活性且具有抗多药耐药活性的抗肿瘤新化合物。方法 将4β-氨基-4-脱氧鬼臼毒素与醇类化合物以丁二酸为桥连接合成了7个鬼臼毒素衍生物,其结构经1H-NMR、TOF-MS证实。用K562和K562/AO2细胞经MTT法筛选了这些衍生物的体外抗肿瘤活性。结果 7个化合物均为新化合物,其中5b、5d的抗肿瘤活性显著高于VP-16, 并且5b、5c、5d、5e的抗多药耐药活性显著高于VP-16。结论 这些鬼臼毒素衍生物可提高抗肿瘤活性。     

Quantitative structure-activity relationship of quinoline derivatives

Quantum-chemical computations using the Hückel method have been performed on quinoline derivatives that exhibit antibacterial activity against E. coli, in order to obtain quantitative structure-activity relationship and drug-receptor interaction data.     

Synthesis and biological activity of galactopyranoside derivatives of 4'-demethylepipodophyllotoxin showing VP-16 (etoposide)-like activity.

To investigate the role of the glucoside moiety in the biological activity of VP-16 (etoposide; 4'-demethylepipodophyllotoxin-ethylidene-beta-D-glucoside) and VM-26 (teniposide; 4'-demethyl-epipodophyllotoxin-thenylidene-beta-D-glucoside), a number of acetal and ketal derivatives of 4'-demethylepipodophyllotoxin (DMEP)-beta-D-galactoside were synthesized. The compounds synthesized included acetaldehyde, propionaldehyde, 2-thiophenecarboxaldehyde, phenylacetaldehyde and acetone derivatives. In contrast to the glucose derivatives, where the acetal ring is trans to the pyranose ring, in galactose derivatives it is located in the cis position. The activities of the above compounds have been measured in two different biological assays, based on cross resistance towards mutants exhibiting specific resistance to VP-16/VM-26-like drugs and DNA-strand breaks as measured by the alkaline elution technique. All of the above compounds showed specific cross resistance to VpmR mutants (mutants resistant to VP-16 and VM-26) and caused a dose-dependent enhancement in DNA-strand breakage, providing evidence that they possessed the same kind of biological activity as VP-16 and VM-26. The relative activities of the DMEP-galactose derivatives have been compared with the corresponding DMEP-glucoside compounds. These studies reveal that, for the acetal and ketal derivatives with small R groups (acetaldehyde and acetone derivatives), the activities in the two series are comparable. However, for derivatives with larger, more hydrophobic R groups (2-thiophene or phenylacetaldehyde), the glucoside derivatives showed about 8-10-fold higher activity in comparison with the corresponding galactoside compounds.     

娃儿藤生物碱及其类似物的抗肿瘤构效关系研究进展

娃儿藤生物碱因其显著的抑制肿瘤生长活性及新的抗癌作用机制而受到化学和药学研究者的广泛关注。该文对自 2002 年以来关于娃儿藤生物碱和基于该类生物碱设计的类似物的分子结构与抗肿瘤作用的构效关系以及该类化合物抗肿瘤作用机制的最新研究成果进行综述,并对其研发前景加以展望。     

4-烷硫基-4-脱氧-4′-去甲表鬼臼毒素的合成和抗肿瘤活性

对4’-去甲表鬼臼毒素的C₄位进行化学修饰,合成和筛选了10个4-烷硫基-4-脱氧-4’-去甲表鬼臼毒素衍生物以进一步研究C₄位不同的原子和取代基与活性之间的关系及寻找结构简单、活性更强的抗肿瘤新药。4’-去甲表鬼臼毒素与硫醇在三氟化硼·乙醚或三氟乙酸存在下生成相应的硫醚,也可用硫醇与4β-溴-4-脱氧-4’-去甲表鬼臼毒素反应生成相应的硫醚。在体外筛选中,化合物10和12抑制L1210白血病细胞的活性与依托泊甙相当或更强,化合物9,10,12和15抑制KB细胞的活性与依托泊甙相当或更强。     

土槿乙酸衍生物的合成及其抗肿瘤活性

目的:研究土槿乙酸抗肿瘤作用的构效关系。方法:以土槿乙酸为原料,合成8个土槿乙酸衍生物,其结构经1H-NMR,MS证实。经MTT法筛选了衍生物的抗肿瘤活性。结果:8个化合物均为新化合物,除Ⅱc所有化合物均具有抗肿瘤活性,其中Ⅱf,Ⅱg的抗肿瘤活性显著高于土槿乙酸。结论:某些土槿乙酸酯和酰胺可提高抗肿瘤活性。     

A structure-activity relationship study of thiazole derivatives with H1-antihistamine activity

A structure-activity relationship (QSAR) analysis of 19 thiazole derivatives with H1-antihistamine activity was carried out. The semi-empirical method AMI was employed to calculate a set of physicochemical parameters for investigated compounds. The principal component analysis (PCA), discriminant function analysis (DFA) and regression analysis (RA) were employed to reduce dimensionality and investigate which subset of variables is effective for classifying the thiazole derivatives according to their degree of anti-H1 activity. In PCA the studied compounds were separated into two groups: group A with lower degree of H,-antihistamine activity and group B with higher activity. The DFA showed that the parameters: alpha (polarizability), AB (distance between aliphatic and aromatic nitrogen atoms), Eb (binding energy), Hh (hydration energy), eHOMO (HOMO energy), and QAr are responsible for separation between compounds exhibiting higher and lower H1-antihistamine activity. The importance of hydrophobic and steric parameters for thiazole derivatives 1-19 with HL-antihistamine activity was established via RA. On the basis of PCA, DFA and RA methods, a prediction rule for classifying new thiazole derivatives with H1-antihistamine activity was elaborated.     

Salvinorin A 型衍生物分子结构与活性关系研究（英文）

目的建立关于salvinorin A型结构的C-12取代衍生物对KOPR的亲和力参数(LogK_i)及效能参数(LogEC_(50))的分子结构与活性关系模型。方法通过采用与多元线性回归分析相结合的遗传算法技术,结合量子化学参数(最低未占分子轨道能级E_(LUMO),C-7及C-14原子电荷q_(C7)与q_(C14)),建立鼠尾草A型结构的C-12取代衍生物的结构与活性关系模型。结果与结论两模型相关系数分别为0.911和0.951。研究表明鼠尾草A型结构C-12取代衍生物对KOPR的LogK_i值随参数E_(LUMO)的减少及参数q_(C14)的增大而增大;LogEC_(50)值随参数E_(LUMO)的减少及参数q_(C7)的增大而增大。     

大黄素衍生物抗肿瘤活性的定量构效关系

目的 建立大黄素衍生物抗肿瘤活性的构效关系模型.方法 采用量子化学的AM1算法计算了12个大黄素衍生物的分子结构参数,利用逐步回归分析建立构效关系模型.结果 成功建立了大黄素衍生物抗肿瘤活性的构效关系模型.结论 大黄素衍生物抗肿瘤活性与分子体积V、极化率α及C环上净电荷QC相关.     

Synthesis and biological study of a new series of 4'-demethylepipodophyllotoxin derivatives

Etoposide (VP-16) is a potent human DNA topoisomerase II poison, derived from 4'-demethylepipodophyllotoxin, widely used in cancer chemotherapy. Continuous efforts have driven to synthesize new related compounds, presenting decreased toxic side effects, metabolic inactivation, drug resistance, and increased water solubility. Identified structure-activity relationships have pointed out the importance of the 4beta-substitution and of the configuration of the D ring. Here we report the synthesis of two novel series of derivatives of 4'-demethylepipodophyllotoxin. The first bears a carbamate chain in the 4 position (13a-f), whereas, in the second series, in addition to this chain, the lactone ring has been modified by shifting the carbonyl from position 13 to position 11 (27a-f). Moreover, an analogue of TOP-53 having this lactone modification has also been prepared (32). From this study, structure-activity relationships were established. Compounds 13a and 27a displayed potent cytotoxic activity against the L1210 cell line (10 to 20-fold higher than VP-16) and proved to be strong topoisomerase II poisons more potent than VP-16. From preliminary in vivo investigation of both compounds against P388 leukemia and orthotopically grafted human A549 lung carcinoma, it appeared that 13a and 27a constitute promising leads for a new class of antitumor agents.     

Synthesis and structure-activity relationships among glycosidic derivatives of 4'-demethylepipodophyllotoxin and epipodophyllotoxin, showing VM26- and VP16-213-like activities

We have synthesized acetal and ketal derivatives of 4'-demethylepipodophyllotoxin-beta-D-glucoside (DMEPG) and epipodophyllotoxin-beta-D-glucoside (EPG) with a number of different aldehydes (viz. acetaldehyde, propionaldehyde, 2-thiophenecarboxaldehyde, 3-thiophenecarboxaldehyde, 2-furancarboxaldehyde, benzaldehyde, phenylacetaldehyde, hydrocinnamaldehyde) and acetone. The cross resistance of these compounds towards a set of Chinese hamster ovary cell mutants resistant to either podophyllotoxin (PodR mutants) or VM26 (VpmR mutants) which exhibit mutually exclusive cross-resistance patterns toward compounds that show either podophyllotoxin- or VM26-like activities have been examined. Results of our studies show that, with the exception of 2-furan derivatives, all the remaining acetals and ketals of DMEPG and EPG showed similar cross-resistance patterns towards the VpmR and the PodR mutants, as seen with VM26 and VP16-213. These results provide strong suggestive evidence that all of these derivatives (except 2-furan) possess biological activities similar to VM26 and VP16-213, and that their cellular toxicities were due to this type of activity. The VM26-like behavior of different EPG derivatives, which lack the free 4'-OH group, provide evidence that a free 4'-OH group is not essential for VM26-like activity. However, in comparison to the EPG derivatives, the corresponding DMEPG compounds showed 10- to 30-fold higher activities, indicating an enhancing effect of the free 4'-OH group on this kind of activity. Some of the newly synthesized DMEPG and EPG derivatives show higher activity in comparison to VM26 and VP16-213, and structure-activity relationship among this group of compounds is discussed.