Anti-cancer drug design最新文献_第2页

Design, synthesis and in vitro cytotoxicity studies of novel pyrrolo[2,1-c][1,4]benzodiazepine (PBD)--polymade conjugates and 2,2'-PBD dimers. 新型吡咯[2,1-c][1,4]苯二氮卓(PBD)-聚偶联物和2,2'-PBD二聚体的设计、合成和体外细胞毒性研究。

Anti-cancer drug design Pub Date : 2000-06-01

B S Reddy, Y Damayanthi, B S Reddy, J W Lown

引用次数: 0

DNA intercalation, topoisomerase II inhibition and cytotoxic activity of the plant alkaloid neocryptolepine. 植物生物碱新cryptolepine的DNA嵌入、拓扑异构酶II抑制及细胞毒活性。

Anti-cancer drug design Pub Date : 2000-06-01

C Bailly, W Laine, B Baldeyrou, M C De Pauw-Gillet, P Colson, C Houssier, K Cimanga, S Van Miert, A J Vlietinck, L Pieters

{"title":"DNA intercalation, topoisomerase II inhibition and cytotoxic activity of the plant alkaloid neocryptolepine.","authors":"C Bailly, W Laine, B Baldeyrou, M C De Pauw-Gillet, P Colson, C Houssier, K Cimanga, S Van Miert, A J Vlietinck, L Pieters","doi":"","DOIUrl":"","url":null,"abstract":"Cryptolepine and neocryptolepine are two indoloquinoline alkaloids isolated from the roots of the African plant Cryptolepis sanguinolenta. Both drugs have revealed antibacterial and antiparasitic activities and are strongly cytotoxic to tumour cells. We have recently shown that cryptolepine can intercalate into DNA and stimulates DNA cleavage by human topoisomerase II. In this study, we have investigated the mechanism of action and cytotoxicity of neocryptolepine, which differs from the parent isomer only by the orientation of the indole unit with respect to the quinoline moiety. The biochemical and physicochemical results presented here indicate that neocryptolepine also intercalates into DNA, preferentially at GC-rich sequences, but exhibits a reduced affinity for DNA compared with cryptolepine. The two alkaloids interfere with the catalytic activity of human topoisomerase II but the poisoning activity is slightly more pronounced with cryptolepine than with its isomer. The data provide a molecular basis to account for the reduced cytotoxicity of neocryptolepine compared with the parent drug.","PeriodicalId":7927,"journal":{"name":"Anti-cancer drug design","volume":"15 3","pages":"191-201"},"PeriodicalIF":0.0,"publicationDate":"2000-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21877053","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Synthesis and antiproliferative activity of unsaturated quinoline derivatives. 不饱和喹啉衍生物的合成及其抗增殖活性。

Anti-cancer drug design Pub Date : 2000-06-01

G J Montgomery, P McKeown, A T McGown, D J Robins

{"title":"Synthesis and antiproliferative activity of unsaturated quinoline derivatives.","authors":"G J Montgomery, P McKeown, A T McGown, D J Robins","doi":"","DOIUrl":"","url":null,"abstract":"In our previous work Knoevenagel condensation of quinoline 2-, 3- and 4-carbaldehyde with malononitrile derivatives was used to produce a series of heteroarylidene malononitrile derivatives. Some of these heteroaromatic tyrphostins were potent inhibitors of the epidermal growth factor (EGF) receptor kinase. This work has now been extended by using 6-, 7-, and 8-quinolinecarbaldehyde to prepare 23 new quinoline-tyrphostins 1-23. Most of these compounds were moderately active against the MCF7 breast cancer cell line. The order of potency was 7- > 6 > 8-substituted quinoline, which indicates that increased activity of the 7-substituted quinolines is associated with electron deficiency at the 7-position in the quinoline ring. The most active compound, 12, formed from 7-quinolinecarbaldehyde and ethyl cyanoacetate, had an IC50 value of 2.3 microM. Compounds 1-23 showed similar IC50 values against the MCF7 and MCF7/ADR cell lines (the latter shows fourfold increased protein tyrosine kinase activity) except for the compounds 1 and 15 formed from 6-quinolinecarbaldehyde and malononitrile and 7-quinolinecarbaldehyde and cyanoacetamide, which showed a significant (11- and 42-fold, respectively) increase in potency against the MCF7/ADR cell line. Furthermore, no association was found between growth inhibition and inhibition of the EGFR protein tyrosine kinase (PTK), using a cell-free assay. In addition, new compounds were prepared from 2- and 4-quinolinecarbaldehyde with extended conjugation in the side chains (24-27) or with methoxypolyethoxyethyl esters in the side chain to increase water solubility (28 and 29). These compounds showed substantial cytotoxicity, with IC50 values in the range 1-25 microM, but similar values were observed against both cell lines. No association was found between inhibition of PTK and growth inhibition, again indicating that their mode of action may not be specific for the EGF receptor.","PeriodicalId":7927,"journal":{"name":"Anti-cancer drug design","volume":"15 3","pages":"171-81"},"PeriodicalIF":0.0,"publicationDate":"2000-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21877051","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Synthesis of new homochiral bispyrrolidines as potential DNA cross-linking antitumour agents. 新型同手性双吡咯烷类潜在DNA交联抗肿瘤药物的合成。

Anti-cancer drug design Pub Date : 2000-04-01

F M Anderson, C C O'Hare, J A Hartley, D J Robins

{"title":"Synthesis of new homochiral bispyrrolidines as potential DNA cross-linking antitumour agents.","authors":"F M Anderson, C C O'Hare, J A Hartley, D J Robins","doi":"","DOIUrl":"","url":null,"abstract":"We are seeking to develop more effective bifunctional alkylating agents as antitumour agents. We previously synthesized conformationally restricted nitrogen mustards containing one piperidine ring, then bispiperidine derivatives were designed and prepared with varying lengths of carbon chain between the two rings and structure-activity relationships in these systems were studied. A bispiperidine with the shortest bridge of two carbon atoms was the most reactive bifunctional alkylating agent. In order to extend this work and investigate the effects of a change in the size of the heterocyclic systems, new bispyrrolidine salts 17-23 with chloromethyl groups at the 2-positions and a bridge between the two nitrogen atoms of 2-8 carbon atoms were synthesized from L-proline so that only the LL-enantiomers were produced. The free bases were designed to be bifunctional alkylating agents via aziridinium ion formation with different distances between the two alkylating sites. All of the bispyrrolidines were efficient cross-linkers of naked DNA apart from those with three-carbon (18) and four-carbon (19) bridges, in contrast to the results with the bispiperidines. A piperazine derivative 24 with two potential alkylating sites was also shown to be an efficient cross-linker, as was an alicyclic compound 25 with six carbon atoms between the two alkylating sites. Compounds 26 and 30 with an extra carbon atom between the nitrogen and the leaving group were not cross-linkers, as expected if aziridinium ion formation is crucial for cross-linking ability. The preformed aziridine 27 with a further alkylating site was an efficient cross-linker. Compounds 28-29 with only one potential alkylating centre were not cross-linkers of DNA. None of the compounds, however, produced significant cytotoxicity in human tumour cells in vitro.","PeriodicalId":7927,"journal":{"name":"Anti-cancer drug design","volume":"15 2","pages":"119-26"},"PeriodicalIF":0.0,"publicationDate":"2000-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21743036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Synthesis and antitumor cytotoxicity evaluation of pyrido[4,3,2-de]quinolines and isoquinolino[6,5,4,3-cde]quinolines. 吡啶类[4,3,2-de]喹啉和异喹啉类[6,5,4,3- de]喹啉的合成及抗肿瘤细胞毒性评价

Anti-cancer drug design Pub Date : 2000-04-01

Q Ding, G Jia, J W Lown

{"title":"Synthesis and antitumor cytotoxicity evaluation of pyrido[4,3,2-de]quinolines and isoquinolino[6,5,4,3-cde]quinolines.","authors":"Q Ding, G Jia, J W Lown","doi":"","DOIUrl":"","url":null,"abstract":"A series of novel pyrido[4,3,2-de]quinoline and isoquinolino[6,5,4,3-cde] quinoline compounds was synthesized and evaluated for cytotoxicity in the National Cancer Institute developmental therapeutics program. The tricyclic compound 7 was synthesized by the cyclization of 3,4-diamino-1,2dimethoxybenzene with diethyl 1,3-acetonedicarboxylate. Oxidation of monochloropyrido[4,3,2-de]quinoline 8 selectively produced 2,3-diketopyrido[4,3,2-de]quinoline 9 as deep violet crystals. Compound 9, when treated with acetone or acetophenone, affords the tetracyclic isoquinolino[6,5,4,3-cde]quinolines 13 and 14, respectively. 2,3-Diketopyrido[4,3,2-de]quinolines 9 and 10 exhibit higher cytotoxic potency than isoquinolino[6,5,4,3-cdelquinolines 13, 14, 15 and 16. Compound 9 selectively affects the cell growth against leukemia CCRF-CEM and HL-60 cell lines, the non-small cell lung cancer HOP-92 cell line, and breast cancer MDA-MB231/ ATCC and MDA-MB- 435 cell lines with GI(50) values of <2.0 microM. Modification of compound 9 with an ester group at the N-1 position afforded compound 10, which exhibits a wide spectrum of anticancer activities with a mean graph midpoint value of 1.8 microM against the 60 cancer cell lines.","PeriodicalId":7927,"journal":{"name":"Anti-cancer drug design","volume":"15 2","pages":"99-108"},"PeriodicalIF":0.0,"publicationDate":"2000-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21743034","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Biological properties of 5,11-dimethyl-6H-pyrido[3,2-b]carbazoles: a new class of potent antitumour drugs. 一类新型强效抗肿瘤药物- 5,11-二甲基- 6h -吡啶[3,2-b]咔唑的生物学特性

Anti-cancer drug design Pub Date : 2000-04-01

V Moinet-Hedin, T Tabka, L Poulain, T Godard, M Lechevrel, C Saturnino, J C Lancelot, J Y Le Talaër, P Gauduchon

{"title":"Biological properties of 5,11-dimethyl-6H-pyrido[3,2-b]carbazoles: a new class of potent antitumour drugs.","authors":"V Moinet-Hedin, T Tabka, L Poulain, T Godard, M Lechevrel, C Saturnino, J C Lancelot, J Y Le Talaër, P Gauduchon","doi":"","DOIUrl":"","url":null,"abstract":"Thirteen 5,11-dimethyl-6H-pyrido[3,2-b]carbazoles, structurally related to the antitumour drug ellipticine, were tested for their cytotoxicity against the L1210 murine leukaemia cell line and their antitumour activity against both leukaemias and solid tumours. Most of them showed an interesting antitumour activity against L1210 leukaemia, 4-hydroxy-9-chloro-2,3, 5,11-tetramethyl-6H-pyrido[3,2-b]carbazole displaying a high antitumour activity against L1210 and P388 leukaemias, B16 melanoma and M5076 sarcoma. Despite promising cytotoxic activity, 4-ethoxy-5,11-dimethyl-6H-pyrido-[3,2-b]carbazole had no antitumour activity. The ability of four drugs to induce strand breaks in DNA was studied using the single cell gel electrophoresis assay (comet assay). Most of the molecules induced DNA breaks that were totally or partially repaired after 1 h. The effects of these compounds on the L1210 cell cycle were tested as well as their abilities to induce apoptosis in these cells. Three of them induced a G2/M blockade, without any obvious evidence of apoptosis. The other compound, 4-ethoxy-5,11-dimethyl-6H-pyrido[3,2b]carbazole, did not lead to phase-specific blockade, but was a strong inductor of apoptosis in L1210 cells.","PeriodicalId":7927,"journal":{"name":"Anti-cancer drug design","volume":"15 2","pages":"109-18"},"PeriodicalIF":0.0,"publicationDate":"2000-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21743035","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Photosensitizing properties of palladium-tetraphenylporphycene on cultured tumour cells. 钯-四苯基卟啉对培养肿瘤细胞的光敏特性。

Anti-cancer drug design Pub Date : 2000-04-01

M Cañete, A Ortiz, A Juarranz, A Villanueva, S Nonell, J I Borrell, J Teixidó, J C Stockert

{"title":"Photosensitizing properties of palladium-tetraphenylporphycene on cultured tumour cells.","authors":"M Cañete, A Ortiz, A Juarranz, A Villanueva, S Nonell, J I Borrell, J Teixidó, J C Stockert","doi":"","DOIUrl":"","url":null,"abstract":"In this study we describe photokilling properties and effects on the mitotic index (MI) of cultured HeLa cells induced by palladium(II)-tetraphenylporphycene (PdTPP(0)). The drug was synthesized by refluxing tetraphenylporphycene (TPP(0)) and PdCl2 in dimethylformamide, followed by evaporation and purification by chromatography. Cells were treated with different concentrations of PdTPPo incorporated into dipalmitoylphosphatidylcholine liposomes, and red light irradiation (lambda > 600 nm) was performed at 21 mW/cm2. No dark toxicity was found when the drug was applied under our experimental conditions. Using lethal (LD(100)) treatments, cells showed the immediate occurrence of bubbles on the plasma membrane, whereas homogeneous nuclear condensation and loss of cytoplasm appeared 3-24 h later. An increased MI was found 6-8 h after sublethal LD(25) and LD(40) treatments as well as a high proportion of abnormal metaphases with altered spindle microtubules. Chromatin condensation and fragmentation were observed 8 h after LD(75) treatments. These results show that in comparison with TPP(0), the new sensitizer PdTPPo has more efficient photokilling properties which could be very valuable for the photodynamic therapy of cancer.","PeriodicalId":7927,"journal":{"name":"Anti-cancer drug design","volume":"15 2","pages":"143-50"},"PeriodicalIF":0.0,"publicationDate":"2000-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21743039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

In vitro characterization of the anticancer activity of membrane-active cationic peptides. I. Peptide-mediated cytotoxicity and peptide-enhanced cytotoxic activity of doxorubicin against wild-type and p-glycoprotein over-expressing tumor cell lines. 膜活性阳离子肽抗癌活性的体外表征。肽介导的细胞毒性和肽增强的阿霉素对野生型和p糖蛋白过表达肿瘤细胞系的细胞毒性活性。

Anti-cancer drug design Pub Date : 2000-04-01

S A Johnstone, K Gelmon, L D Mayer, R E Hancock, M B Bally

{"title":"In vitro characterization of the anticancer activity of membrane-active cationic peptides. I. Peptide-mediated cytotoxicity and peptide-enhanced cytotoxic activity of doxorubicin against wild-type and p-glycoprotein over-expressing tumor cell lines.","authors":"S A Johnstone, K Gelmon, L D Mayer, R E Hancock, M B Bally","doi":"","DOIUrl":"","url":null,"abstract":"Cationic amphipathic peptides, such as the defensins and cecropins, induce cell death in prokaryotic and eukaryotic cells by increasing membrane permeability. Increased permeability may lead to cell lysis or, alternatively, may produce subtle changes in the membrane's barrier function that promote cell death. The in vitro cytotoxic and lytic activity of short mammalian-derived extended-helical cationic peptides and insect-derived alpha-helical peptides was measured in this study with the objective of establishing the anticancer potential of these agents. Two specific aims were addressed: (i) to assess the activity of peptides against non-malignant cells (sheep erythrocytes and human umbilical vein endothelial cells) versus tumor cells; and (ii) to characterize the cytotoxic activity using multidrug-resistant tumor cell lines in the presence and absence of the anthracycline doxorubicin. Cell lysis assays demonstrated that the lytic activity of the peptides tested was 2->50 times more cytotoxic to tumor cells than to non-malignant cells. Further, the cytotoxic activity of these peptides was equivalent when tested against sensitive and multidrug-resistant cell lines. In addition to their inherent cytotoxic activity, these membrane-active peptides can also augment the in vitro cytotoxic activity of doxorubicin against multidrug-resistant tumor cells.","PeriodicalId":7927,"journal":{"name":"Anti-cancer drug design","volume":"15 2","pages":"151-60"},"PeriodicalIF":0.0,"publicationDate":"2000-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21743040","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Characterization of anticancer agents by their growth inhibitory activity and relationships to mechanism of action and structure. 抗癌药物生长抑制活性的表征及其作用机制和结构的关系。

Anti-cancer drug design Pub Date : 2000-04-01

O Keskin, I Bahar, R L Jernigan, J A Beutler, R H Shoemaker, E A Sausville, D G Covell

{"title":"Characterization of anticancer agents by their growth inhibitory activity and relationships to mechanism of action and structure.","authors":"O Keskin, I Bahar, R L Jernigan, J A Beutler, R H Shoemaker, E A Sausville, D G Covell","doi":"","DOIUrl":"","url":null,"abstract":"An analysis of the growth inhibitory potency of 122 anticancer agents available from the National Cancer Institute anticancer drug screen is presented. Methods of singular value decomposition (SVD) were applied to determine the matrix of distances between all compounds. These SVD-derived dissimilarity distances were used to cluster compounds that exhibit similar tumor growth inhibitory activity patterns against 60 human cancer cell lines. Cluster analysis divides the 122 standard agents into 25 statistically distinct groups. The first eight groups include structurally diverse compounds with reactive functionalities that act as DNA-damaging agents while the remaining 17 groups include compounds that inhibit nucleic acid biosynthesis and mitosis. Examination of the average activity patterns across the 60 tumor cell lines reveals unique 'fingerprints' associated with each group. A diverse set of structural features are observed for compounds within these groups, with frequent occurrences of strong within-group structural similarities. Clustering of cell types by their response to the 122 anticancer agents divides the 60 cell types into 21 groups. The strongest within-panel groupings were found for the renal, leukemia and ovarian cell panels. These results contribute to the basis for comparisons between log(GI(50)) screening patterns of the 122 anticancer agents and additional tested compounds.","PeriodicalId":7927,"journal":{"name":"Anti-cancer drug design","volume":"15 2","pages":"79-98"},"PeriodicalIF":0.0,"publicationDate":"2000-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"21743033","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The interaction of chalcones with tubulin. 查尔酮与微管蛋白的相互作用。

Anti-cancer drug design Pub Date : 2000-04-01

N J Lawrence, A T McGown, S Ducki, J A Hadfield

引用次数: 0