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1.
Rangarajan M Kim JS Jin S Sim SP Liu A Pilch DS Liu LF LaVoie EJ 《Bioorganic & medicinal chemistry》2000,8(6):1371-1382
5-Phenylterbenzimidazole (1) is active as a topoisomerase I poison (topo I) and is cytotoxic to human tumor cells. No cross-resistance was observed for 1 when it was evaluated against the camptothecin-resistant cell line, CPT-K5. Derivatives of 1 substituted at the 2"-position, however, did exhibit cross-resistance to this cell line. The basis for the resistance of this cell line towards CPT is that it possesses a mutant form of topo I. These results suggest that substituents at the 2"-position may be in proximity to the wild-type enzyme. Therefore, we hypothesized that terbenzimidazoles with 2"-substituents could be capable of interacting with the enzyme and thereby influence activity within this class of topo I poisons. 5-Phenylterbenzimidazoles with a hydroxy, hydroxymethyl, mercapto, amino, N-benzoylaminomethyl, chloro, and trifluoromethyl group at the 2"-position were synthesized. In addition, several 2"-ethyl-5-phenylterbenzimidazoles were prepared containing either a methoxy, hydroxy, amino, or N-acetylamino group at the 2-position of the ethyl side-chain. These 2"-substituted 5-phenylterbenzimidazoles were evaluated as topo I poisons and for cytotoxic activity. The presence of a strong electron-withdrawing group at the 2"-position, such as a chloro or trifluoromethyl group, did enhance both topo I poisoning activity and cytotoxicity. Studies on the relative DNA binding affinity of 1 to its 2"-amino and 2"-trifluoromethyl derivatives did exhibit a correlation with their relative differences in biological activity. 相似文献
2.
Spindle poisons, such as paclitaxel and vinblastine, exert their potent anti-neoplastic effects through activation of the spindle assembly checkpoint (SAC), thereby arresting cells in mitosis. Unfortunately, only certain cancers are susceptible to these drugs, and many patients fail to respond to treatment. We review the pathways that are triggered by spindle poisons and highlight recent studies that describe the great variability of tumor cells in responding to these drugs. We also describe the recent identification of an apoptotic pathway that is activated by mitotic arrest in response to spindle poisons. Emerging from these studies is not only a greater understanding of how these classic antimitotic agents bring about cell death, but also a wealth of potential new targets of anticancer therapeutics. 相似文献
3.
药(毒)物对尸食性蝇类生长发育影响的研究进展 总被引:1,自引:0,他引:1
药(毒)物对尸食性蝇类生长发育影响是法医昆虫毒理学领域里一个十分重要的研究方向,其研究结果可对与药(毒)物相关死亡案件的死亡时间作出修正。随着近年来全球毒品及药物滥用情况的日趋严重,其所导致的死亡案件也越来越多。这类案件常常需要应用尸食性蝇类生长发育历期来推算死后经历时间(postmortem interval, PMI)。为了阐明该领域的研究进展以及未来研究的焦点和难点,本文在阐述法医昆虫毒理学概念和特点的基础上,按照不同的药(毒)物分类,对近年来药(毒)物对尸食性蝇类生长发育影响在国内外的研究进展进行了综述。研究表明,某些药(毒)物对尸食性蝇类生长发育具有一定的影响,且这种影响存在种属差异。目前,该领域的研究尚限于宏观现象观察阶段,其研究范围在不断拓宽,既有的研究也在进一步深化,但还有许多问题有待进一步探讨。 相似文献
4.
Gálvez M Martín-Cordero C Ayuso MJ 《Journal of enzyme inhibition and medicinal chemistry》2005,20(4):389-392
The discovery of new topoisomerase I inhibitors is necessary since most of the antitumor drugs are targeted against type II and only a very few can specifically affect type I. Topoisomerase poisons generate toxic DNA damage by stabilization of the covalent DNA-topoisomerase cleavage complex and some have therapeutic efficacy in human cancer. Two iridoids, aucubin and geniposide, have shown antitumoral activities, but their activity against topoisomerase enzymes has not been tested. Here it was found that both compounds are able to stabilize covalent attachments of the topoisomerase I subunits to DNA at sites of DNA strand breaks, generating cleavage complexes intermediates so being active as poisons of topoisomerase I, but not topoisomerase II. This result points to DNA damage induced by topoisomerase I poisoning as one of the possible mechanisms by which these two iridoids have shown antitumoral activity, increasing interest in their possible use in cancer chemoprevention and therapy. 相似文献
5.
Marina Gálvez Carmen Martín-Cordero María Jesús Ayuso 《Journal of enzyme inhibition and medicinal chemistry》2013,28(4):389-392
The discovery of new topoisomerase I inhibitors is necessary since most of the antitumor drugs are targeted against type II and only a very few can specifically affect type I. Topoisomerase poisons generate toxic DNA damage by stabilization of the covalent DNA-topoisomerase cleavage complex and some have therapeutic efficacy in human cancer. Two iridoids, aucubin and geniposide, have shown antitumoral activities, but their activity against topoisomerase enzymes has not been tested. Here it was found that both compounds are able to stabilize covalent attachments of the topoisomerase I subunits to DNA at sites of DNA strand breaks, generating cleavage complexes intermediates so being active as poisons of topoisomerase I, but not topoisomerase II. This result points to DNA damage induced by topoisomerase I poisoning as one of the possible mechanisms by which these two iridoids have shown antitumoral activity, increasing interest in their possible use in cancer chemoprevention and therapy. 相似文献
6.
M Farhat A Poissonnier A Hamze C Ouk-Martin J-D Brion M Alami J Feuillard C Jayat-Vignoles 《Cell death & disease》2014,5(5):e1201
Defects in apoptosis are frequently the cause of cancer emergence, as well as cellular resistance to chemotherapy. These phenotypes may be due to mutations of the tumor suppressor TP53 gene. In this study, we examined the effect of various mitotic spindle poisons, including the new isocombretastatin derivative isoNH2CA-4 (a tubulin-destabilizing molecule, considered to bind to the colchicine site by analogy with combretastatin A-4), on BL (Burkitt lymphoma) cells. We found that resistance to spindle poison-induced apoptosis could be reverted in tumor protein p53 (TP53)-mutated cells by EBV (Epstein Barr virus) infection. This reversion was due to restoration of the intrinsic apoptotic pathway, as assessed by relocation of the pro-apoptotic molecule Bax to mitochondria, loss of mitochondrial integrity and activation of the caspase cascade with PARP (poly ADP ribose polymerase) cleavage. EBV sensitized TP53-mutated BL cells to all spindle poisons tested, including vincristine and taxol, an effect that was systematically downmodulated by pretreatment of cells with inhibitors of p38 and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinases. Exogenous activation of p38 and JNK pathways by dihydrosphingosine reverted resistance of TP53-mutated BL cells to spindle poisons. Dihydrosphingosine treatment of TP53-deficient Jurkat and K562 cell lines was also able to induce cell death. We conclude that activation of p38 and JNK pathways may revert resistance of TP53-mutated cells to spindle poisons. This opens new perspectives for developing alternative therapeutic strategies when the TP53 gene is inactivated. 相似文献
7.
López-Lázaro M Martín-Cordero C Toro MV Ayuso MJ 《Journal of enzyme inhibition and medicinal chemistry》2002,17(1):25-29
The therapeutic anticancer potential of flavonoids shown by recent research needs a greater understanding of these compounds. They are antioxidants and antimutagenic agents that can inhibit tumor promotion and transformation and can modify the activity of a large number of mammalian enzyme systems, such as human DNA-topoisomerases. Poisons of topoisomerases generate toxic DNA damage by stabilization of the covalent DNA-topoisomerase cleavage complex and some of them have therapeutic efficacy in human cancer. The present investigation has assayed ten flavonoids, isolated in our laboratory, as topoisomerase I poisons obtaining myricetin and myricetin-3-galactoside as two new topoiosomerase I poisons. These two flavonoids, and the plant extract from which they were isolated, were assayed for cytotoxic activity against three human cancer cell lines using the SRB assay. Taking into account our previous research, structural requisites implicated in the topoisomerase poisoning are discussed. 相似文献
8.
Phytochemicals are a rich source of anticancer drugs and chemopreventive agents. Several of these chemicals appear to exert at least some of their effects through interactions with topoisomerase II, an essential enzyme that regulates DNA supercoiling and removes knots and tangles from the genome. Topoisomerase II-active phytochemicals function by stabilizing covalent protein-cleaved DNA complexes that are intermediates in the catalytic cycle of the enzyme. As a result, these compounds convert topoisomerase II to a cellular toxin that fragments the genome. Because of their mode of action, they are referred to as topoisomerase II poisons as opposed to catalytic inhibitors. The first sections of this article discuss DNA topology, the catalytic cycle of topoisomerase II, and the two mechanisms (interfacial vs. covalent) by which different classes of topoisomerase II poisons alter enzyme activity. Subsequent sections discuss the effects of several phytochemicals on the type II enzyme, including demethyl-epipodophyllotoxins (semisynthetic anticancer drugs) as well as flavones, flavonols, isoflavones, catechins, isothiocyanates, and curcumin (dietary chemopreventive agents). Finally, the leukemogenic potential of topoisomerase II-targeted phytochemicals is described. 相似文献
9.
Qun Sun Barbra Gatto Chiang Yu Angela Liu Leory F. Liu Edmond J. LaVoie 《Bioorganic & medicinal chemistry letters》1994,4(24):2871-2876
A series of bisbenzimidazoles related to Hoechst 33342 were synthesized. Data on the relative activity of these bisbenzimidazoles as topoisomerase I poisons suggest that considerable flexibility exists in the location of the tertiary alkylamine moeity. With the exception of arylamine analogs, cytotoxicity was generally consistent with their relative potency as topoisomerase I poisons. 相似文献
10.
STATISTICAL ASPECTS OF THE INDEPENDENT JOINT ACTION OF POISONS, PARTICULARLY INSECTICIDES 总被引:1,自引:0,他引:1
Methods are described for discovering whether a mixture of two poisons is as toxic as predicted on the hypothesis of independent joint action. These include X2 tests and a procedure for finding the maximum likelihood estimate of the coefficient of correlation in resistance to the poisons. The methods are illustrated using data from insecticidal tests.
In the insecticidal tests, flour beetles, Tribolium castaneum Herbst, were sprayed with, or exposed to films of, different insecticides in solution in Shell oil P 31. The insecticides were pyrethrins, D.D.T., and B.H.C., singly and in pairs. The statistical analysis of the results showed that pyrethrins and D.D.T. could have acted independently both as films and as direct sprays; D.D.T. and B.H.C. could have acted independently as films but not as direct sprays; and B.H.C. and pyrethrins could not have acted independently either as films or as direct sprays.
These findings are discussed, and it is concluded that independent action should be regarded as a special case of a more general type of joint action for which the term dissimilar is proposed. A general method of approach is suggested for the conception and development of hypotheses of the joint action of poisons. 相似文献
In the insecticidal tests, flour beetles, Tribolium castaneum Herbst, were sprayed with, or exposed to films of, different insecticides in solution in Shell oil P 31. The insecticides were pyrethrins, D.D.T., and B.H.C., singly and in pairs. The statistical analysis of the results showed that pyrethrins and D.D.T. could have acted independently both as films and as direct sprays; D.D.T. and B.H.C. could have acted independently as films but not as direct sprays; and B.H.C. and pyrethrins could not have acted independently either as films or as direct sprays.
These findings are discussed, and it is concluded that independent action should be regarded as a special case of a more general type of joint action for which the term dissimilar is proposed. A general method of approach is suggested for the conception and development of hypotheses of the joint action of poisons. 相似文献
11.
Abasic sites are the most commonly formed DNA lesions in the cell and are produced by numerous endogenous and environmental insults. In addition, they are generated by the initial step of base excision repair (BER). When located within a topoisomerase II DNA cleavage site, "intact" abasic sites act as topoisomerase II poisons and dramatically stimulate enzyme-mediated DNA scission. However, most abasic sites in cells are not intact. They exist as processed BER intermediates that contain DNA strand breaks proximal to the damaged residue. When strand breaks are located within a topoisomerase II DNA cleavage site, they create suicide substrates that are not religated readily by the enzyme and can generate permanent double-stranded DNA breaks. Consequently, the effects of processed abasic sites on DNA cleavage by human topoisomerase IIalpha were examined. Unlike substrates with intact abasic sites, model BER intermediates containing 5'- or 3'-nicked abasic sites or deoxyribosephosphate flaps were suicide substrates. Furthermore, abasic sites flanked by 5'- or 3'-nicks were potent topoisomerase II poisons, enhancing DNA scission approximately 10-fold compared with corresponding nicked oligonucleotides that lacked abasic sites. These findings suggest that topoisomerase II is able to convert processed BER intermediates to permanent double-stranded DNA breaks. 相似文献
12.
We report a mechanism-based screening technique to rapidly identify eukaryotic topoisomerase I targeting agents. The method is based on genetic tagging of topoisomerase I to immobilize the enzyme on a solid surface in a microtiter well format. DNA is added to the wells, and retained DNA is detected by Pico Green fluorescence. Compounds that result in an increase in Pico Green staining represent potential topoisomerase interfacial poisons, whereas those that reduce fluorescence report catalytic inhibitors; therefore, the solid phase assay represents a "bimodal" readout that reveals mechanisms of action. The method has been demonstrated to work with known interfacial poisons and catalytic inhibitors. This method is rapid, robust, economical, and scalable for large library screens. 相似文献
13.
《Bioorganic & medicinal chemistry》2016,24(7):1469-1479
Fluorine and chlorine are metabolically stable, but generally less active replacements for a nitro group at the 3-position of indenoisoquinoline topoisomerase IB (Top1) poisons. A number of strategies were employed in the present investigation to enhance the Top1 inhibitory potencies and cancer cell growth inhibitory activities of halogenated indenoisoquinolines. In several cases, the new compounds’ activities were found to rival or surpass those of similarly substituted 3-nitroindenoisoquinolines, and several unusually potent analogs were discovered through testing in human cancer cell cultures. A hydroxyethylaminopropyl side chain on the lactam nitrogen of two halogenated indenoisoquinoline Top1 inhibitors was found to also impart inhibitory activity against tyrosyl DNA phosphodiesterases 1 and 2 (TDP1 and TDP2), which are enzymes that participate in the repair of DNA damage induced by Top1 poisons. 相似文献
14.
Korzeniewski B 《Biophysical chemistry》2002,96(1):21-31
A potential kinetic impact of parallel activation of different steps during an increased energy demand on the effect of inborn enzyme deficiencies, physiological inhibitors, external poisons and substrate shortage on oxidative phosphorylation was studied in the theoretical way. Numerical simulations were performed with the aid of the previously developed computer model of oxidative phosphorylation. It was demonstrated that the parallel activation mechanism diminishes significantly changes in fluxes and metabolite concentrations occurring at a given degree of inactivation of the system by one of the above-mentioned factors. It was also shown that parallel activation decreases greatly the threshold value of the relative activity of oxidative phosphorylation, below which the oxygen consumption flux and ATP turnover flux become significantly affected. Finally, computer simulations predicted that parallel activation leads to a considerable increase in the apparent affinity of oxidative phosphorylation to oxygen, which delays the effect of inhibitors and poisons competing with oxygen for the active centre of cytochrome oxidase. It is concluded that one of possible functions of parallel direct activation of different steps of oxidative phosphorylation is to increase the resistance of the system to a decrease in the concentration/activity of different oxidative phosphorylation complexes. 相似文献
15.
Teratogenic effect of two mitotic poisons, griseofulvin and colchicine, was confirmed. A similar effect of another antimitotic agent, vinblastin, was demonstrated. The teratogenic effect of these poisons is expressed as a reduction of ommatidia in adult flies when the drug is fed to larvae. The highest frequency of phenocopies was recorded in temperature- and mutagen-sensitive strains. The mutagenic activity of vinblastin and griseofulvin was confirmed by the wing-spot test (somatic mutation and recombination test, SMART) in Drosophila melanogaster. In addition, this test demonstrated mutagenic activity of colchicine. All of the mitotic poisons induced small single spots but did not increase frequency of twin spots mwh/flr. Spot frequency was significantly higher in mutagen-sensitive mutants having defective excision repair. Heat shock (45-min exposure at 37 degrees C) decreased the frequency of phenocopies induced by the mitotic poisons. When third-instar larvae were subjected to heat shock prior to drug administration, the frequency of mutant cell clones was significantly reduced. These results indicate participation of heat-shock proteins in the protection of microtubules in actively proliferating cells of D. melanogaster. 相似文献
16.
Coralyne and several other synthetic benzo[a,g]quinolizium derivatives related to protoberberine alkaloids have exhibited activity as topoisomerase poisons. These compounds are characterized by the presence of a positively charged iminium group, which has been postulated to be associated with their pharmacological properties. The objective of the present study was to devise stable noncharged bioisosteres of these compounds. Several similarly substituted benz[a]acridine and benz[c]acridine derivatives were synthesized and their relative activity as topoisomerase poisons was determined. While the benz[c]acridine derivatives evaluated as part of this study were devoid of topoisomerase poisoning activity, several dihydrobenz[a]acridines were able to enhance DNA cleavage in the presence of topo I. In contrast to certain protoberberine derivatives that did exhibit activity as topo II poisons, none of the benz[a]acridines derivatives enhanced DNA cleavage in the presence of topo II. Among the benz[a]acridines studied, 5,6-dihydro-3,4-methylenedioxy-9,10-dimethoxybenz[a]acridine, 13e, was the most potent topo I poison, with comparable potency to coralyne. These data suggest that heterocyclic compounds structurally related to coralyne can exhibit potent topo I poisoning activity despite the absence of an iminium cation within their structure. In comparison to coralyne or other protoberberine derivatives, these benz[a]acridine derivatives possess distinctly different physicochemical properties and represent a novel series of topo I poisons. 相似文献
17.
Flatten K Dai NT Vroman BT Loegering D Erlichman C Karnitz LM Kaufmann SH 《The Journal of biological chemistry》2005,280(14):14349-14355
Agents that target topoisomerase I are widely utilized to treat human cancer. Previous studies have indicated that both the ataxia telangiectasia mutated (ATM)/checkpoint kinase (Chk) 2 and ATM- and Rad 3-related (ATR)/Chk1 checkpoint pathways are activated after treatment with these agents. The relative contributions of these two pathways to survival of cells after treatment with topoisomerase I poisons are currently unknown. To address this issue, we assessed the roles of ATR, Chk1, ATM, and Chk2 in cells treated with the topoisomerase I poisons camptothecin and 7-ethyl-10-hydroxycamptothecin (SN-38), the active metabolite of irinotecan. Colony forming assays demonstrated that down-regulation of ATR or Chk1 sensitized cells to SN-38 and camptothecin. In contrast, ATM and Chk2 had minimal effect of sensitivity to SN-38 or camptothecin. Additional experiments demonstrated that the Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin, which down-regulates Chk1, also sensitized a variety of human carcinoma cell lines to SN-38. Collectively, these results show that the ATR/Chk1 pathway plays a predominant role in the response to topoisomerase I inhibitors in carcinoma cells and identify a potential approach for enhancing the efficacy of these drugs. 相似文献
18.
Patterns of strongly protein-associated simian virus 40 DNA replication intermediates resulting from exposures to specific topoisomerase poisons 总被引:5,自引:0,他引:5
Exposure of infected CV-1 cells to specific type I and type II topoisomerase poisons caused strong protein association with distinct subsets of simian virus 40 (SV40) DNA replication intermediates. On the basis of the known specificity and mechanisms of action of these drugs, the proteins involved are assumed to be the respective topoisomerases. Camptothecin, a topoisomerase I poison, caused strong protein association with form II (relaxed circular) and form III (linear) viral genomes and replication intermediates having broken DNA replication forks but not with form I (superhelical) viral DNA or normal late replication intermediates which were present. In contrast, type II topoisomerase poisons caused completely replicated forms and late viral replication forms to be tightly bound to protein--some to a greater extent than others. Different type II topoisomerase inhibitors caused distinctive patterns of protein association with the replication intermediates present. Both intercalating and nonintercalating type II topoisomerase poisons caused a small amount of form I (superhelical) SV40 DNA to be protein-associated in vivo. The protein complex with form I viral DNA was entirely drug-dependent and strong, but apparently noncovalent. The protein associated with form I DNA may represent a drug-stabilized "topological complex" between type II topoisomerase and SV40 DNA. 相似文献
19.
Microtubule poisons such as colchicine, colcemid and vinblastine caused extrusion of nuclei of murine suspension culture cells (mastocytoma p-815 cells, myeloma PU-3 cells, leukemia M1 cells). Enucleation did not follow spontaneously in most cells, but it did occur when the treated cells were centrifuged in Separate-L gradient. These poisons did not induce nuclear extrusion in cells growing in monolayer (L cells, BALB/c 3T3 cells, SV40-transformed BALB/c 3T3 cells, histiocytoma HC-11 cells). Cytochalasin B (CB) that had been reported to cause nuclear extrusion in the cells cultured in monolayer [1] did not induce the extrusion in the suspension culture cells but inhibited the colchicine-induced nuclear extrusion. 相似文献
20.
Peter P. Mager 《Biometrical journal. Biometrische Zeitschrift》1983,25(3):223-232
There are some serious pitfalls if the usual multiple and multivariate regression analysis are applied to correlate the biological activity of compounds against parameters describing the chemical molecule structure if the observations consist of an inhomogeneous data set. By contrast to the more known methods of cluster analysis, it must be required that a partition into homogeneous groups is possible and, in addition, that the members inside any group are normally distributed. The principle of the Q-mode regression analysis dealing with that problem is exemplified on the antidotal action of bispyridinium oximes in intoxication with organophosphorus poisons (soman, tabun, sarin, VX). 相似文献