A facile one-pot procedure has been developed for the synthesis of GL331 in 26% overall yield.In addition,molecular modeling study was carried out to predict the binding site of GL331 with human topoisomerase IIα.The...A facile one-pot procedure has been developed for the synthesis of GL331 in 26% overall yield.In addition,molecular modeling study was carried out to predict the binding site of GL331 with human topoisomerase IIα.The result showed that GL331 exhibited high affinity for the ATPase domain of human topoisomerase IIα and suggested that GL331 probably acts as a competitor of ATP for binding with the human topoisomerase IIα.展开更多
DNA topoisomerase IIα(170 kDa,TOP2α/170)induces transient DNA double-strand breaks in proliferating cells to resolve DNA topological entanglements during chromosome condensation,replication,and segregation.Therefore...DNA topoisomerase IIα(170 kDa,TOP2α/170)induces transient DNA double-strand breaks in proliferating cells to resolve DNA topological entanglements during chromosome condensation,replication,and segregation.Therefore,TOP2α/170 is a prominent target for anticancer drugs whose clinical efficacy is often compromised due to chemoresistance.Although many resistance mechanisms have been defined,acquired resistance of human cancer cell lines to TOP2αinterfacial inhibitors/poisons is frequently associated with a reduction of Top2α/170 expression levels.Recent studies by our laboratory,in conjunction with earlier findings by other investigators,support the hypothesis that a major mechanism of acquired resistance to TOP2α-targeted drugs is due to alternative RNA processing/splicing.Specifically,several TOP2αmRNA splice variants have been reported which retain introns and are translated into truncated TOP2αisoforms lacking nuclear localization sequences and subsequent dysregulated nuclear-cytoplasmic disposition.In addition,intron retention can lead to truncated isoforms that lack both nuclear localization sequences and the active site tyrosine(Tyr805)necessary for forming enzyme-DNA covalent complexes and inducing DNA damage in the presence of TOP2α-targeted drugs.Ultimately,these truncated TOP2αisoforms result in decreased drug activity against TOP2αin the nucleus and manifest drug resistance.Therefore,the complete characterization of the mechanism(s)regulating the alternative RNA processing of TOP2αpre-mRNA may result in new strategies to circumvent acquired drug resistance.Additionally,novel TOP2αsplice variants and truncated TOP2αisoforms may be useful as biomarkers for drug resistance,prognosis,and/or direct future TOP2α-targeted therapies.展开更多
The focus of this research is on the study of a series of copper (II) benzoylpyridine thiosemicarbazone complexes. Of the six benzoylpyridine thiosemicarbazone ligands used in this study, two are reported for the firs...The focus of this research is on the study of a series of copper (II) benzoylpyridine thiosemicarbazone complexes. Of the six benzoylpyridine thiosemicarbazone ligands used in this study, two are reported for the first time;2-benzoylpyridine tert-butyl thiosemicarbazone (BZP-tBTSC), and 2-benzoylpyridine benzyl thiosemicarbazone (BZP-BzTSC). Once characterized by NMR, melting point, and MS, these mono-anionic tridentate ligands were then reacted with Cu<sup>2+</sup> to form the new square planar metal complexes [Cu(BZP-tBTSC)Cl] and [Cu(BZP-BzTSC)Cl]. All of the copper complexes display marked inhibition of human topoisomerase IIα. The [Cu(BZP-tBTSC)Cl] complex shows marked activity against human breast cancer cell lines.展开更多
Objective.To determine the apoptotic and proliferative activities in various ovarian epithelial tumors.Methods.Formalin-fixed,paraffin-embedded tissues of 86ovarian epithelial tu mors,including 52adenocarcino-mas,23bo...Objective.To determine the apoptotic and proliferative activities in various ovarian epithelial tumors.Methods.Formalin-fixed,paraffin-embedded tissues of 86ovarian epithelial tu mors,including 52adenocarcino-mas,23borderline tumors and 11cystadenomas,were retrieved.Apoptoti c(AI )and proliferative(PI )index were estimated using the monoclonal antibodies:M30,Ki-67and Ki-S1in t hese tumors.Quantitative assess-ment of AI and PI was estimated by calc ulating the percentage of positive c ells among no less than 1000tumor cells.Results.Statistically significant differe nce in AI was found between benign and borderline tumors or carcino-mas(P=0.028,0.001,respectively).Significant differences in PI,as a ssessed by both Ki-67and topo IIα,were demonstrated between carcinom as and benign or borderline tumors(both P<0.001).Benign tumors had both low PI and AI;borderline tumors had lower PI but higher AI,while aden ocarcinomas had both high prolifera-tive and high apoptotic rates.Among borderline tumors,serous tumors had significantly lower AI and higher PI than mucinous ones.Conclusions.The results suggest that apoptotic a nd proliferative activities play im portant roles in the pathogene-sis and development of ovarian borderline and malignant tumors.The high apoptotic rate in borderline tumor m ay explain its relatively indolent beh avior while the high proliferative r ate in carcinomas tends to explain its aggres-sive behavior.展开更多
文摘A facile one-pot procedure has been developed for the synthesis of GL331 in 26% overall yield.In addition,molecular modeling study was carried out to predict the binding site of GL331 with human topoisomerase IIα.The result showed that GL331 exhibited high affinity for the ATPase domain of human topoisomerase IIα and suggested that GL331 probably acts as a competitor of ATP for binding with the human topoisomerase IIα.
基金This work was supported by the National Institutes of Health National Cancer Institute(Grant R01 CA226906-01A1).
文摘DNA topoisomerase IIα(170 kDa,TOP2α/170)induces transient DNA double-strand breaks in proliferating cells to resolve DNA topological entanglements during chromosome condensation,replication,and segregation.Therefore,TOP2α/170 is a prominent target for anticancer drugs whose clinical efficacy is often compromised due to chemoresistance.Although many resistance mechanisms have been defined,acquired resistance of human cancer cell lines to TOP2αinterfacial inhibitors/poisons is frequently associated with a reduction of Top2α/170 expression levels.Recent studies by our laboratory,in conjunction with earlier findings by other investigators,support the hypothesis that a major mechanism of acquired resistance to TOP2α-targeted drugs is due to alternative RNA processing/splicing.Specifically,several TOP2αmRNA splice variants have been reported which retain introns and are translated into truncated TOP2αisoforms lacking nuclear localization sequences and subsequent dysregulated nuclear-cytoplasmic disposition.In addition,intron retention can lead to truncated isoforms that lack both nuclear localization sequences and the active site tyrosine(Tyr805)necessary for forming enzyme-DNA covalent complexes and inducing DNA damage in the presence of TOP2α-targeted drugs.Ultimately,these truncated TOP2αisoforms result in decreased drug activity against TOP2αin the nucleus and manifest drug resistance.Therefore,the complete characterization of the mechanism(s)regulating the alternative RNA processing of TOP2αpre-mRNA may result in new strategies to circumvent acquired drug resistance.Additionally,novel TOP2αsplice variants and truncated TOP2αisoforms may be useful as biomarkers for drug resistance,prognosis,and/or direct future TOP2α-targeted therapies.
文摘The focus of this research is on the study of a series of copper (II) benzoylpyridine thiosemicarbazone complexes. Of the six benzoylpyridine thiosemicarbazone ligands used in this study, two are reported for the first time;2-benzoylpyridine tert-butyl thiosemicarbazone (BZP-tBTSC), and 2-benzoylpyridine benzyl thiosemicarbazone (BZP-BzTSC). Once characterized by NMR, melting point, and MS, these mono-anionic tridentate ligands were then reacted with Cu<sup>2+</sup> to form the new square planar metal complexes [Cu(BZP-tBTSC)Cl] and [Cu(BZP-BzTSC)Cl]. All of the copper complexes display marked inhibition of human topoisomerase IIα. The [Cu(BZP-tBTSC)Cl] complex shows marked activity against human breast cancer cell lines.
文摘Objective.To determine the apoptotic and proliferative activities in various ovarian epithelial tumors.Methods.Formalin-fixed,paraffin-embedded tissues of 86ovarian epithelial tu mors,including 52adenocarcino-mas,23borderline tumors and 11cystadenomas,were retrieved.Apoptoti c(AI )and proliferative(PI )index were estimated using the monoclonal antibodies:M30,Ki-67and Ki-S1in t hese tumors.Quantitative assess-ment of AI and PI was estimated by calc ulating the percentage of positive c ells among no less than 1000tumor cells.Results.Statistically significant differe nce in AI was found between benign and borderline tumors or carcino-mas(P=0.028,0.001,respectively).Significant differences in PI,as a ssessed by both Ki-67and topo IIα,were demonstrated between carcinom as and benign or borderline tumors(both P<0.001).Benign tumors had both low PI and AI;borderline tumors had lower PI but higher AI,while aden ocarcinomas had both high prolifera-tive and high apoptotic rates.Among borderline tumors,serous tumors had significantly lower AI and higher PI than mucinous ones.Conclusions.The results suggest that apoptotic a nd proliferative activities play im portant roles in the pathogene-sis and development of ovarian borderline and malignant tumors.The high apoptotic rate in borderline tumor m ay explain its relatively indolent beh avior while the high proliferative r ate in carcinomas tends to explain its aggres-sive behavior.
