Simplified aminocoumarin analogues,either noviosylated or simple basic heterocycle attached 3-amido-coumarin compounds,are known to be promising anticancer agents targeting the C-terminal ATP-binding site of Hsp90.In ...Simplified aminocoumarin analogues,either noviosylated or simple basic heterocycle attached 3-amido-coumarin compounds,are known to be promising anticancer agents targeting the C-terminal ATP-binding site of Hsp90.In this study,3＇-amino isosteric replacement in the noviose moiety of two known noviose containing Hsp90 C-terminal inhibitors was synthetically realized for the first time.In vitro evaluation of these compounds suggested that the introduction of a basic amino group into the noviose subunit resulted in significant improvement of their cytotoxicities.展开更多
A new derivative of geldanamycin was synthesized by introducing the 6-cinnamamido-hexyl-amino group into the 17-site of geldanamycin, a heat shock protein 90 （Hsp90） inhibitor, to obtain 17-（6-cinnamamido-hexylamin...A new derivative of geldanamycin was synthesized by introducing the 6-cinnamamido-hexyl-amino group into the 17-site of geldanamycin, a heat shock protein 90 （Hsp90） inhibitor, to obtain 17-（6-cinnamamido-hexylamino）-17-demethoxygel-danamycin （CNDG）. Its in vitro and in vivo antitumor effects were evaluated by MTT assay and xenograft in nude mice.展开更多
热休克蛋白90(heat shock protein 90,HSP90)属于热应激性蛋白,参与真菌耐药性的产生.氟康唑(fluconazole,FCZ)作为临床侵袭性真菌感染治疗的一线治疗药物之一,因其仅具有抑菌活性,长期反复用药容易产生耐药性.因此,本文以HSP90抑制剂AU...热休克蛋白90(heat shock protein 90,HSP90)属于热应激性蛋白,参与真菌耐药性的产生.氟康唑(fluconazole,FCZ)作为临床侵袭性真菌感染治疗的一线治疗药物之一,因其仅具有抑菌活性,长期反复用药容易产生耐药性.因此,本文以HSP90抑制剂AUY922(AUY)为对象,研究其与FCZ合用时对FCZ敏感和耐药真菌的活性.通过棋盘式微量稀释法、生长实验、时间-杀菌曲线、菌丝生长、抑菌圈等实验综合评价AUY和FCZ合用时的抗真菌活性.结果显示:化合物AUY单用时对热带念珠菌、敏感和耐药白念珠菌、新生隐球菌有中等到弱的抑菌活性(MIC值为16~64μg/mL);当AUY与FCZ合用时对耐药白念珠菌和热带念珠菌表现明显的协同抗菌甚至杀菌活性;且两药合用后对真菌菌丝形成的抑制活性亦明显强于单用.因此,HSP90抑制剂AUY与FCZ合用具有协同抗真菌活性,这为抗真菌药物联合应用奠定基础.展开更多
基金support from Youth Science Foundation of Peking Union Medical College & Chinese Academy of Medical Sciences(No.521164)
文摘Simplified aminocoumarin analogues,either noviosylated or simple basic heterocycle attached 3-amido-coumarin compounds,are known to be promising anticancer agents targeting the C-terminal ATP-binding site of Hsp90.In this study,3＇-amino isosteric replacement in the noviose moiety of two known noviose containing Hsp90 C-terminal inhibitors was synthetically realized for the first time.In vitro evaluation of these compounds suggested that the introduction of a basic amino group into the noviose subunit resulted in significant improvement of their cytotoxicities.
文摘A new derivative of geldanamycin was synthesized by introducing the 6-cinnamamido-hexyl-amino group into the 17-site of geldanamycin, a heat shock protein 90 （Hsp90） inhibitor, to obtain 17-（6-cinnamamido-hexylamino）-17-demethoxygel-danamycin （CNDG）. Its in vitro and in vivo antitumor effects were evaluated by MTT assay and xenograft in nude mice.
文摘热休克蛋白90(heat shock protein 90,HSP90)属于热应激性蛋白,参与真菌耐药性的产生.氟康唑(fluconazole,FCZ)作为临床侵袭性真菌感染治疗的一线治疗药物之一,因其仅具有抑菌活性,长期反复用药容易产生耐药性.因此,本文以HSP90抑制剂AUY922(AUY)为对象,研究其与FCZ合用时对FCZ敏感和耐药真菌的活性.通过棋盘式微量稀释法、生长实验、时间-杀菌曲线、菌丝生长、抑菌圈等实验综合评价AUY和FCZ合用时的抗真菌活性.结果显示:化合物AUY单用时对热带念珠菌、敏感和耐药白念珠菌、新生隐球菌有中等到弱的抑菌活性(MIC值为16~64μg/mL);当AUY与FCZ合用时对耐药白念珠菌和热带念珠菌表现明显的协同抗菌甚至杀菌活性;且两药合用后对真菌菌丝形成的抑制活性亦明显强于单用.因此,HSP90抑制剂AUY与FCZ合用具有协同抗真菌活性,这为抗真菌药物联合应用奠定基础.
