This study reports the capacity of three nitro substituted benzazolo[3,2-a]quinolinium salts NBQs: NBQ 95 (NSC-763304), NBQ 38 (NSC 763305), and NBQ 97 (NSC-763306) as potential antitumor agents. NBQ’s are unnatural ...This study reports the capacity of three nitro substituted benzazolo[3,2-a]quinolinium salts NBQs: NBQ 95 (NSC-763304), NBQ 38 (NSC 763305), and NBQ 97 (NSC-763306) as potential antitumor agents. NBQ’s are unnatural alkaloids possessing a positive charge that could facilitate interaction with cell organelles. The anticancer activities of these compounds were evaluated through the National Cancer Institute (NCI) 60 cell line screening which represents diverse histologies. The screening was performed at 10 μM on all cell lines. Results from the NCI screening indicated cytotoxicity activity on six cell lines. In order to explore a possible mechanism of action, a detailed biological activity study of NBQ 95 and NBQ 38 was performed on A431 human epidermoid carcinoma cells to determine an apoptotic pathway involving, cell cycle changes, DNA fragmentation, mutations, mitochondrial membrane permeabilization and caspases activation. DNA fragmentation, cell cycle effects, mutagenesis, mitochondrial permeabilization and activation of caspases were determined by fluorimetry and differential imaging. Our data showed that A431 growth was inhibited with an average IC50 of 30 mM. In terms of the mechanism, these compounds interacted with DNA causing fragmentation and cell cycle arrest at sub G0/G1 stage. Mutagenesis was higher for NBQ 38 and moderate for NBQ 95 Mitochondrial permeabilization was observed with NBQ 38 and slightly for NBQ 95. Both compounds caused activation of Caspases 3 and 7 suggesting an apoptotic cell death pathway through an intrinsic mechanism. This study reports evidence of the toxicity of these novel compounds with overlapping structural and mechanistic similarities to ellipticine, a known anti-tumor compound.展开更多
Abnormal accumulation of intracellular and extrac-ellularβ-amyloid(Aβ)aggregates is closely related to the pathogenesis of Alzheimer’s disease(AD).In this work,we use quinolinium derivatives with electron-rich anil...Abnormal accumulation of intracellular and extrac-ellularβ-amyloid(Aβ)aggregates is closely related to the pathogenesis of Alzheimer’s disease(AD).In this work,we use quinolinium derivatives with electron-rich aniline substituents as the skeletons to develop a set of spontaneous blinking ffuorophores by the formation of long-lived radicals.These probes can target Aβ_(1−40) aggregates and exhibit strong deep-red emission upon binding to Aβ_(1−40) aggregates.More importantly,at the single-molecule level,these probes display spontaneous blinking,low duty cycle,and high photon output,which are suitable for the nanoscopic imaging of Aβ aggregates in living cells.The assembly process of the Aβ aggregates was then tracked with nanoscopic imaging.The elongation rate on the cell membrane was noticeably fast over that in the solution.This work provides a feasible strategy for the design of spontaneous blinking ffuorophores for Aβ aggregates.展开更多
文摘This study reports the capacity of three nitro substituted benzazolo[3,2-a]quinolinium salts NBQs: NBQ 95 (NSC-763304), NBQ 38 (NSC 763305), and NBQ 97 (NSC-763306) as potential antitumor agents. NBQ’s are unnatural alkaloids possessing a positive charge that could facilitate interaction with cell organelles. The anticancer activities of these compounds were evaluated through the National Cancer Institute (NCI) 60 cell line screening which represents diverse histologies. The screening was performed at 10 μM on all cell lines. Results from the NCI screening indicated cytotoxicity activity on six cell lines. In order to explore a possible mechanism of action, a detailed biological activity study of NBQ 95 and NBQ 38 was performed on A431 human epidermoid carcinoma cells to determine an apoptotic pathway involving, cell cycle changes, DNA fragmentation, mutations, mitochondrial membrane permeabilization and caspases activation. DNA fragmentation, cell cycle effects, mutagenesis, mitochondrial permeabilization and activation of caspases were determined by fluorimetry and differential imaging. Our data showed that A431 growth was inhibited with an average IC50 of 30 mM. In terms of the mechanism, these compounds interacted with DNA causing fragmentation and cell cycle arrest at sub G0/G1 stage. Mutagenesis was higher for NBQ 38 and moderate for NBQ 95 Mitochondrial permeabilization was observed with NBQ 38 and slightly for NBQ 95. Both compounds caused activation of Caspases 3 and 7 suggesting an apoptotic cell death pathway through an intrinsic mechanism. This study reports evidence of the toxicity of these novel compounds with overlapping structural and mechanistic similarities to ellipticine, a known anti-tumor compound.
基金supported by National Natural Science Foundation of China(NSFC,Project No.22174079,21974073)Natural Science Foundation of Hunan Province(2022JJ40266)the Scientific Research Foundation of Hunan Provincial Education Department(20A299).
文摘Abnormal accumulation of intracellular and extrac-ellularβ-amyloid(Aβ)aggregates is closely related to the pathogenesis of Alzheimer’s disease(AD).In this work,we use quinolinium derivatives with electron-rich aniline substituents as the skeletons to develop a set of spontaneous blinking ffuorophores by the formation of long-lived radicals.These probes can target Aβ_(1−40) aggregates and exhibit strong deep-red emission upon binding to Aβ_(1−40) aggregates.More importantly,at the single-molecule level,these probes display spontaneous blinking,low duty cycle,and high photon output,which are suitable for the nanoscopic imaging of Aβ aggregates in living cells.The assembly process of the Aβ aggregates was then tracked with nanoscopic imaging.The elongation rate on the cell membrane was noticeably fast over that in the solution.This work provides a feasible strategy for the design of spontaneous blinking ffuorophores for Aβ aggregates.
