期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 238, 期 -, 页码 -出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2022.114418
关键词
Zn(II) complexes; Cryptolepine-cyclen; DNA damage; Cell apoptosis
资金
- Nature Science Foundation of China [21861014, 21867017, 21761033]
- Natural Science Foundation of Guangxi [2020GXNSFAA297077, 2022GXNSFAA035478]
- Program of the Collaborative Innovation Center for Exploration of Hidden Nonferrous Metal Deposits and Development of New Materials in Guangxi [GXYSXTZX2017-II-3]
- Talent introduction program of Guangdong Institute of Petrochemical Technology [2020rc033]
- PhD Research Startup Program of Yulin Normal University [G2019ZK25]
The four novel bifluorescent Zn(II)-cryptolepine-cyclen complexes showed strong anticancer activity against cisplatin-resistant A549R lung tumor cells, selectively imaging the nucleus and mitochondria of cells while efficiently inhibiting DNA synthesis and causing DNA impairments in the nuclear and mitochondrial fractions.
Four novel bifluorescent Zn(II)-cryptolepine-cyclen complexes, namely [Zn(BQTC)]Cl-2 (Zn(BQTC)), [Zn(BQA) (Cur)Cl] (Zn(BQACur)), [Zn (TC)]Cl-2 (Zn(TC)), and [Zn (AP) (Cur)Cl] (Zn(APCur)), bearing curcumin (H-Cur), cyclen (TC), 1,10-phenanthrolin-5-amine (AP), and novel cryptolepine-cyclen derivatives (BQTC and BQA) were prepared for cell nucleus-and mitochondria-specific imaging. MTT assay results indicated that Zn(BQTC) and Zn (BQACur) exhibit stronger anticancer activity against cisplatin-resistant A549R lung tumor cells than ZnClaz, Zn (TC), Zn(APCur), H-Cur, TC, AP, BQTC, and BQA. Due to the dual fluorescence characteristic of Zn(BQTC), selective fluorescence imaging of the nucleus and mitochondria of A549R cancer cells was conducted. Further, Zn(BQTC), obtained by the functionalization of Zn(TC) with cryptolepine derivative substituents, efficiently inhibited DNA synthesis, thus resulting in high cytotoxicity (selective for A549R lung tumor cells) accompanied by DNA impairment in nuclear and mitochondrial fractions. Additionally, Zn(BQTC) caused severe damage to the mitochondrial DNA (mtDNA) and nuclear DNA (nDNA), sequentially disrupted mitochondrial and nuclear functions, and promoted the DNA damage-induced apoptotic signaling pathway and adenosine triphosphate depletion (ATP). Thus, Zn(BQTC) can be used as an anticancer drug by targeting mtDNA and nDNA. Most importantly, Zn(BQTC) showed higher efficacy in inhibiting cancer growth (55.9%) in A549R tumor-bearing mice than Zn(TC) (31.2%) and cisplatin, along with a promising in vivo safety profile. These results demonstrate the applicability of the developed novel bifluorescent Zn(II)-cryptolepine-cyclen complexes as promising DNA-targeting anticancer agents for cancer treatment.
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