Preparation of 6/8/11-amino/chloro-oxoisoaporphine and group-10 metal complexes and evaluation of their in vitro and in vivo antitumor activity

QP Qin, JL Qin, T Meng, GA Yang, ZZ Wei, YC Liu… - Scientific Reports, 2016 - nature.com
QP Qin, JL Qin, T Meng, GA Yang, ZZ Wei, YC Liu, H Liang, ZF Chen
Scientific Reports, 2016nature.com
A series of group-10 metal complexes 1–14 of oxoisoaporphine derivatives were designed
and synthesized. 1–14 were more selectively cytotoxic to Hep-G2 cells comparing with
normal liver cells. In vitro cytotoxicity results showed that complexes 1–6, 7, 8, 10 and 11,
especially 3, were telomerase inhibitors targeting c-myc, telomeric, and bcl-2 G4s and
triggered cell senescence and apoptosis; they also caused telomere/DNA damage and S
phase arrest. In addition, 1–6 also caused mitochondrial dysfunction. Notably, 3 with 6 …
Abstract
A series of group-10 metal complexes 114 of oxoisoaporphine derivatives were designed and synthesized. 114 were more selectively cytotoxic to Hep-G2 cells comparing with normal liver cells. In vitro cytotoxicity results showed that complexes 16, 7, 8, 10 and 11, especially 3, were telomerase inhibitors targeting c-myc, telomeric, and bcl-2 G4s and triggered cell senescence and apoptosis; they also caused telomere/DNA damage and S phase arrest. In addition, 16 also caused mitochondrial dysfunction. Notably, 3 with 6-amino substituted ligand La exhibited less side effects than 6 with 8-amino substituted ligand Lb and cisplatin, but similar tumor growth inhibition efficacy in BEL-7402 xenograft model. Complex 3 has the potential to be developed as an effective anticancer agent.
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