Preparation of 6/8/11-Amino/Chloro-Oxoisoaporphine and Group-10 Metal Complexes and Evaluation of Their in Vitro and in Vivo Antitumor Activity

Abstract

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-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.

Three novel transition metal complexes of 6-methyl-2-oxo-quinoline-3-carbaldehyde thiosemicarbazone: synthesis, crystal structure, cytotoxicity, and mechanism of action

“…The ESI † provides the detailed procedures of other experimental methods, including the measurement of mitochondrial membrane potential (by JC-1 staining), ROS generation, intracellular free Ca 2+ , Western blot, and caspase-3/9 activity. The procedures were similar to those given in the previous work of Chen et al 40…”

Oxoisoaporphine Alkaloids: Prospective Anti‐Alzheimer's Disease, Anticancer, and Antidepressant Agents

“…An extensive study on complexes of Group 10 metals with oxoisoaporphine ligands (6‐amino‐, 8‐amino‐, 8‐chloro‐, and 10‐chloro‐11‐aminooxoisoaporphine; Figure ) has been performed . The findings demonstrated that 34 – 47 exhibited remarkably increased in vitro cytotoxicity and tumor growth inhibition against a panel of tumor cell lines, such as Hep‐G2, NCI‐H460, SK‐OV‐3, HCT‐8, and BEL‐7402, compared with those of the ligands alone.…”

Synthesis, Characterization, and Cytotoxicity of the Cobalt (III) Complex with N,N‐Diethyl‐4‐(2,2′:6′,2′′‐terpyridin‐4′‐yl)aniline

“…Treating the T‐24 cells with 0.5 μ m complex 1 and 18.0 μ m cisplatin for 24 h led to notable accumulation of cellular cobalt ((20.96 ± 1.06) ng Co/10 6 cells) and platinum ((12.03 ± 0.86) ng Pt/10 6 cells) compared with the control ( Figure ), respectively, suggesting that the uptake of the Co(III) complex 1 in T‐24 cells was higher than that of cisplatin. [ ][ ]…”

“…After the T‐24 cells were exposed to the Co(III) complex 1 (0.5 μ m ) for 24 h, the cobalt distributions in the nuclear fraction and the mitochondria fractions of the T‐24 cells were examined according to the reported method. [ ][ ] Figure shows that the cobalt accumulation was high in all fractions, especially in the mitochondrial fraction, probably because 1 activated the apoptotic pathways of the cells. However, cisplatin (18.0 μ m ) appears predominantly localized in the mitochondrial membrane fraction, with lesser accumulation in the nucleus.…”

“…Treating the T-24 cells with 0.5 lM complex 1 and 18.0 lM cisplatin for 24 h led to notable accumulation of cellular cobalt ((20.96 AE 1.06) ng Co/10 6 cells) and platinum ((12.03 AE 0.86) ng Pt/10 6 cells) compared with the control (Figure 2), respectively, suggesting that the uptake of the Co(III) complex 1 in T-24 cells was higher than that of cisplatin. [29] [30] After the T-24 cells were exposed to the Co(III) complex 1 (0.5 lM) for 24 h, the cobalt distributions in the nuclear fraction and the mitochondria fractions of the T-24 cells were examined according to the reported method. [29][30] Figure 2 shows that the cobalt accumulation was high in all fractions, especially in the mitochondrial fraction, probably because 1 activated the apoptotic pathways of the cells.…”