High in vivo antitumor activity of cobalt oxoisoaporphine complexes by targeting G-quadruplex DNA, telomerase and disrupting mitochondrial functions

Qin, Qi‐Pin; Qin, Jiao-Lan; Meng, Ting; Lin, Wenchu; Zhang, Chuanhui; Wei, Zu‐Zhuang; Chen, Jia-Nian; Liu, Yancheng; Liang, Hong; Chen, Zhen-Feng

doi:10.1016/j.ejmech.2016.08.063

Cited by 63 publications

(38 citation statements)

References 57 publications

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“…To exploit other metal complexes,Q in et al combined cobalt, one of the importantt race elements in cellsr eported to have potential anticancer activity,w ith oxoisoaporphine ligands (6-hydroxyoxoisoaporphine and 4,6-di(2-pyridinyl)benzo[h]isoindolo[4,5,6-de]quinolin-8(5H)-one;F igure 12). [45] The cobalt complexes exhibited remarkable tumor growth inhibition activity and selectivec ytotoxicity to SK-OV-3/DDP cells compared with that for HL-7702 cells. An investigation of their mechanism indicated that both 48 a and 48 b were telomerase inhibitors that targeted c-myc, telomere, and bcl-2 G4s;t hus triggering cell senescence and apoptosis, finally causing Sphase arrest.…”

Section: Metal and Oxoisoaporphinec Omplexesmentioning

confidence: 95%

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

2018

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Oxoisoaporphine alkaloids are a family of oxoisoquinoline-derived alkaloids that were first isolated from the rhizome of Menispermum dauricum DC. (Menispermaceae). It has been demonstrated that oxoisoaporphine alkaloids possess various biological properties, such as cholinesterase and β-amyloid inhibition, acting as a topoisomerase intercalator, monoamine oxidase A inhibition, and are expected to become anti-Alzheimer's disease, anticancer, and antidepressant drugs. This review provides an overview of natural sources, synthetic routes, bioactivities, structure-function relationship, and modification investigations into oxoisoaporphine alkaloids, with the aim of providing references to the structure-activity relationships for the design and development of oxoisoaporphine derivatives with higher efficacy and therapeutic potential.

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Section: Metal and Oxoisoaporphinec Omplexesmentioning

confidence: 95%

“…Chemical structures of 48 a,b. [45] ChemMedChem 2018, 13,1262 -1274 www.chemmedchem.org cacy as that of cisplatin at high doses, as well as better in vivo safety.…”

Section: Metal and Oxoisoaporphinec Omplexesmentioning

confidence: 99%

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

2018

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“…In addition, Co(II), Ni(II) and Zn(II) complexes of oxoaporphine or oxoisoaporphine have also been synthesized and their antitumor activities have been studied, which were listed in Table 12728293031. However, the mechanism of cell death on the molecular level (such as necrosis and apoptotic regulation) of these Co(II), Ni(II) and Zn(II) complexes with new oxoaporphine alkaloids has not yet been fully explored.…”

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confidence: 99%

Oxoaporphine Metal Complexes (CoII, NiII, ZnII) with High Antitumor Activity by Inducing Mitochondria-Mediated Apoptosis and S-phase Arrest in HepG2

Qin

Shen

Chen

et al. 2017

Sci Rep

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Three new oxoaporphine Co(II), Ni(II) and Zn(II) complexes 1–3 have been synthesized and fully characterized. 1–3 have similar mononuclear structures with the metal and ligand ratio of 1:2. 1–3 exhibited higher cytotoxicity than the OD ligand and cisplatin against HepG2, T-24, BEL-7404, MGC80–3 and SK-OV-3/DDP cells, with IC50 value of 0.23−4.31 μM. Interestingly, 0.5 μM 1–3 significantly caused HepG2 arrest at S-phase, which was associated with the up-regulation of p53, p21, p27, Chk1 and Chk2 proteins, and decrease in cyclin A, CDK2, Cdc25A, PCNA proteins. In addition, 1–3 induced HepG2 apoptosis via a caspase-dependent mitochondrion pathway as evidenced by p53 activation, ROS production, Bax up-regulation and Bcl-2 down-regulation, mitochondrial dysfunction, cytochrome c release, caspase activation and PARP cleavage. Furthermore, 3 inhibited tumor growth in HepG2 xenograft model, and displayed more safety profile in vivo than cisplatin.

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“…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. [ ][ ]…”

Section: Resultsmentioning

confidence: 99%

“…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.…”

Section: Resultsmentioning

confidence: 99%

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

Zou

Wang

Qin

et al. 2018

Chemistry & Biodiversity

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A cobalt(III) complex, [Co(L) ](ClO ) (1), in which the ligand L was N,N-diethyl-4-(2,2':6',2''-terpyridin-4'-yl)aniline (L), was synthesized and fully characterized. This new cobalt(III) complex 1 exhibited selective cytotoxicity against HeLa, T-24, A549, MGC80-3, HepG2, and SK-OV-3 cells with IC values in the micromolar range (0.52 - 4.33 μm), and it exhibited low cytotoxicity against normal HL-7702 cells. The complex 1 was the most potent against the T-24 cells. It was found that 1 could cause the cell cycle arrest in G1 phase, and it exerted its antitumor activity mainly via disruption of mitochondrial function.

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High in vivo antitumor activity of cobalt oxoisoaporphine complexes by targeting G-quadruplex DNA, telomerase and disrupting mitochondrial functions

Cited by 63 publications

References 57 publications

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

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

Oxoaporphine Metal Complexes (CoII, NiII, ZnII) with High Antitumor Activity by Inducing Mitochondria-Mediated Apoptosis and S-phase Arrest in HepG2

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

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