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Design, synthesis and biological evaluation of dihydro-2-quinolone platinum(iv) hybrids as antitumor agents displaying mitochondria injury and DNA damage mechanism.
- Source :
-
Dalton transactions (Cambridge, England : 2003) [Dalton Trans] 2021 Jan 07; Vol. 50 (1), pp. 362-375. Date of Electronic Publication: 2020 Dec 15. - Publication Year :
- 2021
-
Abstract
- The design of novel platinum(iv) complexes with mitochondria injury competence, besides the DNA damage mechanism, is a promising way to develop new platinum drugs. Herein, dihydro-2-quinolone (DHQLO) as a mitocan was incorporated into the platinum(iv) system for the first time to prepare a new series of DHQLO platinum(iv) compounds. Complex 1b could effectively inhibit the proliferation of tumor cells in vitro and in vivo. It accumulated at higher levels in both whole cells and DNA, and easily underwent intercellular reduction to release platinum(ii) and DHQLO moieties. The released platinum(ii) complex caused serious DNA damage by covalent conjunction with the DNA duplex, and remarkably increased the expression of the γ-H2AX protein. Moreover, 1b also caused serious mitochondria injury to induce mitochondrial membrane depolarization and increase ROS generation. Such actions upon DNA and mitochondria activate the p53 apoptotic pathway synergetically in tumor cells by upregulating the protein p53 and apoptotic proteins caspase9 and caspase3, which efficiently promoted the apoptotic death of tumor cells. Compound 1b with such synergic mechanism exhibited great potential in reversing cisplatin resistance and improving antitumor efficacies.
- Subjects :
- Animals
Antineoplastic Agents chemistry
Apoptosis drug effects
Caspase 3 metabolism
Caspase 9 metabolism
Cell Line
DNA metabolism
DNA Damage
Histones metabolism
Humans
Male
Mice, Inbred BALB C
Mitochondria drug effects
Mitochondria physiology
Neoplasms metabolism
Organoplatinum Compounds chemistry
Quinolones chemistry
Reactive Oxygen Species metabolism
Serum Albumin metabolism
Tumor Suppressor Protein p53 metabolism
Mice
Antineoplastic Agents pharmacology
Neoplasms drug therapy
Organoplatinum Compounds pharmacology
Quinolones pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1477-9234
- Volume :
- 50
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Dalton transactions (Cambridge, England : 2003)
- Publication Type :
- Academic Journal
- Accession number :
- 33319888
- Full Text :
- https://doi.org/10.1039/d0dt03194a