PUBLICATION
Potent Ruthenium-Ferrocene Bimetallic Antitumor Antiangiogenic Agent That Circumvents Platinum Resistance: From Synthesis and Mechanistic Studies to In Vivo Evaluation in Zebrafish
- Authors
- M, M., Gadre, S., Chhatar, S., Chakraborty, G., Ahmed, N., Patra, C., Patra, M.
- ID
- ZDB-PUB-221203-5
- Date
- 2022
- Source
- Journal of medicinal chemistry 65(24): 16353-16371 (Journal)
- Registered Authors
- Patra, Chinmoy
- Keywords
- none
- MeSH Terms
-
- Angiogenesis Inhibitors/pharmacology
- Animals
- Antineoplastic Agents*/chemistry
- Cell Line, Tumor
- Coordination Complexes*/chemistry
- Metallocenes
- Platinum/chemistry
- Platinum/pharmacology
- Ruthenium*/chemistry
- Ruthenium*/pharmacology
- Zebrafish
- PubMed
- 36459415 Full text @ J. Med. Chem.
Citation
M, M., Gadre, S., Chhatar, S., Chakraborty, G., Ahmed, N., Patra, C., Patra, M. (2022) Potent Ruthenium-Ferrocene Bimetallic Antitumor Antiangiogenic Agent That Circumvents Platinum Resistance: From Synthesis and Mechanistic Studies to In Vivo Evaluation in Zebrafish. Journal of medicinal chemistry. 65(24):16353-16371.
Abstract
Emergence of resistance in cancer cells and dose-limiting side effects severely limit the widespread use of platinum (Pt) anticancer drugs. Multi-action hybrid anticancer agents that are constructed by merging two or more pharmacophores offer the prospect of circumventing issues of Pt drugs. Herein, we report the design, synthesis, and in-depth biological evaluation of a ruthenium-ferrocene (Ru-Fc) bimetallic agent [(η6-p-cymene)Ru(1,1,1-trifluoro-4-oxo-4-ferrocenyl-but-2-en-2-olate)Cl] and its five analogues. Along with aquation/anation chemistry, we evaluated the in vitro antitumor potency, Pt cross-resistance profile, and in vivo antiangiogenic properties. A structure activity analysis was performed to understand the impact of Fc, CF3, and p-cymene groups on the anticancer potency of the Ru-Fc hybrid. Finally, in addition to assessing cellular uptake and intracellular distribution, we demonstrated that the Ru-Fc hybrid binds to nucleophilic biomolecules and produces reactive oxygen species, which causes mitochondrial dysfunction and induces ER stress, leading to poly(ADP-ribose) polymerase-mediated necroptotic cell death.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping