PUBLICATION
Development of a Highly In Vivo Efficacious Dual Antitumor and Antiangiogenic Organoiridium Complex as a Potential Anti-Lung Cancer Agent
- Authors
- Gadre, S., M, M., Chakraborty, G., Rayrikar, A., Paul, S., Patra, C., Patra, M.
- ID
- ZDB-PUB-231003-60
- Date
- 2023
- Source
- Journal of medicinal chemistry 66(19): 13481-13500 (Journal)
- Registered Authors
- Patra, Chinmoy, Rayrikar, Amey
- Keywords
- none
- MeSH Terms
-
- Animals
- Antineoplastic Agents*/chemistry
- Antineoplastic Agents*/pharmacology
- Antineoplastic Agents*/therapeutic use
- Cell Line, Tumor
- Cisplatin
- Coordination Complexes*/chemistry
- Coordination Complexes*/pharmacology
- Coordination Complexes*/therapeutic use
- Humans
- Iridium/chemistry
- Lung Neoplasms*/drug therapy
- Mice
- Zebrafish
- PubMed
- 37784224 Full text @ J. Med. Chem.
Citation
Gadre, S., M, M., Chakraborty, G., Rayrikar, A., Paul, S., Patra, C., Patra, M. (2023) Development of a Highly In Vivo Efficacious Dual Antitumor and Antiangiogenic Organoiridium Complex as a Potential Anti-Lung Cancer Agent. Journal of medicinal chemistry. 66(19):13481-13500.
Abstract
While the phenomenal clinical success of blockbuster platinum (Pt) drugs is highly encouraging, the inherent and acquired resistance and dose-limiting side effects severely limit their clinical application. To find a better alternative with translational potential, we synthesized a library of six organo-IrIII half-sandwich [(η5-CpX)Ir(N∧N)Cl]+-type complexes. In vitro screening identified two lead candidates [(η5-CpXPh)Ir(Ph2Phen)Cl]+ (5, CpXPh = tetramethyl-phenyl-cyclopentadienyl and Ph2Phen = 4,7-diphenyl-1,10-phenanthroline) and [(η5-CpXBiPh)Ir(Ph2Phen)Cl]+ (6, CpXBiPh = tetramethyl-biphenyl-cyclopentadienyl) with nanomolar IC50 values. Both 5 and 6 efficiently overcame Pt resistance and presented excellent cancer cell selectivity in vitro. Potent antiangiogenic properties of 6 were demonstrated in the zebrafish model. Satisfyingly, 6 and its nanoliposome Lipo-6 presented considerably higher in vivo antitumor efficacy as compared to cisplatin, as well as earlier reported IrIII half-sandwich complexes in mice bearing the A549 non-small lung cancer xenograft. In particular, complex 6 is the first example of this class that exerted dual in vivo antiangiogenic and antitumor properties.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping