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Development of a Highly In Vivo Efficacious Dual Antitumor and Antiangiogenic Organoiridium Complex as a Potential Anti-Lung Cancer Agent.

Shubhankar GadreManikandan MGourav ChakrabortyAmey RayrikarSubhadeep PaulChinmoy PatraMalay Patra
Published in: Journal of medicinal chemistry (2023)
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-Ir III half-sandwich [(η 5 -Cp X )Ir(N∧N)Cl] + -type complexes. In vitro screening identified two lead candidates [(η 5 -Cp XPh )Ir(Ph 2 Phen)Cl] + ( 5 , Cp XPh = tetramethyl-phenyl-cyclopentadienyl and Ph 2 Phen = 4,7-diphenyl-1,10-phenanthroline) and [(η 5 -Cp XBiPh )Ir(Ph 2 Phen)Cl] + ( 6 , Cp XBiPh = tetramethyl-biphenyl-cyclopentadienyl) with nanomolar IC 50 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 Ir III 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.
Keyphrases
  • type diabetes
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  • risk assessment
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