Strategies for conjugating iridium(III) anticancer complexes to targeting peptides via copper-free click chemistry

Wen Ying Zhang, Samya Banerjee, Cinzia Imberti, Guy J. Clarkson, Qian Wang, Qian Zhong, Lawrence S. Young, Isolda Romero-Canelón, Musheng Zeng, Abraha Habtemariam, Peter J. Sadler*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)

Abstract

We report the synthesis and characterization of novel pentamethylcyclopentadienyl (Cp*) iridium(III) complexes [(Cp*)Ir(4-methyl-4′-carboxy-2,2′-bipyridine)Cl]PF6 (Ir-I), the product (Ir-II) from amide coupling of Ir-I to dibenzocyclooctyne-amine, and its conjugate (Ir-CP) with the cyclic nona-peptide c(CRWYDENAC). The familiar three-legged ‘piano-stool’ configuration for complex Ir-I was confirmed by its single crystal X-ray structure. Significantly, copper-free click strategy has been developed for site-specific conjugation of the parent complex Ir-I to the tumour targeting nona-cyclic peptide. The approach consisted of two steps: (i) the carboxylic acid group of the bipyridine ligand in complex Ir-I was first attached to an amine functionalized dibenzocyclooctyne group via amide formation to generate complex Ir-II; and (ii) the alkyne bond of dibenzocyclooctyne in complex Ir-II underwent a subsequent strain-promoted copper-free cycloaddition with the azide group of the modified peptide. Interestingly, while complex Ir-I was inactive towards A2780 human ovarian cancer cells, complex Ir-II exhibited moderate cytotoxic activity. Targeted complexes such as Ir-CP offer scope for enhanced activity and selectivity of this class of anticancer complexes.

Original languageEnglish
Article number119396
JournalINORGANICA CHIMICA ACTA
Volume503
DOIs
Publication statusPublished - 1 Apr 2020

Keywords

  • Anticancer
  • Azide-alkyne cycloaddition
  • Copper-free
  • Cyclic peptide
  • Organo-iridium

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