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Strategies for conjugating iridium(III) anticancer complexes to targeting peptides via copper-free click chemistry
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Zhang, Wen-Ying, Banerjee, Samya, Imberti, Cinzia, Clarkson, Guy J., Wang, Qian, Zhong, Qian, Young, Lawrence S., Romero-Canelón, Isolda, Zeng, Musheng, Habtemariam, Abraha and Sadler, Peter J. (2020) Strategies for conjugating iridium(III) anticancer complexes to targeting peptides via copper-free click chemistry. Inorganica Chimica Acta, 503 . 119396. doi:10.1016/j.ica.2019.119396 ISSN 0020-1693.
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Official URL: http://dx.doi.org/10.1016/j.ica.2019.119396
Abstract
We report the synthesis and characterisation of novel pentamethylcyclopentadienyl (Cp*) iridium(III) complexes [(Cp*)Ir(4-methyl-4'-carboxy-2,2'-bipyridine)Cl]PF6 (Ir-I), the product from amide coupling of Ir-I to dibenzocyclooctyne-amine (Ir-II), and its conjugate with the cyclic nona-peptide c(CRWYDENAC) (Ir-CP). 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 a 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.
| Item Type: | Journal Article | ||||||||||||||||||
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| Subjects: | Q Science > QD Chemistry R Medicine > RC Internal medicine |
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| Divisions: | Faculty of Science, Engineering and Medicine > Science > Chemistry | ||||||||||||||||||
| Library of Congress Subject Headings (LCSH): | Organoindium compounds, Antineoplastic agents, Azides, Ring formation (Chemistry), Cyclic peptides | ||||||||||||||||||
| Journal or Publication Title: | Inorganica Chimica Acta | ||||||||||||||||||
| Publisher: | Elsevier BV | ||||||||||||||||||
| ISSN: | 0020-1693 | ||||||||||||||||||
| Official Date: | 1 April 2020 | ||||||||||||||||||
| Dates: |
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| Volume: | 503 | ||||||||||||||||||
| Article Number: | 119396 | ||||||||||||||||||
| DOI: | 10.1016/j.ica.2019.119396 | ||||||||||||||||||
| Status: | Peer Reviewed | ||||||||||||||||||
| Publication Status: | Published | ||||||||||||||||||
| Access rights to Published version: | Open Access (Creative Commons) | ||||||||||||||||||
| Date of first compliant deposit: | 10 January 2020 | ||||||||||||||||||
| RIOXX Funder/Project Grant: |
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