Royal College of Surgeons in Ireland
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A trans-Pt(ii) hedgehog pathway inhibitor complex with cytotoxicity towards breast cancer stem cells and triple negative breast cancer cells

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posted on 2023-05-17, 15:16 authored by Aisling L. Ryan, Joshua Northcote-Smith, Aoife Mckeon, Andrew RoeAndrew Roe, Paul O'DowdPaul O'Dowd, Brendan Twamley, Triona Ni ChonghaileTriona Ni Chonghaile, Kogularamanan Suntharalingam, Darren GriffithDarren Griffith
The first example of a Pt complex of GANT61, a hedgehog (Hh) pathway inhibitor is reported. Reaction of cis-[Pt(ii)Cl2(dmso)2] with one equivalent of 4-pyridine carboxaldehyde (4-PCA, control ligand) or one equivalent of GANT61 (Hh pathway inhibitor) in acetone at rt for 30 minutes afforded trans-[Pt(ii)Cl2(dmso)(4-PCA)] (1) and trans-[Pt(ii)Cl2(dmso)(GANT61)] (2) respectively, where 4-PCA and GANT61 are N-donor ligands. The structures of 1 and 2 were fully characterised by elemental analysis, 1H NMR, 13C NMR and IR spectroscopy and X-ray crystallography. 1 and 2 undergo isomerisation from trans- to cis-in solution and therefore the biological activity of 2 is also associated with the cis-configuration. The in vitro cytotoxicity data show that 2 is a potent inhibitor of the growth of breast CSC-depleted HMLER and breast CSC-enriched HMLER-shEcad cells. Furthermore 2 markedly reduced the size and viability and significantly reduced the number of CSC-enriched HMLER-shEcad mammospheres formed. 2 also induced apoptosis with low micromolar IC50 values against two triple negative breast cancer lines, MDA-MB-231 (MDA231) and BT549. 2, which possesses the Hh pathway inhibitor GANT61 as an N donor ligand exhibits far superior anti-CSC activity including in the CSC-enriched mammosphere model and activity against TNBC cells as compared to its control analogue, the trans-Pt(ii) 4-PCA complex 1. The trans-Pt GANT61 complex 2 has also been shown to cause DNA damage and inhibit the Hh pathway at the level of GLI.


Irish Research Council (GOIPG/2017/1384)

Synthesis and Solid State Pharmaceutical Centre (SSPC)

Science Foundation Ireland (SFI) and co-funded under the European Regional Development Fund Grant Number 12/RC/2275_P2

Science Foundation Ireland (SFI) under Grant Number 12/IP/1305

EPSRC (EP/S005544/1)

University of Leicester

Science Foundation Ireland (SFI) grant number 19/FFP/6461



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Published Citation

Ryan AL, et al. A trans-Pt(II) hedgehog pathway inhibitor complex with cytotoxicity towards breast cancer stem cells and triple negative breast cancer cells. Dalton Trans. 2022;51(47):18127-18135

Publication Date

10 November 2022

PubMed ID



  • Chemistry
  • Physiology and Medical Physics

Research Area

  • Chemistry and Pharmaceutical Sciences
  • Cancer


Royal Society of Chemistry (RSC)


  • Published Version (Version of Record)