PhD Scientific Days 2023

Pharmaceutical Sciences I.

A link to the future! Linkers to increase potency of Ru(II) piano-stool complexes

Előadó neve

Bedford, Rebecca

Neptun code

N/A UK student

Előadó munkahelye

University of Birmingham

Előadó telefonszáma

07943480075

Előadó e-mail címe

rab710@student.bham.ac.uk

Az előadás címe

A link to the future! Linkers to increase potency of Ru(II) piano-stool complexes

Szerző(k) neve és munkahelye

Rebecca A. Bedford, School of Pharmacy/College of Medical and Dental Sciences, Birmingham
James P. C. Coverdale, School of Pharmacy/College of Medical and Dental Sciences, Birmingham
Isolda Romero-Canelon, School of Pharmacy/College of Medical and Dental Sciences, Birmingham

Bemutatás módja

Szóbeli

Szekció

Pharmaceutical Sciences I.

Language of the presentation

English

Preferred session

Pharmaceutical Sciences

Összefoglaló szövege

With cancer now affecting 1 in 2 of the population, new treatments eligible for all patients need to be developed. Ru(II) piano-stool complexes offer an alternative to Pt(II) complexes by exploiting different mechanisms of action (MOA), avoiding cross resistance. Ru(II) complexes are also often non-toxic in in vitro and in vivo models, in contrast to Pt(II) complexes which lack specificity. In Endothelial ovarian cancer (EOC), Pt(II) complexes are used but suffer from high recurrence and continually increasing death rates demonstrating treatment improvement is required.
We aimed to synthesise and characterise twelve Ru(II) complexes differing in their monodentate and bidentate ligand. Then determine the potential of a CH2 linker for increasing potency and altering MOA.
Synthesis was done by amine-aldehyde nucleophilic addition followed by chelation to the Ru(II) to form the complexes which were assessed by UV-Vis stability studies, NMR, DFT and other physicochemical characterisations. Growth inhibition was tested by MTT, followed by further MOA screening in A2780 by a variety of cellular and molecular techniques including microscopy, flow cytometry and DNA analysis.
All complexes were stable in PBS and a variety of biologically relevant matrices for 24h. Antiproliferative activity screening revealed that complexes with a ‘linker’ (Im-CH2-Py) were significantly more potent (up to 5.4×) than their ‘non-linked’ (Im-Py) counterparts. The most potent complexes, [Ru(Ƞ6-p-Cym)(Im-Py)I]PF6 (RAB23) and [Ru(Ƞ6-p-Cym)(Im-CH2-Py)I]PF6 (RAB38) were investigated further. RAB23 exhibited sub-G1 cell cycle arrest while RAB38 caused G1 arrest. RAB23 induced an increased population of late apoptotic cells compared to RAB38. Neither complex appeared to induce ROS generation or mitochondrial membrane depolarization. Nuclear morphology was significantly distorted by both complexes yet RAB23 and RAB38 do not appear to interact with ctDNA. Comet assays revealed ssDNA damage caused by RAB38 but not RAB23. While δ-H2A.X fluorescence (dsDNA damage) was increased by RAB23.
The structural modification appears to facilitate steric changes in the bidentate ligand, changing MOA from dsDNA to ssDNA breaks, increasing number of breaks, and resulting in greater potency. This highlights the potential improvement of similar highly potent complexes with the addition of a flexible linker.

University and Doctoral School

Other, please specify in the next box

Other university and doctoral school, not listed above

University of Birmingham, College of Medical and Dental Sciences

Supervisor

Dr Isolda Romero-Canelon

Publication of my abstract

I give consent to the publication of my abstract on the website of the congress.

Kind

Szabad

Status

elfogadva

Accepted presentation method

szóbeli

Előadás fájl jóváhagyás

nem rendelkezett róla

Előadó

7510

Start

10:45

End

11:00

Authors (legacy)

Rebecca A. Bedford, School of Pharmacy/College of Medical and Dental Sciences, Birmingham
James P. C. Coverdale, School of Pharmacy/College of Medical and Dental Sciences, Birmingham
Isolda Romero-Canelon, School of Pharmacy/College of Medical and Dental Sciences, Birmingham