Oral Presentation 21st International Conference on Biological Inorganic Chemistry 2025

Organorhodium complexes of bidentate anticancer ligands with improved drug-like properties to target multidrug resistant cancer (121784)

Tamás Pivarcsik 1 , Egon F. Várkonyi 1 2 , Edit Csapó 2 , Orsolya Dömötör 1 , István Szatmári 3 , Szilárd Tóth 4 , Gergely Szakács 4 5 , Éva A. Enyedy 1
  1. Department of Molecular and Analytical Chemistry, Interdisciplinary Excellence Centre, University of Szeged, Szeged, Hungary
  2. MTA-SZTE Lendület “Momentum” Noble Metal Nanostructures Research Group, Department of Physical Chemistry and Materials Science, University of Szeged, Szeged, Hungary
  3. Institute of Pharmaceutical Chemistry, University of Szeged, Szeged, Hungary
  4. Drug Resistance Research Group, Institute of Molecular Life Sciences, HUN-REN Research Centre for Natural Sciences, Budapest, Hungary
  5. Center for Cancer Research, Medical University of Vienna, Vienna, Austria

Multidrug resistance (MDR) is a major obstacle in cancer treatment, which is characterized by several notable features, including upregulated expression level of the MDR1 gene encoding P-glycoprotein (P-gp), which is often responsible for drug efflux. MDR cells exhibit a surprising hypersensitivity to several metal chelating compounds, including 8-hydroxyquinoline (8HQ) and 1,10-phenanthroline (PHEN) derivatives.1 Their basic aromatic skeleton can be modified by different functional groups to optimize biological properties and physico-chemical characteristics. Our previous mechanistic studies have shown that the MDR-selective 8HQs do not inhibit the drug efflux pump, and are therefore free of the off-target effects associated with classical inhibitors.2 A correlation was found between MDR-selectivity and the pKa values of the 8HQs, and their mechanism of action was suggested to be related to complexation with intracellular metals, inducing iron depletion in MDR cells due to the P-gp-mediated efflux of the iron complexes.2 Despite the efficacy of these compounds, solubility issues often pose a significant challenge for the in vivo application. Here, we present the development of half-sandwich Rh(III)(η5-C5Me5) complexes of MDR-selective 8HQ-derived Mannich bases3,4 and PHEN derivatives (Figure 1) with improved drug-like properties.

 

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The complexes were comprehensively characterized by various spectroscopic methods in terms of their structure, solution speciation and interaction with human serum albumin (HSA). Their analogous Ru(II)(η6-p-cymene) complexes were also prepared and studied. The most promising Rh(III) complexes of PHEN derivatives possessing high stability, improved aqueous solubility and HSA binding properties were selected for nanoformulation studies, using cross-linked HSA and its combined version with D-α-tocopheryl polyethylene glycol 1000 succinate and poly(lactic-co-glycolic acid). Cytotoxicity of the complexes was assayed on parental and MDR mono- and cocultured human cancer cells. Some complexes and their encapsulated forms have been identified as optimal candidates for further application.

 

Acknowledgement: NRDI Fund ANN 149481, TKP2021-EGA-32, and FWF 10.55776/PIN1280424.

  1. Szakács, G.; Hall, M.D.; Gottesman, M.M.; Boumendjel, A.; Kachadourian, R.; Day, B.J.; Baubichon-Cortay, H.; Di Pietro, A. Chem. Rev., 2014, 114, 5753-5774.
  2. Pape, V.F.S.; Gaál, A.; Szatmári, I.; Kucsma, N.; Szoboszlai, N.; Streli, C.; Fülöp, F.; Enyedy, É.A.; Szakács, G. Cancers, 2021, 12, 154.
  3. Pivarcsik, T.; Dömötör, O.; Mészáros, J.P.; May, N.V.; Spengler, G.; Csuvik, O.; Szatmári, I.; Enyedy, É.A. Int. J. Mol. Sci., 2021, 22, 11281.
  4. Pivarcsik, T.; Tóth, S.; Pósa, S.P.; May, N.V.; Kováts, É.; Spengler, G.; Kántor, I.; Rolya, A.; Feczkó, T.; Szatmári, I.; Szakács, G.; Enyedy, É.A. Inorg. Chem., 2024, 63, 23983-23998.