Platinum-group metal half-sandwich complexes of sugar-isoxazol(in)e conjugates – synthesis and evaluation of their antineoplastic and antimicrobial activities

Akel, Rahaf and Kacsir, István and Kerekes, Éva and Freytag, Csongor and Szoták, Evelin and Boros-Pál, Dóra and Janka, Eszter Anna and Bényei, Attila Csaba and Kardos, Gábor and Bokor, Éva and Somsák, László and Bay, Péter and Sipos, Adrienn and Kun, Sándor (2025) Platinum-group metal half-sandwich complexes of sugar-isoxazol(in)e conjugates – synthesis and evaluation of their antineoplastic and antimicrobial activities. EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES. No. 107260. ISSN 0928-0987 (In Press)

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Abstract

Platinum-group metal half-sandwich complexes are considered to be potential replacements of the clinically widely used platins which have several side effects and tend to cause resistance to develop. In our previous works, we used a range of 2-pyridyl-substituted N- and C-glycosyl heterocycles as N,N-chelating ligands to prepare ruthenium(II), osmium(II), iridium(III) and rhodium(III) polyhapto arene/arenyl half-sandwich complexes. Some of these complexes, particularly with the C-glucopyranosyl isoxazole derived ligand in its Operbenzoylated form, exhibited greater anticancer efficiency than cisplatin and had minimal or negligible effects on non-transformed fibroblasts. Additionally, these cytostatic compounds exhibited micromolar antibacterial activity against multiresistant Gram-positive bacteria. In the present work, novel modes of conjugation between the sugar and the isoxazole moieties have been studied. Specifically, glycosylidene-spiro-isoxazoline and polyhydroxyalkylisoxazole scaffolds were synthesised and utilised in complex formation reactions. The spiro-isoxazolines were obtained in 1,3-dipolar cycloadditions of exo-glycals and nitrile oxides generated from pyridine-2-carbaldoximes. Ring opening of the spiroisoxazolines under basic or transition-metal-mediated conditions produced polyhydroxyalkylisoxazoles. These compounds were then transformed into their Operacetylated, O-perbenzoylated and O-unprotected variants, which were used for complex formation with the above-mentioned platinum-group metal ions. The complexes induced cytostasis in cellular models of ovarian cancer and pancreatic adenocarcinoma; the best compounds had submicromolar IC50 values (0.4-0.5 µM). A subset of the cytostatic complexes retained their activity on cisplatin resistant ovarian cancer cells. Furthermore, a reasonable therapeutic index was detected when complexes were assessed on primary human fibroblasts pointing towards a potential applicability of the complexes. Unexpectedly, none of the complexes induced bacteriostasis in Gram-positive bacteria as Staphylococcus aureus or Enterococcus species.

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