Half sandwich-type osmium, ruthenium, iridium and rhodium complexes with bidentate glycosyl heterocyclic ligands induce cytostasis in platinum-resistant ovarian cancer cells and bacteriostasis in Gram-positive multiresistant bacteria

Abstract

The toxicity of and resistance to platinum complexes as cisplatin, oxaliplatin or carboplatin calls for the replacement of these therapeutic agents in clinical settings. We have previously identified a set of half sandwich-type osmium, ruthenium and iridium complexes with bidentate glycosyl heterocyclic ligands exerting specific cytostatic activity on cancer cells but not on non-transformed primary cells. The apolar nature of the complexes, conferred by large, apolar benzoyl protective groups on the hydroxyl groups of the carbohydrate moiety, was the main molecular feature to induce cytostasis. We exchanged the benzoyl protective groups to straight chain alkanoyl groups with varying length (3 to 7 carbon units) that increased the IC50 value as compared to the benzoyl-protected complexes and rendered the complexes toxic. These results suggest a need for aromatic groups in the molecule. The pyridine moiety of the bidentate ligand was exchanged for a quinoline group to enlarge the apolar surface of the molecule. This modification decreased the IC50 value of the complexes. The complexes containing [(η6-p-cymene)Ru(II)], [(η6-p-cymene)Os(II)] or [(η5-Cp*)Ir(III)] were biologically active unlike the complex containing [(η5-Cp*)Rh(III)]. The complexes with cytostatic activity were active on ovarian cancer (A2780, ID8), pancreatic adenocarcinoma (Capan2), sarcoma (Saos) and lymphoma cell lines (L428), but not on primary dermal fibroblasts and their activity was dependent on reactive oxygen species production. Importantly, these complexes were cytostatic on cisplatin-resistant A2780 ovarian cancer cells with similar IC50 values as on cisplatin-sensitive A2780 cells. In addition, the quinoline-containing Ru and Os complexes and the short chain alkanoyl-modified complexes (C3 and C4) proved to be bacteriostatic in multiresistant Gram-positive Enterococcus and Staphylococcus aureus isolates. Hereby, we identified a set of complexes with submicromolar to low micromolar inhibitory constants against a wide range of cancer cells, including platinum resistant cells and against multiresistant Gram-positive bacteria.

Half-Sandwich Type Platinum-Group Metal Complexes of C-Glucosaminyl Azines: Synthesis and Antineoplastic and Antimicrobial Activities

“…In the quest for potential substitutes for platins, the half-sandwich type complexes of platinum-group metal ions (e.g., Ru(II), Os(II), Ir(III) and Rh(III)) have emerged as a promising compound class, with a large number of representatives displaying anticancer potencies [ 14 , 15 , 19 , 21 , 22 ]. In addition to the antineoplastic effects, several of these piano-stool complexes have different antimicrobial (e.g., antibacterial [ 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 ], antiparasitic [ 40 , 41 , 42 ], antiviral [ 30 , 43 ] and antifungal [ 44 ]) properties.…”

“…We recently reported a series of half-sandwich complexes with five-membered chelate rings constructed with the use of N - and C -glycopyranosyl heterocyclic N,N-bidentate ligands ( Figure 1 , I ) [ 32 , 45 , 46 ]. Several representatives of I displayed low micromolar or, in certain cases, submicromolar (e.g., Ia ) cytostatic activities against cancer cells, in addition to proving to be selective for such cells.…”

“…Several representatives of I displayed low micromolar or, in certain cases, submicromolar (e.g., Ia ) cytostatic activities against cancer cells, in addition to proving to be selective for such cells. The antiproliferative potency of these complexes is thought to be related to reactive oxygen species production [ 32 , 45 , 46 ]. It is worth mentioning that the complexes with antineoplastic activities (e.g., Ia ) were also shown to be effective against Gram-positive multiresistant bacteria [ 31 , 32 ].…”

“…The antiproliferative potency of these complexes is thought to be related to reactive oxygen species production [ 32 , 45 , 46 ]. It is worth mentioning that the complexes with antineoplastic activities (e.g., Ia ) were also shown to be effective against Gram-positive multiresistant bacteria [ 31 , 32 ]. A short summary of the structure–activity relationships (SARs) of these complexes is presented in Figure 1 , while for a more detailed explanation of the SARs, the reader is referred to our previous publications [ 31 , 32 , 45 , 46 ].…”

“…It is worth mentioning that the complexes with antineoplastic activities (e.g., Ia ) were also shown to be effective against Gram-positive multiresistant bacteria [ 31 , 32 ]. A short summary of the structure–activity relationships (SARs) of these complexes is presented in Figure 1 , while for a more detailed explanation of the SARs, the reader is referred to our previous publications [ 31 , 32 , 45 , 46 ]. One of the most important structural motifs related to biological efficacy is the presence of the sugar moiety O -protected with large hydrophobic acyl, preferably with benzoyl groups.…”