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Inorganic medicinal chemistry is a rapidly growing research area focused on the use of metal- containing drugs, inhibitors of metalloenzymes and metal complexes in the diagnosis of tumor and neurological diseases. The biological action of metal complexes is governed by catalytic activity, redox and photochemical properties and equilibrium reactions of a ligand and a metal ion that lead to the formation of biologically active species.1 Due to its stability, electrochemical properties and low toxicity, ferrocene is an important metallocene in the design of new chemotherapeutics.2 The introduction of ferrocene into biologically active compounds is carried out to increase the interaction of the drug with the receptor, which can be achieved by bioisosteric replacement of a phenyl group with ferrocene. The ferrocene subunit forms stronger interactions with the hydrophobic pocket of the biological target.3 Our recent work is focused on the synthesis and biological evaluation of heterobimetallic ferrocene complexes and their biological activity.4 Ferrocene derivatives of dipyridylamine and their Zn(II) and Cu(II) complexes were synthesized and their cytotoxic effect was explored on tumor cells. The Cu(II) complex with methylmethine linker between ferrocene and dipyridylamine showed the most prominent and selective cytotoxicity. Cell cycle analysis by flow cytometry revealed that the mechanism of cytotoxicity is dependent on the identity of the metal ion.

Acquired drug resistance remains a major problem for successful chemotherapy, contributing to poor long-term prognosis of ovarian cancer (OC) patients. The combination of platinum drugs and taxanes is commonly used to treat patients with OC, due to their different modes of action. Despite the positive initial response to chemotherapy, up to 80% of OC patients will eventually relapse, and become platinum/taxane unresponsive. Moreover, cross-resistance occurs in almost 30% of OC cases. We established two OC cell line models, i.e., MES-OV CBP and SK-OV-3 CBP characterized by clinically relevant acquired resistance to carboplatin (CBP), a mesenchymal- like phenotype, CBP-induced class III β-tubulin (TUBB3) overexpression, and different responsiveness to paclitaxel (TAX) treatment. We showed previously that despite increased TUBB3 protein expression in both CBP resistant variants only MES-OV CBP cells are sensitized to CBP upon TUBB3 silencing. The lack of compensation phenomena with other β-tubulin isotypes noticed in SK-OV-3 CBP, but absent in MES-OV CBP cell line, underlined that pan TUBB should be considered together with TUBB3 for the prediction of treatment efficacy. We noticed further that the presence of compensation phenomena correlated with the expression pattern of miRNA-200 family members, known regulators of TUBB3 expression. We focused on the miR-200c that is predominantly investigated in the context of drug resistance and epithelial-mesenchymal transition. We showed that in MES-OV CBP cells, long-term exposure to CBP induced stable miR-200c downregulation via alterations in epigenetic regulation, and consequently led to the upregulation of TUBB3. Transient transfection of MES-OV CBP cells with mimic miR-200c sensitized them to CBP, while transduction of MES-OV cells with lentiviral particles carrying miR-200c inhibitor rendered them less sensitive to CBP and TAX as well. Most importantly, decreased constitutive expression of miR-200c in MES-OV cells was accompanied by elevated expression of TUBB3 and TUBB. This finding shows for the first time that the miR- 200c/TUBB3 axis is part of the cellular stress response to CBP.

Ovarian cancer (OC) is the seventh most common cancer type in women worldwide. Unfortunately, lack of early detection methods leads to diagnosis of already advanced disease tied with highest fatality-to case ratio among gynecological malignancies. Conventional therapy for OC consists of cytoreductive surgery followed by chemotherapy with carboplatin (CBP) and paclitaxel (TAX). However, 80% of late-diagnosed patients experience relapse due to the acquired resistance and frequently develop metastases. It is important to emphasize that resistance mechanisms to CBP and TAX involve mostly different pathways and up till now these two processes have been studied separately. Here, we explored CBP-induced TAX cross-resistance with aim to identify possible linkers of CBP and TAX drug response and potential use of those molecules as predictive biomarkers. For this purpose, we used two different mesenchymal-like OC cell models developed by stepwise CBP treatment of parental MES-OV and SK- OV-3 cell lines, CBP-resistant and TAX cross- resistant MES-OV CBP cell line and CBP-resistant but TAX sensitive SK-OV-3 CBP cell line. Interestingly, both cell lines showed elevated levels of class III β-tubulin (TUBB3) however, transient silencing of TUBB3 only impacted MES-OV CBP response to CBP while SK-OV-3 CBP did not show any sensitization. Additionally, reduced levels of TUBB3 in MES-OV CBP cell line disturbed the trafficking of RAD50, MRN complex protein involved in DNA damage repair, and increased whole-cell platination levels. Both of these processes implied involvement of TUBB3 silencing in CBP sensitization of MES-OV CBP cells. The difference between these two cell lines was the compensation of TUBB3 silencing with other β-tubulin isotypes noticed in SK-OV-3 CBP, but absent in MES-OV CBP cell line. Based on this we proposed that TUBB3, despite upregulation in both cases, can be used as a predictive marker for treatment efficacy only when β-tubulin isotype compensation is lacking.

Organometallic and metal-based complexes have been widely used in drug discovery and some of them have entered clinical trials for the treatment of cancer. Design of new chemotherapy agents based on metal complexes is a fast-growing research area in which the biological activity of antitumor agents is based on metal-specific modes of action.1 The ferrocene pharmacophore is often introduced into the structure of drug-like molecules and bioactive hybrids with the aim of improvement of physicochemical properties and potency. In continuation of our research on coordination of mono- and bis-1, 2, 3-triazole derivatives, 2 we have synthesized and characterised ferrocene ligands as well as their Zn(II) and Cu(II) complexes by NMR, IR and UV-Vis spectroscopy and SC- XRD. Cytotoxic activity of N-heterocyclic ferrocene derivatives and their Zn(II) and Cu(II) complexes was evaluated.