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Publikation

Eichhorn, T.; Kolbe, F.; Mišić, S.; Dimić, D.; Morgan, I.; Saoud, M.; Milenković, D.; Marković, Z.; Rüffer, T.; Dimitrić Marković, J.; Kaluđerović, G. N.; Synthesis, crystallographic structure, theoretical analysis, molecular docking studies, and biological activity evaluation of Binuclear Ru(II)-1-Naphthylhydrazine Complex Int. J. Mol. Sci. 24, 689, (2023) DOI: 10.3390/ijms24010689

Ruthenium(II)–arene complexes have gained significant research interest due to their possible application in cancer therapy. In this contribution two new complexes are described, namely [{RuCl(η6-p-cymene)}2(μ-Cl)(μ-1-N,N′-naphthyl)]X (X = Cl, 1; PF6, 2), which were fully characterized by IR, NMR, and elemental microanalysis. Furthermore, the structure of 2 in the solid state was determined by a single crystal X-ray crystallographic study, confirming the composition of the crystals as 2·2MeOH. The Hirshfeld surface analysis was employed for the investigation of interactions that govern the crystal structure of 2·2MeOH. The structural data for 2 out of 2·2MeOH was used for the theoretical analysis of the cationic part [{RuCl(η6-p-cymene)}2(μ-Cl)(μ-1-N,N′-naphthyl)]+ (2a) which is common to both 1 and 2. The density functional theory, at B3LYP/6-31+G(d,p) basis set for H, C, N, and Cl atoms and LanL2DZ for Ru ions, was used for the optimization of the 2a structure. The natural bond orbital and quantum theory of atoms in molecules analyses were employed to quantify the intramolecular interactions. The reproduction of experimental IR and NMR spectra proved the applicability of the chosen level of theory. The binding of 1 to bovine serum albumin was examined by spectrofluorimetry and molecular docking, with complementary results obtained. Compound 1 acted as a radical scavenger towards DPPH• and HO• radicals, along with high activity towards cancer prostate and colon cell lines.
Publikation

Predarska, I.; Saoud, M.; Drača, D.; Morgan, I.; Komazec, T.; Eichhorn, T.; Mihajlović, E.; Dunđerović, D.; Mijatović, S.; Maksimović-Ivanić, D.; Hey-Hawkins, E.; Kaluđerović, G. N.; Mesoporous silica nanoparticles enhance the anticancer efficacy of platinum(IV)-phenolate conjugates in breast cancer cell lines Nanomaterials 12, 3767, (2022) DOI: 10.3390/nano12213767

The main reasons for the limited clinical efficacy of the platinum(II)-based agent cisplatin include drug resistance and significant side effects. Due to their better stability, as well as the possibility to introduce biologically active ligands in their axial positions constructing multifunctional prodrugs, creating platinum(IV) complexes is a tempting strategy for addressing these limitations. Another strategy for developing chemotherapeutics with lower toxicity relies on the ability of nanoparticles to accumulate in greater quantities in tumor tissues through passive targeting. To combine the two approaches, three platinum(IV) conjugates based on a cisplatin scaffold containing in the axial positions derivatives of caffeic and ferulic acid were prepared and loaded into SBA-15 to produce the corresponding mesoporous silica nanoparticles (MSNs). The free platinum(IV) conjugates demonstrated higher or comparable activity with respect to cisplatin against different human breast cancer cell lines, while upon immobilization, superior antiproliferative activity with markedly increased cytotoxicity (more than 1000-fold lower IC50 values) compared to cisplatin was observed. Mechanistic investigations with the most potent conjugate, cisplatin-diacetyl caffeate (1), and the corresponding MSNs (SBA-15|1) in a 4T1 mouse breast cancer cell line showed that these compounds induce apoptotic cell death causing strong caspase activation. In vivo, in BALB/c mice, 1 and SBA-15|1 inhibited the tumor growth while decreasing the necrotic area and lowering the mitotic rate.
Publikation

Predarska, I.; Saoud, M.; Morgan, I.; Eichhorn, T.; Kaluđerović, G. N.; Hey-Hawkins, E.; Cisplatin−cyclooxygenase inhibitor conjugates, free and immobilised in mesoporous silica SBA-15, prove highly potent against triple-negative MDA-MB-468 breast cancer cell line Dalton Trans. 51, 857–869, (2022) DOI: 10.1039/d1dt03265h

For the development of anticancer drugs with higher activity and reduced toxicity, two approaches were combined: preparation of platinum(IV) complexes exhibiting higher stability compared to their platinum(II) counterparts and loading them into mesoporous silica SBA-15 with the aim to utilise the passive enhanced permeability and retention (EPR) effect of nanoparticles for accumulation in tumour tissues. Three conjugates based on a cisplatin scaffold bearing the anti-inflammatory drugs naproxen, ibuprofen or flurbiprofen in the axial positions (1, 2 and 3, respectively) were synthesised and loaded into SBA-15 to afford the mesoporous silica nanoparticles (MSNs) SBA-15|1, SBA-15|2 and SBA-15|3. Superior antiproliferative activity of both free and immobilised conjugates in a panel of four breast cancer cell lines (MDA-MB-468, HCC1937, MCF-7 and BT-474) with markedly increased cytotoxicity with respect to cisplatin was demonstrated. All compounds exhibit highest activity against the triple-negative cell line MDA-MB-468, with conjugate 1 being the most potent. However, against MCF-7 and BT-474 cell lines, the most notable improvement was found, with IC50 values up to 240-fold lower than cisplatin. Flow cytometry assays clearly show that all compounds induce apoptotic cell death elevating the levels of both early and late apoptotic cells. Furthermore, autophagy as well as formation of reactive oxygen species (ROS) and nitric oxide (NO) were elevated to a similar or greater extent than with cisplatin.
Publikation

Momčilović, M.; Eichhorn, T.; Blazevski, J.; Schmidt, H.; Kaluđerović, G. N.; Stosic-Grujicic, S.; In vitro effects of binuclear (η6-p-cymene)ruthenium(II) complex containing bridging bis(nicotinate)-polyethylene glycol ester ligand on differentiation pathways of murine Th lymphocytes activated by T cell mitogen J. Biol. Inorg. Chem. 20, 575-583, (2015) DOI: 10.1007/s00775-015-1242-x

T cell differentiation into distinct T helper (Th) subpopulations is crucial in governing acquired immune responses as well as some inflammatory and autoimmune disorders. This study investigated potential of the novel neutral binuclear ruthenium(II) complexes 1–8 with general formula [{RuCl2(η6-p-cym)}2μ-(N∩N)] (N∩N = bis(nicotinate)- and bis(iso-nicotinate)-polyethylene glycol esters; (3-py)COO(CH2CH2O) n CO(3-py) and (4-py)COO(CH2CH2O) n CO(4-py); n = 1–4), as well as [RuCl2(η6-p-cym)(nic)] (R1, nic = nicotinate) and [RuCl2(η6-p-cym)(inic)] (R2, inic = isonicotinate) as an immunomodulatory agents capable to direct Th cell differentiation. From all investigated complexes, [{RuCl2(η6-p-cym)}2μ-{(3-py)COO(CH2CH2O)4CO(3-py)}] (4) was selected for further study because it did not affect splenocyte viability (in concentration up to 50 μM), but significantly reduced secretion of representative Th1 cytokine, IFN-γ induced by T cell mitogen. Besides IFN-γ, 4 inhibited dose dependently expression and production of representative Th17 cytokine, IL-17, in these cells. Otherwise, the production of anti-inflammatory cytokines IL-4 and IL-10 was upregulated. Also, 4 significantly increased CD4+CD25+FoxP3+ Treg cell frequency in the activated splenocytes. Moreover, ConA-induced expression of Th1 transcription factors, T-bet and STAT1, as well as of Th17-related protein STAT3 was attenuated upon exposure to 4, while the expression of Th2-related transcription factor GATA3 remained stable. In conclusion, ruthenium(II) complex 4 modulates immune system cell functions in vitro by inhibiting T cell differentiation towards pathogenic Th1/Th17 phenotype and inducing a regulatory phenotype characterized by IL-10 and IL-4 production, which may provide novel therapeutic opportunities for immune-inflammatory and/or autoimmune disorders.

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