👤 Sağlık Özkan BN

Sorafenib, a multiple kinase inhibitor, is widely used as a first-line treatment for hepatocellular carcinoma. However, there is a need for more effective alternatives when sorafenib proves insufficient. In this study, we aimed to design a structure that surpasses sorafenib's efficacy, leading us to synthesize sorafenib-ruthenium complexes for the first time and investigate their properties. Our results indicate that the sorafenib-ruthenium complexes exhibit superior epidermal growth factor receptor (EGFR) inhibition compared to sorafenib alone. Interestingly, among these complexes, Ru3S demonstrated high activity against various cancer cell lines including sorafenib-resistant HepG2 cells while exhibiting significantly lower cytotoxicity than sorafenib in healthy cell lines. Further evaluation of cell cycle, cell apoptosis, and antiangiogenic effects, molecular docking, and molecular dynamics studies revealed that Ru3S holds great potential as a drug candidate. Additionally, when free Ru3S was encapsulated into polymeric micelles M1, enhanced cytotoxicity on HepG2 cells was observed. Collectively, these findings position Ru3S as a promising candidate for EGFR inhibition and warrant further exploration for drug development purposes. Show less

In this study, half-sandwich Ru(II) complexes containing acylthiourea ligands of the general type [Ru(η⁶-p-cymene)(PPh₃)(S)Cl]PF₆ (1m-6m) and [Ru(η⁶-p-cymene)(PPh₃)(S-O)]PF₆ (1b-6b) where S/S-O = N',N'-disubstituted acylthiourea were synthesized and characterized (via elemental analyses, IR spectroscopy, ¹H NMR spectroscopy, ¹³C{¹H} NMR spectroscopy, and X-ray diffractometry), and their cytotoxic activity was evaluated. The different coordination modes of the acylthiourea ligands, monodentately via S (1m-6m) and bidentately via S,O (1b-6b), to ruthenium were modulated from different synthetic routes. The cytotoxicity of the complexes was evaluated in five human cell lines (DU-145, A549, MDA-MB-231, MRC-5, and MCF-10A) by MTT assay. The IC₅₀ values for prostate cancer cells (2.89-7.47 μM) indicated that the complexes inhibited cell growth, but that they were less cytotoxic than cisplatin (2.00 μM). Unlike for breast cancer cells (IC₅₀ = 0.28-0.74 μM) and lung cancer cells (IC₅₀ = 0.51-1.83 μM), the complexes were notably more active than the reference drug, and a remarkable selectivity index (SI 4.66-19.34) was observed for breast cancer cells. Based on both the activity and selectivity, complexes 5b and 6b, as well as their respective analogous complexes in the monodentate coordination 5m and 6m, were chosen for further investigation in the MDA-MB-231 cell line. These complexes not only induced morphology changes but also were able to inhibit colony formation and migration. In addition, the complexes promoted cell cycle arrest at the sub-G₁ phase inducing apoptosis. Interaction studies by viscosity measurements, gel electrophoresis, and fluorescence spectroscopy indicated that the complexes interact with the DNA minor groove and exhibit an HSA binding affinity. Show less

In this study, Ru(II)-arene complexes with acylthiourea ligands of the type [Ru(η⁶‑p‑cymene)(PPh₃)(T)Cl]PF₆(1-5) and [Ru(η⁶‑p‑cymene)(PPh₃)(T)]PF₆(1a, 4a), where PPh₃ = triphenylphosphine and T = N‑acyl‑N'(monosubstituted)thiourea, were synthesized and characterized, and their cytotoxic properties were also evaluated. 1a and 4a were obtained from the hydrolysis reaction of 1 and 4. All complexes showed unusual coordination modes for acylthiourea ligands, which are coordinated in a monodentate fashion (S) in 1-5, while they found to be bidentate (S,N), in 1a and 4a. To the best of our knowledge, 1a and 4a are the first crystallographically reported ruthenium compounds with acylthiourea coordinated via S and N(amide) atoms. The cytotoxicity of the compounds was evaluated in human lung cells, A549 and MRC-5. The IC₅₀ values ranging from 0.25 to 0.61 μM after 48 h incubation in lung cancer cells indicate that the compounds showed high cytotoxicity with values significantly lower than the reference drug, cisplatin (11.84 μM). Interaction studies were carried out using human serum albumin (HSA) and DNA. All complexes showed similar cytotoxic activity, however complex 1a, which is the hydrolysis product of 1, presented the highest activity and selectivity among all seven compounds synthesized here. Complexes 1 and 1a inhibited the colony formation decreasing the colony size and inducing morphology changes in A549 cells. These complexes induced apoptosis cell death and promoted cell cycle arrest in the Sub-G1 phase with a decrease in the cell number at the S phase. Show less