👤 Timblin GA

Background

Melanoma is the most aggressive and lethal skin cancer that affects thousands of people worldwide. Ruthenium complexes have shown promising results as cancer chemotherapeutics, offering several advantages over platinum drugs, such as potent efficacy, low toxicity, and less drug resistance. Additionally, anthraquinone derivatives have broad therapeutic applications, including melanoma.

Objectives

Thus, two new ruthenium complexes with 1-hydroxy-9,10-anthraquinone were obtained: trans-[Ru(HQ)(PPh₃)₂(bipy)]PF₆ (1) and cis-[RuCl₂(HQ)(dppb)] (2), where HQ = 1-hydroxy-9,10-anthraquinone, PPh₃ = triphenylphospine, bipy = 2,2'-bipyridine, PF₆ = hexafluorophosphate, and dppb = 1,4-bis(diphenylphosphine)butane.

Methods

The complexes were characterized by infrared (IR), UV-vis, ¹H, ¹³C{¹H}, and ³¹P{¹H} NMR spectroscopies, molar conductivity, cyclic voltammetry, and elemental analysis. Furthermore, density functional theory (DFT) calculations were performed.

Results

Compound (2) was determined by single-crystal X-ray diffraction, which confirms the bidentate coordination mode of HQ through the carbonyl and phenolate oxygens. Additionally, DNA-binding experiments yielded constants of 10⁵ M^-1 (Kb = 6.93 × 10⁵ for (1) and 1.60 × 10⁵ for (2)) and demonstrate that both complexes can interact with DNA through intercalation, electrostatic attraction, or hydrogen bonding.

Conclusions

The cytotoxicity profiles of the compounds were evaluated in human melanoma cell lines (SK-MEL-147, CHL-1, and WM1366), revealing greater cytotoxic activity for (1) on the CHL-1 cell line with an IC₅₀ of 14.50 ± 1.09 µM. Subsequent studies showed that (1) inhibits the proliferation of CHL-1 cells and induces apoptosis, associated at least in part with the pro-oxidant effect and cell cycle arrest at the G1/S transition. Show less

In order to discover new dual-active agents, novel ruthenium (η⁶-p-cymene) complexes of the general formula [(η⁶-p-cym)Ru(OO)Cl] with O,O-diketo ester ligands ethyl 2-hydroxy-4-aryl-4-oxobut-2-enoate (1-3), were synthesized. The complexes 1-3 were characterized by spectral techniques (UV-Vis, IR, ¹H and ¹³C NMR, and ESI-HRMS), elemental analysis, and X-ray crystallography. Based on in vitro DNA/HSA experiments, complex 1 exhibited the highest DNA/HSA-activity, suggesting that the presence of an alkene chain contributes to increased activity. The cytotoxic activity of 1-3 was evaluated in a panel of human cancer cell lines (A549, MDA-MB-231, LS-174, HeLa), and in one normal cell line (MRC-5), both in the absence and presence of biocompatible ionic liquids (BIO-ILs) such as cholinium glycinate (Cho-Gly), cholinium β-alaninate (Cho-Ala), and cholinium glutamate (Cho-Glu). Complex 1 exhibited the highest cytotoxicity and demonstrated selectivity toward HeLa cells. Additionally, its cytotoxicity was enhanced when combined with the BIO-ILs Cho-Gly and Cho-Ala. This study suggests that ionic liquids can influence the efficacy and selectivity of cancer treatments, highlighting the potential for enhancing therapeutic outcomes. However, it also emphasizes the need for a deeper understanding of BIO-IL interactions with cellular processes. Furthermore, compound 1 displayed strong antimicrobial activity against Staphylococcus aureus and Escherichia coli (MIC = 0.078 mg/mL). Among the assessed species, Candida albicans showed the highest sensitivity to antifungal activity. These results suggest that investigated compounds may have potential for further development as clinical candidates, pending additional studies. Show less

Drug discovery is a complex and expensive procedure involving several timely and costly phases through which new potential pharmaceutical compounds must pass to get approved. One of these critical steps is the identification and optimization of lead compounds, which has been made more accessible by the introduction of computational methods, including deep learning (DL) techniques. Diverse DL model architectures have been put forward to learn the vast landscape of interaction between proteins and ligands and predict their affinity, helping in the identification of lead compounds. Show less

Efforts to identify anti-cancer therapeutics and understand tumor-immune interactions are built with in vitro models that do not match the microenvironmental characteristics of human tissues. Using in vitro models which mimic the physical properties of healthy or cancerous tissues and a physiologically relevant culture medium, we demonstrate that the chemical and physical properties of the microenvironment regulate the composition and topology of the glycocalyx. Remarkably, we find that cancer and age-related changes in the physical properties of the microenvironment are sufficient to adjust immune surveillance via the topology of the glycocalyx, a previously unknown phenomenon observable only with a physiologically relevant culture medium. Show less

Title: Photoinduced cytotoxic activity of a rare ruthenium nitrosyl phenanthroline complex showing NO generation in human cells. Abstract: A new nitro-nitrosyl complex [RuNO(Phen)(NO2)2OH] (1) was synthesized and characterized by X-ray diffraction, where Phen = 1,10-phenanthroline. The complex was crystallized in two different modifications without (1) and with a solvent molecule of DMF (1a). The photolysis process together with the determination of the quantum yield of NO release was investigated in acetonitrile solution using a special flow-through system for the simultaneous registration of infrared (IR) and optical absorption (UV-vis) spectra under irradiation with 450 nm light. The quantum yield of photoinduced NO release was 4.0 ± 0.2%. DFT calculations showed that the main contribution to the absorption band at 450 nm is made by the HOMO/HOMO-1 → LUMO transitions, which are represented by the transfer of electron density from the -OH and -NO2 ligands to the orbitals located on the Ru-NO bond. The dark and photoinduced cytotoxicity of the complex was studied against the human breast adenocarcinoma (MCF-7) and lung carcinoma (A549) cell lines and human non-tumor lung fibroblasts (MRC5). The complex shows a low cytotoxicity on MCF-7 cells (ICdark50 = 90.6 ± 6.2 μM and ICirr.50 = 95.3 ± 11.4 μM) and a moderate dark cytotoxicity on A549 and MRC5 cells (ICdark50 = 33.4 ± 2.6 μM and ICdark50 = 62.6 ± 3.1 μM, respectively), which slightly increases after irradiation (ICirr.50 = 21.2 ± 3.3 μM and ICirr.50 = 47.2 ± 2.3 μM, respectively). Show less

Organometallic Ru(II)-cymene complexes linked to ferrocene (Fc) via nitrogen heterocycles have been synthesized and studied as cytotoxic agents. These compounds are analogues of Ru(II)-arene piano-stool anticancer complexes such as RAPTA-C. The Ru center was coordinated by pyridine, imidazole, and piperidine with 0-, 1-, or 2-carbon bridges to Fc to give six bimetallic, dinuclear compounds, and the properties of these complexes were compared with their non-Fc-functionalized parent compounds. Crystal structures for five of the compounds, their Ru-cymene parent compounds, and an unusual trinuclear compound were determined. Cyclic voltammetry was used to determine the formal M^III/II potentials of each metal center of the Ru-cymene-Fc complexes, with distinct one-electron waves observed in each case. The Fc-functionalized complexes were found to exhibit good cytotoxicity against HT29 human colon adenocarcinoma cells, whereas the parent compounds were inactive. Similarly, antibacterial activity from the Ru-cymene-Fc compounds was observed against Bacillus subtilis, but not from the unfunctionalized complexes. In both cases, the IC₅₀ values correlated quantitatively with the Fc^+/0 reduction potentials. This is consistent with more facile oxidation to give ferrocenium, and subsequent generation of toxic reactive oxygen species, leading to greater cytotoxicity. The antioxidant properties of the complexes were quantified by a 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay. EC₅₀ values indicate that linking of the Ru and Fc centers promotes antioxidant activity. Show less

Loss of function mutations in Kelch-like ECH Associated Protein 1 (KEAP1), or gain-of-function mutations in nuclear factor erythroid 2-related factor 2 (NRF2), are common in non-small cell lung cancer (NSCLC) and associated with therapeutic resistance. To discover novel NRF2 inhibitors for targeted therapy, we conducted a quantitative high-throughput screen using a diverse set of ∼400 000 small molecules (Molecular Libraries Small Molecule Repository Library, MLSMR) at the National Center for Advancing Translational Sciences. We identified ML385 as a probe molecule that binds to NRF2 and inhibits its downstream target gene expression. Specifically, ML385 binds to Neh1, the Cap 'N' Collar Basic Leucine Zipper (CNC-bZIP) domain of NRF2, and interferes with the binding of the V-Maf Avian Musculoaponeurotic Fibrosarcoma Oncogene Homologue G (MAFG)-NRF2 protein complex to regulatory DNA binding sequences. In clonogenic assays, when used in combination with platinum-based drugs, doxorubicin or taxol, ML385 substantially enhances cytotoxicity in NSCLC cells, as compared to single agents. ML385 shows specificity and selectivity for NSCLC cells with KEAP1 mutation, leading to gain of NRF2 function. In preclinical models of NSCLC with gain of NRF2 function, ML385 in combination with carboplatin showed significant antitumor activity. We demonstrate the discovery and validation of ML385 as a novel and specific NRF2 inhibitor and conclude that targeting NRF2 may represent a promising strategy for the treatment of advanced NSCLC. Show less