👤 DeNicola GM

Three half-sandwich organometallic ruthenium(ii) complexes containing purine analogs such as triazolopyrimidines of general formula [(η⁶-p-cym)Ru(L)Cl₂], where p-cym represents p-cymene and L is 5,6,7-trimethyl-1,2,4-triazolo[1,5-a]pyrimidine (tmtp for 1), 5,7-diethyl-1,2,4-triazolo[1,5-a]pyrimidine (detp for 2) and 5-methyl-1,2,4-triazolo[1,5-a]pyrimidin-7(4H)-one (HmtpO for 3), have been synthesized and characterized by elemental analysis, infrared, multinuclear magnetic resonance spectroscopic techniques (¹H, ¹³C, ¹⁵N), and single-crystal X-ray diffraction (for 1 and 2). All these complexes have been thoroughly screened for their in vitro cytotoxicity against MCF-7 and HeLa cell lines as well as L929 murine fibroblast cells, indicating [(η⁶-p-cym)Ru(HmtpO)Cl₂] (3) as the most active representative against the HeLa cell line and simultaneously being 64-fold less toxic to normal L929 murine fibroblast cells than cisplatin. At the same time, 3 has shown antimetastatic activity comparable to NAMI-A against HeLa cells both after 24 and 48 h of treatment in a wound healing assay. In order to better understand the mechanism of anticancer action and differences in the cytotoxic activity of 1-3, the studies were expanded to determining their lipophilicity, the kinetic stability at pH 6.5-8, the effect on reactive oxygen species (ROS) production in HeLa cells and interactions with significant biomolecules (DNA and albumin) by using molecular docking and circular dichroism (CD) experiments. Furthermore, antiparasitic studies against L. braziliensis, L. infantum and T. cruzi reveal that the newly synthesized complexes 1-3 are very promising candidates which can compete with commercial antiparasitic drugs. Complex 3 in particular, on top of exhibiting a high antiparasitic effect (IC₅₀ < 1 μM against two strains), reaches a selectivity index >1000. Show less

The transcription factor NRF2 (nuclear factor-erythroid 2 p45-related factor 2 or NFE2L2) plays a critical role in response to cellular stress. Following an oxidative insult, NRF2 orchestrates an antioxidant program, leading to increased glutathione levels and decreased reactive oxygen species (ROS). Mounting evidence now implicates the ability of NRF2 to modulate metabolic processes, particularly those at the interface between antioxidant processes and cellular proliferation. Notably, NRF2 regulates the pentose phosphate pathway, NADPH production, glutaminolysis, lipid and amino acid metabolism, many of which are hijacked by cancer cells to promote proliferation and survival. Moreover, deregulation of metabolic processes in both normal and cancer-based physiology can stabilize NRF2. We will discuss how perturbation of metabolic pathways, including the tricarboxylic acid (TCA) cycle, glycolysis, and autophagy can lead to NRF2 stabilization, and how NRF2-regulated metabolism helps cells deal with these metabolic stresses. Finally, we will discuss how the negative regulator of NRF2, Kelch-like ECH-associated protein 1 (KEAP1), may play a role in metabolism through NRF2 transcription-independent mechanisms. Collectively, this review will address the interplay between the NRF2/KEAP1 complex and metabolic processes. Show less

This study performed in vitro and in vivo biological assays of the ruthenium (II) compound ct-[RuCl(CO)(dppb)(bipy)]PF₆ (where, dppb=1,4-bis(diphenylphosphine)butane and bipy=2,2'-bipyridine). The cytotoxic activity of this compound was evaluated against different tumor cell lines (HeLa, human cervical adenocarcinoma; MCF7, human breast adenocarcinoma; MO59J, human glioblastoma; HepG2, hepatocellular carcinoma and B16F10, murine melanoma) and healthy cell line (V79, Chinese hamster lung fibroblasts), by XTT (sodium 2,3'-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)-carbonyl]-3,4-tetrazolium-bis(4-methoxy-6-nitro)benzene-sulfonic acid hydrate) method. A syngeneic murine melanoma tumor model (B16F10) was used to evaluate its antitumor activity. Additionally, experiments were performed to assess the interactions with ctDNA (calf thymus DNA) and BSA (bovine serum albumin). The results showed that ct-[RuCl(CO)(dppb)(bipy)]PF₆ was cytotoxic against all tumor cell lines tested. Furthermore, the compound was more effective against tumor cells compared to the normal cell line, indicating selectivity, especially in B16F10 cells. Significant tumor growth reduction was observed in animals treated with the compound compared to the untreated control. Histopathological analysis of tumor tissue revealed a significant reduction of mitosis in animals treated with the compound compared to the untreated control. In the ctDNA and BSA interaction experiments, the compound in study showed weak interactions with ctDNA and hydrophobic interactions with BSA. The ruthenium compound investigated showed promising results in in vitro and in vivo biological assays. Show less