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Antioxidant supplements are widely used during cancer treatment to prevent oxidative stress, reduce treatment toxicities, and improve patient outcomes. However, current literature reveals significant gaps suggesting that antioxidants may protect both healthy and tumor cells from oxidative damage, thereby reducing treatment efficacy. It is for this reason that antioxidant supplements have become a source of therapeutic controversy. Show less

DNA damage occurs throughout life from a variety of sources, and it is imperative to repair damage in a timely manner to maintain genome stability. Thus, DNA repair mechanisms are a fundamental part of life. Nucleotide excision repair (NER) plays an important role in the removal of bulky DNA adducts, such as cyclobutane pyrimidine dimers from ultraviolet light or DNA crosslinking damage from platinum-based chemotherapeutics, such as cisplatin. A main component for the NER pathway is transcription factor IIH (TFIIH), a multifunctional, 10-subunit protein complex with crucial roles in both transcription and NER. In transcription, TFIIH is a component of the pre-initiation complex and is important for promoter opening and the phosphorylation of RNA Polymerase II (RNA Pol II). During repair, TFIIH is important for DNA unwinding, recruitment of downstream repair factors, and verification of the bulky lesion. Several different disease states can arise from mutations within subunits of the TFIIH complex. Most strikingly are xeroderma pigmentosum (XP), XP combined with Cockayne syndrome (CS), and trichothiodystrophy (TTD). Here, we summarize the recruitment and functions of TFIIH in the two NER subpathways, global genomic (GG-NER) and transcription-coupled NER (TC-NER). We will also discuss how TFIIH's roles in the two subpathways lead to different genetic disorders. Show less

Monofunctional platinum complexes offer a promising alternative to cisplatin in cancer chemotherapy, showing a unique mechanism of action. Their ability to induce minor helix distortions effectively inhibits DNA transcription. In our study, we synthesized and characterized three monofunctional Pt(II) complexes with the general formula [Pt(en)(L)Cl]NO3, where en = ethylenediamine, and L = pyridine (py), 2-methylpyridine (2-mepy), and 2-phenylpyridine (2-phpy). The hydrolysis rates of [Pt(en)(py)Cl]NO3 (1) and [Pt(en)(2-mepy)Cl]NO3 (2) decrease with the bulkiness of the auxiliary ligand with k(1) = 2.28 ± 0.15 × 10-4 s-1 and k(2) = 8.69 ± 0.98 × 10-5 s-1 at 298 K. The complex [Pt(en)(2-phpy)Cl]Cl (3) demonstrated distinct behavior. Upon hydrolysis, an equilibrium (Keq = 0.385 mM) between the complexes [Pt(en)(2-phpy)Cl]+ and [Pt(en)(2-phpy-H+)]+ was observed with no evidence (NMR or HR-ESI-MS) for the presence of the aquated complex [Pt(en)(2-phpy)(H2O)]2+. Despite the kinetic similarities between phenanthriplatin and (2), complexes (1) and (2) exhibit minimal activity against A549 lung cancer cell line (IC50 > 100 μΜ), whereas complex (3) exhibits notable cytotoxicity (IC50 = 41.11 ± 2.1 μΜ). In examining the DNA binding of (1) and (2) to the DNA model guanosine (guo), we validated their binding through guoN7, which led to an increased population of the C3'-endo sugar conformation, as expected. However, we observed that the rapid transition 2E (C2'-endo) ↔ 3E (C3'-endo), in the case of [Pt(en)(py)(guo)](NO3)2 ([1-guo]), slows down in the case of [Pt(en)(2-mepy)(guo)](NO3)2 ([2-guo]), resulting in separate signals for the two conformers in the 1H NMR spectra. This phenomenon arises from the steric hindrance between the methyl group of pyridine and the sugar moiety of guanosine. Notably, this hindrance is absent in [2-(9-MeG)] (9-MeG = 9-methylguanine), probably due to the absence of a bulky sugar unit in 9-MeG. In the case of (3), where the bulkiness of the substitution on the pyridine is further increased by a phenyl group, we observed a notable proximity between 9-MeGH8 and the phenyl ring of 2-phpy. Considering that only (3) exhibited good cytotoxicity against the A549 cancer cell line, it is suggested that auxiliary ligands, L, with an extended aromatic system and proper orientation in complexes of the type cis-[Pt(en)(L)Cl]NO3, may enhance the cytotoxic activity of such complexes. 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

The versatility of cellular response arises from the communication, or crosstalk, of signaling pathways in a complex network of signaling and transcriptional regulatory interactions. Understanding the various mechanisms underlying crosstalk on a global scale requires untargeted computational approaches. We present a network-based statistical approach, MuXTalk, that uses high-dimensional edges called multilinks to model the unique ways in which signaling and regulatory interactions can interface. We demonstrate that the signaling-regulatory interface is located primarily in the intermediary region between signaling pathways where crosstalk occurs, and that multilinks can differentiate between distinct signaling-transcriptional mechanisms. Using statistically over-represented multilinks as proxies of crosstalk, we infer crosstalk among 60 signaling pathways, expanding currently available crosstalk databases by more than five-fold. MuXTalk surpasses existing methods in terms of model performance metrics, identifies additions to manual curation efforts, and pinpoints potential mediators of crosstalk. Moreover, it accommodates the inherent context-dependence of crosstalk, allowing future applications to cell type- and disease-specific crosstalk. Show less

Expert curation is essential to capture knowledge of enzyme functions from the scientific literature in FAIR open knowledgebases but cannot keep pace with the rate of new discoveries and new publications. In this work we present EnzChemRED, for Enzyme Chemistry Relation Extraction Dataset, a new training and benchmarking dataset to support the development of Natural Language Processing (NLP) methods such as (large) language models that can assist enzyme curation. EnzChemRED consists of 1,210 expert curated PubMed abstracts where enzymes and the chemical reactions they catalyze are annotated using identifiers from the protein knowledgebase UniProtKB and the chemical ontology ChEBI. We show that fine-tuning language models with EnzChemRED significantly boosts their ability to identify proteins and chemicals in text (86.30% F1 score) and to extract the chemical conversions (86.66% F1 score) and the enzymes that catalyze those conversions (83.79% F1 score). We apply our methods to abstracts at PubMed scale to create a draft map of enzyme functions in literature to guide curation efforts in UniProtKB and the reaction knowledgebase Rhea. Show less

In the era of high throughput sequencing, special software is required for the clinical evaluation of genetic variants. We developed REEV (Review, Evaluate and Explain Variants), a user-friendly platform for clinicians and researchers in the field of rare disease genetics. Supporting data was aggregated from public data sources. We compared REEV with seven other tools for clinical variant evaluation. REEV (semi-)automatically fills individual ACMG criteria facilitating variant interpretation. REEV can store disease and phenotype data related to a case to use these for phenotype similarity measures. Users can create public permanent links for individual variants that can be saved as browser bookmarks and shared. REEV may help in the fast diagnostic assessment of genetic variants in a clinical as well as in a research context. REEV (https://reev.bihealth.org/) is free and open to all users and there is no login requirement. Show less

PubTator 3.0 (https://www.ncbi.nlm.nih.gov/research/pubtator3/) is a biomedical literature resource using state-of-the-art AI techniques to offer semantic and relation searches for key concepts like proteins, genetic variants, diseases and chemicals. It currently provides over one billion entity and relation annotations across approximately 36 million PubMed abstracts and 6 million full-text articles from the PMC open access subset, updated weekly. PubTator 3.0's online interface and API utilize these precomputed entity relations and synonyms to provide advanced search capabilities and enable large-scale analyses, streamlining many complex information needs. We showcase the retrieval quality of PubTator 3.0 using a series of entity pair queries, demonstrating that PubTator 3.0 retrieves a greater number of articles than either PubMed or Google Scholar, with higher precision in the top 20 results. We further show that integrating ChatGPT (GPT-4) with PubTator APIs dramatically improves the factuality and verifiability of its responses. In summary, PubTator 3.0 offers a comprehensive set of features and tools that allow researchers to navigate the ever-expanding wealth of biomedical literature, expediting research and unlocking valuable insights for scientific discovery. Show less

Ruthenium complexes bearing bis pyrazole (pzH) ligands, cis-[Ru(bpy)₂(R-pzH)₂]²⁺ (bpy = 2,2'-bipyridine, R = -H, -Cl), were examined as photoactivated anticancer prodrugs. A dicationic pyrazole complex deprotonated to give monocationic pyrazole-pyrazolate complexes, cis-[Ru(bpy)₂(R-pz^-)(R-pzH)]⁺, in an aqueous solution with pK_a values of 9.5 and 7.2 for R = H and R = Cl, respectively. Upon deprotonation, relative quantum yields of photosubstitution decreased while lipophilicity of the complexes increased according to the measurements of water-octanol coefficients. The ruthenium complex with 4-chloropyrazole ligands displayed high cytotoxicity upon light irradiation (IC₅₀ = 0.060 ± 0.016 μM) toward lung cancer cells, which was 7 times higher than that in the dark (IC₅₀ = 0.44 ± 0.07 μM). Additional experiments for the ruthenium R-pyrazole complexes indicated that (1) selective photodissociation of the 4-chloropyrazole ligand occurs from cis-[Ru(bpy)₂(4-Clpz^-)(4-ClpzH)]⁺, (2) photoinduced ligand dissociation is dominant rather than photoinduced generation of singlet oxygen (¹O₂), and (3) induction of cell death occurs via the intrinsic pathway of apoptosis. Show less

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

The need for a systematic approach in developing new metal-based drugs with dual anticancer-antimicrobial properties is emphasized by the vulnerability of cancer patients to bacterial infections. In this context, a novel organometallic assembly was designed, featuring ruthenium(II) coordination with p-cymene, one chlorido ligand, and a bidentate neutral Schiff base derived from 4-methoxybenzaldehyde and N,N-dimethylethylenediamine. The compound was extensively characterized in both solid-state and solution, employing single crystal X-ray diffraction, nuclear magnetic resonance, infrared, ultraviolet-visible spectroscopy, and density functional theory, alongside Hirshfeld surface analysis. The hydrolysis kinetic was thoroughly investigated, revealing the important role of the chloro-aqua equilibrium in the dynamics of binding with deoxyribonucleic acid and bovine serum albumin. Notably, the aqua species exhibited a pronounced affinity for deoxyribonucleic acid, engaging through electrostatic and hydrogen bonding interactions, while the chloro species demonstrated groove-binding properties. Interaction with albumin revealed distinct binding mechanisms. The aqua species displayed covalent binding, contrasting with the ligand-like van der Waals interactions and hydrogen bonding observed with the chloro specie. Molecular docking studies highlighted site-specific interactions with biomolecular targets. Remarkably, the compound exhibited wide spectrum moderate antimicrobial activity against Staphylococcus aureus, Pseudomonas aeruginosa, and Candida albicans, coupled with low micromolar cytotoxic activity against human colorectal adenocarcinoma cells and significant activity against human leukemic monocyte lymphoma cells. The presented findings encourage further development of this compound, promising avenues for its evolution into a versatile therapeutic agent targeting both infectious diseases and cancer. Show less

The modular synthesis of the heteroscorpionate core is explored as a tool for the rapid development of ruthenium-based therapeutic agents. Starting with a series of structurally diverse alcohol-NN ligands, a family of heteroscorpionate-based ruthenium derivatives was synthesized, characterized, and evaluated as an alternative to platinum therapy for breast cancer therapy. In vitro, the antitumoral activity of the novel derivatives was assessed in a series of breast cancer cell lines using UNICAM-1 and cisplatin as metallodrug control. Through this approach, a bimetallic heteroscorpionate-based metallodrug (RUSCO-2) was identified as the lead compound of the series with an IC₅₀ value range as low as 3-5 μM. Notably, RUSCO-2 was found to be highly cytotoxic in TNBC cell lines, suggesting a mode of action independent of the receptor status of the cells. As a proof of concept and taking advantage of the luminescent properties of one of the complexes obtained, uptake was monitored in human breast cancer MCF7 cell lines by fluorescence lifetime imaging microscopy (FLIM) to reveal that the compound is evenly distributed in the cytoplasm and that the incorporation of the heteroscorpionate ligand protects it from aqueous processes, conversion in another entity, or the loss of the chloride group. Finally, ROS studies were conducted, lipophilicity was estimated, the chloride/water exchange was studied, and stability studies in simulated biological media were carried out to propose structure-activity relationships. Show less

Title: Rational design of a red-light absorbing ruthenium polypyridine complex as a photosensitizer for photodynamic therapy. Abstract: Herein, the computer-guided design, chemical synthesis, and biological evaluation of a RuC polypyridine complex, that could eradicate cancerous cells upon excitation with red light at 630 nm, is reported. Show less

Title: Trinuclear ruthenium(II) polypyridyl complexes: Evaluation as photosensitizers for enhanced cervical cancer treatment. Abstract: Trinuclear ruthenium(II) polypyridyl complexes anchored to benzimidazole-triazine / trisamine scaffolds were investigated as photosensitizers for photodynamic therapy. The trinuclear complexes were noted to produce a significant amount of singlet oxygen in both DMF and aqueous media, are photostable and show appreciable emission quantum yields (ɸem). In our experimental setting, despite the moderate phototoxic activity in the HeLa cervical cancer cell line, the phototoxic indices (PI) of the trinuclear complexes are superior relative to the PIs of a clinically approved photosensitizer, Photofrin®, and the pro-drug 5-aminolevulinic acid (PI: >7 relative to PI: >1 and PI: 4.4 for 5-aminolevulinic acid and Photofrin®, respectively). Furthermore, the ruthenium complexes were noted to show appreciable long-term cytotoxicity upon light irradiation in HeLa cells in a concentration-dependent manner. Consequently, this long-term activity of the ruthenium(II) polypyridyl complexes embodies their ability to reduce the probability of the recurrence of cervical cancer. Taken together, this presents a strong motivation for the development of polymetallic complexes as anticancer agents. Show less

Ruthenium(II) complexes containing diimine ligands have contributed to the development of agents for photoactivated chemotherapy. Several approaches have been used to obtain photolabile Ru(II) complexes. The two most explored have been the use of monodentate ligands and the incorporation of steric effects between the bidentate ligands and the Ru(II). However, the introduction of electronic effects in the ligands has been less explored. Herein, we report a systematic experimental, theoretical, and photocytotoxicity study of a novel series of Ru(II) complexes Ru1-Ru5 of general formula [Ru(phen)₂(N^∧N')]²⁺, where N^∧N' are different minimal strained ligands based on the 1-aryl-4-benzothiazolyl-1,2,3-triazole (BTAT) scaffold, being CH₃ (Ru1), F (Ru2), CF₃ (Ru3), NO₂ (Ru4), and N(CH₃)₂ (Ru5) substituents in the R4 of the phenyl ring. The complexes are stable in solution in the dark, but upon irradiation in water with blue light (λ_ex = 465 nm, 4 mW/cm²) photoejection of the ligand BTAT was observed by HPLC-MS spectrometry and UV-vis spectroscopy, with t_1/2 ranging from 4.5 to 14.15 min depending of the electronic properties of the corresponding BTAT, being Ru4 the less photolabile (the one containing the more electron withdrawing substituent, NO₂). The properties of the ground state singlet and excited state triplet of Ru1-Ru5 have been explored using density functional theory (DFT) and time-dependent DFT (TD-DFT) calculations. A mechanism for the photoejection of the BTAT ligand from the Ru complexes, in H₂O, is proposed. Phototoxicity studies in A375 and HeLa human cancer cell lines showed that the new Ru BTAT complexes were strongly phototoxic. An enhancement of the emission intensity of HeLa cells treated with Ru5 was observed in response to increasing doses of light due to the photoejection of the BTAT ligand. These studies suggest that BTAT could serve as a photocleavable protecting group for the cytotoxic bis-aqua ruthenium warhead [Ru(phen)₂(OH₂)₂]²⁺. Show less

A series of aryl-isatin Schiff base derivatives (3a-d) and their piano-stool ruthenium complexes (4a-d) were synthesized and characterized via ¹H and ¹³C NMR and Fourier transform infrared (FTIR) spectroscopy. In addition, the purity of all of the compounds (3a-c and 4a-d) was determined via elemental analysis. Complex 4d was analyzed using X-ray crystallography. An in vitro antiproliferative study of the compounds (3a-c and 4a-d) against human hepatocellular carcinoma (HEPG2), human breast cancer (MCF-7), human prostate cancer (PC-3), and human embryonic kidney (HEK-293) cells exhibited their considerable antiproliferative activity. 4d exhibited effective cytotoxicity against HEPG2 and MCF-7. It displayed higher cytotoxicity than the reference metallo-drug cisplatin. Moreover, the stability of 4d was studied via ¹H NMR spectroscopy, and the binding model between 4d and DNA was investigated via ultraviolet-visible spectroscopy. The lipophilicity of the synthesized complexes was determined using an extraction method. Show less

Glioblastoma multiforme (GBM) is the most common highly aggressive malignant brain tumor, with a very limited chance for survival post-diagnosis and post-treatment. Despite significant advancement in GBM genomics implicated in molecularly targeted chemotherapies, the prognosis remains poor and requires new drug discovery approaches. We used fluoropyrimidine 5-fluorouracil (5-FU), an antimetabolite anticancer drug conjugated or 'caged' within a lipophilic Ru(II)-diphosphine (dppe) core formulated as [Ru^II(dppe)₂(5-FU)]PF₆ (Ru-DPPE-5FU), where dppe = 1,2-bis(diphenylphosphino)ethane, and evaluated its in vitro cytotoxicity in depth with aggressive GBM cells (LN229). The hydrophilic nature of 5-FU limits its passage through the blood-brain barrier (BBB), which prevents its effective accumulation and efficacy for GBM tumors. Herein, we attempted to modulate the lipophilicity of 5-FU by inserting it within a well-designed lipophilic {Ru(dppe)₂}-core with anticipated higher efficiency towards GBM. The physicochemical properties of [Ru^II(dppe)₂(5-FU)]PF₆ (Ru-DPPE-5FU) were studied using various spectroscopic and analytical techniques. The molecular structure was determined using X-ray crystallography, showing a distorted {RuP₄NO} octahedral geometry with bidentate (N, O) binding of 5-FU and its aromatization in the Ru(II)-bound form. The ³¹P-NMR spectra of Ru-DPPE-5FU showed four closely spaced distinct ³¹P-signals, indicating four unique chemical environments around P, and the strong coupling constants between them make it a second-order spectrum. The Ru^II/Ru^III redox potential in Ru-DPPE-5FU shifted by ∼0.91 V towards the anodic region as compared to its precursor complex cis-[Ru(dppe)₂Cl₂] (Ru-DPPE-Cl). DFT-based theoretical calculations have been performed to correlate the experimental electronic absorption spectra and redox behaviours of the complexes. The electrostatic potential (ESP) plots indicate the delocalization of the charge density on the O-/F-atom from the 5-FU ligand towards Ru(II) upon its complexation. The antioxidant properties of all the compounds were quantified by a 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay. The hyphenation of the 5-fluorouracil (5-FU) ligand to the lipophilic {Ru(dppe)₂}-core endowed lipophilicity to Ru-DPPE-5FU with higher in vitro cytotoxicity (IC₅₀ = 2.37 μM) against the LN229 GBM cells as compared to the hydrophilic 5-FU, suggesting efficient cellular uptake. Further biological assays indicated that the complex is highly potent in inhibiting significant proliferation and spheroid formation and restricting the migratory potentials of the GBM cells. Increased caspase 3/7 activity and the presence of apoptotic bodies at the center of 3-D GBM spheroids as revealed by AO/EB dual staining indicated a deeper penetration of the lipophilic complex. The Ru-DPPE-5FU complex displayed lower cytotoxicity in HaCaT normal cells (IC₅₀ = 7.27 μM) in comparison to LN229 cancer cells with a selectivity index (S.I.) of ≥3. Overall, the synergism and caging of 5-FU within the hydrophobic {Ru(dppe)₂}-core improves the pharmacokinetic profile of Ru-DPPE-5FU as a potent anticancer agent for glioblastoma. Show less

Liver cancer is one of the leading causes of death that motivating scientists worldwide to synthesize novel chemotherapeutics. Ru(II)-polypyridyl complexes are extensively studied for possible therapeutic and cellular applications due to their tunable coordination chemistry, structural diversity, ligand-exchange kinetics, accessible redox states, and rich photophysical or photochemical properties. Herein, we have synthesized a series of Ru(II) polypyridyl complexes [Ru^II(N^N)₂(ox)] (1-3), where ox is oxalate (C₂O₄^2-) and N^N is 1,10-phenanthroline (phen) (1), dipyrido[3,2-d:2',3'-f]quinoxaline (dpq) (2), and dipyrido[3,2,-a:2',3'-c]phenazine (dppz) (3). Oxalate (ox^2-) was opted as a bioactive dioxo ligand to prevent facile hydrolysis in aqueous media, thereby increasing the stability of the Ru(II)-polypyridyl complexes in physiological media. We thoroughly characterized all the complexes using ESI-MS, FT-IR, UV-vis, and ¹H NMR spectroscopy and other physicochemical methods. The complexes were stable under physiological conditions and under low-energy green LED light (λ_irr = 530 nm). However, the photoirradiation of complexes resulted in the efficient generation of singlet oxygen (¹O₂) as a major reactive oxygen species (ROS). The role of the extended aromatic conjugation of the N^N-donor ligands in the complexes was demonstrated by their binding propensities with CT-DNA and bovine serum albumin (BSA). Both DNA intercalation and groove binding were evidenced, while tryptophan (Trp) and tyrosine (Tyr) binding site preferences were revealed from the synchronous fluorescence spectra (SFS) of BSA. The cytotoxic profiling of the complexes performed on hepatocellular carcinoma cells (HepG2) in the dark and in the presence of green light indicated their dose-dependent cytotoxicity. The [Ru^II(N^N)₂(ox)] complexes exhibited enhanced photocytotoxicity mediated by efficient generation of cytotoxic ¹O₂ and effective interaction with DNA. All the complexes were internalized by the HepG2 liver cancer cells efficiently and localized to the cytoplasm and nucleus. The complexes exhibited potent anti-proliferative, anti-clonogenic, and anti-migratory effects on the cancer cells, suggesting their potential for therapeutic applications. Show less

Title: Insights into Mechanisms and Promising Triple Negative Breast Cancer Therapeutic Potential for a Water-Soluble Ruthenium Compound. Abstract: Triple negative breast cancer (TNBC) represents a subtype of breast cancer that does not express the three major prognostic receptors of human epidermal growth factor receptor 2 (HER2), progesterone (PR), and estrogen (ER). This limits treatment options and results in a high rate of mortality. We have reported previously on the efficacy of a water-soluble, cationic organometallic compound (Ru-IM) in a TNBC mouse xenograft model with impressive tumor reduction and targeted tumor drug accumulation. Ru-IM inhibits cancer hallmarks such as migration, angiogenesis, and invasion in TNBC cells by a mechanism that generates apoptotic cell death. Ru-IM displays little interaction with DNA and appears to act by a P53-independent pathway. We report here on the mitochondrial alterations caused by Ru-IM treatment and detail the inhibitory properties of Ru-IM in the PI3K/AKT/mTOR pathway in MDA-MB-231 cells. Lastly, we describe the results of an efficacy study of the TNBC xenografted mouse model with Ru-IM and Olaparib monotherapy and combinatory treatments. We find 59% tumor shrinkage with Ru-IM and 65% with the combination. Histopathological analysis confirmed no test-article-related toxicity. Immunohistochemical analysis indicated an inhibition of the angiogenic marker CD31 and increased levels of apoptotic cleaved caspase 3 marker, along with a slight inhibition of p-mTOR. Taken together, the effects of Ru-IM in vitro show similar trends and translation in vivo. Our investigation underscores the therapeutic potential of Ru-IM in addressing the challenges posed by TNBC as evidenced by its robust efficacy in inhibiting key cancer hallmarks, substantial tumor reduction, and minimal systemic toxicity. Show less

Organometallic η⁶-arene ruthenium(II) complexes with 3-chloro-6-(1H-pyrazol-1-yl)pyridazine (Ru1, Ru2, and Ru5) and 3-chloro-6-(3,5-dimethyl-1H-pyrazol-1-yl)pyridazine (Ru3-4) N,N' heterocyclic and η⁶-arene (cymene (Ru1-4) or toluene (Ru 5)) have been synthesized. The ruthenium(II) complexes have common "three-legged piano-stool" pseudo-octahedral structures known for half-sandwich complexes. Evolution of their UV-Visible absorption spectra in PBS buffer or DMSO over 24 h confirmed their good solvolysis stability. Titrations of the complexes with the calf thymus DNA (CT-DNA) were monitored using UV-Visible absorption and fluorescence spectroscopies. The complexes interact moderately with CT-DNA and their binding constants are in the order of 10⁴ M^-1. Competitive binding of the complexes to a DNA-Hoechst 33,258 depicted competitive displacement of Hoechst from DNA's minor grooves. These complexes bind to glutathione forming GSH-adducts through S coordination by replacement of a halide, with the iodo-analogues having higher binding constants than the chloro-complexes. Cyclic voltammograms of the complexes exhibited one electron-transfer quasi-reversible process. Trends in the molecular docking data of Ru1-5/DNA were similar to those for DNA binding constants. Of the five, only Ru1, Ru3 and Ru5 showed some activity (moderate) against the MCF-7 breast cancer cells with IC₅₀ values in the range of 59.2-39.9 for which Ru5 was the most active. However, the more difficult-to-treat cell line, MDA-MB 231 cell was recalcitrant to the treatment by these complexes. Show less

The therapeutic approach to many solid tumors, including non-small cell lung cancer (NSCLC), is mainly based on the use of platinum-containing anticancer agents and is often characterized by acquired or intrinsic resistance to the drug. Therefore, the search for safer and more effective drugs is still an open challenge. Two organometallic ruthenium(II)-cyclopentadienyl compounds [Ru(η⁵-C₅H₄CHO)(Me₂bipy)(PPh₃)]⁺ (RT150) and [Ru(η⁵-C₅H₄CH₂OH)(Me₂bipy)(PPh₃)][CF₃SO₃] (RT151) were tested against a panel of cisplatin-resistant NSCLC cell lines and xenografts. They were more effective than cisplatin in inducing oxidative stress and DNA damage, affecting the cell cycle and causing apoptosis. Importantly, they were found to be inhibitors of drug efflux transporters. Due to this property, the compounds significantly increased the retention and cytotoxicity of cisplatin within NSCLC cells. Notably, they did not display high toxicity in vitro against non-transformed cells (red blood cells, fibroblasts, bronchial epithelial cells, cardiomyocytes, and endothelial cells). Both compounds induced vasorelaxation and reduced endothelial cell migration, suggesting potential anti-angiogenic properties. RT151 confirmed its efficacy against NSCLC xenografts resistant to cisplatin. Either alone or combined with low doses of cisplatin, RT151 showed a good biodistribution profile in the liver, kidney, spleen, lung, and tumor. Hematochemical analysis and post-mortem organ pathology confirmed the safety of the compound in vivo, also when combined with cisplatin. To sum up, we have confirmed the effectiveness of a novel class of drugs against cisplatin-resistant NSCLC. Additionally, the compounds have a good biocompatibility and safety profile. Show less

A synthetic procedure was designed for the preparation and characterization of Ag and Ru complexes containing NHC ligands functionalized with PEG fragments. Stability studies were conducted to gain insight of the species in water and other solvents like DMSO, or with reagents like imidazole as representative group for histidine amino acid. The presence of Cl atoms instead of H in the 4,5 positions of the N-heterocyclic carbene afforded higher water stability. The complexes containing PEG units must be considered inactive as anticancer agents. To enhance the anticancer activity of PEG-containing complexes, the balance between hydrophilicity and hydrophobicity was adjusted using a silane moiety, and an anionic carbosilane dendrimer as a lipophilic carrier. Show less

Organometallic complexes of the formula [Ru(N^N)(p-cymene)Cl][X] (N^N = bidentate polypyridyl ligands, p-cymene = 1-methyl-4-(1-methylethyl)-benzene, X = counter anion), are currently studied as possible candidates for the potential treatment of cancer. Searching for new organometallic compounds with good to moderate cytotoxic activities, a series of mononuclear water-soluble ruthenium(II)-arene complexes incorporating substituted pyridine-quinoline ligands, with pending -CH₂OH, -CO₂H and -CO₂Me groups in the 4-position of quinoline ring, were synthesized, for the first time, to study their possible effect to modulate the activity of the ruthenium p-cymene complexes. These include the [Ru(η⁶-p-cymene)(pqhyme)Cl][X] (X = Cl^- (1-Cl), PF₆^- (1-PF₆), pqhyme = 4-hydroxymethyl-2-(pyridin-2-yl)quinoline), [Ru(η⁶-p-cymene)(pqca)Cl][Cl] ((2-Cl), pqca = 4-carboxy-2-(pyridin-2-yl)quinoline), and [Ru(η⁶-p-cymene)(pqcame)Cl][X] (X = Cl^- (3-Cl), PF₆^- (3-PF₆), pqcame = 4-carboxymethyl-2-(pyridin-2-yl)quinoline) complexes, respectively. Identification of the complexes was based on multinuclear NMR and ATR-IR spectroscopic methods, elemental analysis, conductivity measurements, UV-Vis spectroscopic, and ESI-HRMS techniques. The solid-state structures of 1-PF₆ and 3-PF₆ have been elucidated by single-crystal X-ray diffraction revealing a three-legged piano stool geometry. This is the first time that the in vitro cytotoxic activities of these complexes are studied. These were conducted in HEK293T (human embryonic kidney cells) and HeLa cells (cervical cancer cells) via the MTT assay. The results show poor in vitro anticancer activities for the HeLa cancer cell lines and 3-Cl proved to be the most potent (IC₅₀ > 80 μΜ). In both cell lines, the cytotoxicity of the ligand precursor pqhyme is significantly higher than that of cisplatin. Show less

Title: Analysis of antiproliferative activity of new half-sandwich arene Ru(II) thiophene based aroylhydrazone complexes. Abstract: Efforts in researching the efficient anti-tumor properties of three novel arene ruthenium(II) complexes incorporating thiophene-based aroylhydrazone ligands have been undertaken. The complexes' elemental composition was [(η6-p-cymene)Ru(L)Cl]. They were comprehensively characterized through elemental and spectroscopic analyses (FT-IR, UV-vis, NMR, and HR-MS). Single crystal X-ray diffraction studies revealed a pseudo-octahedral geometry with bidentate coordination of the ligands in a representative complex. The in vitro assessment of the complexes' cancer cell growth inhibition was conducted using the MTT assay against A549 (human lung carcinoma), HeLa (human cervical carcinoma), HuH-7 (hepatocellular carcinoma), and NIH-3T3 (mouse fibroblast non-cancerous cell line). Results indicated significant cytotoxicity across all cancer cell lines, with IC50 concentrations of complex 2 being 6.8 μM for A549, 11.6 μM for HeLa, and 9.4 μM for HuH-7, compared to cisplatin with IC50 values of 18.9 μM, 17.68 μM, and 24 μM respectively. Notably, complex 2 demonstrated particularly promising cytotoxicity against all tested cancerous cell lines. Fluorescent staining analysis such as acridine orange/ethidium bromide (AO-EB) and HOECHST 33342 revealed cell death mechanisms involving membrane disintegration and nuclear condensation following treatment with complex 2. Further studies were conducted to measure reactive oxygen species (ROS) levels using the dichlorodihydrofluorescein diacetate (DCFH-DA) assay, and mitochondrial membrane potential (MMP) was assessed using the JC-1 dye assay. These studies demonstrated that complex 2 increased ROS levels, decreased membrane potential, and promoted mitochondrial dysfunction-mediated cell death pathways. Additionally, flow cytometry analysis, utilizing dual staining of Annexin V-FITC and propidium iodide (PI), was employed to quantitatively study apoptosis induction. Show less