👤 Zhang YQ

Proteins are of great significance in living organisms. However, understanding their functions encounters numerous challenges, such as insufficient integration of multimodal information, a large number of training parameters, limited flexibility of classification-based methods, and the lack of systematic evaluation metrics for protein question answering systems. To tackle these issues, we propose the Prot2Chat framework. Show less

Title: A Bioactive Benzimidazole-Cyclometalated Iridium(III) Complex as an Epigenetic Regulator through Effectively Interrupting the EED-EZH2 Interaction. Abstract: Epigenetic regulation plays a fundamental role in controlling gene expression and maintaining cellular identity. Among epigenetic processes, the translocation of methyltransferases is critical for the modification of chromatin structure and transcriptional activity. The regulation of these translocation events and the mechanisms involved are complex, yet critical for understanding and manipulating epigenetic states. Therefore, novel strategies are required for detecting and visualizing the movement and interaction of methyltransferases within cells. Using enhancer of zeste homolog 2 (EZH2) methyltransferase as an example, a bifunctional compound capable of both monitoring and disrupting its translocation process is developed by targeting the protein-protein interaction (PPI) between embryonic ectoderm development (EED) and EZH2. The Ir(III) complex 1 bound enthalpically to EED and effectively inhibited the methyltransferase activity of EZH2. Moreover, disruption of the EED-EZH2 PPI led to increased transcriptional activity of P21 and P27, resulting in the suppression of triple-negative breast cancer (TNBC) cell proliferation. Excitingly, 1 suppressed tumor metastasis in a TNBC mouse model in vivo. To our knowledge, complex 1 is the first metal-based bifunctional therapeutic agent designed to probe and inhibit the EED-EZH2 PPI, highlighting the feasibility and significance of using metal complexes to monitor and influence methyltransferase translocations for therapeutic applications. Show less

Cyclometalated iridium complexes with mitochondrial targeting show great potential as substitutes for platinum-based complexes because of their strong anti-cancer properties. Three novel cyclometalated iridium(III) compounds were synthesized and evaluated in five different cell lines as part of the ongoing systematic investigations of these compounds. The complexes were prepared using 4,7-dichloro-1,10-phenanthroline ligands. The cytotoxicity of complexes Ir1-Ir3 towards HeLa cells was shown to be high, with IC₅₀ values of 0.83±0.06, 4.73±0.11, and 4.95±0.62 μM, respectively. Complex Ir1 could be ingested by HeLa cells in 3 h and has shown high selectivity toward mitochondria. Subsequent investigations demonstrated that Ir1 triggered apoptosis in HeLa cells by augmenting the generation of reactive oxygen species (ROS), reducing the mitochondrial membrane potential, and depleting ATP levels. Furthermore, the movement of cells was significantly suppressed and the progression of the cell cycle was arrested in the G0/G1 phase following the administration of Ir1. The Western blot analysis demonstrated that the induction of apoptosis in HeLa cells by Ir1 involves the activation of the mitochondria-dependent channel and the PI3K/AKT signaling pathway. No significant cytotoxicity was observed in zebrafish embryos at concentrations less than or equal to 16 µM, e.g., survival rate and developmental abnormalities. In vivo, antitumor assay demonstrated that Ir1 suppressed tumor growth in mice. Therefore, our work shows that complex Ir1 could be a promising candidate for developing novel antitumor drugs. Show less

Title: In vitro and in vivo anticancer activity of novel Rh(III) and Pd(II) complexes with pyrazolopyrimidine derivatives. Abstract: Six pyrazolopyrimidine rhodium(III) or palladium(II) complexes, [Rh(L1)(H2O)Cl3] (1), [Rh(L2)(CH3OH)Cl3] (2), [Rh(L3)(H2O)Cl3] (3), [Rh2(L4)Cl6]·CH3OH (4), [Rh(L5)(CH3CN)Cl3]·0.5CH3CN (5), and [Pd(L5)Cl2] (6), were synthesized and characterized. These complexes showed high cytotoxicity against six tested cancer cell lines. Most of the complexes showed higher cytotoxicity to T-24 cells in vitro than cisplatin. Mechanism studies indicated that complexes 5 and 6 induced G2/M phase cell cycle arrest through DNA damage, and induced apoptosis via endoplasmic reticulum stress response. In addition, complex 5 also induced cell apoptosis via mitochondrial dysfunction. Complexes 5 and 6 showed low in vivo toxicity and high tumor growth inhibitory activity in mouse tumor models. The inhibitory effect of rhodium complex 5 on tumor growth in vivo was more pronounced than that of palladium complex 6. Show less

Title: Rhodium(III)-Picolinamide Complexes Act as Anticancer and Antimetastasis Agents via Inducing Apoptosis and Autophagy. Abstract: As a continuation of our endeavors in discovering metal-based drugs with cytotoxic and antimetastatic activities, herein, we reported the syntheses of 11 new rhodium(III)-picolinamide complexes and the exploration of their potential anticancer activities. These Rh(III) complexes showed high antiproliferative activity against the tested cancer cell lines in vitro. The mechanism study indicated that Rh1 ([Rh(3a)(CH3CN)Cl2]) and Rh2 ([Rh(3b)(CH3CN)Cl2]) inhibited cell proliferation by multiple modes of action via cell cycle arrest, apoptosis, and autophagy and inhibited cell metastasis via FAK-regulated integrin β1-mediated suppression of EGFR expression. Furthermore, Rh1 and Rh2 significantly inhibited bladder cancer growth and breast cancer metastasis in a xenograft model. These rhodium(III) complexes could be developed as potential anticancer agents with antitumor growth and antimetastasis activity. Show less

Ruthenium complexes with good biological properties have attracted increasing attention in recent decades. In this work, three ruthenium polypyridine complexes containing 5-fluorouracil derivatives as ligands, [Ru(bpy)₂(L)]²⁺ (Ru1), [Ru(phen)₂(L)]²⁺ (Ru2), [Ru(dip)₂(L)]²⁺ (Ru3) (L = 1-((1,10-phenanthroline-5-amino) pentyl)-5-fluorouracil; bpy = 2,2'-bipyridine; phen =1,10-phenanthroline; dip = 4,7-diphenyl-1,10-phenanthroline), were synthesized and characterized. Based on in vitro cytotoxicity tests, Ru3 (IC₅₀ = 7.35 ± 0.39 μM) showed the best anticancer activity among three compounds in the selected cell lines. It is worth noting that Ru3 also exerts less cytotoxicity on LO2 cell lines, with an IC₅₀ value 5 times higher than that on HeLa cells, indicating its selective activity. Mechanism studies revealed that Ru3 can specifically target lysosomes and induce cell apoptosis in a caspase-dependent manner. Specifically, Ru3 can arrest cell cycle at the G0/G1 phase, increase the intracellular reactive oxygen species (ROS) level, and then damage DNA. In short, Ru3 can eventually cause cell death through the synergy of inducing apoptosis and autophagy, which was further proven by western blot assay results. Show less

Targeting metabolic reprogramming to treat cancer could increase overall survival and reduce side effects. Here, we put forward a strategy using arene-ruthenium(II)/osmium(II) complexes to potentiate the anticancer effect of metformin (Met.) via glucose metabolism reprogramming. Complexes 1-6 with oxoglaucine derivatives as ligands were synthesized and their anti-tumor activities were tested under hypoglycemia. Results indicated that 2 and 5 potentiated the anticancer effects of Met. under hypoglycemia, exhibiting lower toxicity, slower blood glucose decline and inhibition of early tumor liver metastasis. Combination of 5 with Met. could be used as a new strategy to treat cancer under hypoglycemia through glucose metabolism reprogramming. Show less

Title: Ru(III) complexes with pyrazolopyrimidines as anticancer agents: bioactivities and the underlying mechanisms. Abstract: Three ruthenium(III) complexes with pyrazolopyrimidine [Ru(Ln)(H2O)Cl3] (1-3, n = 1-3) were prepared and characterized. These Ru(III) compounds show strong cytotoxicity against six cancer cell lines and low toxicity to normal human liver cells. Particularly, they exhibited stronger cytotoxicity to SK-OV-3 cells than cisplatin. Mechanism studies revealed that complex 1 inhibited tumor cell invasion and suppressed cell proliferation, induced apoptosis by elevating the levels of intracellular ROS (reactive oxygen species) and free calcium (Ca2+), and reduced mitochondrial membrane potential (ΔΨ). It also activated the caspase cascade, accompanied with upregulation of cytochrome c, Bax, p53, Apaf-1 and downregulation of Bcl-2. Moreover, complex 1 caused cell cycle arrest at S phase by inhibiting the expression of CDC 25, cyclin A2 and CDK 2 proteins, and induced DNA damage by interacting with DNA and inhibiting the topoisomerase I enzyme. Complex 1 exhibited efficient in vivo anticancer activity in a model of SK-OV-3 tumor xenograft. Show less

Title: Rhenium-guanidine complex as photosensitizer: trigger HeLa cell apoptosis through death receptor-mediated, mitochondria-mediated, and cell cycle arrest pathways. Abstract: The growing evidence over the past few decades has indicated that the photodynamic antitumor activity of transition metal complexes, and Re(I) compounds are potential candidates for photodynamic therapy. This study reports the synthesis, characterization, and anti-tumor activity of three new Re(I)-guadinium complexes. Cytotoxicity tests reveal that complex Re1 increased cytotoxicity by 145-fold from IC50 > 180 μM in the dark to 1.3 ± 0.7 μM following 10 min of light irradiation (425 nm) in HeLa cells. Further, the mechanism by which Re1 induces apoptosis in the presence or absence of light irradiation was investigated, and results indicate that cell death was caused through different pathways. Upon irradiation, Re1 first accumulates on the cell membrane and interacts with death receptors to activate the extrinsic death receptor-mediated signaling pathway, and then is transported into the cell cytoplasm. Most of the intracellular Re1 locates within mitochondria, improving the reactive oxygen species level, and decreasing mitochondrial membrane potential and ATP levels, and inducing the activation of caspase-9 and, thus, apoptosis. Subsequently, the residual Re1 can translocate into the cell nucleus, and activates the p53 pathway, causing cell cycle arrest and eventually cell death. Show less

The photophysical and biological properties of two new phenanthroline-based ligand ruthenium complexes were investigated in detail. Their DNA interaction modes were determined to be the intercalation mode using spectra titration and viscosity measurements. Under irradiation, obvious photo-reduced DNA cleavages were observed in the two complexes via singlet oxygen generation. Furthermore, complex 2 showed higher DNA affinity, photocleavage activity, and singlet oxygen quantum yields than complex 1. The two complexes showed no toxicity towards tumor cells (HeLa, A549, and A375) in the dark. However, obvious photocytotoxicities were observed in the two complexes. Complex 2 exhibited large PIs (phototherapeutic indices) (ca. 400) towards HeLa cells. The study suggests that these complexes may act as DNA intercalators, DNA photocleavers, and photocytotoxic agents. Show less

Alpha lipoic acid (LA) is a natural compound and coenzyme with sufficient safety information for serving as a promising anticancer agent. To further clarify the mechanism of action (MoA), two Ir(iii) complexes with the functionalized α-lipoic acid (N^∧N-LA, N^∧N, 2,2-bipyridine derivative), namely Ir1 and Ir2, were synthesized, where Ir1 possessed a half-sandwich structure with the formula [Ir(Cp*)(N^∧N-LA)Cl]PF₆ (Cp* = 1,2,3,4,5-pentamethyl-cyclopentadiene) and Ir2 possessed the cyclometalated structure with the formula [Ir(C^∧N)₂(N^∧N-LA)]PF₆ (C^∧N = 2-phenylpyridine). Even though both complexes were constructed based on the same N^∧N-LA ligand, Ir1 showed no cytotoxicity (IC₅₀ > 200 μM), which was due to its low lipophilicity for hard penetration into the cancer cells, easy hydrolysis, and reaction with GSH. Ir2 exhibited excellent cytotoxicity (IC₅₀ = 3.43-6.74 μM) toward diverse cancer cell lines in vitro and a promising ability to overcome the cisplatin-resistance in A549R cells. The anticancer mechanism of Ir2 in A549 cells was investigated in detail, and it was found it could localize and accumulate in the lysosomes of A549 cells, induce ROS, arrest the cycle at G₀/G₁, and lead to cell death by autophagy. Comparison with Ir-NH₂ ([Ir(C^∧N)₂(N^∧N-NH₂)]PF₆) demonstrated that introduction of the LA ligand to Ir2 could highly enhance the cytotoxicity and help to overcome the cisplatin-resistance. This study of the half-sandwich and cyclometalated Ir(iii)-based anticancer agents highlighted the different MoAs toward cancer cells and provided new insights for understanding their structure-property relationships. 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