Charge Transfer-Promoted Excited State of a Heavy-Atom-Free Photosensitizer for Efficient Application of Mitochondria-Targeted Fluorescence Imaging and Hypoxia Photodynamic Therapy.

Conventional photosensitizers (PSs) used in photodynamic therapy (PDT) have shown preliminary success; however, they are often associated with several limitations including potential dark toxicity in healthy tissues, limited efficacy under acidic and hypoxic conditions, suboptimal fluorescence imaging capabilities, and nonspecific targeting during treatment. In response to these challenges, we developed a heavy-atom-free PS, denoted as Cz-SB, by incorporating ethyl carbazole into a thiophene-fused BODIPY core. A comprehensive investigation into the photophysical properties of Cz-SB was conducted through a synergistic approach involving experimental and computational investigations. The enhancement of intersystem crossing (kISC) and fluorescence emission (kfl) rate constants was achieved through a donor-acceptor pair-mediated charge transfer mechanism. Consequently, Cz-SB demonstrated remarkable efficiency in generating reactive oxygen species (ROS) under acidic and low-oxygen conditions, making it particularly effective for hypoxic cancer PDT. Furthermore, Cz-SB exhibited good biocompatibility, fluorescence imaging capabilities, and a high degree of localization within the mitochondria of living cells. We posit that Cz-SB holds substantial prospects as a versatile PS with innovative molecular design, representing a potential "one-for-all" solution in the realm of cancer phototheranostics.

Design, Synthesis, and Pharmacological Evaluation of Spiro[carbazole-3,3'-pyrrolidine] Derivatives as cGAS Inhibitors for Treatment of Acute Lung Injury.

Overactivation of cyclic GMP-AMP synthase (cGAS) is implicated in the occurrence of many inflammatory and autoimmune diseases, and inhibition of cGAS with a specific inhibitor has been proposed as a potential therapeutic strategy. However, only a few low-potency cGAS inhibitors have been reported, and few are suitable for clinical investigation. As a continuation of our structural optimization on the reported cGAS inhibitor 6 (G140), we developed a series of spiro[carbazole-3,3'-pyrrolidine] derivatives bearing a unique 2-azaspiro[4.5]decane structural motif, among which compound 30d-S was identified with high cellular effects against cGAS. This compound showed improved plasma exposure, lower clearance, and an oral bioavailability of 35% in rats. Moreover, in the LPS-induced acute lung injury (ALI) mice model, oral administration of compound 30d-S at 30 mg/kg markedly reduced lung inflammation and alleviated histopathological changes. These results confirm that 30d-S is a new efficacious cGAS inhibitor and is worthy of further investigation.

Carbazole and Quinazolinone Derivatives from a Fluoride-Tolerant Streptomyces Strain OUCMDZ-5511.

Six new 9H-carbazole derivatives (1-6) and nine previously reported compounds (7-15) were isolated from a fermented solid medium of the Thailand mangrove-derived Streptomyces strain, OUCMDZ-5511, under fluoride stress. Compounds 2-5, 12, and 15 were exclusively present in the fluoride-supplemented fermentation medium, while compounds 7-9, 13, and 14 were newly discovered natural products. The molecular structures of the compounds were identified by a spectroscopic analysis. The new compound 2 displayed antiquorum sensing activity against Chromobacterium violaceum ATCC 12472 by reducing the violacein production and inhibiting the biofilm formation in a concentration-dependent manner. The study revealed that compound 2 could be a novel potential inhibitor of quorum sensing.

Facile synthesis of 2-hydroxy-ß-cyclodextrin/polyacrylamide/carbazole hydrogel and its application for the treatment of infected wounds in a murine model.

This work aimed to synthesize hydrogels by combining carbazole (Carb) with 2-hydroxy, ß-cyclodextrin (HPßCD)/polyacrylamide (PAA) hybrid complexes. The hydrogels were then evaluated for their potential use in treating infected wounds. The physicochemical structures of the preparations were evaluated using several characterization methods including FTIR, FESEM, EDX, XRD, pH sensitivity, and TGA. Moreover, In vitro release, toxicity, antibacterial activity and in vivo infected wound healing activity were evaluated. Physicochemical testing verified the effective synthesis of the preparations and the timely release of Carb. The P(AA-co-AM)/HPßCD material exhibited an open structure characterized by macroscopic voids, whereas the hydrogels displayed surfaces that were not uniform. The FTIR analysis revealed the creation of a novel polymeric hydrogel composed of HPßCD as the main polymer structure. The hydrogels exhibited good reversible swelling and recoverable deformation, with an optimal swelling ratio of 30.12 achieved at pH 7.4. The antibacterial and safety of the formulations were validated by in vitro studies. ß.Dex/PAA/Carb hydrogels have been shown to effectively expedite the healing of infected wounds by promoting the production of CD31, FGF-2, and COL1A, while reducing the levels of ROS, CD68, COX-2, and NF-κB. Overall, the combination of Carb, ß.Dex, and PAA molecules had a synergistic impact on the healing process of infected wounds.

Overcoming Solubility Challenges: Liposomal isoCoQ-Carbazole as a Promising Anti-Tumor Agent for Inoperable and Radiation-Insensitive cancers.

This study evaluated the potential of isoCoQ-Carbazole, a diheterocyclic analog of isoCA-4, as an anti-tumor agent. To overcome its low aqueous solubility, liposomes were developed as a delivery system for the compound. In vitro experiments showed that loaded liposomes exhibited similar activity to the free form on multiple human tumor cell lines. In vivo experiments using a palliative intratumoral injection chemotherapy approach further demonstrated that isoCoQ-Carbazole loaded liposomes significantly reduced tumor growth in a CA-4-resistant HT29 cell model, without inducing any observable toxicity or weight loss in the treated mice. These findings suggest that liposomal isoCoQ-Carbazole may hold promise as a potential therapeutic agent for the treatment of inoperable, radiation-insensitive cancers.

Generation of streptocarbazoles with cytotoxicities by pathway engineering and insights into their biosynthesis.

Streptocarbazoles are a class of indolocarbazole (ICZ) compounds produced by Streptomyces strains that feature unique cyclic N-glycosidic linkages between the 1,3-carbon atoms of the glycosyl moiety and the two indole nitrogen atoms. Although several streptocarbazole compounds display effective cytotoxic activity, their biosynthesis remains unclear. Herein, through the inactivation of the aminotransferase gene spcI in the staurosporine biosynthetic gene cluster spc followed by heterologous expression, two new streptocarbazole derivatives (1 and 3) and three known ICZs (2, 4, and 5) were generated. Their structures were determined by a combination of spectroscopic methods, circular dichroism measurements, and single-crystal X-ray diffraction. Compounds 1-4 displayed moderate cytotoxicity against HCT-116 cell line, and compounds 3 and 4 were effective against Huh 7 cell line. Double-gene knockout experiments allowed us to propose a biosynthetic pathway for streptocarbazole productions. Furthermore, by overexpression of the involving key enzymes, the production of streptocarbazoles 1 and 3 were improved by approximately 1.5-2.5 fold. IMPORTANCE: Indolocarbazoles (ICZs) are a group of antitumor agents, with several analogs used in clinical trials. Therefore, the identification of novel ICZ compounds is important for drug discovery. Streptocarbazoles harbor unique N-glycosidic linkages (N13-C1' and N12-C3'), distinguishing them from the representative ICZ compound staurosporine; however, their biosynthesis remains unclear. In this study, two new streptocarbazoles (1 and 3) with cytotoxic activities were obtained by manipulating the staurosporine biosynthetic gene cluster spc followed by heterologous expression. The biosynthetic pathway of streptocarbazoles was proposed, and their productions were improved through the overexpression of the key enzymes involved. This study enriches the structural diversity of ICZ compounds and would facilitate the discovery of new streptocarbazoles via synthetic biological strategies.

6-Formylindolo[3,2-b]carbazole, a potent ligand for the aryl hydrocarbon receptor, attenuates concanavalin-induced hepatitis by limiting T-cell activation and infiltration of proinflammatory CD11b+ Kupffer cells.

FICZ (6-formylindolo[3,2-b]carbazole) is a potent aryl hydrocarbon receptor agonist that has a poorly understood function in the regulation of inflammation. In this study, we investigated the effect of aryl hydrocarbon receptor activation by FICZ in a murine model of autoimmune hepatitis induced by concanavalin A. High-throughput sequencing techniques such as single-cell RNA sequencing and assay for transposase accessible chromatin sequencing were used to explore the mechanisms through which FICZ induces its effects. FICZ treatment attenuated concanavalin A-induced hepatitis, evidenced by decreased T-cell infiltration, decreased circulating alanine transaminase levels, and suppression of proinflammatory cytokines. Concanavalin A revealed an increase in natural killer T cells, T cells, and mature B cells upon concanavalin A injection while FICZ treatment reversed the presence of these subsets. Surprisingly, concanavalin A depleted a subset of CD55+ B cells, while FICZ partially protected this subset. The immune cells showed significant dysregulation in the gene expression profiles, including diverse expression of migratory markers such as CCL4, CCL5, and CXCL2 and critical regulatory markers such as Junb. Assay for transposase accessible chromatin sequencing showed more accessible chromatin in the CD3e promoter in the concanavalin A-only group as compared to the naive and concanavalin A-exposed, FICZ-treated group. While there was overall more accessible chromatin of the Adgre1 (F4/80) promoter in the FICZ-treated group, we observed less open chromatin in the Itgam (CD11b) promoter in Kupffer cells, supporting the ability of FICZ to reduce the infiltration of proinflammatory cytokine producing CD11b+ Kupffer cells. Taken together, these data demonstrate that aryl hydrocarbon receptor activation by FICZ suppresses liver injury through the limitation of CD3+ T-cell activation and CD11b+ Kupffer cell infiltration.

Inflammation-related molecular signatures involved in the anticancer activities of brigatinib as well as the prognosis of EML4-ALK lung adenocarcinoma patient.

Although ALK tyrosine kinase inhibitors (ALK-TKIs) have shown remarkable benefits in EML4-ALK positive NSCLC patients compared to conventional chemotherapy, the optimal sequence of ALK-TKIs treatment remains unclear due to the emergence of primary and acquired resistance and the lack of potential prognostic biomarkers. In this study, we systematically explored the validity of sequential ALK inhibitors (alectinib, lorlatinib, crizotinib, ceritinib and brigatinib) for a heavy-treated patient with EML4-ALK fusion via developing an in vitro and in vivo drug testing system based on patient-derived models. Based on the patient-derived models and clinical responses of the patient, we found that crizotinib might inhibit proliferation of EML4-ALK positive tumors resistant to alectinib and lorlatinib. In addition, NSCLC patients harboring the G1269A mutation, which was identified in alectinib, lorlatinib and crizotinib-resistant NSCLC, showed responsiveness to brigatinib and ceritinib. Transcriptomic analysis revealed that brigatinib suppressed the activation of multiple inflammatory signaling pathways, potentially contributing to its anti-tumor activity. Moreover, we constructed a prognostic model based on the expression of IL6, CXCL1, and CXCL5, providing novel perspectives for predicting prognosis in EML4-ALK positive NSCLC patients. In summary, our results delineate clinical responses of sequential ALK-TKIs treatments and provide insights into the mechanisms underlying the superior effects of brigatinib in patients harboring ALKG1269A mutation and resistant towards alectinib, lorlatinib and crizotinib. The molecular signatures model based on the combination of IL6, CXCL1 and CXCL5 has the potential to predict prognosis of EML4-ALK positive NSCLC patients.

Palindromic carbazole derivatives: unveiling their antiproliferative effect via topoisomerase II catalytic inhibition and apoptosis induction.

Human DNA topoisomerases are essential for crucial cellular processes, including DNA replication, transcription, chromatin condensation, and maintenance of its structure. One of the significant strategies employed in cancer treatment involves the inhibition of a specific type of topoisomerase, known as topoisomerase II (Topo II). Carbazole derivatives, recognised for their varied biological activities, have recently become a significant focus in oncological research. This study assesses the efficacy of three symmetrically substituted carbazole derivatives: 2,7-Di(2-furyl)-9H-carbazole (27a), 3,6-Di(2-furyl)-9H-carbazole (36a), and 3,6-Di(2-thienyl)-9H-carbazole (36b) - as anticancer agents. Among investigated carbazole derivatives, compound 3,6-di(2-furyl)-9H-carbazole bearing two furan moieties emerged as a novel catalytic inhibitor of Topo II. Notably, 3,6-di(2-furyl)-9H-carbazole effectively selectively inhibited the relaxation and decatenation activities of Topo IIα, with minimal effects on the IIß isoform. These findings underscore the potential of compound 3,6-Di(2-furyl)-9H-carbazole as a promising lead candidate warranting further investigation in the realm of anticancer drug development.

6-formylindolo[3, 2-b]carbazole alters gut microbiota and prevents the progression of ankylosing spondylitis in mice.

Ankylosing spondylitis (AS), is known as a chronic inflammatory autoimmune disease, there is evidence to suggest that gut microbiota disorders may be related to the occurrence and development of AS. Studies have shown that 6-formylindolo[3, 2-b]carbazole (FICZ) has the ability to modulate intestinal homeostasis and inhibit inflammatory responses. The purpose of this work is to evaluate the protective role of FICZ in treating AS and elucidate potential mechanisms. FICZ was administered to the proteoglycan (PG)-induced AS mice for 7 consecutive weeks. The effects of FICZ on AS mice were evaluated by the disease severity, intestinal histopathology, proinflammatory cytokine levels, and intestinal mucosal barrier function. The gut microbiota compositions were profiled through 16S rDNA high-throughput sequencing. We found that FICZ significantly reduced the severity of AS and resulted in the downregulating of TNF-α and IL-17A inflammatory cytokines. Moreover, FICZ ameliorated pathological changes in the ileal and improved intestinal mucosal barrier function. Furthermore, FICZ altered the composition of the gut microbiota by increasing the Bacteroidetes/Firmicutes phylum ratio and enriched the genes related to "glycan biosynthesis and metabolism", thus reversing the process of AS. In conclusion, FICZ suppressed the progression of AS and altered gut microbiota in AS mice, which provided new insight into AS therapy strategy.

A novel fluorescent probe based on carbazole-thiophene for the recognition of hypochlorite and its applications.

A carbazole thiophene-aldehyde and 4-methylbenzenesulfonhydrazide conjugate CSH was synthesized by introducing 5-thiophene aldehyde at the 3-position of the carbazole group as the precursor and then condensing it with 4-methylbenzenesulfonhydrazide. CSH has high selectivity and sensitivity towards ClO-, which can specifically identify ClO- by UV-Vis and fluorescence spectroscopy. CSH can rapidly respond to ClO- in the physiological pH range through a fluorescence quenching pattern, accompanied by the color of CSH changing markedly from turquoise to yellowish green under the 365 nm UV light. Probe CSH exhibits a quantitative response to ClO- (0-11 µM) with a low detection limit (1.16 × 10-6 M). Cell imaging experiments have shown that CSH can capture fluorescent signals in the cyan and yellow channels of HeLa cells through fluorescence confocal microscopy, and can successfully identify exogenous ClO- in HeLa cells. In addition, probe CSH can also be used to detect ClO- in environmental water samples. These results indicate that CSH has potential application prospects in the environmental analysis and biological aspects.

Carbazole derivatives as promising competitive and allosteric inhibitors of human serotonin transporter: computational pharmacology.

The human serotonin transporters (hSERTs) are neurotransmitter sodium symporters of the aminergic G protein-coupled receptors, regulating the synaptic serotonin and neuropharmacological processes related to neuropsychiatric disorders, notably, depression. Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine and (S)-citalopram are competitive inhibitors of hSERTs and are commonly the first-line medications for major depressive disorder (MDD). However, treatment-resistance and unpleasant aftereffects constitute their clinical drawbacks. Interestingly, vilazodone emerged with polypharmacological (competitive and allosteric) inhibitions on hSERTs, amenable to improved efficacy. However, its application usually warrants adjuvant/combination therapy, another subject of critical adverse events. Thus, the discovery of alternatives with polypharmacological potentials (one-drug-multiple-target) and improved safety remains essential. In this study, carbazole analogues from chemical libraries were explored using docking and molecular dynamics (MD) simulation. Selectively, two IBScreen ligands, STOCK3S-30866 and STOCK1N-37454 predictively bound to the active pockets and expanded boundaries (extracellular vestibules) of the hSERTs more potently than vilazodone and (S)-citalopram. For instance, the two ligands showed docking scores of -9.52 and -9.59 kcal/mol and MM-GBSA scores of -92.96 and -65.66 kcal/mol respectively compared to vilazodone's respective scores of -7.828 and -59.27 against the central active site of the hSERT (PDB 7LWD). Similarly, the two ligands also docked to the allosteric pocket (PDB 5I73) with scores of -8.15 and -8.40 kcal/mol and MM-GBSA of -96.14 and -68.46 kcal/mol whereas (S)-citalopram has -6.90 and -69.39 kcal/mol respectively. The ligands also conferred conformational stability on the receptors during 100 ns MD simulations and displayed interesting ADMET profiles, representing promising hSERT modulators for MDD upon experimental validation.Communicated by Ramaswamy H. Sarma.

Computational molecular perspectives on novel carbazole derivative as an anti-cancer molecule against CDK1 of breast and colorectal cancers via gene expression studies, novel two-way docking strategies, molecular mechanics and dynamics.

With increase in cancer incidences, alternative strategies for disease management are of utmost importance. Carbazole, is a compound that is being studied extensively as an anti-cancer compound. In this work, we aimed to investigate a carbazole derivative against specific cancer types such as breast and colorectal, based on the off-target analyses of carbazole derivative. The present work shortlisted 6 proteins that have an association in both cancer types, and then employed two different molecular docking strategies to examine the binding stability of carbazole derivative: a blind-docking state, where the pockets were undefined and mutation-docking state, where possible mutations were induced within the proteins. The results showed that CDK1 bound best in both states to carbazole derivative, and performed better than an array of positive controls. Molecular dynamic simulations at 100 ns further proved its stability, with carbazole derivative-CDK1-blind and mutated complex having RMSD values between 3.2 and 3.6 Å, and 2.8-3.2 Šrespectively. Molecular-mechanics generalized born and surface area solvation disclosed free energy of binding for the complexes as -28.79 ± 3.97 kcal/mol and -31.86 ± 5.09 kcal/mol respectively, with carbazole derivative bound stably within the binding pocket at every 10 ns of the 100 ns trajectory. Radial distribution functions showed that the bell curve was well within 6 Å, thus showing that carbazole derivative and its atoms do not deviate away from the pocket, suggesting its ability to be used as a good anti-cancer compound against breast and colorectal.

Discovery of a far-red carbazole-benzoindolium fluorescent ligand that selectively targets mitochondrial DNA and suppresses breast cancer growth.

G-quadruplex (G4) formation was considered to be more prevalent in the mitochondrial DNA (mtDNA) of cancer cells compared with normal cells. Stabilization of these G4s may induce mtDNA instability and cause mitochondrial dysfunction and subsequent cell death, which may be treated as a new strategy for cancer treatment. However, few ligands were developed to target mtG4s, leaving a huge room to improve. In this study, we designed and synthesized a series of carbazole-based ligands, among which, BKN-1 was identified as the most promising mitochondrial targeting fluorescent ligand with far-red emission. Then, we demonstrated that BKN-1 may robustly interact with mtG4s via a variety of biophysical, biological experiments. Subsequently, we proved that BKN-1 may cause mtDNA loss, disrupt mitochondrial integrity, decrease ATP level and trigger unbalanced ROS, thereby leading to apoptosis and autophagy. Finally, we verified that BKN-1 had good anti-tumor activity in both cellular and in vivo models. Altogether, this study provided a dual-function ligand that may not only track the formation of mtG4s but also induce mitochondrial dysfunction, which may be developed into an applicable chemical tool for investigating the structure and function of mtG4s, and moreover, an effective therapeutic agent for cancer interference.

Acquired resistance to crizotinib in novel CDK14-ALK and CLTC-ALK fusions of ALK-positive large B-cell lymphoma identified by next-generation sequencing.

Anaplastic lymphoma kinase-positive large B-cell lymphoma (ALK+ LBCL) is a rare subtype of non-Hodgkin lymphoma. ALK inhibitors are being tried to treat recurrent/refractory ALK+ LBCL. A majority of patients with ALK+ tumors respond to crizotinib, but partial cases ultimately develop resistance about a year later. Here, we report a case of ALK+ LBCL carrying a new fusion gene involving CDK14 and ALK, CLTC-ALK gene rearrangements and MTOR gene mutation. The patient had progressive disease after combination of crizotinib and chemotherapy treatment about 5.5 months later, accompanied by reduced abundance of CDK14-ALK, increased abundance of CLTC-ALK and a novel MFHAS1 gene mutation. However, MTOR mutation turned negative. The patient received alectinib combined with hyper-CVAD, then followed by alectinib as monotherapy for 21 months. The patient achieved partial response and remained in a stable condition. This case suggests that CDK14-ALK fusion gene may be more sensitive to crizotinib than CLTC-ALK fusion gene. MTOR is associated with the anti-tumor mechanism of ALK inhibitors. MFHAS1 gene mutation and/or CLTC-ALK gene copy number amplification may involve resistance to crizotinib. Furthermore, alectinib may inhibit the carcinogenicity of these gene changes and improve the prognosis of ALK+ LBCL.

The novel CDK14-ALK fusion gene in ALK+ LBCL was sensitive to crizotinib.MFHAS1 gene mutation and/or CLTC-ALK gene copy number amplification may involve resistance to crizotinib.

Repurposing anti-inflammatory drugs for fighting planktonic and biofilm growth. New carbazole derivatives based on the NSAID carprofen: synthesis, in silico and in vitro bioevaluation.

Introduction: One of the promising leads for the rapid discovery of alternative antimicrobial agents is to repurpose other drugs, such as nonsteroidal anti-inflammatory agents (NSAIDs) for fighting bacterial infections and antimicrobial resistance. Methods: A series of new carbazole derivatives based on the readily available anti-inflammatory drug carprofen has been obtained by nitration, halogenation and N-alkylation of carprofen and its esters. The structures of these carbazole compounds were assigned by NMR and IR spectroscopy. Regioselective electrophilic substitution by nitration and halogenation at the carbazole ring was assigned from H NMR spectra. The single crystal X-ray structures of two representative derivatives obtained by dibromination of carprofen, were also determined. The total antioxidant capacity (TAC) was measured using the DPPH method. The antimicrobial activity assay was performed using quantitative methods, allowing establishment of the minimal inhibitory/bactericidal/biofilm eradication concentrations (MIC/MBC/MBEC) on Gram-positive (Staphylococcus aureus, Enterococcus faecalis) and Gram-negative (Escherichia coli, Pseudomonas aeruginosa) strains. Computational assays have been performed to assess the drug- and lead-likeness, pharmacokinetics (ADME-Tox) and pharmacogenomics profiles. Results and discussion: The crystal X-ray structures of 3,8-dibromocarprofen and its methyl ester have revealed significant differences in their supramolecular assemblies. The most active antioxidant compound was 1i, bearing one chlorine and two bromine atoms, as well as the CO2Me group. Among the tested derivatives, 1h bearing one chlorine and two bromine atoms has exhibited the widest antibacterial spectrum and the most intensive inhibitory activity, especially against the Gram-positive strains, in planktonic and biofilm growth state. The compounds 1a (bearing one chlorine, one NO2 and one CO2Me group) and 1i (bearing one chlorine, two bromine atoms and a CO2Me group) exhibited the best antibiofilm activity in the case of the P. aeruginosa strain. Moreover, these compounds comply with the drug-likeness rules, have good oral bioavailability and are not carcinogenic or mutagenic. The results demonstrate that these new carbazole derivatives have a molecular profile which deserves to be explored further for the development of novel antibacterial and antibiofilm agents.

EGFR suppression contributes to growth inhibitory activity of G-quadruplex ligands in non-small cell lung cancers.

Non-small cell lung carcinomas (NSCLCs) commonly harbor activating mutations in the epidermal growth factor receptor (EGFR). Drugs targeting the tyrosine kinase activity of EGFR have shown effectiveness in inhibiting the growth of cancer cells with EGFR mutations. However, the development of additional mutations in cancer cells often leads to the persistence of the disease, necessitating alternative strategies to overcome this challenge. We explored the efficacy of stabilizing the G-quadruplex structure formed in the promoter region of EGFR as a means to suppress its expression and impede the growth of cancer cells with EGFR mutations. We revealed that the carbazole derivative BMVC-8C3O effectively suppressed EGFR expression and demonstrated significant growth inhibition in EGFR-mutated NSCLC cells, both in cell culture and mouse xenograft models. Importantly, the observed repression of EGFR expression and growth inhibition were not exclusive to carbazole derivatives, as several other G-quadruplex ligands exhibited similar effects. The growth-inhibitory activity of BMVC-8C3O is attributed, at least in part, to the repression of EGFR, although it is possible that additional cellular targets are also affected. Remarkably, the growth-inhibitory effect was observed even in osimertinib-resistant cells, indicating that BMVC-8C3O holds promise for treating drug-resistant NSCLC. Our findings present a promising and innovative approach for inhibiting the growth of NSCLC cells with EGFR mutations by effectively suppressing EGFR expression. The demonstrated efficacy of G-quadruplex ligands in this study highlights their potential as candidates for further development in NSCLC therapy.

Photophysical Exploration of Alectinib and Rilpivirine: Insights from Theory and Experiment.

Due to the excellent characteristics of fluorescence-based imaging, such as non-invasive detection of biomarkers in vitro and in vivo with high sensitivity, good spatio-temporal resolution and fast response times, it has shown significant prospects in various applications. Compounds with both biological activities and fluorescent properties have the potential for integrated diagnosis and treatment application. Alectinib and Rilpivirine are two excellent drugs on sale that represent a clinically approved targeted therapy for ALK-rearranged NSCLC and have exhibited more favorable safety and tolerance profiles in Phase III clinical trials, ECHO and THRIVE, respectively. The optical properties of these two drugs, Alectinib and Rilpivirine, were deeply explored, firstly through the simulation of molecular structures, electrostatic potential, OPA/TPA and emission spectral properties and experiments on UV-vis spectra, fluorescence and cell imaging. It was found that Alectinib exhibited 7.8% of fluorescence quantum yield at the 450 nm excited wavelength, due to a larger electronic transition dipole moment (8.41 Debye), bigger charge transition quantity (0.682 e) and smaller reorganization energy (2821.6 cm-1). The stronger UV-vis spectra of Rilpivirine were due to a larger electron-hole overlap index (Sr: 0.733) and were also seen in CDD plots. Furthermore, Alectinib possessed obvious active two-photon absorption properties (δmaxTPA* ϕ = 201.75 GM), which have potential TPA imaging applications in bio-systems. Lastly, Alectinib and Rilpivirine displayed green fluorescence in HeLa cells, suggesting the potential ability for biological imaging. Investigation using theoretical and experimental methods is certainly encouraged, given the particular significance of developing integrated diagnosis and treatment.