Docetaxel (DTX) is the preferred chemotherapeutic drug for prostate cancer (Pca), but the emergence of resistance has significantly reduced its efficacy. Polyphyllin VII (PPVII), a small molecule natural product derived from the traditional herb Paris polyphylla, has shown anticancer potential. This study aims to investigate the effects and mechanisms of PPVII combined with DTX in treating Pca. DTX-sensitive DU-145 cells and DTX-resistant DU145/DTX cells were utilized for experiments in this study. Cell viability was assessed using MTT assays, while apoptosis, cell cycles, and ferroptosis were analyzed through flow cytometry and Western blot. Mitochondrial function was evaluated using immunofluorescence. Additionally, the expression of proteins related to the AMP-activated protein kinase/mammalian target of the rapamycin/S6 kinase (AMPK/mTOR/S6K) signaling pathway was also examined to further investigate the underlying mechanisms. PPVII significantly enhanced the inhibitory effect of DTX, reduced cell viability (p < 0.05), and promoted apoptosis (p < 0.05) and cell cycle arrest (p < 0.05). Specifically, PPVII increased the sensitivity of Pca cells to DTX by inducing ferroptosis and affecting mitochondrial function. Notably, the activation of the AMPK/mTOR/S6K signaling pathway played a crucial role in this process. This study revealed the synergistic effects and potential mechanisms of PPVII combined with DTX in Pca cells, and provided a reference for effectively overcoming DTX resistance in the clinical treatment of Pca.

Cerebral ischemia/reperfusion injury (IRI) is pathologically associated with ferroptosis. Dexmedetomidine (Dex) exerts neuroprotective activity after cerebral IRI. Our work focused on probing the pharmacologic effect of Dex on ferroptosis during cerebral IRI and the mechanisms involved. Cerebral IRI models were established by oxygen-glucose deprivation/reoxygenation (OGD/R) and middle cerebral artery occlusion (MCAO). 2,3,5-Triphenyltetrazolium chloride (TTC) staining was utilized to detect cerebral infarct size and mNSS was performed to evaluate neurologic deficits. Brain pathologic changes were analyzed by HE staining. Lipid peroxidation level was detected by C11-BODIPY staining, and Fe and MDA levels were measured using the kits. Cell vitality was examined by CCK-8 assay. Dual-luciferase reporter and ChIP assays were adopted to determine the interaction between SOX9 and DMT1 promoter. Dex ameliorated ferroptosis and neuronal death induced by MCAO and OGD/R. SOX9 upregulation abolished the inhibitory effect of Dex on OGD/R-induced ferroptosis and neuronal death in SH-SY5Y cells. Our further trials showed that SOX9 transcriptionally activated DMT1 expression. As expected, DMT1 overexpression prevented Dex-induced decrease in ferroptosis and neuronal death in OGD/R-treated SH-SY5Y cells. Dex inhibited ferroptosis to exert neuroprotection effects on cerebral IRI by inactivating the SOX9/DMT1 axis.

Oxadiazole compounds are of great interest because they have a range of biological activities ranging from antioxidants to anticancer agents. Against this background, we wanted to demonstrate the antioxidant, enzyme inhibitory, and anticancer effects of 5(4-hydroxyphenyl)-2-(N-phenylamino)-1,3,4-oxadiazole (Hppo). Antioxidant abilities were measured through free radical scavenging and reducing power tests. Enzyme inhibitory effects were studied by cholinesterases, tyrosinase, amylase, and glucosidase. The anticancer effect was tested on pancreatic cancer cell lines (PANC-1, CRL-169) and on HEK293 cell lines. The compound showed significant antioxidant activity (particularly in the CUPRAC (cupric acid-reducing antioxidant capacity) assay) and enzyme inhibitory properties (particularly glucosidase inhibition). In the anticancer test, the compound showed strong anticancer activity in pancreatic cancer with apoptotic signaling pathways. These results were confirmed by molecular modeling and bioinformatics tools. Thus, our findings can provide novel and versatile compounds for the development of multidirectional drugs in the pharmaceutical industry.

Hepatocellular carcinoma (HCC) presents an escalating public health challenge globally. However, drug resistance has emerged as a major impediment to successful HCC treatment, limiting the efficacy of curative interventions. Despite numerous investigations into the diverse impacts of hsa-miR-125a-5p on tumor growth across different cancer types, its specific involvement in chemotherapy resistance in HCC remains elusive. Our study aims to explore the potential involvement of hsa-miR-125a-5p in HCC drug resistance using HA22T cell lines: HA22T and HA22T-HDACi-resistance cells. The HA22T-HDACi-resistance cell line is an established liver cancer cell line that is resistant to histone deacetylase inhibitors (HDACi), apicidin, and suberoylanilide hydroxamic acid (SAHA). Utilizing qPCR, the levels of hsa-miR-125a-5p showed a notable decrease in the HA22T-HDACi-resistance cell line compared with HA22T cells. Subsequently, we examined the influence of hsa-miR-125a-5p expression on cell death in both cell lines. The findings demonstrated that alterations in hsa-miR-125a-5p levels directly impacted apoptosis in both HA22T and HA22T-HDACi-resistance cell lines with SAHA treatment. Afterwards, we recognized TRAF6 as a target gene of hsa-miR-125a-5p, shedding light on its potential role in modulating apoptosis via targeting TRAF6 in HCC. These findings underscore the potential significance of hsa-miR-125a-5p in overcoming drug resistance in HCC, offering insights into its dual role in apoptosis modulation and TRAF6 targeting. The study suggests that hsa-miR-125a-5p may inhibit expression of TRAF6 in HCC, presenting a promising avenue for gene therapy in HCC with HDACi resistance.

A new series of 13 ritonavir-like inhibitors of human drug-metabolizing CYP3A4 was rationally designed to study the R side-group and R end-group interplay when the R side-group is represented by phenyl. Spectral, functional, and structural characterization showed no improvement in the binding affinity and inhibitory potency of R/R-phenyl inhibitors upon elongation and/or fluorination of R-Boc (tert-butyloxycarbonyl) or its replacement with benzenesulfonyl. When R is pyridine, the impact of R-phenyl-to-indole/naphthalene substitution was multidirectional and highly dependent on side-group stereo configuration. Overall, the R-naphthalene/R-pyridine containing 2f (R/S) was the series lead compound and one of the strongest binders/inhibitors designed thus far (K = 0.009 μM; IC = 0.10 μM). Introduction of a larger biphenyl or fluorene as R did not lead to any improvements. Contrarily, fluorene-containing 13 was the series weakest binder and inhibitor (K = 0.734 μM; IC = 1.32 μM), implying that the fluorene moiety is too large to allow unrestricted access to the active site. The R-biphenyl, however, can switch positions with R-Boc to enable heme ligation. Thus, for small and chemically simple end-groups such as Boc and pyridine, the R/R interplay could lead to conformational rearrangement that would be difficult to foresee without structural information.

A set of coumarin-3-carboxamide analogues were designed, synthesized, and evaluated for their ability to impede pancreatic lipase (PL) activity. Out of all the analogues, 5dh and 5de demonstrated promising inhibitory activity against PL, as indicated by their respective IC values of 9.20 and 11.4 μM, as compared to Orlistat (IC = 0.97 μM). It was found that analogue 5dh inhibited PL in a competitive manner with an inhibition constant (K) of 4.504 μM. Additionally, the docking analysis validated the interactions between the analogue 5dh (MolDock score of -140.251 kcal/mol) and key amino acids in the active site, including Leu 153, Gly 76, Arg 256, His 151, Phe 77, and His 263. The inhibitory activity of these analogues was significantly correlated with their MolDock scores (Pearson's r = 0.6586). Finally, molecular dynamics simulation was also performed for 100 ns in order to elucidate the stability, confirmation and intermolecular interactions of the active analogue 5dh. The results of this investigation suggested that the complex maintained its stability despite the dynamic conditions exhibiting interactions with important amino acids. In summary, the outcomes indicated that the synthesized analogues exhibited the potential to inhibit PL activity.

Bazhen Decoction (Eight Treasures Decoction) has demonstrated efficacy in the treatment of colorectal cancer (CRC), yet the active ingredients in it and the mechanisms underlying their anti-cancer properties are not well understood. Through network pharmacology, the effective components of Bazhen Decoction against CRC and their corresponding key genes were delineated. Molecular docking was executed to identify the active component targeting the key gene CXCL8, which led to the discovery of Quercetin. The cellular thermal shift assay method was then used to verify the binding interaction. CRC cells were treated with incremental concentrations of Quercetin, cell viability was evaluated by the Cell Counting Kit-8 assay to calculate the IC, and apoptosis rates were determined by flow cytometry. Expression of the apoptosis-related proteins Bcl-2 and Cleaved caspase-3 was measured using western blot. The impact of Quercetin on macrophage polarization was studied by co-culturing the treated CRC cells with macrophages, assessing M1 and M2 macrophage distribution via flow cytometry, and quantifying cytokine levels (IL-6, IL-10, IL-12, and CXCL8) with enzyme-linked immunosorbent assay (ELISA). The active ingredient Quercetin from Bazhen Decoction exhibited a targeted binding affinity with the key gene CXCL8, which enabled it to inhibit the proliferation of CRC cells and induce cell apoptosis. The overexpression of CXCL8 was associated with the promotion of CRC malignancy, yet the presence of Quercetin could lessen the impact of CXCL8 overexpression on CRC cells. Moreover, the treatment with Quercetin leads to a diminished abundance of M2 macrophages and an increase in the levels of cytokines IL-6 and IL-12, while reducing the levels of IL-10 and CXCL8, which indicates that Quercetin has an inhibitory effect on macrophage M2 polarization. Quercetin, the active component in Bazhen Decoction that is known for anti-CRC effects, targets and inhibits CXCL8 to impede the malignant behaviors and the M2 polarization of macrophages. Thus, Quercetin may be utilized as an immunomodulatory agent in CRC treatment.

Alzheimer's disease is a neurodegenerative chronic disease with a severe social and economic impact in the societies, which still lacks an efficient therapy. Several pathophysiological events (β-amyloid [Aβ] deposits, τ-protein aggregation, loss of cholinergic activity, and oxidative stress) occurs in the progression of the disease. Therefore, the search for efficient multi-targeted agents for the treatment of Alzheimer's disease becomes indispensable. In this paper we evaluated the AChE inhibition by Ellman's method and antioxidant activity by DPPH assay of nine synthetic compounds: two hydroxy-benzene derivatives (1 and 2), three bis-thioureidic derivatives (3-5), two imidazole derivatives (6 and 7), and two phenylacetamide derivatives (8 and 9). The compound 2, (3s,5s,7s)-adamantan-1-yl 4-(((E)-2,5-dihydroxybenzylidene)amino)benzoate, exhibited the best antioxidant activity (30.00 ± 1.05 μM eq Trolox) and compound 4 showed the highest AChE inhibition value (IC [μM] 8.40 ± 0.32). In the search for a compound showing combined activities (antioxidant and AChE inhibition), the compound 4, octane-1,8-diyl-bis-S-amidinothiourea dihydrobromide, (19.02 ± 1.52 μM eq Trolox; IC [μM] 8.40 ± 0.32) was chosen to carry out a molecular docking study. The results showed that compound 4 has the ability to bind the active site of acetylcholinesterase with considerable affinity (estimated binding energies of -8.5 kcal/mol). All data indicate that compound 4 has the potential to be further investigated as a possible candidate in the Alzheimer's disease treatment.

Gallbladder cancer is the most prevalent malignancy of the biliary tract and has a dismal overall survival even in the present day. The development of new drugs holds promise for improving the prognosis of this lethal disease. The possible anti-neoplastic role of morusin was investigated both in vitro and in vivo. Through cell viability and colony formation assays, we observed that morusin inhibited the proliferation of gallbladder cancer cells in vitro. Wound healing and transwell assays revealed that morusin impeded the migration and invasion of gallbladder cancer cells. Given the observed morphological changes, we examined epithelial-mesenchymal transition (EMT) markers. Subsequent investigations demonstrated that morusin treatment, both in vitro and in vivo, downregulated the expression of phospho-STAT3 (Signal transducer and activator of transcription 3) and HIF-1α (Hypoxia-inducible factor 1α) in gallbladder cancer cells. Furthermore, morusin effectively reversed EMT induced by phospho-STAT3 or HIF-1α. Morusin has a reversing effect on the EMT of gallbladder cancer cells by modulating STAT3/HIF-1α signaling.

Depression is a mental health disorder and is the fourth most prevalent disease. Previous studies have suggested that statins are involved in the reduction of neuroinflammation. However, the potential mechanism for this relationship is unclear. The current study aimed to elucidate this by examining the effects of simvastatin on the P2X7/NLRP3 pathway in rats exposed to chronic mild stress (CMS). To achieve this goal, a depression database was first constructed, and simvastatin was used as an input to predict potential targets using machine/deep learning methods. Interestingly, the P2X7/NLRP3 pathway was predicted as a potential target for simvastatin. Subsequently, a depression rat model was established by inducing CMS for 4 weeks. Behavioral changes were detected via a sucrose preference test and forced swim test. The depression rats were then treated with simvastatin (10 mg/kg/day) for 14 days. Following treatment, changes in behavior and the activation of the NLRP3/ASC/caspase-1 inflammasome pathway in the depression model rats were observed. The P2X7 agonist (ATP) and selective P2X7 antagonist brilliant blue G (BBG) were also used for in vivo intervention. Data from the experiment showed that treatment with simvastatin and BBG significantly reduced the depressive-like behaviors in depression model rats, as well as the protein and mRNA expression levels of P2X7 and NLRP3 inflammasome. The protein and mRNA levels of the pro-inflammatory cytokine interleukin-1β significantly increased. These results demonstrate that simvastatin exerted an antidepressant-like effect in the CMS model of rats, and this effect was dependent on the inhibition of the P2X7/NLRP3 inflammasome pathway.

Drug targeting strategies, such as peptide-drug conjugates (PDCs), have arisen to combat the issue of off-target toxicity that is commonly associated with chemotherapeutic small molecule drugs. Here we investigated the ability of PDCs comprising a human protein-derived cell-penetrating peptide-platelet factor 4-derived internalization peptide (PDIP)-as a targeting strategy to improve the selectivity of camptothecin (CPT), a topoisomerase I inhibitor that suffers from off-target toxicity. The intranuclear target of CPT allowed exploration of PDC design features required for optimal potency. A suite of PDCs with various structural characteristics, including alternative conjugation strategies (such as azide-alkyne cycloaddition and disulfide conjugation) and linker types (non-cleavable or cleavable), were synthesized and investigated for their anticancer activity. Membrane permeability and cytotoxicity studies revealed that intact PDIP-CPT PDCs can cross membranes, and that PDCs with disulfide- and protease-cleavable linkers liberated free CPT and killed melanoma cells with nanomolar potency. However, selectivity of the PDIP carrier peptide for melanoma compared to noncancerous epidermal cells was not maintained for the PDCs. This study emphasizes the distinct role of the peptide, linker, and drug for optimal PDC activity and highlights the need to carefully match components when assembling PDCs as targeted therapies.

Infectious diseases, including bacterial, fungal, and viral, have once again gained urgency in the drug development pipeline after the recent COVID-19 pandemic. Tuberculosis (TB) is an old infectious disease for which eradication has not yet been successful. Novel agents are required to have potential activity against both drug-sensitive and drug-resistant strains of Mycobacterium tuberculosis (Mtb), the causative agent of TB. In this study, we present a series of 2-phenyl-N-(pyridin-2-yl)acetamides in an attempt to investigate their possible antimycobacterial activity, cytotoxicity on the HepG2 liver cancer cell line, and-as complementary testing-their antibacterial and antifungal properties against a panel of clinically important pathogens. This screening resulted in one compound with promising antimycobacterial activity-compound 12, MIC = 15.625 μg/mL (56.26 μM). Compounds 17, 24, and 26 were further screened for their antiproliferative activity against human epithelial kidney cancer cell line A498, human prostate cancer cell line PC-3, and human glioblastoma cell line U-87MG, where they were found to possess interesting activity worth further exploration in the future.

Invasive fungal infections (IFIs) pose significant challenges in clinical settings, particularly due to their high morbidity and mortality rates. The rising incidence of these infections, coupled with increasing antifungal resistance, underscores the urgent need for novel therapeutic strategies. Current antifungal drugs target the fungal cell membrane, cell wall, or intracellular components, but resistance mechanisms such as altered drug-target interactions, enhanced efflux, and adaptive cellular responses have diminished their efficacy. Recent research has highlighted the potential of dual inhibitors that simultaneously target multiple pathways or enzymes involved in fungal growth and survival. Combining pharmacophores, such as lanosterol 14α-demethylase (CYP51), heat shock protein 90 (HSP90), histone deacetylase (HDAC), and squalene epoxidase (SE) inhibitors, has led to the development of compounds with enhanced antifungal activity and reduced resistance. This dual-target approach, along with novel chemical scaffolds, not only represents a promising strategy for combating antifungal resistance but is also being utilized in the development of anticancer agents. This review explores the development of new antifungal agents that employ mono-, dual-, or multi-target strategies to combat IFIs. We discuss emerging antifungal targets, resistance mechanisms, and innovative therapeutic approaches that offer hope in managing these challenging infections.

Target cyclooxygenase 2 (COX-2) and 5-lipoxygenase (5-LOX) inhibitors; 5-([2,5-Dihydroxybenzyl]amino)salicylamides (Compounds 1-11) were examined for potential anticancer activity, with a trial to assess the underlying possible mechanisms. Compounds were assessed at a single dose against 60 cancer cell lines panel and those with the highest activity were tested in the five-dose assay. COMPARE analysis was conducted to explore potential mechanisms underlying their biological activity. In vitro epidermal growth factor receptor (EGFR) inhibitory activity was performed, as well as cell cycle and apoptosis assays, in addition to molecular docking to rationalize the potential of these compounds as potent EGFR inhibitors. The compounds revealed broad-spectrum anticancer activity against most cancer cell lines, particularly those of leukemia. Compound 9 showed the maximum growth inhibition (99.65%) against leukemia HL-60 (TB) cell line. Compound 5 produced the uppermost cytotoxic activity (62.28%) against non-small cell lung cancer cell line (NCI-H522), and the most potent antiproliferative and cytotoxic activities against the same cell line in the five-dose assay. Flow cytometry of cell cycle distribution on NCI-H522 showed arrest of cells at different phases of the cycle by Compounds 4, 5, 9-11. These compounds induced apoptosis in NCI-H522, particularly Compounds 4 and 5. They showed a remarkable in vitro EGFR inhibitory activity that was comparable to erlotinib, and a predicted ADME pharmacokinetic profile. In conclusion, the N-substituted aminosalicylamides exhibited considerable anticancer activity. The pattern of N-substitution is important in their activity. The compounds exhibited polypharmacology; one of the targets is the EGFR, as supported by molecular docking.

RET (Rearranged during transfection) kinase is a validated target for non-small cell lung cancer (NSCLC). In 2020, two selective RET inhibitors, selpercatinib and pralsetinib were approved by the US FDA. However, high treatment costs and clinically acquired resistance (e.g., G810C/S/R) become the new challenges for RET-based therapies. In this work, we discovered a series of 2-aminopyrazolpyrimidopyridone RET inhibitors to overcome the V804M and G810C resistant mutations. One of the compounds, 8w, exhibited inhibitory potency against the BaF3 cells harboring CCDC6-RET mutation with an IC50 value of 0.715 μM. The compound also dose-dependently suppressed the activation of RET and downstream signals. Another compound, 8s suppressed BaF3 cells harboring CCDC6-RET mutation with an IC value of 2.91 μM. However, the poor solubility of these compounds will limit their further development. Therefore, compound 8w and 8s might be promising lead compounds for the development of novel RET and RET inhibitors overcoming the clinically acquired resistance.

Ischemic stroke (IS) often causes fearful sequela, even death. Curcumin was beneficial to IS, but its underlying molecular mechanism is unclear. Mice were subjected to middle cerebral artery occlusion (MCAO) surgery, and BV-2 cells were treated with oxygen-glucose deprivation/reoxygenation (OGD/R) induction to establish IS models in vivo and in vitro. Abundance of genes and proteins was determined using quantitative real-time polymerase chain reaction (RT-qPCR), immunofluorescence (IF), and western blot. Interleukin-1β (IL-1β), interleukin-6 (IL-6), and interleukin-10 (IL-10) levels were analyzed using enzyme-linked immunosorbent assay (ELISA). Modified neurological severity score (mNSS), corner test, foot fault test, adhesive removal test, and 2,3,5-triphenyltetrazolium chloride (TTC) staining were applied to evaluate the brain injury of mice. The correlation between miR-205-5p and Kruppel-like factor 2 (KLF2) was affirmed using dual luciferase reporter assay. Our results revealed that curcumin alleviated brain damage in MCAO mice through driving microglia M2 polarization. Of note, curcumin resulted in decreased miR-205-5p expression in MCAO mice. miR-205-5p knockdown resulted in promoted microglia M2 polarization in OGD/R conditions and achieved similar results to curcumin treatment in MCAO mice. Moreover, curcumin played a promoting role in microglia M2 polarization under OGD/R conditions, while miR-205-5p overexpression or KLF2 knockdown abolished these effects. On the mechanism, miR-205-5p was a target of curcumin, and miR-205-5p further interacted with KLF2 to inhibit activating transcription factor 2 (ATF2) expression. miR-205-5p, decreased by curcumin, suppressed microglia M2 polarization to worsen IS injury through the mediating KLF2/ATF2 axis.

The immune system is essential for the defense against infections and is critically implicated in various disorders, including immunodeficiency, autoimmunity, inflammation and cancer. The current study includes a new design of palmitoylated derivatives of thioglycolic acids (PTGAs) capable of triggering innate immune responses. The new series were accessible through a three-step synthetic route, including N-palmitoylation, Claisen-Schmidt condensation and thia-Michael addition. Their structures were elucidated using different 1D and 2D NMR spectroscopic techniques and their purity was confirmed by elemental analysis. The most active PTGAs induced a 12-26-fold increase in the expression of TNF-α and IL-1β mRNA and triggered a marked release of NO in isolated macrophages. These levels were comparable to the responses elicited by heat-killed E. coli and S. aureus. The position of the palmitamide chain and aryl substitution had a significant effect on the TNF-α and IL-1β mRNA expression and NO release. Simulations of molecular dockings showed that the new PTGA derivatives occupy the same TLR2/TLR6 heterodimer active binding site of the microbial diacylated lipoproteins. The new immunomodulators may have a profound impact on various clinical disorders associated with dysfunctional innate immunity.

Vascular endothelial growth factor-A (VEGF-A) is a growth factor and pluripotent cytokine that promotes angiogenesis in cancer cells, transitioning to an angiogenic phenotype. The binding of VEGF-A protein to VEGF receptors (VEGFR-1 and VEGFR-2) initiates a cascade of events that stimulates angiogenesis by facilitating the migration and enhancing the permeability of endothelial cells. The proximal promoter of the VEGF gene encompasses a 36-base pair region (from -85 to -50) that can form a stable G-quadruplex (G4) structure in specific conditions. The activity of the VEGF promoter is reliant on this structure. During cancer progression, the VEGF-A G4 succumbs to cellular pressure and fails to maintain a stable structure. This shifts the balance to form a duplex structure, increasing the transcription rate. Earlier research has tried to develop small-molecule ligands to target and stabilise G4, demonstrating the possibility of suppressing VEGF expression. However, they either lack specificity or toxic. Peptides, on the other hand, are significantly less studied as G4 binders. Here, we designed a peptide that successfully binds and stabilises the VEGF-A G4 while reducing its gene expression. This further alters the expression fate of the VEGF-A signalling cascade and blocks angiogenesis in cancer cells. We employed high-resolution nuclear magnetic resonance (NMR) spectroscopy and molecular dynamics simulation to elucidate the chemical details of G4-peptide interaction. In addition, we used qPCR and western blot techniques to investigate the expression pattern of the molecules implicated in the VEGF-A signalling cascade. The study explores the intricate relationship between peptides and quadruplex structures, revealing valuable insights that can improve the design of pharmacophores targeting the dynamic quadruplex structure. The results of our study are encouraging, opening possibilities for advancements in, the characterisation and optimisation of peptides as G-quadruplex ligands in view of their potential therapeutic uses.

Cervical cancer is the fourth most common cancer among women globally. Its development is closely linked to accelerated cell cycle progression and the inhibition of apoptosis in cervical cancer tissues. Gefitinib has demonstrated efficacy in inhibiting cervical cancer cells, and the 1,2,3-triazole structure is widely recognized for its role in inducing mitochondrial apoptosis in tumor cells. In this study, we employed click chemistry to modify the structure of gefitinib, leading to the synthesis of 16 derivatives containing the 1,2,3-triazole moiety. These compounds were evaluated for their in vitro activity against Hela cells. Among them, compound 3p exhibited the most promising anticancer activity, with an IC value of 4.09 ± 0.54 μM. Compound 3p significantly inhibited Hela cell colony formation in a dose-dependent manner, accompanied by noticeable morphological changes. Further investigations revealed that 3p induced apoptosis and caused G2/M phase cell cycle arrest in Hela cells. Western blot analysis showed that 3p increased the Bax/Bcl-2 ratio and elevated the levels of cleaved caspase-3 and PARP1, indicating that apoptosis was mediated through the mitochondrial pathway. Additionally, 3p inhibited indoleamine 2,3-dioxygenase 1 (IDO1) enzymatic activity, and molecular docking studies revealed a strong interaction between 3p and the IDO1 active site, suggesting that IDO1 may be a potential target. In conclusion, compound 3p shows promise as a potential therapeutic agent for cervical cancer.

Non-small-cell lung cancer (NSCLC) stands as a primary contributor to cancer-related deaths worldwide. It has been demonstrated that Lycorine (LYD), a naturally occurring active sesquiterpene present in Chinese medicinal plants, exhibits anti-cancer properties across various cancer cell lines. However, the underlying mechanisms of LYD-induced anti-tumor in NSCLC are not fully known. This study demonstrated that LYD significantly reduced the proliferation of NSCLC and induced apoptosis by increasing intracellular ROS levels. The inhibition of ROS using N-acetylcysteine (NAC) eliminated the apoptosis effects of LYD, resulting in increased cell viability. Additionally, LYD treatment significantly activated the STING pathway in NSCLC and induced the expression of CXCL10, CXCL9 and CCL5 in NSCLC cells. Mechanistically, LYD was found to significantly reduce the protein levels of P70S6K and S6K, which are key proteins involved in cell growth and survival. Notably, in vivo experiments demonstrated that LYD significantly inhibited the growth of H358 xenograft and LLC1 tumor, exhibiting anti-tumor activity by elevating CD8 T cells in the NSCLC mouse model. Our findings suggest that LYD possesses potent anti-cancer properties in NSCLC by inducing apoptosis through ROS generation and modulating the STING pathway and key chemokines. Furthermore, LYD also exerts its antitumor effects by inhibiting crucial proteins involved in cell growth. Overall, LYD shows promise as a potential therapeutic agent for NSCLC treatment.

Suitable structural modifications of the functional groups at N-substituent of (-)-cis-N-normetazocine nucleus modulate the affinity and activity profile of related ligands toward opioid receptors. Our research group has developed several compounds and the most interesting ligands, LP1 and LP2, exhibited a dual-target profile for mu-opioid receptor (MOR) and delta-opioid receptor (DOR). Recent structure-affinity relationship studies led to the discovery of novel LP2 analogs (compounds 1 and 2), which demonstrated high MOR affinity in the nanomolar range. Here, we reported the synthesis of the new (-)-cis-N-normetazocine derivatives (3-8) characterized by the absence of the phenyl ring in the N-substituent compared to all previous reported ligands. Compounds 3 and 4, featuring a methyl ester functional group in the N-substituent, retained significant MOR affinity and exhibited similar affinity for the kappa-opioid receptor (KOR). In contrast, compounds 7 and 8, which contain a hydroxamic acid functionality, maintained affinity exclusively toward MOR. Neither of compounds (3-8) showed DOR affinity. Molecular modeling studies confirmed a similar docking pose in the MOR binding pocket for these compounds. Additionally, the in silico ADME profile of the most interesting ligands (3, 4, 7, and 8) was investigated revealing a favorable profile for compound 7 regarding the blood-brain barrier permeability, suggesting its potential as a peripherally restricted opioid ligand.