Potent Antiproliferative Activity Research Articles

Design, synthesis, and antitumor evaluation of quinazoline-4-tetrahydroquinoline chemotypes as novel tubulin polymerization inhibitors targeting the colchicine site.

We designed, synthesized, and evaluated the antitumor activity of a series of novel quinazoline-4-(6-methoxytetrahydroquinoline) analogues. Among the tested compounds, 4a4 exhibited the most potent antiproliferative activities across four human cancer cell lines with half-maximal inhibitory concentration (IC50) values ranging from 0.4 to 2.7nM, more potent than the lead compound. The 2.71Å resolution co-crystal structure of 4a4 with tubulin (PDB code: 8YER) confirmed its critical binding at the colchicine site. Moreover, 4a4 inhibited the polymerization of tubulin, colony formation, and tumor cell migration, while inducing G2/M phase arrest and apoptosis. In vivo, 4a4 significantly delayed primary tumor growth in the SKOV3 xenograft model without obvious side effect. Our research enhances the structure-activity relationships (SARs) understanding of the quinazoline-4-tetrahydroquinoline scaffold and provides new insights for potential structural optimization and the development of novel colchicine binding site inhibitors (CBSIs).

Synthesis of Polymethoxylated 3-Styrylflavones and their Antiproliferative Activity in HL60 Cells.

Flavonoids are a large group of naturally occurring compounds with a wide range of biological properties and thus they represent a privileged scaffold in medicinal chemistry. We designed and synthesized a series of polymethoxylated 3-styrylflavones as a novel class of styryl-bearing flavone compounds. 3-Styrylflavones were systematically synthesized using Wittig reaction between various benzaldehyde derivatives and polymethoxylated 3-(bromomethyl)flavones, and evaluated their antiproliferative activity against HL60. Among the compounds synthesized, 2',3',4'-trimethoxy-3-(E)-styrylflavone (IC50=68 μM) and 2',3',3‴,4',4‴,5‴-hexamethoxy-3-(E)-styrylflavone (IC50=92 μM) demonstrated potent anti-proliferative activity. Introduction of 3-styryl substituent in 3-methylflavone increased the antiproliferative activity. Structure-activity relationship studies and theoretical calculations indicated the importance of 2',3',4'-trimethoxy-phenyl substituent in enhancing the activity.

Chemical Profiling, Antioxidant, and Antiproliferative Activities of Algerian Cistus creticus L. Leaf Extracts: Evidence from In vitro and In Silico Studies.

Research into oxidative stress, cancer, and natural products revealed promising avenues for therapeutic intervention. Natural products are considered potent pharmaceuticals in combating oxidative stress and its relationship with cancer. This study was carried out to evaluate the chemical profile and antioxidant activities using DPPH, ABTS, Phenanthroline, Cupric, Phosphomolybdenum, FRAP, Hydroxyl, Iron chelation in vitro assays, and anticancer properties by MTT method of Cistus creticus extracts. The chemical composition was determined using the LC/MS-MS technique. Therefore, in silico methods, particularly molecular docking and dynamic simulation were applied for molecular interaction analysis. The obtained results revealed a wide variety of phenolic compounds in all studied fractions, in their qualitative and quantitative distribution. In most antioxidant assays, the butanol and ethyl acetate extracts exhibited the most effective effects, followed by the aqueous extract, while the petroleum ether and chloroform fractions exhibited much lower activity in comparison with standards. In parallel, ethyl acetate, n-butanol, and chloroform extracts exhibited potent antiproliferative activity against T47D and A549 cell lines, while the aqueous extract showed an IC50 in the range of mg/ml. Moreover, the analysis of interactions identified compounds against particular targets in studied cell lines using molecular docking showed a great affinity, especially for the ligands Hesperidin, Luteolin-7-O-glucoside and Rutin. Also, the molecular dynamic simulation of the interacting complexes Hesperidin-mTOR, Lutin-EGFR and Apigenin-HER2 revealed precise interaction, providing insights into their stability and dynamic behavior. Furthermore, the studied ligand exhibited interesting pharmacokinetic properties with no reported toxicity. These findings confirmed the potential of Algerian Cistus creticus L. leaf extracts as promising therapeutic molecules for combating oxidative stress and cancer.

Discovery of Highly Potent and Orally Bioavailable Histone Deacetylase 3 Inhibitors as Immunomodulators and Enhancers of DNA-Damage Response in Cancer Therapy.

Histone deacetylase 3 (HDAC3) is a well-established target for cancer therapy. Herein, we developed LSQ-28 as a novel HDAC3 inhibitor, which exhibited high HDAC3 inhibitory activity (IC50 = 42 nM, SI > 161) and displayed potent antiproliferative activity against four cancer cells and further demonstrated excellent antimigratory, anti-invasive, and antiwound healing activities. Further studies revealed that LSQ-28 induced a dose-dependent increase in Ac-H3 expression and promoted the degradation of PD-L1. Additionally, LSQ-28 enhanced the DNA damage response induced by PARP inhibitor, as evidenced by regulated expression of PARP1 and γ-H2AX. Notably, LSQ-28 also possessed favorable pharmacokinetic properties with significant oral bioavailability (F = 95.34%). Importantly, the combination of LSQ-28 with the PD-L1 inhibitor NP-19 could enhance antitumor immune response (TGI = 80%). When combined with olaparib, LSQ-28 significantly enhanced the in vivo tumor-suppression activity (TGI = 91%). Collectively, LSQ-28 represents a promising HDAC3 inhibitor for further exploration in cancer therapeutic strategies.

Phytochemical, antioxidant, in silico, and in vitro anti-breast cancer effects of Erigeron sumatrensis from Gayo Highlands (Indonesia) against MCF-7 cells

Abstract. Puspa VR, Adista MA, Djufri. 2024. Phytochemical, antioxidant, in silico, and in vitro anti-breast cancer effects of Erigeron sumatrensis from Gayo Highlands (Indonesia) against MCF-7 cells. Biodiversitas 25: 5123-5137. This study investigated the therapeutic potential of Erigeron sumatrensis, a wild herb from the Gayo Highlands, by evaluating its methanol stem extract's phytochemical profile, antioxidant activity, biological activity, molecular docking, ADMET prediction, and MTT assay using MCF-7 cells. Phytochemical analysis revealed the presence of various secondary metabolites, including flavonoids, phenolics, terpenoids, steroids, tannins, and alkaloids. The stem extract exhibited the highest total phenolic content at 959.091 mgQE/g. Antioxidant activity, assessed using the DPPH assay, was strong with an IC50 value of 96 ?g/mL. Gas chromatography-mass spectrometry analysis of the methanol extract of E. sumatrensis stems led to the identification of 24 compounds. Molecular docking studies identified three compounds-Stigmast-7-en-3-ol, (3?,5?,24S)-, Caryophyllene oxide and 1H-Cycloprop[e]azulen-7-ol, decahydro- 1,1,7-trimethyl-4-methylene-, [1ar(1a?,4a?,7?,7a?,7b?)] exhibiting potential anti-proliferative activity against MCF-7 cells. ADMET analysis predicted compliance with all identified compounds, suggesting their suitability as oral drug candidates. The in vitro cytotoxicity assay against MCF-7 cells yielded a moderate cytotoxic classification with an IC50 of 192.90 ?g/mL. These findings highlight the promising potential of E. sumatrensis as a source of bioactive compounds for developing novel anti-breast cancer drugs. However, further research is needed to explore its full therapeutic potential and facilitate its development into pharmaceutical products.

Design, synthesis, and biological evaluation of Flavokavain B derivatives as potent TRF2 inhibitors for the treatment of Osteosarcoma.

Telomere repeat-binding factor 2 (TRF2) is a crucial component of the shelterin complex, commonly overexpressed in osteosarcoma (OS) and positively correlated with its progression. To date, effective TRF2 inhibitors for in vivo applications remain limited. In this study, a series of Flavokavain B derivatives were designed and synthesized, and their TRF2 inhibition and antitumor activity were evaluated. Among the tested compounds, the active compound F2 showed remarkable inhibition of TRF2 expression, along with potent antiproliferative activity in U2OS and MG63cells, with IC50 values of 5.28μM and 1.52μM, respectively. Moreover, F2 significantly suppressed OS cell proliferation and induced apoptosis by accelerating telomere shortening and loss due to TRF2 inhibition. Mechanically, F2 selectively inhibited TRF2 protein expression and telomeric localization by directly binding to the TRF2TRFH domain. Furthermore, F2 demonstrated strong antitumor efficacy with minimal toxicity in an MG63-derived xenograft mouse model. These findings demonstrate that F2 is a promising drug candidate for the treatment of osteosarcoma.

Targeting of the G9a, DNMT1 and UHRF1 epigenetic complex as an effective strategy against pancreatic ductal adenocarcinoma

BackgroundPancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with limited treatment options and a poor prognosis. The critical role of epigenetic alterations such as changes in DNA methylation, histones modifications, and chromatin remodeling, in pancreatic tumors progression is becoming increasingly recognized. Moreover, in PDAC these aberrant epigenetic mechanisms can also limit therapy efficacy. This study aimed to investigate the expression and prognostic significance of a key epigenetic complex encompassing DNA methyltransferase-1 (DNMT1), the histone methyltransferase G9a, and the scaffold protein UHRF1 in PDAC. We also evaluated the therapeutic potential of an innovative inhibitor targeting these epigenetic effectors.MethodsImmunohistochemical analysis of DNMT1, G9a, and UHRF1 expression was conducted in human PDAC tissue samples. Staining was semi-quantitatively scored, and overexpression was defined as moderate to strong positivity. The prognostic impact was assessed by correlating protein expression with patient survival. The antitumoral effects of the dual DNMT1-G9a inhibitor CM272 were tested in PDAC cell lines, followed by transcriptomic analyses to identify underlying mechanisms. The in vivo antitumoral efficacy of CM272 was evaluated in PDAC xenograft and syngeneic mouse models, both alone and in combination with anti-PD1 immunotherapy.ResultsDNMT1, G9a, and UHRF1 were significantly overexpressed in PDAC cells and stroma compared to normal pancreatic tissues. Simultaneous overexpression of the three proteins was associated with significantly reduced survival in resected PDAC patients. CM272 exhibited potent antiproliferative activity in PDAC cell lines, inducing apoptosis and altering key metabolic and cell cycle-related genes. CM272 also enhanced chemotherapy sensitivity and significantly inhibited tumor growth in vivo without detectable toxicity. Combination of CM272 with anti-PD1 therapy further improved antitumor responses and immune cell infiltration, particularly CD4 + and CD8 + T cells.ConclusionsThe combined overexpression of DNMT1, G9a, and UHRF1 in PDAC is a strong predictor of poor prognosis. CM272, by targeting this epigenetic complex, shows promising therapeutic potential by inducing apoptosis, reprogramming metabolic pathways, and enhancing immune responses. The combination of CM272 with immunotherapy offers a novel, effective treatment strategy for PDAC.

Quinizarin Gold(I) N-Heterocyclic Carbene Complexes with Synergistic Activity Against Anthracycline-Resistant Leukaemia Cells: Synthesis and Biological Activity Studies.

New, asymmetric quinizarin-Au(I)-NHC complexes were designed, isolated, and fully characterised including by single crystal X-ray crystallography. Cytotoxicity studies showed effective growth inhibition in HeLa cervical cancer cells with IC50 values ranging from 2.4 μM to 5.3 μM. The successful cellular uptake was evidenced by X-ray fluorescence imaging on cryo-preserved whole HeLa cells and the sub-cellular localisation was monitored by live-cell fluorescence microscopy. Notably, complex 2 b showed circumvention of acquired anthracycline resistance in K562 leukaemia cells as well as synergistic activity with doxorubicin against both wild-type and anthracycline-resistant Nalm-6 leukaemia cells. Interestingly, sub-cellular localisation towards mitochondria proved to be more important than the compounds' overall cytotoxicity for potent antiproliferative activity and to achieve effective resistance circumvention.

Synthesis, biological evaluation and mechanism study of a novel indole-pyridine chalcone derivative as antiproliferative agent against tumor cells through dual targeting tubulin and HK2.

Chalcones have the characteristics of simple structure, easy synthesis and potent anti-tumor activity. Herein, a small library of fifty-five novel indole-chalcone derivatives were rationally designed and facilely synthesized. Consequently, their antiproliferative activity was systematically evaluated. Among which, compound 26 exhibited the most potent antiproliferative activity, with IC50 value of 0.764μM against MD-MBA-231cells. Moreover, it displayed a 5-fold selectivity compared with normal human cells. Further investigation revealed that compound 26 bound at the colchicine binding site of tubulin, disrupted their fibrous structure, thereby blocking the progression of the cell cycle and inducing apoptosis. Molecular docking and cellular thermal shift assay (CETSA) experiments further demonstrated that compound 26 could specifically bind to hexokinase 2 (HK2) and inhibit its activity, leading to impaired mitochondrial function and hindered mitochondrial respiration. Based on the quantitative structure-activity relationship study, further structure modifications were performed. Employing biotin probe pull-down assays, we demonstrated that compound 26 exerted its antiproliferative activity through a dual targeting mechanism, which simultaneously disrupted microtubule function and inhibited HK2 activity. Taken together, these results highlighted that compound 26 might be a promising antiproliferative agent for human cancer therapy.

Development of novel tetrazole-based pyruvate kinase M2 inhibitors targeting U87MG glioblastoma cells.

Glioblastoma (GB), the most aggressive and life-threatening primary brain tumor in adults, poses significant therapeutic challenges. Tumor pyruvate kinase M2 (PKM2) has been implicated in the proliferation and survival of glioma cells. In this study, we designed and synthesized a series of 23 novel tetrazole-based derivatives. The compounds were thoroughly characterized using 1H, 13C, 19F NMR, along with HRMS analysis. Among them, 1-(imidazo[1,2-a]pyrimidin-3-yl)-2-(5-(naphthalen-2-yl)-2H-tetrazol-2-yl)ethan-1-one (9b) exhibited potent and selective antiproliferative activity against U87MG glioma cells, with minimal effects on bEnd (brain endothelial cell line) non-glioma cells. It emerged as a potent PKM2 inhibitor, with an IC50 of 0.307µM. Apoptosis assays and cell cycle analysis revealed that compound 9b induced early apoptosis and caused G1 phase arrest. A significant decrease in pyruvate concentration further suggested PKM2 inhibition. In silico studies confirmed the binding affinity to the PKM2 inhibitory site, and RT-PCR data demonstrated its inhibitory activity against PKM2. Additionally, it reduced lactate levels, indicating its potential impact on cellular metabolism. Collectively, these findings suggest that the most potent compound holds promise as a therapeutic candidate against GB.

N-Substituted-5- [(2,5-Dihydroxybenzyl)amino]salicylamides as Lavendustin Analogs: Antiproliferative Activity, COMPARE Analyses, Mechanistic, Docking, ADMET and Toxicity Studies.

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. Invitro 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 invitro 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.

Activities of Polysaccharides Derived from Commiphora Gileadensis on Colorectal Cancer Cell Lines

Background:-CRC is a common malignancy leading to cause mortality globally. Commiphora gileadensis was used to treat respiratory infections, neuralgic pain, wounds and arthritis. Methods:-Commiphora gileadensis was harvested; then polysaccharides were extracted. The antiproliferative activity was assessed on two colorectal cancer cell lines; then, an apoptosis assay was conducted to determine cell death. Polysaccharides with antiproliferative effects were digested and separated. Results:-Commiphora gileadensis separation confirmed the presence polysaccharides that showed anti-proliferative activities on SW480 and SW620 with IC50 13.15 µg/mL and 32.02 µg/mL, respectively. Cell death was activated via apopstosis on SW480, with some resistance on WS620 cell line. Discussion: The cytotoxic effects of Commiphora gileadensis polysaccharides on SW480 and SW620 were significant as it activated the cellular apoptosis pathway. Conclusion:-Commiphora gileadensis polysaccharide extracts induce cellular apoptosis on CRC cell line with potent antiproliferative activity.

Design, Synthesis, and Biological Evaluation of 3,4-Dihydroisoquinolin-1(2H)-one Derivatives as Protein Arginine Methyltransferase 5 Inhibitors for the Treatment of Non-Hodgkin's Lymphoma.

Through catalyzing the transfer of methyl groups onto the guanidinium of arginine, protein arginine methyltransferase 5 (PRMT5) was essential to the cell growth of cancer cells. By utilizing a scaffold hopping strategy, a novel series of 3,4-dihydroisoquinolin-1(2H)-one derivatives were designed and synthesized. Through a systematic SAR study, D3 demonstrated excellent PRMT5 inhibitory activity, potent antiproliferative activity against Z-138, favorable pharmacokinetic profiles, and low hERG toxicity. Molecular docking, molecular dynamic (MD) simulation, and surface plasmon resonance (SPR) study indicated that D3 was tightly interacted with PRMT5. Meanwhile, D3 exhibited high selectivity against PRMT5, which could inhibit the growth of various cancer cells, induce apoptosis, and arrest the cell cycle in the G0/G1 phase. Additionally, D3 possessed excellent antitumor efficacy in Z-138 xenograft models, low toxicity in vivo, and acceptable drug metabolism and pharmacokinetics (DMPK) profiles in vitro. Therefore, D3 can be developed as a promising candidate for the treatment of non-Hodgkin's lymphoma (NHL).

Unlocking the pharmacological potential of Brennnesselwurzel (Urtica dioica L.): an in-depth study on multifaceted biological activities

Brennnesselwurzel (Urtica dioica L.) is recognized for its diverse pharmacological properties. With a range of chemical constituents, such as vitamins, minerals, phenolic compounds, fibers, and amino acids, Brennnesselwurzel (BWE) has a long history of traditional medicinal use in Europe and Asia. The correlation between a plant's metabolite composition and its activity can vary depending on considerations such as geographic location, environmental conditions, and genetic variations. In the present study, we explore the phytochemical profile and biological activity of the 70% acetone extract of the BWE plant. The chemical profile of the BWE extract was explored using several techniques, including amino acid analyzer, HPLC, GC–MS, and other colorimetric analysis. The antioxidant activity of the BWE extract was assessed by evaluating the total antioxidant, free radical scavenging activity (DPPH, ABTS, H2O2), and metal chelating scavenging activity (FRAP, CUPRAC, metal chelating). Furthermore, we assessed the antimicrobial and antiproliferation activities of the BWE extract against 29 microbial strains and 15 cell lines, respectively. Our phytochemical analyzes revealed that the BWE extract has a unique profile of metabolites including amino acids, flavonoids, phenolics, volatile oils, lipids, and vitamins. The BWE extract showed a total antioxidant capacity of 30.94 ± 1.58 mg GAE/g, together with potential free radical scavenging activity towards ABTS (IC50 = 153.51 ± 3.97 µg/ml), DPPH (IC50 = 195.75 ± 5.91 µg/ml), and H2O2 (IC50 = 230.67 ± 5.98 µg/ml). Although the BWE extract showed no significant antifungal activity, our findings revealed that the BWE extract possesses substantial antibacterial activity against Staphylococcus epidermidi, Streptococcus mutants, Enterococcus faecalis, Micrococcus sp., Klebsiella pneumonia and Porphyromonas gingivalis. Furthermore, the BWE extract demonstrated potential antiproliferative activity toward a panel of cancer cell lines with a high selectivity index. Among the cells examined, the BWE extract exhibited significant cytotoxic activity toward HCT-116, A-549, MDA-MB-231 cells with IC50 of 15.11, 15.32, 15.79 µg/mL, respectively, while it possessed no significant cytotoxic activity towards WI-38 cells (IC50 119.62 µg/mL). Taken together, our findings reveal that BWE extract possesses a wide spectrum of biological activities, including antioxidant, antibacterial, and antitumor activities, and could be considered for further research to explore its potential as a natural plant-based supplement for human diseases.

Evaluation of the Leaves and Seeds of Cucurbitaceae Plants as a New Source of Bioactive Compounds for Colorectal Cancer Prevention and Treatment.

The Cucurbitaceae family represents an important source of bioactive compounds with antioxidant, antimicrobial, anti-inflammatory and antitumor activities. This study aims to investigate the potential application of Cucurbitaceae leaves and seed extracts to prevent and treat colorectal cancer (CRC). Four extracts (ethanol extracts and protein extracts and hydrolysates) from the leaves and seeds of cucurbits were tested in T-84, HCT-15 and HT-29 CRC cells. The antitumor, antiangiogenic, antioxidant and chemopreventive potentials and bioactive composition of the active extracts were characterized. Cold ethanolic extracts from the leaves and seeds of two interspecific Cucurbita genera (CLU01002 and COK01001) exhibited potent antiproliferative, specific and non-hepatotoxic activity against CRC cell lines, with a slight synergistic effect in combination with oxaliplatin. This antitumor activity was related to G2/M cell cycle arrest, the extrinsic apoptosis pathway, cytokinesis inhibition and autophagy. The extracts also inhibited tumor clonogenicity and angiogenesis, and modulated cancer stem cell (CSC) gene expression, as well as expressing antioxidant and chemopreventive cellular capabilities. Finally, phenolic and cucurbitane-type triterpenoid compounds (pengxianencins and cucurbitacins) were tentatively identified in the active extracts by UPLC-MS analysis and bioguided fractionation. Extracts from leaves the and seeds of two interspecific Cucurbita genera (CLU01002 and COK01001) may contribute to the improvement of prevention and treatment strategies for CRC patients.

N-Glycoside of Indolo[2,3-a]pyrrolo[3,4-c]carbazole LCS1269 Exerts Anti-Glioblastoma Effects by G2 Cell Cycle Arrest and CDK1 Activity Modulation: Molecular Docking Studies, Biological Investigations, and ADMET Prediction.

Background/Objectives: Indolo[2,3-a]pyrrolo[3,4-c]carbazole scaffold is successfully used as an efficient structural motif for the design and development of different antitumor agents. In this study, we investigated the anti-glioblastoma therapeutic potential of glycosylated indolocarbazole analog LCS1269 utilizing in vitro, in vivo, and in silico approaches. Methods: Cell viability was estimated by an MTT assay. The distribution of cell cycle phases was monitored using flow cytometry. Mitotic figures were visualized by fluorescence microscopy. Quantitative RT-PCR was used to evaluate the gene expression. The protein expression was assessed by Western blotting. Molecular docking and computational ADMET were approved for the probable protein target simulations and predicted pharmacological assessments, respectively. Results: Our findings clearly suggest that LCS1269 displayed a significant cytotoxic effect against diverse glioblastoma cell lines and patient-derived glioblastoma cultures as well as strongly suppressed xenograft growth in nude mice. LCS1269 exhibited more potent anti-proliferative activity toward glioblastoma cell lines and patient-derived glioblastoma cultures compared to conventional drug temozolomide. We further demonstrated that LCS1269 treatment caused the severe G2 phase arrest of cell cycle in a dose-dependent manner. Mechanistically, we proposed that LCS1269 could affect the CDK1 activity both by targeting active site of this enzyme and indirectly, in particular through the modulation of the Wee1/Myt1 and FOXM1/Plk1 signaling pathways, and via p21 up-regulation. LCS1269 also showed favorable pharmacological characteristics in in silico ADME prediction in comparison with staurosporine, rebeccamycin, and becatecarin as reference drugs. Conclusions: Further investigations of LCS1269 as an anti-glioblastoma medicinal agent could be very promising.

Optimization and Biological Evaluation of Novel 1H-Pyrrolo[2,3-c]pyridin Derivatives as Potent and Reversible Lysine Specific Demethylase 1 Inhibitors for the Treatment of Acute Myelogenous Leukemia.

Lysine-specific demethylase 1 (LSD1) plays a vital role in the epigenetic regulation of various cancers, making it a promising therapeutic target for anticancer treatments. Herein, we designed and synthesized a novel series of 1H-pyrrolo[2,3-c]pyridin derivatives as potent LSD1 inhibitors. A detailed structure-activity relationship exploration was carried out to discover multiple derivatives with nanomolar enzymatic IC50 values. Further biological evaluation demonstrated that these compounds acted as selective and reversible LSD1 inhibitors. The representative compounds exhibited highly potent antiproliferative activity against both AML (MV4-11 and Kasumi-1) and SCLC (NCI-H526) cell lines. Additionally, they effectively activated CD86 mRNA expression in MV4-11 cells and induced differentiation of AML cell lines. Notably, the most promising compound 23e showed a favorable oral PK profile and effectively suppressed the tumor growth in an AML xenograft model. Overall, our medicinal chemistry efforts provide compound 23e as a lead compound for developing LSD1 inhibitors for the treatment of AML and other advanced malignancies.

Bacteriophage Mediated Chitosan Nano-carriers for (+)-Catechin Delivery: Potent Antiproliferative Activity against Cancer Cells and Gram-Negative Bacteria

Bacteriophage Mediated Chitosan Nano-carriers for (+)-Catechin Delivery: Potent Antiproliferative Activity against Cancer Cells and Gram-Negative Bacteria

A comprehensive study on the bioactive flavonoids in Paulownia flowers: Uncovering metabolic pathways, effective components, and regulatory genes for industrial applications

The study explores Paulownia flowers as an emerging resource in medicine, food, health supplements, cosmetics, and animal feed, despite a lack of characterization of their secondary metabolite accumulation mechanisms. We conducted a comprehensive investigation into the biological activities, metabolite profiles, and gene expression patterns of flavonoids in Paulownia flowers. Our results, obtained using ABTS/FRAP/DPPH assays, MTT assays, and colorimetric analyses, demonstrate the potent antioxidant, antibacterial, hypolipidemic, and antiproliferative activities of Paulownia flower flavonoid (PFF) extracts. Notably, the Paulownia elongata tetraploid (M4) exhibited particularly notable effects. HPLC fingerprinting, molecular docking, and density functional theory calculations led to the identification of rhoifolin and luteolin as key bioactive flavonoids. UV-Vis, fluorescence, and circular dichroism spectroscopy confirmed PFF's role as a reversible and mixed inhibitor of xanthine oxidase (XOD). Transcriptome and metabolomic analyses further revealed substantial enrichment in phenylpropanoid, flavonol, and flavonoid biosynthetic pathways, with PfPP2C, PfPYR, PfPYL, PfNPR1, PfMYBs, and PfbHLHs identified as crucial regulators. This work provides a foundational understanding of flavonoid biosynthesis in Paulownia flowers, paving the way for targeted genetic modification and biotechnological interventions aimed at enhancing flavonoid accumulation for industrial applications.

New 5, 6, 7, 8-Tetrahydro-Isoquinolines Bearing 2-Nitrophenyl Group Targeting RET Enzyme: Synthesis, Anticancer Activity, Apoptotic Induction and Cell Cycle Arrest.

In this work, we synthesized new 5, 6, 7, 8-tetrahydroisoquinolines and 6, 7, 8, 9-tetrahydrothieno[2, 3-c]isoquinolines derivatives, and the structures of these new compounds were confirmed with different spectroscopic techniques. Furthermore, the anticancer activities of these compounds were assessed against eight tumor cell lines and one normal human skin fibroblast cell line (HSF). Subsequently, IC50 values of the synthesized compounds were determined for two specific cancer cell lines. Compound 3 exhibited the most potent antiproliferative activity against the HEPG2 cell line, whereas compound 9c demonstrated superior efficacy against the HCT116 cell line. Moreover, the mechanism of action for compound 3 on HEPG2 cells using flow cytometry and Annexin V-FITC apoptosis analysis was studied. Compound 3 caused cell cycle arrest at the G2/M with a 50-fold increase in apoptosis of the HEPG2 cell line. Finally, a molecular docking study was conducted to assess the inhibitory potential of compounds 3 and 7 against the RET enzyme. Results indicated that compounds 3 and 7 bind to the RET enzyme with binding energies of -5.2 and -5.6kcal/mol, respectively. Although these values suggest inhibitory activity, they are less potent than the standard inhibitor, alectinib, which exhibits a binding energy of -7.2kcal/mol.