Antimycobacterial and healing effects of Pranlukast against MTB infection and pathogenesis in a preclinical mouse model of tuberculosis.

It is essential to understand the interactions and relationships between Mycobacterium tuberculosis (Mtb) and macrophages during the infection in order to design host-directed, immunomodulation-dependent therapeutics to control Mtb. We had reported previously that ornithine acetyltransferase (MtArgJ), a crucial enzyme of the arginine biosynthesis pathway of Mtb, is allosterically inhibited by pranlukast (PRK), which significantly reduces bacterial growth. The present investigation is centered on the immunomodulation in the host by PRK particularly the activation of the host's immune response to counteract bacterial survival and pathogenicity. Here, we show that PRK decreased the bacterial burden in the lungs by upregulating the population of pro-inflammatory interstitial macrophages (IMs) and reducing the population of Mtb susceptible alveolar macrophages (AMs), dendritic cells (DCs), and monocytes (MO). Additionally, we deduce that PRK causes the host macrophages to change their metabolic pathway from fatty acid metabolism to glycolytic metabolism around the log phage of bacterial multiplication. Further, we report that PRK reduced tissue injury by downregulating the Ly6C-positive population of monocytes. Interestingly, PRK treatment improved tissue repair and inflammation resolution by increasing the populations of arginase 1 (Arg-1) and Ym1+Ym2 (chitinase 3-like 3) positive macrophages. In summary, our study found that PRK is useful not only for reducing the tubercular burden but also for promoting the healing of the diseased tissue.

Eosinophil peroxidase promotes bronchial epithelial cells to secrete asthma-related factors and induces the early stage of airway remodeling.

Asthma is a heterogeneous disease characterized by chronic airway inflammation, reversible airflow limitation, and airway remodeling. Eosinophil peroxidase (EPX) is the most abundant secondary granule protein unique to activated eosinophils. In this study, we aimed to illustrate the effect of EPX on the epithelial-mesenchymal transition (EMT) in BEAS-2B cells. Our research found that both EPX and ADAM33 were negatively correlated with FEV1/FVC and FEV1%pred, and positively correlated with IL-5 levels. Asthma patients had relatively higher levels of ADAM33 and EPX compared to the healthy control group. The expression of TSLP, TGF-ß1 and ADAM33 in the EPX intervention group was significantly higher. Moreover, EPX could promote the proliferation, migration and EMT of BEAS-2B cells, and the effect of EPX on various factors was significantly improved by the PI3K inhibitor LY294002. The findings from this study could potentially offer a novel therapeutic target for addressing airway remodeling in bronchial asthma, particularly focusing on EMT.

Chaetoxylariones A-G: undescribed chromone-derived polyketides from co-culture of Chaetomium virescens and Xylaria grammica enabled via the molecular networking strategy.

By co-culturing two endophytic fungi (Chaetomium virescens and Xylaria grammica) collected from the medicinal and edible plant Smilax glabra Roxb. and analyzing them with MolNetEnhancer module on GNPS platform, seven undescribed chromone-derived polyketides (chaetoxylariones A-G), including three pairs of enantiomer ones (2a/2b, 4a/4b and 6a/6b) and four optical pure ones (1, 3, 5 and 7), as well as five known structural analogues (8-12), were obtained. The structures of these new compounds were characterized by NMR spectroscopy, single-crystal X-ray diffraction, 13C NMR calculation and DP4+ probability analyses, as well as the comparison of the experimental electronic circular dichroism (ECD) data. Structurally, compound 1 featured an unprecedented chromone-derived sulfonamide tailored by two isoleucine-derived δ-hydroxy-3-methylpentenoic acids via the acylamide and NO bonds, respectively; compound 2 represented the first example of enantiomeric chromone derivative bearing a unique spiro-[3.3]alkane ring system; compound 3 featured a decane alkyl side chain that formed an undescribed five-membered lactone ring between C-7' and C-10'; compound 4 contained an unexpected highly oxidized five-membered carbocyclic system featuring rare adjacent keto groups; compound 7 featured a rare methylsulfonyl moiety. In addition, compound 10 showed a significant inhibition towards SW620/AD300 cells with an IC50 value of PTX significantly decreased from 4.09 µM to 120 nM, and a further study uncovered that compound 10 could obviously reverse the MDR of SW620/AD300 cells.

Synthesis, molecular docking studies and biological evaluation of N-(4-oxo-2-(trifluoromethyl)-4H-chromen-7-yl) benzamides as potential antioxidant, and anticancer agents.

A series of novel chromone derivatives of (N-(4-oxo-2-(trifluoromethyl)-4H-chromen-6-yl) benzamides) were synthesized by treating 7-amino-2-(trifluoromethyl)-4H-chromen-4-one with K2CO3 and/or NaH, suitable alkyl halides and acetonitrile and/or 1,4-dioxane. The obtained products are in high yields (87 to 96%) with various substituents in short reaction times with no more by-products and confirmed by FT-IR, 1H, and 13C-NMR Spectral data. The in vitro cytotoxic activity was examined against two human cancer cell lines, namely the human lung adenocarcinoma (A-549) and the human breast (MCF-7) cancer cell line. Compound 4h showed promising cytotoxicity against both cell lines with IC50 values of 22.09 and 6.40 ± 0.26 µg/mL respectively, compared to that of the standard drug. We also performed the in vitro antioxidant activity by DPPH radical, hydrogen peroxide, NO scavenging, and total antioxidant capacity (TAC) assay methods, and they showed significant activities. The possible binding interactions of all the synthesized chromone derivatives are also investigated against selective pharmacological targets of human beings, such as HERA protein for cytotoxic activity and Peroxiredoxins (3MNG) for antioxidant activity which showed closer binding free energies than the standard drugs and evidencing the above two types of activities.

Iguratimod prevents renal fibrosis in unilateral ureteral obstruction model mice by suppressing M2 macrophage infiltration and macrophage-myofibroblast transition.

Iguratimod is a novel synthetic, small-molecule immunosuppressive agent used to treat rheumatoid arthritis. Through ongoing exploration of its role and mechanisms of action, iguratimod has been observed to have antifibrotic effects in the lung and skin; however, its effect on renal fibrosis remains unknown. This study aimed to investigate whether iguratimod could affect renal fibrosis progression. Three different concentrations of iguratimod (30 mg/kg/day, 10 mg/kg/day, and 3 mg/kg/day) were used to intervene in unilateral ureteral obstruction (UUO) model mice. Iguratimod at 10 mg/kg/day was observed to be effective in slowing UUO-mediated renal fibrosis. In addition, stimulating bone marrow-derived macrophages with IL-4 and/or iguratimod, or with TGF-ß and iguratimod or SRC inhibitors in vitro, suggested that iguratimod mitigates the progression of renal fibrosis in UUO mice, at least in part, by inhibiting the IL-4/STAT6 signaling pathway to attenuate renal M2 macrophage infiltration, as well as by impeding SRC activation to reduce macrophage-myofibroblast transition. These findings reveal the potential of iguratimod as a treatment for renal disease.

Synthesis, bioactivity assessment, molecular docking and ADMET studies of new chromone congeners exhibiting potent anticancer activity.

In consideration of the chromones' therapeutic potential and anticancer activity, a new series of chromanone derivatives have been synthesized through a straightforward reaction between 6-formyl-7-hydroxy-5-methoxy-2-methylchromone (2) and various organic active compounds. The cytotoxic activity of the newly synthesized congeners was investigated against MCF-7 (human breast cancer), HCT-116 (colon cancer), HepG2 (liver cancer), and normal skin fibroblast cells (BJ1). The obtained data indicated that compounds 14b, 17, and 19 induce cytotoxic activity in the breast MCF7, while compounds 6a, 6b, 11 and 14c showed highly potent activity in the colon cancer cell lines. Overall, the results demonstrate that the potential cytotoxic effects of the studied compounds may be based on their ability to induce DNA fragmentation in cancer cell lines, down-regulate the expression level of CDK4 as well as the anti-apoptotic gene Bcl-2 and up-regulate the expression of the pro-apoptotic genes P53 and Bax. Furthermore, compounds 14b and 14c showed a dual mechanism of action by inducing apoptosis and cell cycle arrest. The docking studies showed that the binding affinity of the most active cytotoxic compounds within the active pocket of the CDK4 enzyme is stronger due to hydrophobic and H-bonding interactions. These results were found to be consistent with the experimental results.

A potential strategy for bladder cancer treatment: inhibiting autophagy to enhance antitumor effects of Nectin-4-MMAE.

Research and development on Nectin-4 antibody-drug conjugates (ADC) have been greatly accelerated since the approval of enfortumab vedotin to treat uroepithelial cancer. During the course of this study, we identified that autophagy serves as a cytoprotective mechanism during Nectin-4-MMAE treatment and proposed a strategy to enhance the antitumor effects of Nectin-4-MMAE in bladder cancer. Nectin-4-MMAE rapidly internalized into bladder cancer cells in 30 minutes and released MMAE, inducing the onset of caspase-mediated apoptosis and leading to the inhibition of tumor cell growth. Transcriptomics showed significant alterations in autophagy-associated genes in bladder cancer cells treated with Nectin-4-MMAE, which suggested autophagy was activated by Nectin-4-MMAE. Furthermore, autophagy activation was characterized by ultrastructural analysis of autophagosome accumulation, immunofluorescence of autophagic flux, and immunoblotting autophagy marker proteins SQSTM1 and LC3 I/II. Importantly, inhibiting autophagy by LY294002 and chloroquine significantly enhances the cytotoxicity effects of Nectin-4-MMAE in bladder cancer cells. Additionally, we detected the participation of the AKT/mTOR signaling cascade in the induction of autophagy by Nectin-4-MMAE. The combination of Nectin-4-MMAE and an autophagy inhibitor demonstrated enhanced antitumor effects in the HT1376 xenograft tumor model. After receiving a single dose of Nectin-4-MMAE, the group that received the combination treatment showed a significant decrease in tumor size compared to the group that received only one type of treatment. Notably, one mouse in the combination treatment group achieved complete remission of the tumor. The combination group exhibited a notable rise in apoptosis and necrosis, as indicated by H&E staining and immunohistochemistry (cleaved caspase-3, ki67). These findings demonstrated the cytoprotective role of autophagy during Nectin-4-MMAE treatment and highlighted the potential of combining Nectin-4-MMAE with autophagy inhibitors for bladder cancer treatment.

Ribosomal S6 kinase 2-forkhead box protein O4 signaling pathway plays an essential role in melanogenesis.

Although previous studies have examined the signaling pathway involved in melanogenesis through which ultraviolet (UV) or α-melanocyte-stimulating hormones (α-MSH) stimuli act as key inducers to produce melanin at the stratum basal layer of the epidermis, the signaling pathway regulating melanogenesis is still controversial. This study reports that α-MSH, not UVA and UVB, acted as a major stimulus of melanogenesis in B16F10 melanoma cells. Signaling pathway analysis using gene knockdown technology and chemical inhibitors, the mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK)/p90 ribosomal S6 kinase 2 (RSK2) played an important role in melanogenesis. Unexpectedly, LY294002, a PI3K inhibitor, increased melanogenesis without UV or α-MSH stimulation, suggesting that the PI3K/AKT signaling pathway may not be a major signaling pathway for melanogenesis. Chemical inhibition of the MEKs/ERKs/RSK2 signaling pathway using U0126 or BI-D1870 suppressed melanogenesis by stimulation of UVA or α-MSH stimulation, or both. In particular, the genetic depletion of RSK2 or constitutive active (CA)-RSK2 overexpression showed that RSK2 plays a key role in melanogenesis. Interestingly, forkhead box protein O4 (FOXO4) was phosphorylated by RSK2, resulting in the increase of FOXO4's transactivation activity. Notably, the FOXO4 mutant harboring serine-to-alanine replacement at the phosphorylation sites totally abrogated the transactivation activity and reduced melanin production, indicating that RSK2-mediated FOXO4 activity plays a key role in melanogenesis. Furthermore, kaempferol, a flavonoid inhibiting the RSK2 activity, suppressed melanogenesis. In addition, FOXO4-wt overexpression showed that FOXO4 enhance melanin synthesis. Overall, the RSK2-FOXO4 signaling pathway plays a key role in modulating melanogenesis.

Iguratimod inhibits protein citrullination and inflammation by downregulating NBCe2 in patients with rheumatoid arthritis.

BACKGROUND: Bicarbonate has recently been identified as a crucial factor affecting peptidylarginine deiminase (PAD) activity; however, the mechanism underlying its role in rheumatoid arthritis (RA) remains unclear. Iguratimod (IGU), a small-molecule disease-modifying anti-rheumatic drug, requires further investigation. This study aimed to explore the mechanism by which bicarbonate affects citrullination and inflammation in RA and identify new targets for IGU. METHODS: We enrolled 20 patients with RA in the study. Sodium bicarbonate cotransporter 2 (NBCe2) was detected in the peripheral blood neutrophils and peripheral blood mononuclear cells (PBMCs) of these patients. The effects of varying concentrations of IGU, methotrexate (MTX), dexamethasone (DXM), and S0859 (an NBCe2 inhibitor) on NBCe2, PAD2, PAD4, and citrullinated histone H3 (cit-H3) levels in, migration ability of, and cytokine production from neutrophils and PBMCs were examined. RESULTS: Our findings showed that in patients with RA, citrullinated protein production by peripheral blood neutrophils instead of PBMCs, which showed higher NBCe2 expression levels, increased with an increase in the bicarbonate concentration. In addition, tumor necrosis factor-alpha (TNF-α) promoted NBCe2 expression in neutrophils from patients with RA. Furthermore, we revealed that the inhibitory effects of IGU on neutrophil NBCe2 and cit-H3 levels, degrees of inhibition of neutrophil and PBMC migration, and suppression of interleukin 6, TNF-α, and metalloproteinase-9 secretion from neutrophil-like differentiated HL-60 cells did not substantially differ from those of MTX, DXM, and S0859 at specific doses. CONCLUSIONS: Bicarbonate promotes protein citrullination and inflammation in RA via NBCe2, and IGU can downregulate NBCe2.

The antitumor effects of herbal medicine Triphala on oral cancer by inactivating PI3K/Akt signaling pathway: based on the network pharmacology, molecular docking, in vitro and in vivo experimental validation.

BACKGROUND: This research aimed to investigate the anti-tumor effects and underlying genetic mechanisms of herbal medicine Triphala (TRP) in oral squamous cell carcinoma (OSCC). METHODS: The target genes of Triphala (TRP) in oral squamous cell carcinoma (OSCC) were identified, and subsequent functional enrichment analysis was conducted to determine the enriched signaling pathways. Based on these genes, a protein-protein interaction network was constructed to identify the top 10 genes with the highest degree. Genes deregulated in OSCC tumor samples were identified to be hub genes among the top 10 genes. In vitro experiments were performed to investigate the influence of TRP extracts on the cell metabolic activity, migration, invasion, apoptosis, and proliferation of two OSCC cell lines (CAL-27 and SCC-9). The functional rescue assay was conducted to investigate the effect of applying the inhibitor and activator of an enriched pathway on the phenotypes of cancer cells. In addition, the zebrafish xenograft tumor model was established to investigate the influence of TRP extracts on tumor growth and metastasis in vivo. RESULTS: The target genes of TRP in OSCC were prominently enriched in the PI3K-Akt signaling pathway, with the identification of five hub genes (JUN, EGFR, ESR1, RELA, and AKT1). TRP extracts significantly inhibited cell metabolic activity, migration, invasion, and proliferation and promoted cell apoptosis in OSCC cells. Notably, the application of TRP extracts exhibited the capacity to downregulate mRNA and phosphorylated protein levels of AKT1 and ESR1, while concomitantly inducing upregulation of mRNA and phosphorylated protein levels in the remaining three hub genes (EGFR, JUN, and RELA). The functional rescue assay demonstrated that the co-administration of TRP and the PI3K activator 740Y-P effectively reversed the impact of TRP on the phenotypes of OSCC cells. Conversely, the combination of TRP and the PI3K inhibitor LY294002 further enhanced the effect of TRP on the phenotypes of OSCC cells. Remarkably, treatment with TRP in zebrafish xenograft models demonstrated a significant reduction in both tumor growth and metastatic spread. CONCLUSIONS: Triphala exerted significant inhibitory effects on cell metabolic activity, migration, invasion, and proliferation in OSCC cell lines, accompanied by the induction of apoptosis, which was mediated through the inactivation of the PI3K/Akt pathway.

The colonization factor CS6 of enterotoxigenic Escherichia coli contributes to host cell invasion.

Enterotoxigenic Escherichia coli (ETEC) is one of the main causes of diarrhea in children and travelers in low-income regions. The virulence of ETEC is attributed to its heat-labile and heat-stable enterotoxins, as well as its colonization factors (CFs). CFs are essential for ETEC adherence to the intestinal epithelium. However, its invasive capability remains unelucidated. In this study, we demonstrated that the CS6-positive ETEC strain 4266 can invade mammalian epithelial cells. The invasive capability was reduced in the 4266 ΔCS6 mutant but reintroduction of CS6 into this mutant restored the invasiveness. Additionally, the laboratory E. coli strain Top 10, which lacks the invasive capability, was able to invade Caco-2 cells after gaining the CS6-expressing plasmid pCS6. Cytochalasin D inhibited cell invasion in both 4266 and Top10 pCS6 cells, and F-actin accumulation was observed near the bacteria on the cell membrane, indicating that CS6-positive bacteria were internalized via actin polymerization. Other cell signal transduction inhibitors, such as genistein, wortmannin, LY294002, PP1, and Ro 32-0432, inhibited the CS6-mediated invasion of Caco-2 cells. The internalized bacteria of both 4266 and Top10 pCS6 strains were able to survive for up to 48 h, and 4266 cells were able to replicate within Caco-2 cells. Immunofluorescence microscopy revealed that the internalized 4266 cells were present in bacteria-containing vacuoles, which underwent a maturation process indicated by the recruitment of the early endosomal marker EEA-1 and late endosomal marker LAMP-1 throughout the infection process. The autophagy marker LC3 was also observed near these vacuoles, indicating the initiation of LC-3-associated phagocytosis (LAP). However, intracellular bacteria continued to replicate, even after the initiation of LAP. Moreover, intracellular filamentation was observed in 4266 cells at 24 h after infection. Overall, this study shows that CS6, in addition to being a major CF, mediates cell invasion. This demonstrates that once internalized, CS6-positive ETEC is capable of surviving and replicating within host cells. This capability may be a key factor in the extended and recurrent nature of ETEC infections in humans, thus highlighting the critical role of CS6.

Comparative study on Antibacterial efficacy of a series of chromone sulfonamide derivatives against drug-resistant and MDR-isolates.

Sulfonamide derivatives have numerous pharmaceutical applications having antiviral, antibacterial, antifungal, antimalarial, anticancer, and antidepressant activities. The structural flexibility of sulfonamide derivatives makes them an excellent candidate for the development of new multi-target agents, although long-time exposure to sulfonamide drugs results in many toxic impacts on human health. However, sulfonamides may be functionalized for developing less toxic and more competent drugs. In this work, sulfonamides including Sulfapyridine (a), Sulfathiazole (b), Sulfamethoxazole (c), and Sulfamerazine (d) are used to synthesize Schiff bases of 7-hydroxy-4-methyl-2-oxo-2H-chromene-8-carbalde-hyde (1a-1d). The synthesized compounds were spectroscopically characterized and tested against hospital isolates of three Gram-positive (Methicillin-resistant Staphylococcus aureus PH217, Ampicillin-resistant Coagulase-negative Staphylococcus aureus, multidrug-resistant (MDR) Enterococcus faecalis PH007R) and two Gram-negative bacteria (multidrug-resistant Escherichia coli, and Salmonella enterica serovar Typhi), compared to the quality control strains from ATCC (S. aureus 29213, E. faecalis 25922, E. coli 29212) and MTCC (S. Typhi 734). Two of the four Schiff bases 1a and 1b are found to be more active than their counterpart 1c and 1d; while 1a have showed significant activity by inhibiting MRSA PH217 and MDR isolates of E. coli at the minimum inhibitory concentration (MIC) of 150 µg/mL and 128 µg/mL with MBC of 1024 µg/mL, respectively. On the other hand, the MIC of 1b was 150 µg/mL against both S. aureus ATCC 29213 and Salmonella Typhi MTCC 734, compared to the control antibiotics Ampicillin and Gentamycin. Scanning electron microscopy demonstrated the altered surface structure of bacterial cells as a possible mechanism of action, supported by the in-silico molecular docking analysis.

A pair of new chromone enantiomers from Xylaria nigripes.

A pair of new chromone derivative enantiomers, (+)-xylarichromone A (1a) and (-)-xylarichromone A (1b), were isolated from the solid fermentation of Xylaria nigripes. The planar structure of 1 was determined by extensive NMR spectroscopic data, and its absolute configuration was assigned by comparison the ECD spectra with the known chromone derivatives. Compound 1 was the first chromone derivative reported from this medicinal fungus. The neuroprotective effects of 1 against oxygen and glucose deprivation (OGD) induced pheochromocytoma-12 cells (PC12) injury was investigated.

Enzymatic biosynthesis of novel 2-(2-phenylethyl)chromone glycosides catalyzed by UDP-glycosyltransferase UGT71BD1.

2-(2-Phenylethyl)chromones (PECs) are the main bioactive components of agarwood which showed diverse pharmaceutical activities. Glycosylation is a useful structural modification method to improve compounds' druggability. However, PEC glycosides were rarely reported in nature which largely limited their further medicinal investigations and applications. In this study, the enzymatic glycosylation of four naturally separated PECs 1-4 was achieved using a promiscuous glycosyltransferase UGT71BD1 identified from Cistanche tubulosa. It could accept UDP-Glucose, UDP-N-acetylglucosamine and UDP-xylose as sugar donors and conduct the corresponding O-glycosylation of 1-4 with high conversion efficiencies. Three O-glucosylated products 1a (5-hydroxy-2-(2-phenylethyl)chromone 8-O-ß-D-glucopyranoside), 2a (8-chloro-2-(2-phenylethyl)chromone 6-O-ß-D-glucopyranoside) and 3a (2-(2-phenylethyl)chromone 6-O-ß-D-glucopyranoside) were prepared and structurally elucidated as novel PEC glucosides based on NMR spectroscopic analyses. Subsequent pharmaceutical evaluation found that 1a showed remarkably improved cytotoxicity against HL-60 cells, whose cell inhibition rate was 19 times higher than that of its aglycon 1. The IC50 value of 1a was further determined to be 13.96 ± 1.10 µM, implying its potential as a promising antitumor-leading candidate. To improve the production of 1, docking, simulation and site-directed mutagenesis were performed. The important role of P15 in the glucosylation of PECs was discovered. Besides, a mutant K288A with a two-fold increased yield for 1a production was also afforded. This research reported the enzymatic glycosylation of PECs for the first time, and also provide an eco-friendly pathway for the alternative production of PEC glycosides for leading compounds discovery.

Selective Induction of DNA Damage and Cell Cycle Arrest Mediated by Chromone-Triazole Dyads Derivatives: Effects on Breast and Prostate Cancer Cells.

Chromones and triazoles are groups of heterocyclic compounds widely known to exhibit a broad spectrum of biological activities. The combination of these two pharmacophores could result in multiple mechanisms of action to increase the potency of anticancer drugs and reduce their side effects. The in vitro antitumor effect of eight chromone-based compounds was evaluated in breast (T-47D and MDA-MB-231) and prostate (PC3) cancer cell lines, and in non-cancerous human mammary epithelial cells (HuMEC) using a resazurin-based method. Flow cytometry was used to evaluate the cell cycle and cell death, and É£-H2AX detection to identify DNA damage. The compounds showed selective cytotoxicity against cancer cell lines, with (E)-2-(2-(5-(4-methoxyphenyl)-2H-1,2,3-triazol-4-yl)vinyl)-4H-chromen-4-one (compound 2 a) being more potent in non-metastatic T-47D cells (IC50 0.65 µM). Replacing the hydrogen by a methyl group on the triazole ring in compound 2 b enhanced the cytotoxic activity up to IC50 0.24 µM in PC3, 0.32 µM in MDA-MB-231 and 0.52 µM in T-47D. Compound 2 b was 3-fold more potent than doxorubicin in PC3 (IC50 0.73 µM) and 4-fold in MDA-MB-231 (IC50 1.51 µM). The addition of tetrahydroisoindole-1,3-dione moiety in compound 5 did not improve its effectiveness in any of the cell lines but it exerted the lowest cytotoxic effect in HuMEC (IC50 221.35 µM). The compounds revealed different cytotoxic mechanisms: 2 a and 2 b induced G2/M arrest, and compound 5 did not affect the cell cycle.

AZD8186 in Combination With Paclitaxel in Patients With Advanced Gastric Cancer: Results From a Phase Ib/II Study (KCSG ST18-20).

BACKGROUND: Loss of PTEN function leads to increased PI3Kß signaling. AZD8186, a selective PI3Kß/δ inhibitor, has shown anti-tumor activity in PTEN-deficient preclinical models. Although the combination of AZD8186 and paclitaxel was well tolerated, limited clinical efficacy was observed in advanced gastric cancer with PTEN loss. METHODS: In the phase Ib dose-escalation, subjects with advanced solid tumors received oral AZD8186 (60 mg or 120 mg; twice daily (BID); 5 days on/2 days off) plus intravenous paclitaxel (70 mg/m2 or 80 mg/m2; days 1, 8, and 15) every 4 weeks. In the phase II part, MRGC patients with PTEN loss or PTEN/PIK3CB gene abnormality were enrolled and received recommended phase II dose (RP2D) of AZD8186 plus paclitaxel. Primary endpoints were to determine maximum tolerated dose (MTD) and RP2D in phase Ib and 4-month progression-free survival (PFS) rate in phase II. RESULTS: In phase Ib, both MTD and RP2D were determined at paclitaxel 80 mg/m2 and AZD8186 120 mg BID. In phase II, 18 patients were enrolled [PTEN loss (n = 18) and PIK3CB mutation (n = 1)]. The 4-month PFS rate was 18.8% (3 of 16 evaluable patients) and further enrollment stopped due to futility. CONCLUSION: Although the combination of AZD8186 and paclitaxel was well tolerated, limited clinical efficacy was observed.ClinicalTrials.gov Identifier: NCT04001569.

Pauciflorins A-E, Unexpected Chromone-Monoterpene-Derived Meroterpenoids from Centrapalus pauciflorus.

Five unusual meroterpenoids based on new carbon skeletons, pauciflorins A-E (1-5), were isolated by multistep chromatographic separations of a methanol extract of the aerial parts of Centrapalus pauciflorus. Compounds 1-3 are derived by the connection of a 2-nor-chromone and a monoterpene unit, whereas 4 and 5 are dihydrochromone-monoterpene adducts with a rarely occurring orthoester functionality. The structures were solved using 1D and 2D NMR, HRESIMS, and single-crystal X-ray diffraction. Pauciflorins A-E were evaluated for antiproliferative activity against human gynecological cancer cell lines, but were inactive (IC50 < 10 µM) in each case.

Molecular docking, QSAR, pharmacophore modeling, and dynamics studies of some chromone derivatives for the discovery of anti-breast cancer agents against hormone-dependent breast cancer.

In search of new anti-breast cancer agents, the present study envisaged the design and synthesis of a series of benzopyran-chalcones. All the synthesized compounds were assayed for their in-vitro anticancer activity against ER + MCF-7 and triple-negative MDA-MB-231 breast cancer cell lines using SRB assay. The synthesized compounds were found active against ER + MCF-7 cell lines. Based on the in-vitro data, in-silico analysis was performed using hormone-dependent breast cancer targets such as hER-α and aromatase because the compounds showed activity against MCF-7 cells and none was active against MDA-MB-231. The in-silico results supported the in-vitro anticancer activity suggesting the affinity of compounds toward hormone-dependant breast cancer. Compounds 4A1 to 4A3 were found to be most cytotoxic to MCF-7 cells with IC50 values of 31.87, 22.95, and 20.34 µg/ml, respectively (Doxorubicin IC50: <10 µg/ml). In addition, they showed the interactions with the amino acid residues of a binding cavity of an hER-α. Furthermore, quantitative structure-activity relationship (QSAR) studies were performed to reveal the vital structural features required for anticancer activity against breast cancer. Molecular dynamic simulation studies of hER-α and 4A3 in comparison with the raloxifene complex ensure the appropriate refinement of compounds in the dynamic system. Additionally, a generated pharmacophore model explored the essential pharmacophoric features of the synthesized scaffolds with respect to clinically used drug molecules for optimal hormone-dependant anti-breast cancer activity.Communicated by Ramaswamy H. Sarma.

Field and atom-based 3D-QSAR models of chromone (1-benzopyran-4-one) derivatives as MAO inhibitors.

Monoamine oxidases (MAOs) are flavo-enzymes that aid in the oxidative deamination of neurotransmitters like dopamine, serotonin, and epinephrine. MAO inhibitors are antidepressants that work by preventing the breakdown of brain neurotransmitters and regulating mood. MAO inhibitors that use the chromone (1-benzopyran-4-one) structure have been found to be quite effective in studies. The current study involves the creation of pharmacophore models, 3-D QSAR, virtual screening, and docking investigations, all of which are evaluated using various criteria. The investigation included 39 ligands that emerged pharmacophore AHRRR_1, as the best pharmacophore model with a survival score of 5.6485. The 3D QSAR investigation revealed a significant model with the values of R2 = 0.9064 and Q2 = 0.8239. Docking study revealed that compound 18 had the highest docking (-10.402 kcal/mol) score in the series and showed interactions with the essential amino acid TYR398 required for MAO inhibitory activity. ZINC compounds were screened using the created pharmacophore model, which was followed up with a virtual screening study. The ZINC compounds with the best XP docking scores are ZINC03113255, ZINC07777127, ZINC05166353 and ZINC09341502 (with docking scores -10.021, -9.486, -8.031 and -7.792 kcal/mol, respectively). ZINC03113255, which showed the best score, has binding interactions with amino acid residues, TYR326, TYR398 and LYS296 of monoamine oxidase B. The ADME analysis demonstrated the compound's drug-like characteristics. The findings of this study may be used in the development of chromone compounds that target the MAO inhibitor.Communicated by Ramaswamy H. Sarma.

Seven new 2-(2-phenethyl)chromone derivatives from agarwood of Aquilaria walla.

Two rare flavonoid-2-(2-phenylethyl)chromones and five new dimeric 2-(2-phenylethyl)chromones were isolated from ethanol extract of agarwood of Aquilaria walla by LC-MS-guided fractionation procedure. Their structures were established based on extensive spectroscopic methods including HRESIMS, 1D and 2D NMR, as well as by comparison with the literature. Compound 1 showed cytotoxic activity against five human cancer cell lines with IC50 values ranging from 13.40 to 28.96 µM with cisplatin as the positive control.