Synthesis of bioactive evodiamine and rutaecarpine analogues under ball milling conditions.

Mechanochemical reactions achieved by processes such as milling and grinding are promising alternatives to traditional solution-based chemistry. This approach not only eliminates the need for large amounts of solvents, thereby reducing waste generation, but also finds applications in chemical and materials synthesis. The focus of this study is on the synthesis of quinazolinone derivatives by ball milling, in particular evodiamine and rutaecarpine analogues. These compounds are of interest due to their diverse bioactivities, including potential anticancer properties. The study examines the reactions carried out under ball milling conditions, emphasizing their efficiency in terms of shorter reaction times and reduced environmental impact compared to conventional methods. The ball milling reaction of evodiamine and rutaecarpine analogues resulted in yields of 63-78% and 22-61%, respectively. In addition, these compounds were tested for their cytotoxic activity, and evodiamine exhibited an IC50 of 0.75 ± 0.04 µg mL-1 against the Ca9-22 cell line. At its core, this research represents a new means to synthesise these compounds, providing a more environmentally friendly and sustainable alternative to traditional approaches.

Boesenbergia stenophylla-Derived Stenophyllol B Exerts Antiproliferative and Oxidative Stress Responses in Triple-Negative Breast Cancer Cells with Few Side Effects in Normal Cells.

Triple-negative breast cancer (TNBC) is insensitive to target therapy for non-TNBC and needs novel drug discovery. Extracts of the traditional herb Boesenbergia plant in Southern Asia exhibit anticancer effects and contain novel bioactive compounds but merely show cytotoxicity. We recently isolated a new compound from B. stenophylla, stenophyllol B (StenB), but the impact and mechanism of its proliferation-modulating function on TNBC cells remain uninvestigated. This study aimed to assess the antiproliferative responses of StenB in TNBC cells and examine the drug safety in normal cells. StenB effectively suppressed the proliferation of TNBC cells rather than normal cells in terms of an ATP assay. This preferential antiproliferative function was alleviated by pretreating inhibitors for oxidative stress (N-acetylcysteine (NAC)) and apoptosis (Z-VAD-FMK). Accordingly, the oxidative-stress-related mechanisms were further assessed. StenB caused subG1 and G2/M accumulation but reduced the G1 phase in TNBC cells, while normal cells remained unchanged between the control and StenB treatments. The apoptosis behavior of TNBC cells was suppressed by StenB, whereas that of normal cells was not suppressed according to an annexin V assay. StenB-modulated apoptosis signaling, such as for caspases 3, 8, and 9, was more significantly activated in TNBC than in normal cells. StenB also caused oxidative stress in TNBC cells but not in normal cells according to a flow cytometry assay monitoring reactive oxygen species, mitochondrial superoxide, and their membrane potential. StenB induced greater DNA damage responses (γH2AX and 8-hydroxy-2-deoxyguanosine) in TNBC than in normal cells. All these StenB responses were alleviated by NAC pretreatment. Collectively, StenB modulated oxidative stress responses, leading to the antiproliferation of TNBC cells with little cytotoxicity in normal cells.

Synthesis and Anticancer Evaluation of 4-Anilinoquinolinylchalcone Derivatives.

A series of 4-anilinoquinolinylchalcone derivatives were synthesized and evaluated for antiproliferative activities against the growth of human cancer cell lines (Huh-7 and MDA-MB-231) and normal lung cells (MRC-5). The results exhibited low cytotoxicity against human lung cells (MRC-5). Among them, (E)-3-{4-{[4-(benzyloxy)phenyl]amino}quinolin-2-yl}-1-(4-methoxyphenyl) prop-2-en-1-one (4a) was found to have the highest cytotoxicity in breast cancer cells and low cytotoxicity in normal cells. Compound 4a causes ATP depletion and apoptosis of breast cancer MDA-MB-231 cells and triggers reactive oxygen species (ROS)-dependent caspase 3/7 activation. In conclusion, it is worth studying 4-anilinoquinolinylchalcone derivatives further as new potential anticancer agents for the treatment of human cancers.

Marine Sponge Aaptos suberitoides Extract Improves Antiproliferation and Apoptosis of Breast Cancer Cells without Cytotoxicity to Normal Cells In Vitro.

The anticancer effects and mechanisms of marine sponge Aaptos suberitoides were rarely assessed, especially for methanol extract of A. suberitoides (MEAS) to breast cancer cells. This study evaluated the differential suppression effects of proliferation by MEAS between breast cancer and normal cells. MEAS demonstrated more antiproliferation impact on breast cancer cells than normal cells, indicating oxidative stress-dependent preferential antiproliferation effects on breast cancer cells but not for normal cells. Several oxidative stress-associated responses were highly induced by MEAS in breast cancer cells but not normal cells, including the generations of cellular and mitochondrial oxidative stress as well as the depletion of mitochondrial membrane potential. MEAS downregulated cellular antioxidants such as glutathione, partly contributing to the upregulation of oxidative stress in breast cancer cells. This preferential oxidative stress generation is accompanied by more DNA damage (γH2AX and 8-hydroxy-2-deoxyguanosine) in breast cancer cells than in normal cells. N-acetylcysteine reverted these MEAS-triggered responses. In conclusion, MEAS is a potential natural product for treating breast cancer cells with the characteristics of preferential antiproliferation function without cytotoxicity to normal cells in vitro.

Burmannic Acid Inhibits Proliferation and Induces Oxidative Stress Response of Oral Cancer Cells.

Burmannic acid (BURA) is a new apocarotenoid bioactive compound derived from Indonesian cinnamon; however, its anticancer effect has rarely been investigated in oral cancer cells. In this investigation, the consequences of the antiproliferation of oral cancer cells effected by BURA were evaluated. BURA selectively suppressed cell proliferation of oral cancer cells (Ca9-22 and CAL 27) but showed little cytotoxicity to normal oral cells (HGF-1). In terms of mechanism, BURA perturbed cell cycle distribution, upregulated mitochondrial superoxide, induced mitochondrial depolarization, triggered γH2AX and 8-hydroxy-2-deoxyguanosine DNA damage, and induced apoptosis and caspase 3/8/9 activation in oral cancer cells. Application of N-acetylcysteine confirmed oxidative stress as the critical factor in promoting antiproliferation, apoptosis, and DNA damage in oral cancer cells.

Soft Coral-Derived Dihydrosinularin Exhibits Antiproliferative Effects Associated with Apoptosis and DNA Damage in Oral Cancer Cells.

Dihydrosinularin (DHS) is an analog of soft coral-derived sinularin; however, the anticancer effects and mechanisms of DHS have seldom been reported. This investigation examined the antiproliferation ability and mechanisms of DHS on oral cancer cells. In a cell viability assay, DHS showed growth inhibition against several types of oral cancer cell lines (Ca9-22, SCC-9, OECM-1, CAL 27, OC-2, and HSC-3) with no cytotoxic side effects on non-malignant oral cells (HGF-1). Ca9-22 and SCC-9 cell lines showing high susceptibility to DHS were selected to explore the antiproliferation mechanisms of DHS. DHS also causes apoptosis as detected by annexin V, pancaspase, and caspase 3 activation. DHS induces oxidative stress, leading to the generation of reactive oxygen species (ROS)/mitochondrial superoxide (MitoSOX) and mitochondrial membrane potential (MitoMP) depletion. DHS also induced DNA damage by probing γH2AX phosphorylation. Pretreatment with the ROS scavenger N-acetylcysteine (NAC) can partly counter these DHS-induced changes. We report that the marine natural product DHS can inhibit the cell growth of oral cancer cells. Exploring the mechanisms of this cancer cell growth inhibition, we demonstrate the prominent role DHS plays in oxidative stress.

Bioequivalence for a Fixed-Dose Combination Formulation of Bazedoxifene and Cholecalciferol Compared With the Corresponding Single Entities Given Together.

A fixed-dose combination (FDC) formulation of bazedoxifene 20 mg and cholecalciferol 8 mg was developed to increase medication compliance and convenience for osteoporosis patients. This study was conducted to demonstrate bioequivalence by comparing the pharmacokinetic (PK) profiles and tolerability of an FDC tablet and the individual component tablets. A randomized, open-label, single-dosing, 2-treatment, 2-period, 2-sequence crossover study was conducted in 52 healthy subjects. All subjects were randomly assigned to 2 sequences, and they received FDC tablets of bazedoxifene and cholecalciferol and individual component tablets. Serial blood samples for PK evaluation were collected up to 24 hours predose and 120 hours postdose, and the PK parameters were estimated by noncompartmental methods. Throughout the study, tolerability was assessed based on adverse events, vital signs, and clinical laboratory tests. Of the enrolled 52 subjects, 47 subjects completed the study. The results, the geometric mean ratios (GMRs) and 90% confidence intervals (90%CIs), of bazedoxifene Cmax and AUC0-t for FDC to single entities given together were 0.98 (0.91-1.05) and 1.02 (0.97-1.07), respectively. The GMRs (90%CIs) of cholecalciferol Cmax and AUC0-t for FDC to single entities given together were 0.96 (0.91-1.00) and 0.94 (0.90-0.99), respectively. Overall, the GMRs (90%CIs) of the PK parameter of bazedoxifene and cholecalciferol fell within the conventional bioequivalence range of 0.8-1.25. There were no clinically significant differences in the safety profile between the 2 treatments. In conclusion, this study confirmed the development of a new FDC drug by demonstrating that the FDC formulation of bazedoxifene and cholecalciferol is biologically equivalent to the coadministered individual formulations.

Comparison of pharmacokinetics and safety characteristics between two olopatadine hydrochloride 5 mg tablet formulations in healthy Korean subjects.

Histamine acts by binding to four histamine receptors (H1 to H4), of which the H1 is known to participate in dilate blood vessels, bronchoconstriction, and pruritus. Olopatadine hydrochloride blocks the release of histamine from mast cells and it inhibits H1 receptor activation. Olopatadine hydrochloride is anti-allergic agent that is effectively used. The object of this study had conducted to compare the pharmacokinetics (PKs) and safety characteristics between olopatadine hydrochloride 5 mg (test formulation) and olopatadine hydrochloride 5 mg (reference formulation; Alerac ®) in Korean subjects. This study had conducted an open-label, randomized, fasting condition, single-dose, 2-treatment, 2-period, 2-way crossover. Subjects received single-dosing of reference formulation or test formulation in each period and blood samples were collected over 24 hours after administration for PK analysis. A wash-out period of 7 days was placed between the doses. Plasma concentration of olopatadine were determined using liquid chromatography-tandem spectrometry mass (LC-MS/MS). A total of 32 subjects were enrolled and 28 subjects completed. There were not clinical significantly different in the safety between two treatment groups for 32 subjects who administered the study drug more than once. The geometric mean ratio of test formulation to reference formulation and its 90% confidence intervals for The peak plasma concentration (Cmax) and the areas under the plasma concentration-time curve from 0 to the last concentration (AUClast) were 1.0845 (1.0107-1.1637) and 1.0220 (1.0005-1.0439), respectively. Therefore, the test formulation was bioequivalent in PK characteristics and was equally safe as the reference formulation. TRIAL REGISTRATION: Clinical Research Information Service Identifier: KCT0005943.

A randomized, open-label, crossover study to compare the safety and pharmacokinetics of two tablet formulations of tenofovir (tenofovir disoproxil and tenofovir disoproxil fumarate) in healthy subjects.

PURPOSE: This study was performed to compare the pharmacokinetic properties and assess bioequivalence for the test formulation (HUG116 tablet; tenofovir disoproxil) and reference formulation (Viread tablet; tenofovir disoproxil fumarate). MATERIALS AND METHODS: A randomized, open-label, single-dosing, two-treatment, two-period, two-sequence cross-over study was conducted in 50 healthy subjects. All subjects were randomly assigned to one of the two sequences, and they received a single dose of test or reference formulation in the first period and the alternative formulation during the next period under fasting conditions. Serial blood samples for pharmacokinetic evaluation were collected up to 72 hours post dose, and the pharmacokinetic parameters were estimated by noncompartmental methods. Throughout the study, tolerability was assessed based on adverse events, vital signs, and clinical laboratory tests. RESULTS: The test formulation showed similar pharmacokinetic profiles to those of the reference formulation. The geometric mean ratio and 90% confidence interval (CI) of the test formulation to the reference formulation for maximum plasma concentration (Cmax) was 0.93 (0.87 - 0.99), and the corresponding value for the area under the concentration-time curve from time zero to time of last quantifiable concentration (AUCt) was 0.94 (0.89 - 0.99). Both CIs were within the conventional bioequivalence range of 0.8 - 1.25. The tolerability profile was not significantly different between the test and reference formulations. CONCLUSION: This study found that the PKs of the test formulation (HUG116 tablet; tenofovir disoproxil) and reference formulation (Viread tablet; tenofovir disoproxil fumarate) were similar, and the test formulation met the regulatory criteria for assuming bioequivalence with the reference formulation.

Pharmacokinetic comparison of two bazedoxifene acetate 20 mg tablet formulations in healthy Korean male volunteers.

Bazedoxifene, used as bazedoxifene acetate, is a selective estrogen receptor modulator that selectively affects the uterus, breast tissue, bone metabolism, and lipid metabolism by antagonizing or enhancing estrogens in the estrogen receptor in the tissue. This study was conducted as an open, randomized, two-period, two-treatment, crossover design to compare the pharmacokinetic (PK) characteristics and tolerability of two bazedoxifene tablets when administered to 50 healthy Korean male volunteers. Enrolled subjects were randomly allocated to 2 sequences of a single oral administration of a test drug and a reference drug, or vice versa with a 14-day washout period between the two doses. Serial blood samples were collected over 96 h for PK analysis. Plasma concentration of bazedoxifene was assayed using liquid chromatography-tandem spectrometry mass. Forty-five participants completed the study with no clinically relevant safety issues. The peak concentrations (Cmax, mean ± strandard deviation) of reference drug and test drug were 3.191 ± 1.080 and 3.231 ± 1.346 ng/mL, respectively, and the areas under the plasma concentration-time curve from 0 to the last measurable concentration (AUClast) were 44.697 ± 21.168 ng∙h/mL and 45.902 ± 23.130 ng∙h/mL, respectively. The geometric mean ratios of test drug to reference drug and their 90% confidence intervals for Cmax and AUClast were 0.9913 (0.8828-1.1132) and 1.0106 (0.9345-1.0929), respectively. The incidence of adverse events between the two formulations was similar. The present study showed that PK and tolerability of two bazedoxifene tablet formulations were comparable when administered to healthy Korean male volunteers. TRIAL REGISTRATION: Clinical Research Information Service Identifier: KCT0003978.