Human Tumor Cell Lines Research Articles

Synthesis of derived Cu(II) complex from Schiff base of Vitamin B6 and antihypertensive hydralazine: DNA interaction, biological application and molecular docking studies

A novel Schiff base ligand (E)-5-(hydroxymethyl)-2-methyl-4-((2-(phthalazin-1-yl)hydrazineylidene)methyl)pyridin-3-ol was synthesized through the condensation of antihypertensive hydralazine and Pyridoxal (Vitamin B6) ligands. This fabricated Schiff base (L) was a precursor for developing a unique Cu(II) complex. TheSchiff base ligand and Cu(II) complex structureswere characterized using various analytical tools, including IR, UV–Vis Spectroscopy and NMR. An octahedron geometry of this complex was proposed for the assigned molecular formula [Cu(L)2].3H2O. The molecular structures of theSchiff base ligand and its Cu(II) complex have been optimized using the B3LYP functional and the 6-311G++(d,p) basis set. Investigating the interaction of this prepared Cu(II) complex with calf thymus DNA (CT-DNA) molecules was operated using UV–Vis spectrophotometry, viscosity measurement, electrochemical studies, gel electrophoresis, and molecular docking. In vitro cytotoxicity was conducted using the MTT assay on four human tumor cell lines including hepatocellular carcinoma, estrogen-dependent breast cancer, melanoma, triple-negative breast cancer as well as healthy human skin fibroblasts.

LncRNA H19 Activates the RAS-MAPK Signaling Pathway via miR-140-5p/SOS1 Axis in Malignant Liver Tumors.

To study the influences of LncRNA H19 (H19) on malignant liver tumor cells and elucidate the underlying molecular mechanisms. H19 expression in liver tumor tissues, matched normal liver tissues, human liver malignant tumor cell lines and the human hepatocyte line LO2 was assessed via quantitative RT-PCR. Cell viability analysis and Matrigel invasion analysis were performed to evaluate the effects of H19 on cell proliferation and invasion. Luciferase reporter analysis was carried out to assess the interaction between miR-140-5p and SOS Ras/Rac guanine nucleotide exchange factor 1 (SOS1). The influence of H19 on the Ras-MAPK signalling pathway was evaluated by detecting key protein levels via active Ras pull-down analysis and Western blot analysis. H19 expression was lower in liver cancer samples than in matched normal liver tissue samples. H19 overexpression enhanced the proliferation and invasion of HepG2 and SMMC-7721 cells. H19 overexpression increased the level of activated Ras. The expression levels of phosphorylated Raf, phosphorylated ERK and phosphorylated MEK were increased by H19 overexpression. H19 knockdown had the opposite effect. Treatment with a MAPK inhibitor significantly reversed the influence of H19 overexpression on liver malignant tumor cell growth and invasion. The MAPK activator reversed the opposing effects of H19 silencing. H19 overexpression increased the protein level of SOS1, and miR-140-5p directly targeted SOS1. H19 can activate the Ras-MAPK signalling pathway via the miR-140-5p/SOS1 axis in malignant liver tumour cells.

Increased cell killing effect in neutron capture enhanced proton beam therapy

Thermal neutrons generated in the body during proton beam therapy (PBT) can be used to cause boron neutron capture reactions and have recently been proposed as neutron capture enhanced PBT (NCEPBT). However, the cell killing effect of NCEPBT remains underexplored. Here, we show an increase in the cell killing effect of NCEPBT. Using Monte Carlo simulations, we showed that neutrons generated by proton beam irradiation are uniformly spread on tissue culture plates. Human salivary gland tumor cell line (HSG), human osteosarcoma cell line (MG63), human tongue squamous cell carcinoma cell line (SAS), and human malignant melanoma cell line (G-361) were irradiated with X-rays, proton beams, and proton beams with 10B-enriched boronophenylalanine (boron concentration of 20 and 80 ppm). The relative biological effectiveness (RBE) values of proton beams alone, proton beams with 20 ppm boron, and proton beams with 80 ppm boron for HSG, MG63, SAS, and G-361 were 1.02, 1.07, and 1.23; 1.01, 1.08, and 1.44; 1.05, 1.09, and 1.46; and 1.04, 1.13, and 1.63, respectively. NCEPBT with high boron concentration showed high RBE and a high sensitizing effect. Our results confirm an increase in the cell killing effect of NCEPBT, should aid in its clinical use, and warrant its further investigation.

EXTH-55. ANTI-TUMOR ACTIVITY OF A NEW ONCOLYTIC ADENOVIRUS DELTA-24-RGDOX-IL15 CO-EXPRESSING OX40L AND IL-15

Abstract Accumulating evidence show that the interaction between oncolytic viruses (OVs) and host immune system plays an essential role in cancer virotherapy. Compared to lytic potency of OVs, enhancement of OV-mediated anti-tumor immunity has become a more attractive strategy to improve OV efficacy. To this end, we have reported that the third-generation oncolytic adenovirus (OA), Delta-24-RGDOX, which expresses the immune co-stimulator OX40 ligand (OX40L), is more potent to elicit anti-tumor immunity than the second-generation OA Delta-24-RGD. Since IL-15 activates T and NK cells and promotes persistence of CD8+ memory T cells, we hypothesize that co-expression of OX40L and IL-15 by OAs will further potentiate their efficacy. For this purpose, we constructed the next generation OA Delta-24-RGDOX-IL15. In cultured human and murine tumor cell lines, this new virus effectively expressed the two molecules and displayed comparable potency in viral replication and oncolysis as OAs expressing either of the two (Delta-24-RGDOX, Delta-24-RGD-IL15). Then, we tested the anti-tumor activity of Delta-24-RGDOX-IL15 (two doses, intratumorally, one week interval) in two syngeneic tumor models in C57BL/6 mice: 1) intracranial (i.c.) gliomas from GL261-5 cells; 2) subcutaneous (s.c.)/i.c. melanomas from B16 cells (virus injected into s.c. tumors only). We found Delta-24-RGDOX-IL15 was more efficacious than the other two OAs to inhibit tumor growth of both treated tumor and the untreated i.c. tumors in the second model, leading to long-term survivors (p < 0.05). Different from adoptive cell therapies with cells engineered to express IL-15, we haven’t observed any obvious toxicity with this new virus when it was injected intratumorally into either the i.c. or s.c. tumors. Further studies are in progress to analyze the modifications of the tumor microenvironment induced by the addition of IL-15 to Delta-24-RGDOX. We expect this virus to be a good candidate to be combined with CAR T cell therapies.

Structurally Diverse Limonoids from Trichilia connaroides and Their Antitumor Activities

Comprehensive SummaryTwelve new limonoids (1—12), named trichilitins A—L, were isolated from the leaves and twigs of Trichilia connaroides, together with ten known compounds (13—22). The structures were elucidated by extensive spectroscopic investigations, X‐ray diffraction analyses, and ECD calculations. Compound 1, which belongs to a unique class of ring B‐seco limonoid, has been identified as 6/7/6/5 tetracyclic due to a key Baeyer‐Villiger oxidation. Compounds 2—7 were identified as ring intact limonoids, while compounds 8—10 were established as ring D‐seco ones, and 11 and 12 were determined to be rearranged ones. All of the compounds were tested for cytotoxicity against three human tumor cell lines (HCT‐116, NCl‐H1975, and SH‐SY5Y). Compounds 6, 7, 13, 14, and 19 exhibited significant cytotoxic effects, especially 7 exhibited significant cytotoxic effects against HCT‐116 with an IC50 value of 0.035 μmol·L–1 and was more active than the positive control, doxorubicin with an IC50 value of 0.20 μmol·L–1. Compound 7 effectively induced apoptosis of HCT‐116, which was associated with S‐phase cell cycle arrest. Furthermore, the Western blot analysis showed that compound 7 could induce cell cycle arrest by promoting the expression levels of p53 and p21.

Synthesis, biological evaluation, and in silico studies of lantadene-derived pentacyclic triterpenoids as anticancer agents targeting IKK-β

We report the anticancer activity, structure-activity relationships (SAR), molecular mechanism, and in silico docking studies of nine pentacyclic triterpenoids derived from lantadene A. The NCI-60 cytotoxicity screening of synthesized compounds on 60 human tumor cell lines, representing nine different cancers revealed that compound 6, bearing dual C-3 and C-22 butyryloxy substitutions at the pentacyclic triterpenoid scaffold, displays remarkable potency with mean growth inhibition of 98.7% at 10 μM. The SRB five-dose assay of compound 6 exhibited that it suppresses the growth of all NCI-60 cell lines with a GI50 value in the single-digit micromolar range, except for one. The Western blot analysis revealed that compound 6 inhibits the expression of IKK-β and its down-stream effector NF-κB (p65). Molecular docking analysis of compound 6 with IKK-β showed hydrogen bond interactions with GLN425 and ARG427 and hydrophobic contact with PHE424 residues as the prominent interactions. Molecular dynamics simulation of the docked complex suggested that the complex was fairly stable. Compound 7, possessing the isobutyryloxy groups at the analogous positions of compound 6 was the second-favorable anticancer agent. Conversely, the substitution of the hydroxy group in compounds emerged as the least favorable substitution at both the C-3 and C-22 positions of the pharmacophore. The presence of the 22β-angeloyloxy side-chain, akin to the natural product lantadene A, exhibited moderate favorability for enhanced activity. As a whole, the cytotoxicity data of compounds underscores the preference for linear and extended substitutions at both the C-3 and C-22 positions of the pharmacophore for heightened activity.

Ly6E on tumor cells impairs anti-tumor T-cell responses: a novel mechanism of tumor-induced immune exclusion

BackgroundLymphocyte antigen 6 complex, locus E (Ly6E) has been initially demonstrated to involve in T cell activity and impair viral infectivity. Recently, high expression levels of Ly6E have been reported in tumor microenvironment (TME) of various types of cancers. However, the immunoregulatory mechanism of Ly6E manipulating TME remains unknown.MethodsTCGA database and Kaplan–Meier plotter database were used to evaluate the correlation between Ly6E expression levels and cancer patient survival. After analyzing Ly6E expression levels in human breast cancer tissues and tumor cell lines, we generated Ly6E knockout (KO) and overexpression (OE) mouse cell lines. Cell proliferation ability in vitro and the ability of growth and metastasis in mouse tumor models were compared between KO/OE and wild-type tumor cells. On day 7 after tumor implantation, tumor tissues were separated for flow cytometric assay, bulk RNA sequencing and single-cell RNA sequencing (ScRNA-seq). The role of Ly6E-expressing tumor cell on macrophage was analyzed in vitro.ResultsOur result surprisingly found that high Ly6E expression levels were associated with CD8+ T cell exclusion in tumor tissues and resistance to immunotherapy. Our data showed that knockout of Ly6E in tumor cells prompts tumor regression and inhibits tumor metastases, and Ly6E-OE tumor cells vice versa. The enhanced anti-tumor effect of Ly6E knockout in tumor cells was dependent on T cell response and formed long-lasting memory. The increase in the CD8+ T-cell infiltration into the tumor islet of Ly6E-KO tumors confirmed the role of Ly6E on T cell exclusion. ScRNA-seq analysis showed that M2 macrophages are particularly abundant in the Ly6E-expressing tumor tissues, especially M2-4 macrophage cluster identified by high levels of Arg-1, indicates that Ly6E-expressing tumor cells might restrict T cell infiltration via M2 macrophages. Moreover, in vitro assay showed that cell culture media derived from Ly6E-positive tumor cells promoted macrophage migration and M2 polarization.ConclusionOur study illuminated that Ly6E-expressing tumor cells facilitated the accumulation of M2 macrophages in TME, which contributes to CD8+ T cell exclusion and provides new insights for improving efficacy of cancer immunotherapy.

Synthesis and Cytotoxic Activity of Quinazoline-benzofuran Conjugates.

In order to study on structure-activity relationships of benzofurans. Benzofuran is a kind of natural compound widely existing in nature with pharmacological effects. The development of new anticancer benzofuran derivatives has attracted more and more attention. We have introduced an active quinazoline unit into piperazine-substituted benzofuran, prepared a series of quinazoline-benzofuran compounds, and evaluated cytotoxic activity against a panel of human tumor cell lines by MTT assay. 48 novel quinazoline-substituted benzofuran derivatives have been prepared, and in vitro, cytotoxic activity against five human tumor cell lines was evaluated. The results indicated that some quinazoline-benzofuran conjugates showed selective inhibitory activity against tumor cell lines. We have found that compound 14x displayed excellent cytotoxic activity, which could be considered a potential anticancer agent.

Design, Synthesis and Biological Activity Evaluation of β-Carboline Derivatives Containing Nitrogen Heterocycles.

A series of β-carboline derivatives containing nitrogen heterocycles were designed and synthesized. All compounds were screened for their antitumor activity against four human tumor cell lines (A549, K562, PC-3, T47D). Notably, compound N-(4-(morpholinomethyl)phenyl)-2-((5-(1-(3,4,5-trimethoxyphenyl)-9H-pyrido[3,4-b]indol-3-yl)-1,3,4-oxadiazol-2-yl)thio)acetamide (8q) exhibited significant inhibitory activity against PC-3 cells with an IC50 value of 9.86 µM. Importantly, compound 8q effectively suppressed both the proliferation and migration of PC-3 cells. Mechanistic studies revealed that compound 8q induced cell apoptosis and caused the accumulation of reactive oxygen species (ROS), leading to cell cycle arrest in the G0/G1 phase in PC-3 cells.

Synthesis and Antitumour Activity of Hybrid Compounds Based on 4-Aminophenylarsonic Acid and Spatially Hindered Phenols.

One of the main modern approaches to the creation of effective drugs is the design of new biologically active substances containing two or more pharmacophore groups in their structure. In recent years, there have been many publications on the synthesis and study of biological activity, including antitumour activity, of new organo-arsenic compounds. It is known that spatially hindered phenols can also have antitumor activity, so the synthesis and study of hybrid compounds based on organo-arsenic compounds and spatially hindered phenols is a relevant area of research. In this work, the modification of 4-aminophenylarsonic acid with 3,5-di-tert-butyl-4-hydroxybenzylacetate was carried out. In contrast to a similar transformation of 2-aminophenylarsonic acid, in this case it was possible to obtain both mono- and di-benzyl derivatives of the acid. Using the Zandmeyer method, the oxime isatin containing an arsonic acid fragment in the fifth position of the heterocycle was synthesised. Azo derivatives containing fragments of para-aminophenylarsonic acid and sterically hindered phenols were obtained. 4-((3,5-Di-tert-butyl-2-hydroxyphenyl)diazenyl)phenylarsonic acid was isolated in pure form. At the same time, it was found that the reaction of the diazonium azo salt of 4-aminophenylarsonic acid with 2-hydroxymethyl-4-tert-butylphenol proceeds in two directions. In addition to the classical diazotisation reaction at the 6-position of 2-hydroxymethyl-4-tert-butylphenol, a diazotisation accompanied by a dehydroxymethylation process occurs. The obtained compounds showed cytotoxic activity against human tumor cell lines M-HeLa (cervical epithelioid carcinoma) and HuTu 80 (duodenal adenocarcinoma cells). The most promising is the sodium salt of 4-((3,5-di-tert-butyl-2-hydroxyphenyl)diazenyl)phenylarsonic acid, which is superior to Tamoxifen and 5-fluorouracil in terms of selectivity index towards M-HeLa and HuTu 80 cells.

Ferroptosis-related gene signature for predicting prognosis and identifying potential therapeutic drug in EGFR wild-type lung adenocarcinoma

Epidermal growth factor receptor wild type lung adenocarcinoma (EGFRWT LUAD) still has limited treatment options and unsatisfactory clinical outcomes. Ferroptosis, as a form of cell death, has been reported to play a dual role in regulating tumor cell survival. In this study, we constructed a 3-ferroptosis-gene signature, FeSig, and verified its accuracy and efficacy in predicting EGFRWT LUAD prognosis at both the RNA and protein levels. Patients with higher FeSig scores were found to have worse clinical outcomes. Additionally, we explored the relationship between FeSig and tumor microenvironment, revealing that enhanced interactions between fibroblasts and tumor cells in FeSighigh patients causing tumor resistance to ferroptosis. To address this challenge, we screened potential drugs from NCI-60 (The US National Cancer Institute 60 human tumour cell line anticancer drug screen) and Connectivity map database, ultimately identifying 6-mercatopurine (6-MP) as a promising candidate. Both in vitro and in vivo experiments demonstrated its efficacy in treating FeSighigh EGFRWT LUAD tumor models. In summary, we develop a novel FeSig for predicting prognosis and guiding drug application.

Quinoline- and coumarin-based ligands and their rhenium(I) tricarbonyl complexes: synthesis, spectral characterization and antiproliferative activity on T-cell lymphoma

Novel 6-substituted 2-(trifluoromethyl)quinoline 5a–5e and coumarin 6a–6d ligands with aldoxime ether linked pyridine moiety were synthesized by O-alkylation of quinoline and coumarin with (E)-picolinaldehyde oxime and subsequently with [Re(CO)5Cl] gave rhenium(I) tricarbonyl complexes 5aRe–5eRe and 6aRe–6dRe that were fully characterized by NMR, single-crystal X-ray diffraction, IR and UV–Vis spectroscopy. The results of antiproliferative evaluation of quinoline and coumarin ligands and their rhenium(I) tricarbonyl complexes on various human tumor cell lines, including acute lymphoblastic leukemia (CCRF-CEM), acute monocytic leukemia (THP1), cervical adenocarcinoma (HeLa), colon adenocarcinoma (CaCo-2), T-cell lymphoma (HuT78), and non-tumor human fibroblasts (BJ) showed that the quinoline complexes 5aRe–5eRe had higher inhibitory activity than coumarin complexes 6aRe–6dRe, particularly against T-cell lymphoma (HuT78) cells. 6-Methoxy-2-(trifluoromethyl)quinoline 5e and 6-methylcoumarin 6d, and their rhenium(I) tricarbonyl complexes 5eRe and 6dRe were found to arrest the cell cycle of HuT78 cells by causing a significant accumulation of cells in the G0/G1 phase and a marked decrease in the number of cells in the G2/M phase. These rhenium(I) tricarbonyl complexes also slightly increased ROS production and significantly decreased the mitochondrial membrane potential by 50 % (5eRe) and 45 % (6dRe) compared to untreated cells and cells treated with 5e and 6d. These results suggest that the cytotoxic effects of these compounds are mediated by their effects on mitochondrial membrane potential and the subsequent increase in ROS production.

A Comparative In Vitro Anticancer Evaluation and In Silico Study of New 1‐(1,3‐Oxazol‐5‐yl)piperidine‐4‐sulfonylamides

AbstractIn this work, we synthesized a series of new 1,3‐oxazole derivatives comprising the sulfonylamide group and tested their activity against the human tumor cell line panel. This study further explores the stereoelectronic characteristics of 1,3‐oxazol‐5‐sulfonylamides and new 1‐(1,3‐oxazol‐5‐yl)piperidine‐4‐sulfonylamides to connect their anticancer activity to the molecular structure. Combining in vitro and in silico methods, we analyzed how the proximity of the sulfonylamide group to the heterocyclic ring affects the structure–activity interplay. Herein, our assessment is based on the purported complexation of 1,3‐oxazoles with targeted biomolecular fragments involving the π‐stacking interaction and hydrogen bonding within the prospective complexes. Defining the probability of the prospective drug–target interactions, we detail conformational properties, donor/acceptor capabilities, electronic characteristics, and thermodynamic preference of produced sulfanylamide group containing 1,3‐oxazoles toward biomolecular fragments, identifying the nature of variations in anticancer activity.

New Discorhabdin D Analogues from Latrunculia spp. Sponges.

Chemical profiles of Latrunculia kaakaariki and Latrunculia brevis were investigated, resulting in the isolation of five new discorhabdin D derivatives 1 and 3-6. Their planar structures were solved by combination of NMR and HR-MS, while J-based configurational analysis, computational techniques, and semisynthetic methods were used for the establishment of their absolute configurations. New natural products were tested for their growth inhibitory activity against the NCI-60 human tumor cell line panel, and two compounds 5 and 6 showed low micromolar potency.

Antitumor activity of PAbs generated by immunization with a novel HER3-targeting protein-based vaccine candidate in preclinical models.

Despite the cumulative evidence supporting HER3 as a target for antitumor therapies, no agents targeting HER3 have been approved for cancer treatment. Most of the agents evaluated in preclinical and clinical trials have been specific monoclonal antibodies (MAbs), with few examples of active immunotherapy directed against this receptor. However, some cancer vaccine formats may generate polyclonal antibodies (PAbs) that replicate the diverse effector mechanisms of MAbs, including ligand neutralization and receptor degradation. In this study, we developed a protein subunit-based monovalent vaccine candidate targeting the extracellular domain (ECD) of HER3. Immunization of mice with a formulation targeting murine ErbB3-ECD successfully overcome tolerance to this self-antigen, inducing high titers of ErbB3-specific PAbs. The antitumor potential of this formulation and the induced PAbs was demonstrated in vivo and in vitro in an ErbB3-overexpressing 3LL-D122-derived tumor model. The immunogenicity of the HER3-ECD-based vaccine candidate was confirmed by the induction of high titers of HER3-specific PAbs. Consistent with the initial results, HER3-ECD-targeting PAbs were cytotoxic in several human epithelial tumor cell lines and exerted antitumor effects in vivo. These results support the value of HER3 as a tumor antigen and the effector mechanisms of HER3-specific therapeutic MAbs, while suggesting the potential of the proposed vaccine candidate for the treatment of HER3-expressing carcinomas.

Fetal hypoxia exposure induced Hif1a activation and autophagy in adult ovary granulosa cells.

Environmental hypoxia adversely impacts the reproduction of humans and animals. Previously, we showed that fetal hypoxia exposure led to granulosa cell (GC) autophagic cell death via the Foxo1/Pi3k/Akt pathway. However, the upstream regulatory mechanisms underlying GC dysfunction remain largely unexplored. Here, we tested the hypothesis that fetal hypoxia exposure altered gene expression programs in adult GCs and impaired ovarian function. We established a fetal hypoxia model in which pregnant mice were maintained in a high-plateau hypoxic environment from gestation day (E) 0--16.5 to study the impact of hypoxia exposure on the ovarian development and subsequent fertility of offspring. Compared with the unexposed control, fetal hypoxia impaired fertility by disordering ovarian function. Specifically, fetal hypoxia caused mitochondrial dysfunction, oxidant stress and autophagy in GCs in the adult ovary. RNA-seq analysis revealed that 437 genes were differentially expressed in the adult GCs of exposed animals. Western blotting results also revealed that fetal exposure induced high levels of hypoxia-inducible factor 1-alpha (Hif1a) expression in adult GCs. We then treated GCs isolated from exposed mice with PX-478, a specific pharmacological inhibitor of Hif-1a, and found that autophagy and apoptosis were effectively alleviated. Finally, by using a human ovarian granulosa-like tumor cell line (KGN) to simulate hypoxia in vitro, we showed that Hif1a regulated autophagic cell death in GCs through the Pi3k/Akt pathway. Together, these findings suggest that fetal hypoxia exposure induced persistent Hif1a expression, which impaired mitochondrial function and led to autophagic cell death in the GCs of the adult ovary.

Efficient Strategy for Synthesizing Vector-Free and Oncolytic Herpes Simplex Type 1 Viruses.

Synthesizing viral genomes plays an important role in fundamental virology research and in the development of vaccines and antiviral drugs. Herpes simplex virus type 1 (HSV-1) is a large DNA virus widely used in oncolytic virotherapy. Although de novo synthesis of the HSV-1 genome has been previously reported, the synthetic procedure is still far from efficient, and the synthesized genome contains a vector sequence that may affect its replication and application. In the present study, we developed an efficient vector-free strategy for synthesis and rescue of synthetic HSV-1. In contrast to the conventional method of transfecting mammalian cells with a completely synthesized genome containing a vector, overlapping HSV-1 fragments synthesized by transformation-associated recombination (TAR) in yeast were linearized and cotransfected into mammalian cells to rescue the synthetic virus. Using this strategy, a synthetic virus, F-Syn, comprising the complete genome of the HSV-1 F strain, was generated. The growth curve and electron microscopy of F-Syn confirmed that its replication dynamics and morphogenesis are similar to those of the parental virus. In addition, by combining TAR with in vitro CRISPR/Cas9 editing, an oncolytic virus, F-Syn-O, with deleted viral genes ICP6, ICP34.5, and ICP47 was generated. The antitumor effect of F-Syn-O was tested in vitro. F-Syn-O established a successful infection and induced dose-dependent cytotoxic effects in various human tumor cell lines. These strategies will facilitate convenient and systemic manipulation of HSV-1 genomes and could be further applied to the design and construction of oncolytic herpesviruses.

Three new cyclopentanoid monoterpenes from the roots of Picrorhiza scrophulariiflora

Three new cyclopentanoid monoterpenes, neopiscrocins A–C (1–3), together with 14 known compounds (4–17), were isolated from the roots of Picrorhiza scrophulariiflora. The structres of these compounds were elucidated on the basis of their spectroscopic data. All compounds were evaluated for cytotoxicity against six human tumor cell lines (PC9, PANC1, HCT-116, Hep-G2, BGC-823, and MCF-7), hepatoprotective activity and anti-inflammatory activity.

Synthesis, Absolute Configuration, Biological Profile and Antiproliferative Activity of New 3,5-Disubstituted Hydantoins.

Hydantoins, a class of five-membered heterocyclic compounds, exhibit diverse biological activities. The aim of this study was to synthesize and characterize a series of novel 3,5-disubstituted hydantoins and to investigate their antiproliferative activity against human cancer cell lines. The new hydantoin derivatives 5a-i were prepared as racemic mixtures of syn- and anti-isomers via a base-assisted intramolecular amidolysis of C-3 functionalized β-lactams. The enantiomers of syn-5a and anti-hydantoins 5b were separated by preparative high-performance liquid chromatography (HPLC) using n-hexane/2-propanol (90/10, v/v) as the mobile phase. The absolute configuration of the four allyl hydantoin enantiomers 5a was assigned based on a comparison of the experimental electronic circular dichroism (ECD) and vibrational circular dichroism (VCD) spectra with those calculated using density functional theory (DFT). The antiproliferative activity evaluated in vitro against three different human cancer cell lines: HepG2 (liver hepatocellular carcinoma), A2780 (ovarian carcinoma), and MCF7 (breast adenocarcinoma), and on the non-tumor cell line HFF1 (normal human foreskin fibroblasts) using the MTT cell proliferation assay. In silico drug-like properties and ADMET profiles were estimated using the ADMET Predictor ver. 9.5 and the online server admetSAR. Eighteen new 3,5-disubstituted hydantoins were synthesized and characterized. The compound anti-5c showed potent cytotoxic activity against the human tumor cell line MCF7 (IC50 = 4.5 µmol/L) and the non-tumor cell line HFF1 (IC50 = 12.0 µmol/L). In silico analyzes revealed that the compounds exhibited moderate water solubility and membrane permeability and are likely substrates for CYP3A4 and P-glycoprotein and have a high probability of antiarthritic activity.

Phytochemical and pharmacological investigation of the non-volatile compounds of Lepidium cartilagineum (J. C. Mayer) Thell. and determination of the essential oil composition of its flowers and fruits

Eighteen compounds, among them phenylpropanoids (1–2), neolignans (3–9), a megastigmane (10), a phenyl glucoside (11), flavonoids (12–14), and N-containing compounds (15–18) were isolated from the methanolic extract of the whole plant of L. cartilagineum. The structures of the compounds were determined by NMR and MS measurements. The composition of the essential oils prepared from the flowers and fruits of L. cartilagineum was investigated using GC and GC–MS measurements. The essential oils were rich in aliphatic aldehydes and hydrocarbons, but low in sulfur-containing compounds, e.g., isothiocyanates. The extracts prepared from the aerial parts and roots of the plant, the essential oil, and the isolated compounds (1–9) were tested for antiproliferative activity against COLO 205 and COLO 320 cell lines and antibacterial activity on Lactobacillus rhamnosus. Dehydrodiconiferyl alcohol γ’-methyl ether (5) possessed marked antiproliferative activity against both human tumor cell lines. Neither the extracts nor the compounds affected the growth of the bacteria and did not influence the biofilm formation of L. rhamnosus. Based on the results, it can be concluded that L. cartilagineum is non-toxic to the human gut microbiome forming L. rhamnosus.