benzofurans and rocaglaol

During the past few years, a group of cyclopenta[b]benzofurans from the plant genus Aglaia has received broad scientific attention as interesting natural product lead compounds with potential anticancer and insecticidal activities. Since the first cyclopenta[b]benzofuran derivative, rocaglamide, from Aglaia elliptifolia, was found to exhibit antileukemic activity in a murine in vivo model, the genus Aglaia has been subjected to further investigation. Over 40 cyclopenta[b]benzofurans have been tested against different human cancer cell lines, and the cumulative results provide some important clues as to how to improve their activity through modification of their chemical structures. The semisynthesis and total synthesis of the cyclopenta[b]benzofurans have been conducted. Although the ultimate molecular target(s) responsible for their antiproliferative activity has not yet been identified, studies on their cellular mechanism of action have demonstrated that some of these compounds inhibit TNF-alpha or PMA-induced NF-kappaB activity in T-lymphocytes and induce apoptosis in different human cancer cell lines. Based on the published data thus far, cyclopenta[b]benzofurans offer excellent potential as therapeutic agent candidates in cancer chemotherapy, even if much work still remains to be done for their further development.

Topics: Aglaia; Animals; Antineoplastic Agents; Benzofurans; Cell Line, Tumor; Drug Screening Assays, Antitumor; Humans; Mice; Xenograft Model Antitumor Assays

Chronic myelogenous leukemia (CML) is a hematological malignancy with increased proliferation of cells of the myeloid series. This can disrupt normal hematopoiesis. The 1-(2-(dimethylamino)acetyl)-rocaglaol (MQ-16) is a new synthetic flavagline compound that showed promising activity in chronic myeloid leukemia K562 cells. This study aims to analyze the underlying mechanisms of MQ-16 against CML.. Growth, cell cycle progression, and apoptosis were assessed in K562 cells following MQ-16 exposure by MTT assay and flow cytometry. The effect of MQ-16 on DNA strands between nucleosomes was examined by 1% agarose gel electrophoresis. PI3K/Akt/mTOR, JAK2/STAT3, and mitogen-activated protein kinase (MAPK) pathway-related proteins were detected in MQ-16-treated K562 cells by Western blot.. MQ-16 significantly inhibited the proliferation of K562 cells and arrested the cell cycle at the G2/M phase in a time- and concentration-dependent manner. MQ-16 induced mitochondria-dependent apoptosis by downregulating the anti-apoptotic proteins Bcl-2 and Bcl-xL and induced time- and concentration-dependent DNA fragmentation. In addition, MQ-16 affected the expression of PI3K/Akt/mTOR, JAK2/STAT3, and MAPK pathway-related proteins.. In summary, MQ-16 appears to be a promising chemotherapeutic drug for treating CML.

Topics: Apoptosis; Benzofurans; Cell Proliferation; Humans; Janus Kinase 2; K562 Cells; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Mitogen-Activated Protein Kinases; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; STAT3 Transcription Factor; TOR Serine-Threonine Kinases

Topics: Antineoplastic Agents; Apoptosis; Benzofurans; beta Catenin; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Glycogen Synthase Kinase 3 beta; Humans; Wnt Signaling Pathway

E26 transformation-specific (ETS) gene family contains a common DNA-binding domain, the ETS domain, responsible for sequence-specific DNA recognition on target promoters. The Fli-1 oncogene, a member of ETS gene family, plays a critical role in hematopoiesis and is overexpressed in diverse hematological malignancies. This ETS transcription factor regulates genes controlling several hallmarks of cancer and thus represents an excellent target for cancer therapy. By screening compounds isolated from the medicinal plant Dysoxylum binectariferum in China, we identified two chemically related flavagline-like compounds including 4'-demethoxy-3',4'-methylenedioxyrocaglaol and rocaglaol that strongly inhibited Fli-1 transactivation ability. These compounds altered expression of Fli-1 target genes including GATA1, EKLF, SHIP1, and BCL2. Consequently, the flavagline-like compounds suppressed proliferation, induced apoptosis, and promoted erythroid differentiation of leukemic cells in culture. These compounds also suppressed erythroleukemogenesis in vivo in a Fli-1-driven mouse model. Mechanistically, the compounds blocked c-Raf-MEK-MAPK/ERK signaling, reduced phosphorylation of eukaryotic translation initiation factor 4E (eIF4E), and inhibited Fli-1 protein synthesis. Consistent with its high expression in myelomas, B-cell lymphoma, and B chronic lymphocytic leukemia (B-CLL), pharmacological inhibition of Fli-1 by the flavagline-like compounds or genetic knock-down via shRNA significantly hindered proliferation of corresponding cell lines and patients' samples. These results uncover a critical role of Fli-1 in growth and survival of various hematological malignancies and point to flavagline-like agents as lead compounds for the development of anti-Fli-1 drugs to treat leukemias/lymphomas overexpressing Fli-1.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Benzofurans; Cell Cycle; Cell Proliferation; High-Throughput Screening Assays; Humans; Leukemia; Mice; Plant Extracts; Plants, Medicinal; Proto-Oncogene Protein c-fli-1; Signal Transduction; Tumor Cells, Cultured

Aglaia odorata Lour. (Meliaceae) was found to have very strong allelopathic activity and a bioherbicide PORGANIC(™) was developed from its leaf extracts. However, the phytotoxic substances causing the strong allelopathic activity of the plants have not yet been determined. Therefore, we investigated allelopathic properties and phytotoxic substances in A. odorata. Aqueous EtOH extracts of A. odorata leaves inhibited root and shoot growth of garden cress (Lepidum sativum), lettuce (Lactuca sativa), alfalfa (Medicago sativa), timothy (Phleum pratense), ryegrass (Lolium multiflorum), and Echinochloa crus-galli with the extract concentration-dependent manner. The extracts were then purified and a major phytotoxic substance with allelopathic activity was isolated and identified by spectral data as rocaglaol. Rocaglaol inhibited the growth of garden cress and E. crus-galli at concentrations > 0.3 and 0.03 μm, respectively. The concentrations required for 50% inhibition ranged from 0.09 to 2.5 μm. The inhibitory activity of rocaglaol on the weed species, E. crus-galli, was much greater than that of abscisic acid. These results suggest that rocaglaol may be a major contributor to the allelopathic effect of A. odorata and bioherbicide PORGANIC(™) .

Topics: Aglaia; Benzofurans; Dose-Response Relationship, Drug; Echinochloa; Lepidium sativum; Molecular Conformation; Plant Extracts; Plant Leaves

Eight new compounds, including two cyclopenta[b]benzopyran derivatives (1, 2), two cyclopenta[b]benzofuran derivatives (3, 4), three cycloartane triterpenoids (5-7), and an apocarotenoid (8), together with 16 known compounds, were isolated from the chloroform-soluble partitions of separate methanol extracts of a combination of the fruits, leaves, and twigs and of the roots of Aglaia perviridis collected in Vietnam. Isolation work was monitored using human colon cancer cells (HT-29) and facilitated with an LC/MS dereplication procedure. The structures of the new compounds (1-8) were determined on the basis of spectroscopic data interpretation. The Mosher ester method was employed to determine the absolute configurations of 5-7, and the absolute configuration of the 9,10-diol unit of compound 8 was established by a dimolybdenum tetraacetate [Mo2(AcO)4] induced circular dichroism procedure. Seven known rocaglate derivatives (9-15) exhibited significant cytotoxicity against the HT-29 cell line, with rocaglaol (9) being the most potent (ED50 0.0007 μM). The new compounds 2-4 were also active against this cell line, with ED50 values ranging from 0.46 to 4.7 μM. The cytotoxic compounds were evaluated against a normal colon cell line, CCD-112CoN. In addition, the new compound perviridicin B (2), three known rocaglate derivatives (9, 11, 12), and a known sesquiterpene, 2-oxaisodauc-5-en-12-al (17), showed significant NF-κB (p65) inhibitory activity in an ELISA assay.

Topics: Aglaia; Antineoplastic Agents, Phytogenic; Benzofurans; Benzopyrans; Drug Screening Assays, Antitumor; HT29 Cells; Humans; Molecular Structure; NF-kappa B; Nuclear Magnetic Resonance, Biomolecular; Triterpenes; Vietnam

Flavaglines constitute a family of natural anticancer compounds. We present here 3 (FL3), the first synthetic flavagline that inhibits cell proliferation and viability (IC(50) approximately 1 nM) at lower doses than did the parent compound, racemic rocaglaol. Compound 3 enhanced doxorubicin cytotoxicity in HepG2 cells and retained its potency against adriamycin-resistant cell lines without inducing cardiomyocyte toxicity. Compound 3 induced apoptosis of HL60 and Hela cells by triggering the translocation of Apoptosis Inducing Factor (AIF) and caspase-12 to the nucleus. A fluorescent conjugate of 3 accumulated in endoplasmic reticulum (ER), suggesting that flavaglines bind to their target in the ER, where it triggers a cascade of events that leads to the translocation of AIF and caspase-12 to the nucleus and probably inhibition of eIF4A. Our studies highlight structural features critical to their antineoplastic potential and suggest that these compounds would retain their activity in cells refractory to caspase activation.

Topics: Active Transport, Cell Nucleus; Antineoplastic Agents; Apoptosis; Apoptosis Inducing Factor; Benzofurans; Caspase 12; Cell Line, Tumor; Cell Nucleus; Cell Proliferation; Cell Survival; Doxorubicin; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Drug Synergism; Endoplasmic Reticulum; G2 Phase; Humans; Stereoisomerism; Structure-Activity Relationship

Two new rocaglamide derivatives, 1-O-formylrocagloic acid (1) and 3'-hydroxy rocagloic acid (2), together with five known compounds, rocaglaol (3), rocagloic acid (4), 3'-hydroxymethylrocaglate (5), 1-O-formylmethyl rocaglate (6), and methylrocaglate (7), were isolated from the fruits of Amoora cucullata. Their structures were elucidated by spectroscopic methods. Compounds 1-3, 6, and 7 exhibited potent cytotoxicity against KB, BC, and NCI-H187 cell lines, whereas 4 and 5 showed selective cytotoxicity against NCI-H187 cell line.

Topics: Benzofurans; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Humans; Magnetic Resonance Spectroscopy; Meliaceae; Molecular Conformation; Reference Standards; Seeds; Sensitivity and Specificity; Stereoisomerism; Structure-Activity Relationship