The design, structural characterization and potential medical application of novel 1,2,4-oxadiazole and trifluoromethylpyridine derivatives are described. Starting from two readily available ...compounds, 4-(3-(tert-butyl)-1,2,4-oxadiazol-5-yl)aniline (1) and 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)ethanamine (10), other bioactive moieties were incorporated (such as pyrazole, pyrazolo3,4-dpyrimidine), in order to modify the lipophilicity of the molecules, so that the transport of the bioactive units though the cell wall barrier could be improved. In vitro anti-cancer activity of these compounds was assessed by a monolayer proliferation assay in a panel of 12 cell lines. A good potency was found for 17, which exhibited a mean IC50 value of 5.66 μM, while the other compounds exhibit minor or no activity. The solid state structures of compounds 3, 5, 7–9, 11, 12 and 17 were established by X-ray diffraction analyses.
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A series of novel 2,5-bis(3′-indolyl)furans and 3,5-bis(3′-indolyl)isoxazoles were synthesized and evaluated as antitumor agents.
A series of novel 2,5-bis(3′-indolyl)furans and ...3,5-bis(3′-indolyl)isoxazoles were synthesized as antitumor agents. The antiproliferative activity was evaluated in vitro toward diverse human tumor cell lines. Initially 5 isoxazoles and 3 furan derivatives were tested against a panel of 10 human tumor cell lines and the most active derivatives
3c and
4a were selected to be evaluated in an extended panel of 29 cell lines. By exhibiting mean IC
50 values of 17.4
μg/mL (
3a) and 20.5
μg/mL (
4c), in particular
4c showed a high level of tumor selectivity toward the 29 cell lines.
Abstract Cetuximab (Erbitux®) targets the epidermal growth factor receptor (EGFR) and is approved for treatment of colorectal and head and neck cancer. Despite wide expression of EGFR, only a ...subgroup of cancer patients responds to cetuximab therapy. In the present study we assessed the cetuximab response in vivo of 79 human patient-derived xenografts originating from five tumour histotypes. We analysed basic tumour characteristics including EGFR expression and activation, mutational status of KRAS, BRAF and NRAS, the expression of EGFR ligands and the activation of HER3 (ErbB3) and the hepatocyte growth factor receptor MET. Based on these results, a cetuximab response score including positive and negative factors affecting therapeutic response is proposed. Positive factors are high expression and activation of EGFR and its ligands epiregulin or amphiregulin, negative factors are markers for downstream pathway activation independent of EGFR. In cetuximab resistant NSCL adenocarcinoma LXFA 526 and LXFA 1647, overexpression due to gene amplification and strong activation of MET was identified. Knock-down of MET by siRNA in the corresponding cell lines showed that anchorage-independent growth and migration are dependent on MET. MET knock down sensitized LXFA 526L and LXFA 1647L to EGF. Combined treatments of a MET inhibitor and cetuximab were additive. Therefore, combination therapy of cetuximab and a MET inhibitor in selected lung cancer patients could be of high clinical significance.
Three novel indolosesquiterpenes, xiamycin B (1b), indosespene (2), and sespenine (3), along with the known xiamycin A (1a) were isolated from the culture broth of Streptomyces sp. HKI0595, a ...bacterial endophyte of the widespread mangrove tree Kandelia candel. Agar diffusion assays revealed moderate to strong antimicrobial activities against several bacteria, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecalis, while no cytotoxicity against human tumor cell lines was observed. Together with the previously reported oridamycin, the endophyte metabolites represent the first indolosesquiterpenes isolated from prokaryotes.
Cancer drug resistance remains a major obstacle in clinical oncology. As most anticancer drugs are of natural origin, we investigated the anticancer potential of a standardized cold-water leaf ...extract from
L., termed Breastin. The phytochemical characterization by nuclear magnetic resonance spectroscopy (NMR) and low- and high-resolution mass spectrometry revealed several monoglycosidic cardenolides as major constituents (adynerin, neritaloside, odoroside A, odoroside H, oleandrin, and vanderoside). Breastin inhibited the growth of 14 cell lines from hematopoietic tumors and 5 of 6 carcinomas. Remarkably, the cellular responsiveness of odoroside H and neritaloside was not correlated with all other classical drug resistance mechanisms, i.e., ATP-binding cassette transporters (ABCB1, ABCB5, ABCC1, ABCG2), oncogenes (EGFR, RAS), tumor suppressors (TP53, WT1), and others (GSTP1, HSP90, proliferation rate), in 59 tumor cell lines of the National Cancer Institute (NCI, USA), indicating that Breastin may indeed bypass drug resistance. COMPARE analyses with 153 anticancer agents in 74 tumor cell lines of the Oncotest panel revealed frequent correlations of Breastin with mitosis-inhibiting drugs. Using tubulin-GFP-transfected U2OS cells and confocal microscopy, it was found that the microtubule-disturbing effect of Breastin was comparable to that of the tubulin-depolymerizing drug paclitaxel. This result was verified by a tubulin polymerization assay in vitro and molecular docking in silico. Proteome profiling of 3171 proteins in the NCI panel revealed protein subsets whose expression significantly correlated with cellular responsiveness to odoroside H and neritaloside, indicating that protein expression profiles can be identified to predict the sensitivity or resistance of tumor cells to Breastin constituents. Breastin moderately inhibited breast cancer xenograft tumors in vivo. Remarkably, in contrast to what was observed with paclitaxel monotherapy, the combination of paclitaxel and Breastin prevented tumor relapse, indicating Breastin's potential for drug combination regimens.
Boshramycinones A-C (1-3), three new anthracyclinones, were isolated from the culture broth of the marine-derived Streptomyces sp. Mei 16-1,2 together with ...2-acetyl-1,8-dihydroxy-3-methyl-anthraquinone (4) and bafilomycins B1, B2, and C1-amide. The isolated compounds were identified by NMR spectroscopy and mass spectrometry, the absolute configuration of 3 was determined by comparison of experimental and ab initio-calculated chiroptical data. The antimicrobial activity of the bacterial extract and the isolated compounds were assayed using a set of microorganisms, and cytotoxic activities were determined against 36 human cancer cell lines.
Cantharis vesicatoria (blister beetle) is used in Chinese medicine and has been categorized as highly toxic in the Chinese pharmacopeia. In Europe, Cantharis patches have been used since ages to ...treat various skin-related diseases. We investigated the cytotoxicity of the Cantharis ingredient, cantharidin, in 41 tumor cell lines (Oncotest panel) and compared the results with those of 60cell lines of the National Cancer Institute, USA. We found profound activity at low micromolar concentrations (log10IC50 values between −6.980 and 5.009M). Cantharidin bound to protein phosphatase 2A (PP2A) with higher affinity (−8.12kcal/mol) than to PP1 (−6.25kcal/mol) in molecular docking analyses. Using a PCR array for 84 apoptosis genes, cantharidin treatment upregulated gene expression of caspase-1 and nerve growth factor receptor, but downregulated mRNA expression of Bcl-2 like protein 10, Fas ligand, and tumor necrosis factor-α. By using COMPARE analysis of microarray-based transcriptome-wide mRNA expressions, 21 genes were found to significantly correlate with response of 60 tumor cell lines to cantharidin. As shown by hierarchical cluster analysis and chi-squared test, the distribution of cell lines in the dendrogram according to their gene expression profiles predicted sensitivity or resistance to cantharidin (P=6.482×10−5). The compassionate use of Cantharis patches in two patients suffering from basalioma and Mycosis fungoides, respectively, considerably improved the diseases without signs of toxicity. In conclusion, these results indicate that cantharidin may be a useful candidate to develop novel strategies for cancer therapy.
A novel pentacyclic indolosesquiterpene, named xiamycin (1), and its methyl ester (2) have been obtained from Streptomyces sp. GT2002/1503, an endophyte from the mangrove plant Bruguiera gymnorrhiza. ...The structures were established by 1D and 2D NMR, MS, and X-ray crystallography, and the absolute configuration of 1 was elucidated by the modified Mosher method. Compound 1 exhibits selective anti-HIV activity; it specifically blocks R5 but has no effects on X4 tropic HIV-1 infection. In a panel of cytotoxicity assays, compound 2 showed to be more potent (geometric mean IC50=10.13μM) compared to compound 1 (geometric mean IC50 >30μM), with antitumor potency being generally less pronounced. Xiamycin represents one of the first examples of indolosesquiterpenes isolated from prokaryotes.
This work presents the synthesis, characterization, and application of several new metal(I) complexes with trifluoromethylpyridine‐containing N‐heterocyclic carbene (NHC) ligands. The metal of choice ...was gold(I) for compounds 7 – 10, rhodium(I) for 11 – 12, and iridium(I) for 13 – 14, respectively. The trifluoromethylpyridine moiety was incorporated, along with other biologically active moieties, with the intention of modifying the lipophilicity of the complexes, so that the transport of the active units (M–NHC) through the cell wall barrier is facilitated. The biological activity of the complexes was investigated. In vitro assessment of antitumor activity in a panel of 12 human tumor cell lines by a monolayer assay revealed good potency (mean IC50 12.6 μm) and tumor selectivity for one compound. The solid‐state structures of two solvates of compound 7, one with MeOH and one with THF, were determined by X‐ray diffraction analysis.
