Design, synthesis, and biological evaluation of 3',4',5'-trimethoxy evodiamine derivatives as potential antitumor agents.

A series of compounds bearing 3',4',5'-trimethoxy module into the core structure of evodiamine were designed and synthesized. The synthesized compounds were screened in vitro for their antitumor potential. MTT results showed that compounds 14a-14c and 14i-14j had significant effects, with compound 14h being the most prominent, with an IC50 value of 3.3 ± 1.5 µM, which was lower than evodiamine and 5-Fu. Subsequent experiments further confirmed that compound 14h could inhibit cell proliferation and migration, and induce G2/M phase arrest to inhibit the proliferation of HGC-27 cells, which is consistent with the results of the cytotoxicity experiment. Besides, 14h could inhibit microtubule assembly and might kill tumor cells by inhibiting VEGF and glycolysis. All experimental results indicate that compound 14h might be a potential drug candidate for the treatment of gastric cancer and was worthy of further study.

FB-15 inhibits MGC-803 cells growth by regulating energy metabolism.

In this study, we scrutinized the anticancer effects of FB-15 on human gastric carcinoma MGC-803 cells in vitro and vivo, and its preliminary effect on tubulin and HIF-1α. We confirmed that FB-15 not only inhibited the proliferation of a large number of cells in a concentration and time-dependent manner but also inhibited proliferation of a single cell to form clones. FB-15 manifested little cytotoxicity for normal stomach cells GES-1. The flow cytometry analysis displayed that FB-15 induced apoptosis MGC-803 cells and mainly arrested cells in the S phase in a concentration-dependent manner. The results of the wound healing assay indicated that FB-15 suppressed cell migration. Furthermore, the western blotting showed that FB-15 down-regulated the expression of ß3-tubulin and HIF-1α, consistent with Immunohistochemical assay. The binding modes of FB-15 with tubulin were clarified by molecular docking. FB-15 significantly suppressed the growth of MGC-803 gastric cancer tumors. The inhibitory effect of FB-15 on tumor growth was superior to 5-Fu. Taken together, these results provided evidence for FB-15 to be used as an effective anticancer drug candidate for gastric cancer.

Synthesis and biological evaluation of novel 5,6,7-trimethoxy flavonoid salicylate derivatives as potential anti-tumor agents.

5,6,7-Trimethoxy flavonoid salicylate derivatives were designed by the joining of three important pharmacophores (TMP, flavonoid, and SA) according to the combination principle. A series of novel trimethoxy flavonoid salicylate derivatives were synthesized and their in vitro anti-tumor activities were evaluated. Among these derivatives, compound 7f exhibited excellent antiproliferative activity against HGC-27 cells and MGC-803 cells with IC50 values of 10.26 ± 6.94 µM and 17.17 ± 3.03 µM, respectively. Subsequently, the effects on cell colony formation (clonogenic survival assay), cell migration (wound healing assay), cell cycle distribution (PI staining assay), cell apoptosis (Hoechst 33258 staining assay and annexin V-FITC/PI dual staining assay), lactate level (lactate measurement), microtubules disarrangement (immunofluorescence staining analysis) and docking posture (molecular docking simulation) were determined. Further western blot analysis confirmed that compound 7f could effectively down-regulate the expression of glycolysis-related proteins HIF-1α, PFKM and PKM2 and tumor angiogenesis-related proteins VEGF. Overall, these studies suggested that compound 7f, as the representative compound of those, might be a promising candidate for the treatment of gastric cancer and deserved the further studies.

Design, synthesis and biological evaluation of tryptamine salicylic acid derivatives as potential antitumor agents.

A series of tryptamine salicylic acid derivatives were synthesized and their antiproliferative activity against MGC-803, MCF-7, HepG2, A549 and HeLa cell lines was evaluated. The structure-activity relationship (SAR) study revealed that different substitutions of the C5 and C3'-C5' positions have certain effects on the anti-proliferation activity. The growth assay revealed that N-[2-(5-bromo-1H-indol-3-yl)-ethyl]-2-hydroxy-3-methyl-benzamide (E20) showed the most potent and broad-spectrum anticancer inhibition of all the cell lines evaluated, and was only more potent than 5-Fu for the gastric cancer cell line. Preliminary studies indicated that compound E20 could inhibit colony formation and migration of MGC-803 cells. The flow cytometry (FCM) results showed that compound E20 arrested the cell cycle in the G2/M phase and induced apoptosis of MGC-803 cells in a concentration-dependent manner. In addition, the western blot results showed that E20 can down-regulate the expression of hexokinase 2. Our studies suggest that the framework of N-[2-(5-bromo-1H-indol-3-yl)-ethyl]-2-hydroxy-3-methyl-benzamide may be consider as a new type of chemical for designing effective anti-cancer drugs targeting gastric cancer cells.

FS-7 inhibits MGC-803 cells growth in vitro and in vivo via down-regulating glycolysis.

In this study, we investigated the anticancer effects of FS-7, a flavonoid salicylate derivative, in human gastric carcinoma MGC-803 cell line and studied its preliminary anticancer effects. FS-7 displayed greater in vitro cytotoxicity against MGC-803 cell line compared with 5-Fu and had a certain extent of selectivity to cancer cells. The flow cytometry analysis revealed that FS-7 induced apoptosis MGC-803 cells and mainly caused cells arrest in the G2/M phase in a concentration-dependent manner. Additionally, FS-7 inhibited the colony formation and cell migration in a concentration-dependent manner. Notably, FS-7 noticeably down-regulated glycolysis-related protein HIF-1α, HK-II and PFKP expression in a concentration-dependent manner, possibly causing glycolysis inhibition. Importantly, compared with 5-Fu, FS-7 showed better anticancer activity in the MGC-803 xenograft murine tumor models. Collectively, the present study provided a promising anticancer drug candidate for gastric cancer therapy.

A pH-sensitive prodrug strategy to co-deliver DOX and TOS in TPGS nanomicelles for tumor therapy.

This work has presented a novel strategy for designing pH-sensitive TOS-H-DOX prodrug-loaded TPGS nanomicelles for co-delivery TOS and DOX to enhance tumor therapy and reduce the toxic side effects. DOX was covalently conjugated to the vitamin E succinate through hydrazone bond to produce an pH-sensitive prodrug TOS-H-DOX (amido bond as a control, TOS-A-DOX), which was responsive to the acidic environment in tumor cells, and the prodrugs were subsequently encapsulated in the core of TPGS nanomicelles via hydrophobic effects with a significant drug loading capacity. The pH-sensitive prodrug nanomicelles TOS-H-DOX/TPGS exhibited potent release of DOX in acidic media relative to the pH-insensitive prodrug nanomicelles TOS-A-DOX/TPGS, and further studies of their intracellular uptake and intracellular localization demonstrated that TOS-H-DOX/TPGS nanomicelles can be effectively taken up by cells and drugs can be released. In vitro results confirmed that TOS-H-DOX/TPGS nanomicelles exhibited significant antitumor cell proliferation activity compared to TOS-A-DOX/TPGS and free DOX, TPGS. Furthermore, in vivo studies further confirmed an excellent synergistic antitumor efficacy in MCF-7 tumor-bearing nude mice model. More importantly, the H&E staining of the heart, liver, kidney tissue sections of experimental nude mice showed that TOS-H-DOX/TPGS nanomicelles can reduce damage to them.

Design, synthesis and broad-spectrum Bcr-Abl inhibitory activity of novel thiazolamide-benzamide derivatives.

Bcr-Abl plays an important role in the pathogenesis and development of chronic myeloid leukemia (CML). But Bcr-Abl is prone to mutation, so it increases the difficulty of clinical treatment. Therefore, it is crucial to design a new class of broad-spectrum Bcr-Abl inhibitors. Herein, forty novel thiazolamide-benzamide derivatives were synthesized and evaluated their broad-spectrum Bcr-Abl inhibitory activities. The newly synthesized compounds were characterized by using spectrum data (1H NMR, APCI-MS and IR) and elemental analysis. The protein kinase results indicated that eight compounds (3a, 3e, 3m, 3n, 3p, 4c, 4f, 4g) showed high activities to wild-type and T315I mutation. The most potent compound 3m exhibited an Abl IC50 value as low as 1.273 µM and showed inhibition to the T315I mutant with IC50 value 39.89 µM. 3m could prove to be a new promising lead compound for the further development of broad-spectrum Bcr-Abl inhibitors to overcome clinical acquired resistance.

Design, synthesis and biological evaluation of 3',4',5'-trimethoxy flavonoid benzimidazole derivatives as potential anti-tumor agents.

A series of 3',4',5'-trimethoxy flavonoids with benzimidazole linked by different chain alkanes have been designed and synthesized. The potential activity of these compounds as anti-tumor agents was evaluated by cytotoxicity assay in MGC-803 (human gastric cancer), MCF-7 (human breast cancer), HepG-2 (human hepatoma) and MFC (mouse gastric cancer) tumor cell lines. Among them, compound 15 7-(3-(2-chloro-1H-benzo[d]imidazol-1-yl)propoxy)-2-(3,4,5-trimethoxyphenyl)-4H-chromen-4-one displayed the most potent antiproliferative activity, with IC50 values of 20.47 ± 2.07, 43.42 ± 3.56, 35.45 ± 2.03 µM and 23.47 ± 3.59 µM, respectively. The flow cytometry (FCM) results showed that compound 15 caused the cell cycle to be arrested in G1 phase and induced apoptosis of MFC cells in a dose-dependent manner. In addition, compound 15 exhibited a significant inhibitory effect on tumor growth in vivo. All the results outlined the great potential of compound 15 for further exploitation as anti-tumor agent.

Fabrication and characterization of a folic acid-bound 5-fluorouracil loaded quantum dot system for hepatocellular carcinoma targeted therapy.

In the present study, we covalently coupled folic acid (FA) and 5-fluorouracil acetic acid (FUA) on the surface of quantum dots (QDs) to produce a tumor targeting drug delivery system, FA-QDs-FUA. The QDs not only act as hepatocellular carcinoma (HCC)-targeted delivery vehicles, but also play a key role in imaging. The structural and optical properties of as-prepared FA-QDs-FUA were characterized using UV-visible spectra, fluorescence spectra, infrared spectra, particle size and zeta potential. In vitro hemolysis activity, cytotoxicity and targeting specificity of the FA-QDs-FUA system were also evaluated. The in vivo anti-tumor efficacy of FA-QDs-FUA in tumor-bearing mice was investigated. The average particle size and zeta potential of FA-QDs-FUA was 220.28 nm and -13.3 mV, respectively. The drug-loading content of FA-QDs-FUA was 36.85% ± 1.61% (n = 3). The in vitro release profile of 5-FU from FA-QDs-FUA demonstrated a slow and sustained release behaviour as compared to free 5-FU drug. The results of the in vitro cellular experiment demonstrated that FA-QDs-FUA reduced cytotoxicity as compared to free 5-FU and targeted more easily hepatocellular carcinoma cells (SMMC-7721 and HepG2) than normal cells. Mice treated with FA-QDs-FUA showed superior tumor suppression compared to those treated with free 5-FU at 4.72 mg kg-1 of 5-FU. Therefore, the FA-QDs-FUA system can be used as a promising candidate for improving 5-FU efficacy and tumor targeting specificity with limited toxicity.

Synthesis and evaluation of antitumour activity in vitro and in vivo of chrysin salicylate derivatives.

A series of chrysin salicylate derivatives as potential antitumour agents were synthesised and evaluated their antitumour activities in vitro and in vivo. Most of the compounds exhibited moderate to good activities against MCF-7 cells, HepG2 cells, MGC-803cells and MFC cells. Among them, compound 3f showed the most potent activity against MGC-803 cells and MFC cells with IC50 values of 23.83 ± 3.68 and 27.34 ± 5.21 µM, respectively. The flow cytometry assay reconfirmed that compound 3f promoted the occurrence of tumour cells' G1/S block under the inhibiting effect of compound 3f. Compound 3f possessed higher antitumour efficacy in tumour-bearing mice, compared with the positive control 5-Fu and the blank control saline.

Design, synthesis and biological evaluation of chrysin benzimidazole derivatives as potential anticancer agents.

A series of chrysin benzimidazole derivatives were synthesised and evaluated for their anticancer activity in the search for potential anticancer agents. Among them, compound 18 displayed the most potent anti-proliferative activity against MFC cells with IC50 values of 25.72 ± 3.95 µM. The flow cytometry results displayed that compound 18 induced apoptosis of MFC cells in a dose-dependent manner and caused the cell cycle to be arrested in the G0/G1 phase. Furthermore, the preliminary anticancer activity in vivo was also studied in tumour-bearing mice, and the compound 18 exerted good inhibition effect on tumour growth. These results suggested that compound 18 had good anticancer activity, which could be a potential anticancer agent after further optimisation and evaluation.