Experimental and computational study on anti-gastric cancer activity and mechanism of evodiamine derivatives.

Introduction: Human topoisomerase 1 (TOP1) is an important target of various anticancer compounds. The design and discovery of inhibitors targeting TOP1 are of great significance for the development of anticancer drugs. Evodiamine and thieno [2,3-d] pyridine hybrids show potential antitumor activity. Herein, the anti-gastric cancer activities of these hybrids were investigated. Methods: The inhibitory effects of different concentrations of ten evodiamine derivatives on the gastric cancer cell line SGC-7901 were assessed using a methyl thiazolyl tetrazolium assay. Compounds EVO-1 and EVO-6 strongly inhibited gastric cancer cell proliferation, with inhibition rates of 81.17% ± 5.08% and 80.92% ± 2.75%, respectively. To discover the relationship between the structure and activity of these two derivatives, density functional theory was used to investigate their optimized geometries, natural population charges, frontier molecular orbitals, and molecular electrostatic potentials. To clarify their anti-gastric cancer mechanisms, molecular docking, molecular dynamics simulations, and binding free energy calculations were performed against TOP1. Results: The results demonstrated that these compounds could intercalate into the cleaved DNA-binding site to form a TOP1-DNA-ligand ternary complex, and the ligand remained secure at the cleaved DNA-binding site to form a stable ternary complex. As the binding free energy of compound EVO-1 with TOP1 (-38.33 kcal·mol-1) was lower than that of compound EVO-6 (-33.25 kcal·mol-1), compound EVO-1 could be a more potent anti-gastric cancer agent than compound EVO-6. Discussion: Thus, compound EVO-1 could be a promising anti-gastric cancer drug candidate. This study may facilitate the design and development of novel TOP1 inhibitors.

Selenochemical modification of low molecular weight polysaccharides from Grifola frondosa and the mechanism of their inhibitory effects on gastric cancer cells.

An important micronutrient involved in immune response and antitumor is selenium. LMW-GFP, a polysaccharide extracted from Grifola frondosa seed bodies, has a relatively weak antitumor effect on BGC-823 and MFC cells in vitro, whereas selenium binding to LMW-GFP can significantly increase the in vitro antitumor activity of LMW-GFP. In this study, Se-LMW-GFP was prepared by the HNO3-Na2SeO3 method, and the structures of LMW-GFP and Se-LMW-GFP were characterized by UV-visible spectroscopy of absorption, FTIR spectroscopy, and electron scanning microscopy, and these structural analyses showed that selenium was successfully complexed to LMW-GFP. The selenium content of Se-LMW-GFP was measured to be 2.08 % ± 0.08 % by ICP-MS. The anti-tumor activity of LMW-GFP before and after selenium modification was compared by cellular experiments, and the findings indicated that the anti-tumor activity of Se-LMW-GFP was considerably improved over that of LMW-GFP, and inhibited the proliferation of BGC-823 cells and MFC cells through a combination of the Fas/FasL-mediated exogenous death receptor pathway as well as the endogenous mitochondrial pathway. Our results suggest that Se-LMW-GFP not only has great potential for natural health food and anti-gastric cancer drug development but is also a good selenium supplement.

Structural features and anti-gastric cancer activity of polysaccharides from stem, root, leaf and flower of cultivated Dendrobium huoshanense.

The structure features and anti-gastric cancer activities in vitro of stem, root, leaf and flower polysaccharides from cultivated Dendrobium huoshanense were investigated systematically. Stem polysaccharide (cDHPS) was composed of →4)-ß-D-Glcp-(1→, →4)-ß-D-Manp-(1→, →4)-3-O-acetyl-ß-D-Manp-(1→ with the molecular weight of 2.59 × 105 Da; root polysaccharide (cDHPR) was composed of →3,5)-α-L-Araf-(1→, →4)-ß-D-Glcp-(1→, →4)-ß-D-Manp-(1→, →4,6)-ß-D-Manp-(1→, →6)-α-D-Galp-(1→ and terminal ß-L-Araf with the molecular weight of 1.41 × 104 Da; leaf polysaccharide (cDHPL) was composed of →4)-ß-D-Glcp-(1→, →4)-ß-D-Manp-(1→, →4)-3-O-acetyl-ß-D-Manp-(1→, →3,6)-ß-D-Manp-(1→ and terminal α-D-Galp with the molecular weight of 2.09 × 105 Da; and flower polysaccharide (cDHPF) was composed of →4)-ß-D-Glcp-(1→, →4)-ß-D-Manp-(1→, →3,6)-ß-D-Manp-(1→ and terminal α-D-Galp with the molecular weight of 4.78 × 105 Da. Among these four polysaccharides, cDHPS showed the best anti-gastric cancer activity evidenced by the inhibited growth and c-myc expression as well as the enhanced apoptosis and p53 expression of murine forestomach carcinoma (MFC) cells, suggesting their difference in anti-gastric cancer activity should be contributed to their difference in structure features.

Novel tertiary sulfonamide derivatives containing benzimidazole moiety as potent anti-gastric cancer agents: Design, synthesis and SAR studies.

With the expectation to find out new anti-gastric cancer agents with high efficacy and selectivity, a series of novel tertiary sulfonamide derivatives were synthesized and the anti-cancer activity was studied in three selected cancer cell lines (MGC-803, PC-3, MCF-7) in vitro. Some of the synthesized compounds could significantly inhibit the proliferation of these tested cancer cells and were more potent than the positive control (5-Fu). The structure-activity relationship of tertiary sulfonamide derivatives was explored in this report. Among the tested compounds, compound 13g containing benzimidazole moiety showed the best anti-proliferation activities against MGC-803 cells (IC50 = 1.02 µM), HGC-27 cells (IC50 = 1.61 µM), SGC-7901 (IC50 = 2.30 µM) cells as well as the good selectivity between the cancer and normal cells. Cellular mechanism studies elucidated compound 13g inhibited the colony formation of gastric cancer cell lines. Meanwhile, compound 13g arrested cell cycle at G2/M phase and induced cell apoptosis. Mechanistically, compound 13g markedly decreased p-Akt and p-c-Raf expression, which revealed that compound 13g targeted gastric cancer cell lines via interfering with AKT/mTOR and RAS/Raf/MEK/ERK pathways. All the findings suggest that compound 13g might be a valuable lead compound for the anti-gastric cancer agents.

Novel 3-(2,6,9-trisubstituted-9H-purine)-8-chalcone derivatives as potent anti-gastric cancer agents: Design, synthesis and structural optimization.

To explore anti-gastric cancer agents with high efficacy and selectivity, we report the design, synthesis and optimization of a novel series of 3-(2,6,9-trisubstituted-9H-purine)-8-chalcone derivatives starting from the compound PCA-15 reported by us previously. Most of the target compounds demonstrated significant antiproliferative effects on MGC803 cancer cell line, and more potent than the positive control (PCA-15 and 5-Fu). Among them, compound 6o was identified to be the most active compound against MGC803 cell line with an IC50 value of 0.84 µM. Additionally, high selectivity was also observed between cancer and normal cells (23.35 µM against GES-1). Further mechanism studies confirmed that compound 6o could inhibit colony formation and migration, induce the apoptosis of MGC803 cells through both the mitochondrial-mediated intrinsic pathway and death receptor-mediated extrinsic pathway, which were evidenced by the up-regulation of Bax, cleaved-caspase 9/3/8, cleaved PARP and down-regulation of Bcl-2. Our systematic studies implied a new scaffold targeting gastric cancer cells for further development of small-molecule compounds with improved potency and selectivity.

Synthesis of (1E,4E)-1,5-bis(2,3-dimethoxyphenyl)penta-1,4-dien-3-one Analogs and Its Anti-gastric Cancer Activity In Vitro / 中国药学杂志

OBJECTIVE: To explore the efficient and economical synthesis method of asymmetric monocarbonyl curcumin ana-logues(AMCACs), design and sgnthesize a series of B19(1E, 4E)-1, 5-bis(2,3-dimethoxyphenyl) penta-1, 4-dien-3-one analogs to in- vestigate their anti-gastric cancer activities in vitro. METHODS: A series of asymmetric B19 analogues containing 2, 3-dimethoxyphenyl were designed via the combination principle of medicinal chemistry, and obtained a method for synthesizing intermediate (E)-2-(2, 3- dimethoxybenzylidene) cyclopentanone by one step catalyzed by L-proline. The targeted compounds were screened by MTT as-say, and colony cloning experiments were used to further verify its anti-gastric cancer activity in vitro. RESULTS: Ten novel target compounds were synthesized, and the structures were confirmed by LC-MS and 1H-NMR spectral analysis Among them, compound 6e had the highest inhibitory activity on the growth of gastric cancer cells SGC-7901 and BGC-823, whose IC50 were 9.80 and 13.50 μmol• L 1, respectively. CONCLUSION: L-proline could be used as a catalyst to synthesize asymmetric monocarbonyl curcumin analogues efficiently and economically Compound 6e could effectively inhibit the growth of gastric cancer cells in vitro, and its toxicity and inhibition mechanism of tumor cell growth need to be further studied.

GC-MS fingerprint of in vitro anti-gastric cancer active parts from roots of Uygur medicine Ferula ferulaeoides / 中草药

Objective: To preliminarily ascertain the anti-gastric cancer active parts from the roots of Ferula ferulaeoide and to study its GC-MS fingerprint Methods: The inhibitory effects of different extraction from the roots of F. ferulaeoide on the cell proliferation of SGC-7901 cells were determined with MTT colorimetric method. GC-MS fingerprint of in vitro anti-gastric cancer active parts from F. ferulaeoide was investigated and analyzed by GC-MS and principal component analysis (PCA). Results: The chloroform extract showed the best inhibition on the growth of SGC-7901 cells. The method on GC-MS fingerprint of in vitro anti-gastric cancer active parts from F. ferulaeoide was established, showing 28 common characteristic peaks. The PCA demonstrated that the common peaks 1, 2, 4, 6, 7, 8, 9, 12, 21, 22, and 23 were connected closely with the in vitro anti-gastric cancer activity, and the seven compounds were 3-methoxy-1,2-propanediol, D-limonene, L-borneol acetate, terpinyl acetate, 1,5,9-undecatriene, 2,6,10-trimethyl, α-cedrene, and a-bergsmotene, β-cedrene, 8-epi-γ-eudesmol, γ-eudesmol, hinesol. Totally 28 common compounds of 10 batches of samples accounted for over 92% of the volatile contents, and the similarity of the GC-MS fingerprints from the 10 batches of samples was over 0.90. Conclusion: The chloroform extract from the roots of F. ferulaeoides with potential inhibitory effect on gastric cancer SGC-7901 cells is tentatively confirmed, and needs further to verify by animal cells in vivo. The method of GC-MS fingerprinting is rapid, simple, and accurate with good reproducibility and stability, and can be used to control the quality of active parts of F. ferulaeoides.