Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • Here we reported series of

    2022-05-25

    Here, we reported series of carbohydrate-modified compounds containing a dibromo substituted benzene ring which was derived from the red alga (). The conformation flexibility of chk1 and their polyol structures give them many unique biological properties as we have described earlier. More interestingly, the presence of sugar molecules may increase the ability of compounds to enter cells through glucose transporter 1 (GLUT1) which is the most common glucose transporter, and widely overexpress in many human cancers. The length of the linker joining saccharide and aglycone might affect the uptake of glycosyl-modified compounds, thus, docking was firstly performed for selecting appropriate linker. Because of the inward open configuration of GLUT1 (PDB: ), the design of compounds was guided by the xylose transporter XylE (PDB: ), which was a GLUT1 homolog with an outward open configuration that compounds would encounter when attempting to enter the cell., The characterize function data of compounds – and the H-bonds interaction in docking simulation were shown in . The total-score of compounds – suggested that the compounds and displayed similar affinity, which were much higher than that of compound . The Gln168, Gln289, Asn294 and Typ392 were involved in the formation of H-bonds of compound complex, which was consistent with that between glucose (original ligand) and XylE (). In contrast, only the hydroxy groups on C2 and C4 of -glucose were involved in hydrogen-bonding interactions with Gln288 and Trp392 in the complex of compound and XylE. Thus, the aliphatic chain containing three carbon atoms was identified as the linker for target glycoside. Additionally, glucosamine, xylose and ribose were also used in the design of glycoside compounds () based on GLUT1 could transport a variety of carbohydrates except for glucose. The synthesis of target compounds was described in . All the synthesized compounds were investigated for their anticancer activity on four human cancer cell lines (). An interesting phenomenon was observed that only ribose derivatives (compound and ) exhibited modest inhibitory activity which was comparable to positive control (gefitinib), while glucose, glucosamine or xylose modified compounds showed no activity against four cancer cell lines. The IC values of compounds and in each of the four cell lines were calculated by testing each compound in a series of concentrations (). The compounds and showed almost the same cytotoxicities in each cell line tested, and which were comparable to gefitinib. Although the micromolar grade IC values were considered to be undesirable in cytotoxic activity studies, compound did show higher activity (2-fold) than that of gefitinib against A549. Thus, the compound was used for further studies of the antiproliferative mechanism. Cancer cell invasion plays a critical role during the carcinomas arising from epithelial tissues progressed to higher pathological grades of malignancy. To investigate the anti-migration effects of compound , a wound healing assay was performed (). Additionally, compound was also examined the effects on apoptosis and on the cell cycle in A549 cell line using flow cytometry analysis (Figs.  and ). The migration of A549 cell was inhibited by 48h treatment with at 8, 16µM concentration compared to the untreated control, and the relative mobility was concentration dependent. Moreover, the compound could induce the A549 cell apoptosis, and the apoptosis rates increased significantly with the increase of the concentration of the compound (). Furthermore, after incubation with 8µM, 16µM and 24µM compound for 48h, the DNA contents of the A549 cells were 59.17%, 76.57% and 89.56% in G0/G1 phase, and were 40.83%, 23.44% and 10.25% in S phase, respectively. Apparently, the newly synthesized ribose-modified compound blocked A549 cell at the G0/G1 phase in a concentration-dependent manner (). As it is widely agreed that the synthesis of RNA occurs in G1 phase and which also prepares for the synthesis of proteins. The ribose is one of materials for RNA synthesis, so ribose-modified compound may be erroneously identified to interfere with RNA synthesis and block cells in G0/G1 phase, which was different from the action of traditional antitumor drug cisplatin (inhibit DNA replication, arrests the cell cycle at the S phase)., The result (cell arrest assay) may be used to explain why other compounds showed no activity against four cancer cell lines.