Synthesis and biological evaluation of novel benzylidene-succinimide derivatives as noncytotoxic antiangiogenic inhibitors with anticolorectal cancer activity in vivo.

A novel series of benzylidene-succinimide derivatives were synthesized, characterized and evaluated for their cytotoxicities against HCT116, and SW480 cancer cells and NCM460 normal human cells. Their antiangiogenic capabilities were evaluated using a chick chorioallantoic membrane (CAM) assay. The compound, XCF-37b, was selected as the most potent antiangiogenic inhibitor with noncytotoxicity to evaluate the pharmacological effects on human umbilical vein endothelial cells (HUVECs) and cancer cells in vivo and in vitro. The results showed that XCF-37b inhibited HT29-cell colon tumor growth in vivo, without showing cytotoxicity against the five other cancer cell lines in vitro. Experiments confirmed that XCF-37b had obvious antiangiogenic activity by HUVEC migration and invasion and rat aortic ring angiogenesis ex vivo. Mechanism studies showed that XCF-37b inhibited the AKT/mTOR and VEGFR2 signaling pathways, as evidenced by decreased expressions of phosphor-AKT (p-AKT), p-mTOR, p-VEGFR2 (Tyr175), p-Src (Tyr416), p-FAK (Tyr925), and p-Erk1/2 (Thr202/Tyr204). Moreover, XCF-37b significantly decreased the protein expressions of matrix metalloproteinase-2 (MMP-2), MMP-9 and hypoxia-inducible factor-1α (HIF-1α). XCF-37b generally regulated angiogenic inhibition through several regulatory pathways, without significantly interfering with colorectal cancer cell growth.

Inclusion complexes of GA3 and the plant growth regulation activities.

Gibberellic acid (GA3) is an important phytohormone that is applied in agriculture, nurseries, tissue culture, tea gardens, etc. However, it has some drawbacks such as potential hazardous effects on mammals and labile in the condition of a weak base or acid. In this study, the enhanced stability and bioavailability of GA3 were achieved by forming the inclusion complexes of GA3 with cyclodextrins (ß- or γ-CD) and its derivative (HP-ß-CD). In the preliminary plant growth regulation assay, GA3/CDs displays superior bioactivity compared to pure GA3 to help with the early seedling growth of cucumber and mung bean and the root growth of cucumber and mung bean, respectively. The results showed that there was a certain relationship between the inclusion ability, stability and bioactivity. The inclusion stability constants of gibberellin clathrate are consistent with the order of stabilities of the inclusion complex. Among these complexes, GA3/HP-ß-CD possess highest inclusion constant, and the binding ability of the HP-ß-CD not only enhances the stability of gibberellic acid in the stability test but also plays a slow release role in the bioactivity assay. Therefore, the complex of GA3 may be used as a promising plant growth regulator.

Investigation of inclusion complex of epothilone A with cyclodextrins.

The inclusion complexation of Epothilone A with native cyclodextrin (ß- or γ-CD) and its derivative hydroxypropyl-ß-cyclodextrin (HPßCD) were prepared. Their behavior, characterization, and binding ability were investigated in both solution and the solid state by means of UV-vis, NMR, XRD, DSC and SEM. The results show that the water solubility and solution stability obviously increased in the inclusion complex with cyclodextrins. Meanwhile, the inclusion complexes still retained anticancer activity against A549 and MCF-7 cells, similar to free Epothilone A. This satisfactory water solubility, high solution stability, and high anticancer activity of the Epothilone A/CD complexes will be potentially useful as an anticancer therapy.

Inclusion complex of GA-13316 with ß-cyclodextrin: preparation, characterization, molecular modeling, and in vitro evaluation.

The inclusion complex of GA-13316 with ß-cyclodextrin (ß-CD) is one of a unique series of gibberellin derivatives possessed of potential anticancer activities. The complex with ß-CD was characterized by means of UV, XRD, DSC, TG, (1)H, and 2D NMR spectroscopy. In addition, we investigated the main aspects of the interaction between GA-13316 and ß-CD using both experimental and molecular modeling approaches. The complex still maintained its anticancer activity, as shown by in vitro cell survival assay on the human colon carcinoma cell line (HCT116) and the human lung cancer cell line (H460). The results showed that the use of ß-CD could be obviously improved the water solubility and stability of GA-13316, implying that the inclusion complex could be a promising future therapeutic agent.

Inclusion complex of GA-13315 with cyclodextrins: preparation, characterization, inclusion mode and properties.

GA-13315 (13-chlorine-3,15-dioxy-gibberllic acid methyl ester) was semi-synthesized by GA3 (gibberellic acid) as a potential anticancer drug. To pursue its promising application, cyclodextrin was used for forming complexes to overcome its drawbacks such as poor water solubility and stability. So, GA-13315/CD complexes were prepared with native ß-cyclodextrin and its derivatives (hydroxypropyl-ß-cyclodextrin (HPßCD)) and their inclusion complexation behavior, characterization and binding ability in both solution and the solid state was studied by means of UV, XRD, DSC, SEM, (1)H and 2D NMR spectroscopy. Furthermore, preliminary in vitro cytotoxicity assay showed that the complexes still maintain antitumor activities, compared with GA-13315 or adriamycin (ADM, positive control) as the positive control. The results showed that the water solubility and stability of GA-13315 were obviously improved in the inclusion complex with cyclodextrins, suggesting the inclusion complexes as promising future therapeutic agents.