Design, synthesis, and biological evaluation of quinolinedione-linked sulfonylpiperazine derivatives as NQO1-directed antitumor agents.

In the current study, a series of novel quinolinedione-linked sulfonylpiperazine derivatives have been reported as NQO1-directed antitumor agents. A majority of compounds in this study were found to be more effective in resisting the proliferation of cancer cells than that of the positive control 5-Fu and TSA. Among the tested compounds, the derivative 22r exhibited considerable effect (IC50, 3.29-5.19 µM) against the proliferation of three NQO1-rich cancer cells (HepG2, MCF-7, and A549), and was recognized to be an excellent NQO1 substrate as revealed by in vitro enzyme reduction assay and molecular docking study with NQO1. In studies on the mechanisms involved, 22r induced reactive oxygen species (ROS) production, caused DNA damage, and induced apoptosis in HepG2 cells. Remarkably, compound 22r exhibited excellent anticancer activity against HepG2 xenograft models in vivo. The study demonstrated that compound 22r provided a promising strategy for the management of malignant tumors.

Recent advances in combretastatin A-4 codrugs for cancer therapy.

CA4 is a potent microtubule polymerization inhibitor and vascular disrupting agent. However, the in vivo efficiency of CA4 is limited owing to its poor pharmacokinetics resulting from its high lipophilicity and low water solubility. To improve the water solubility, CA4 phosphate (CA4P) has been developed and shows potent antivascular and antitumor effects. CA4P had been evaluated as a vascular disrupting agent in previousc linical trials. However, it had been discontinued due to the lack of a meaningful improvement in progression-free survival and unfavorable partial response data. Codrug is a drug design approach to chemically bind two or more drugs to improve therapeutic efficiency or decrease adverse effects. This review describes the progress made over the last twenty years in developing CA4-based codrugs to improve the therapeutic profile and achieve targeted delivery to cancer tissues. It also discusses the existing problems and the developmental prospects of CA4 codrugs.

Dual-functional antitumor conjugates improving the anti-metastasis effect of combretastatin A4 by targeting tubulin polymerization and matrix metalloproteinases.

This study prepared different novel conjugates containing tubulin and MMP inhibitors and assessed their anticancer effects. Typically, the conjugate 15g, which contained combretastatin A4 (CA4) and 2-(4-((diethoxyphosphono)(o-tolyl)methylamino)phenyl)acetic acid (19g) connected by an ester bond, showed the maximum effect against proliferation. Particularly, the conjugate yielded a reduced IC50 value of 0.05 µM in controlling the proliferation of HepG2 cells compared to CA4 alone (0.09 µM). Systematic research indicated that 15g suppressed tubulin polymerization, induced cell cycle arrest at the G2/M phase, led to reactive oxidative stress (ROS) generation of HepG2 cells, and resulted in apoptosis by the mitochondrial-dependent apoptotic pathway. Moreover, 15g showed a potent effect on resistant metastasis by decreasing the levels of the proteins MMP2 and MMP9 in the HepG2 cells. Therefore, this conjugate is a potentially effective approach to improve the anti-metastatic effect of CA4 with high safety.