Summary
Colchicine site tubulin inhibitors are currently developed as vascular disrupting agents (VDAs). However, they were found to have cardiotoxicity in clinical trials. To overcome the problem, we developed a stilbene derivative, cis-3, 4′, 5-trimethoxy-3′-aminostilbene (stilbene 5c), which is highly potent and has no bone marrow and cardiac toxicity in mice. Here we attempt to optimize stilbene 5c using computer-based drug design and synthesize derivatives with benzimidazole or indole group. Biological evaluation showed that they are weaker than stilbene 5c without better water solubility. Alternative approach was thus adopted to make prodrugs of stilbene 5c. A water-soluble prodrug PD7 was synthesized by addition of a morpholino group with carbamate linkage to the amino group of stilbene 5c. In vitro studies show that PD7 induces mitotic arrest and disrupts microtubule similar to stilbene 5c. The cell signaling events in Cdc2, p53, Akt, and aurora kinase are similar in cells treated with stilbene 5c, CA4 or PD7, suggesting that they share the same mechanism. Although PD7 is less effective than stilbene 5c in vitro, the biological activity of PD7 as a single agent is similar to that of stilbene 5c. Combination of PD7 with VEGF inhibitor bevacizumab significantly enhances the therapeutic efficacy of PD7 in mouse xenograft model. These data suggest that PD7 could be a good candidate for further pre-clinical and clinical development as a new VDA for cancer therapy.
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Acknowledgement
The work was supported by Massey Cancer Center and Virginia Commonwealth University pilot program (R.M.L.). The flow cytometry and confocal microscope are supported by Cancer Center Core Grant (P30 CA16059). We thank Drs. Ming Zhao and Michelle Rudek (the Sidney Kimmel Comprehensive Cancer Center, the Johns Hopkins University) for LC/MS/MS study.
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Durrant, D.E., Richards, J., Tripathi, A. et al. Development of water soluble derivatives of cis-3, 4′, 5-trimethoxy-3′-aminostilbene for optimization and use in cancer therapy. Invest New Drugs 27, 41–52 (2009). https://doi.org/10.1007/s10637-008-9139-y
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DOI: https://doi.org/10.1007/s10637-008-9139-y