Development of water soluble derivatives of cis-3, 4', 5-trimethoxy-3'-aminostilbene for optimization and use in cancer therapy.
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.
Massey Cancer Center, and Department of Internal Medicine, Virginia Commonwealth University, 401 College Street, Room 325, Richmond, VA, 23298, USA.
David E
DE
Durrant
Joanna
J
Richards
Ashutosh
A
Tripathi
Glen E
GE
Kellogg
Paolo
P
Marchetti
Marco
M
Eleopra
Giuseppina
G
Grisolia
Daniele
D
Simoni
Ray M
RM
Lee
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D050256:Antimitotic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D017076:Computer-Aided Design; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D051379:Mice; D008819:Mice, Nude; D008870:Microtubules / Q000187:drug effects; D009025:Morpholines / Q000138:chemical synthesis* / Q000494:pharmacology*; D019999:Pharmaceutical Solutions / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology; D013267:Stilbenes / Q000737:chemistry* / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors; D023041:Xenograft Model Antitumor Assays
C539258:1-(5-(2-(3,5-dimethoxyphenyl)vinyl)-2-methoxyphenyl)-3-(2-morpholin-4-ylethyl)urea; D020533:Angiogenesis Inhibitors; D050256:Antimitotic Agents; D009025:Morpholines; D019999:Pharmaceutical Solutions; D010671:Phenylurea Compounds; D011355:Prodrugs; D013267:Stilbenes; D042461:Vascular Endothelial Growth Factor A; C529077:cis-3,4',5-trimethoxy-3'-aminostilbene