Combretastatin dinitrogen-substituted stilbene analogues as tubulin-binding and vascular-disrupting agents.

Abstract

Several stilbenoid compounds having structural similarity to the combretastatin group of natural products and characterized by the incorporation of two nitrogen-bearing groups (amine, nitro, serinamide) have been prepared by chemical synthesis and evaluated in terms of biochemical and biological activity. The 2',3'-diamino B-ring analogue 17 demonstrated remarkable cytotoxicity against selected human cancer cell lines in vitro (average GI 50 = 13.9 nM) and also showed good activity in regard to inhibition of tubulin assembly (IC 50 = 2.8 microM). In addition, a single dose (10 mg/kg) of compound 17 caused a 40% tumor-selective blood flow shutdown in tumor-bearing SCID mice at 24 h, thus suggesting the potential value of this compound and its corresponding salt formulations as new vascular-disrupting agents.

• Authors: Rogelio Siles, J Freeland Ackley, Mallinath B Hadimani, John J Hall, Benon E Mugabe, Rajsekhar Guddneppanavar, Keith A Monk, Jean-Charles Chapuis, George R Pettit, David J Chaplin, Klaus Edvardsen, Mary Lynn Trawick, Charles M Garner, Kevin G Pinney
• Journal: Journal of natural products (J Nat Prod) Vol. 71 Issue 3 Pg. 313-20 (Mar 2008) ISSN: 0163-3864 [Print] United States
• PMID: 18303849 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antineoplastic Agents
• Bibenzyls
• Stilbenes
• Tubulin
• combretastatin

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Bibenzyls (chemical synthesis, chemistry, pharmacology)
• Disease Models, Animal
• Drug Design
• Drug Screening Assays, Antitumor
• Humans
• Inhibitory Concentration 50
• Leukemia P388
• Mice
• Molecular Structure
• Neoplasms (blood supply)
• Regional Blood Flow (drug effects)
• Stilbenes (chemical synthesis, chemistry, pharmacology)
• Tubulin (metabolism)