Increased endothelial cell selectivity of triazole-bridged dihalogenated A-ring analogues of combretastatin A–1

The antiproliferative activity on ovarian cancer (SK-OV-3) cells of a series of triazole-bridged combretastatin analogues (37, 38, 40–43) containing dihalogenation of the A-ring is reported, and compared with their trimethoxy analogues (5, 15, 39). It was found that dihalogenation with either bromin...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2012-03, Vol.20 (5), p.1749-1759
Main Authors: Beale, Thomas M., Bond, Peter J., Brenton, James D., Charnock-Jones, D. Stephen, Ley, Steven V., Myers, Rebecca M.
Format: Article
Language:English
Subjects:
Angiogenesis Inhibitors - chemistry
Angiogenesis Inhibitors - pharmacokinetics
Angiogenesis Inhibitors - pharmacology
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacokinetics
Antineoplastic Agents - pharmacology
Biological and medical sciences
Cell Cycle - drug effects
Cell Growth Processes - drug effects
Cell Line, Tumor
Combretastatin
Dihalogenation
Female
Human umbilical vein endothelial cell
Human Umbilical Vein Endothelial Cells - cytology
Human Umbilical Vein Endothelial Cells - drug effects
Human Umbilical Vein Endothelial Cells - metabolism
Humans
Medical sciences
Models, Molecular
Ovarian cancer
Ovarian Neoplasms - drug therapy
Ovarian Neoplasms - metabolism
Pharmacology. Drug treatments
Stilbenes - chemistry
Stilbenes - pharmacokinetics
Stilbenes - pharmacology
Structure-Activity Relationship
Triazoles
Triazoles - chemistry
Triazoles - pharmacokinetics
Triazoles - pharmacology
Tubulin - metabolism
Vascular disrupting agent
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Summary:The antiproliferative activity on ovarian cancer (SK-OV-3) cells of a series of triazole-bridged combretastatin analogues (37, 38, 40–43) containing dihalogenation of the A-ring is reported, and compared with their trimethoxy analogues (5, 15, 39). It was found that dihalogenation with either bromine or iodine was a tolerated modification when compared to the parent compound combretastatin (CA–4, 1) and had less effect than B-ring modification on potency. These compounds exhibited G2/M arrest, and maintained antitubulin activity. Further assays on human umbilical vein endothelial cells (HUVECs) demonstrated the potential antivascular effects of these triazoles. Of particular note was a 3,5-diiodo-4-methoxyaryl triazole (43) which had promising 7-fold selectivity for HUVECs over ovarian cancer cells.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2012.01.010