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 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 G(2)/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.
Department of Chemistry, Lensfield Road, University of Cambridge, Cambridge, United Kingdom.
Thomas M
TM
Beale
Peter J
PJ
Bond
James D
JD
Brenton
D Stephen
DS
Charnock-Jones
Steven V
SV
Ley
Rebecca M
RM
Myers
D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism; D013267:Stilbenes / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D014404:Tubulin / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D013267:Stilbenes; D014230:Triazoles; D014404:Tubulin; C063690:combretastatin A-1