Design, synthesis, and biological evaluation of combretastatin nitrogen-containing derivatives as inhibitors of tubulin assembly and vascular disrupting agents.
A series of analogs with nitro or serinamide substituents at the C-2'-, C-5'-, or C-6'-position of the combretastatin A-4 (CA4) B-ring was synthesized and evaluated for cytotoxic effects against heart endothelioma cells, blood flow reduction to tumors in SCID mice, and as inhibitors of tubulin polymerization. The synthesis of these analogs typically featured a Wittig reaction between a suitably functionalized arylaldehyde and an arylphosphonium salt followed by separation of the resultant E- and Z-isomers. Several of these nitrogen-modified CA4 derivatives (both amino and nitro) demonstrate significant inhibition of tubulin assembly as well as cytotoxicity and in vivo blood flow reduction. 2'-Aminostilbenoid 7 and 2'-amino-3'-hydroxystilbenoid 29 proved to be the most active in this series. Both compounds, 7 and 29, have the potential for further pro-drug modification and development as vascular disrupting agents for treatment of solid tumor cancers and certain ophthalmological diseases.
Monk
Keith A
KA
Baylor University, Department of Chemistry and Biochemistry and The Center for Drug Discovery, One Bear Place # 97348, Waco, TX 76798, USA.
Siles
Rogelio
R
Hadimani
Mallinath B
MB
Mugabe
Benon E
BE
Ackley
J Freeland
JF
Studerus
Scott W
SW
Edvardsen
Klaus
K
Trawick
Mary Lynn
ML
Garner
Charles M
CM
Rhodes
Monte R
MR
Pettit
George R
GR
Pinney
Kevin G
KG
D000818:Animals; D001547:Benzaldehydes / Q000737:chemistry; D001632:Bibenzyls / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D002417:Cattle; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D007536:Isomerism; D051379:Mice; D015394:Molecular Structure; D009369:Neoplasms / Q000098:blood supply; D012039:Regional Blood Flow / Q000187:drug effects; D013267:Stilbenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D001547:Benzaldehydes; D001632:Bibenzyls; D013267:Stilbenes; D014404:Tubulin; C040105:combretastatin; C100058:vanillin