Combretastatin dinitrogen-substituted stilbene analogues as tubulin-binding and vascular-disrupting agents.
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.
Siles
Rogelio
R
Department of Chemistry and Biochemistry, Baylor University, Waco, TX 76798-7348, USA.
Ackley
J Freeland
JF
Hadimani
Mallinath B
MB
Hall
John J
JJ
Mugabe
Benon E
BE
Guddneppanavar
Rajsekhar
R
Monk
Keith A
KA
Chapuis
Jean-Charles
JC
Pettit
George R
GR
Chaplin
David J
DJ
Edvardsen
Klaus
K
Trawick
Mary Lynn
ML
Garner
Charles M
CM
Pinney
Kevin G
KG
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001632:Bibenzyls / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004195:Disease Models, Animal; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020128:Inhibitory Concentration 50; D007941:Leukemia P388; 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*; D014404:Tubulin / Q000378:metabolism*
D000970:Antineoplastic Agents; D001632:Bibenzyls; D013267:Stilbenes; D014404:Tubulin; C040105:combretastatin