Fluorinated colchicinoids: antitubulin and cytotoxic properties.
The synthesis of B-ring and C-ring trifluoroacetamide-substituted colchicinoids and fluoro-substituted colchicineethylamides is presented. The B-ring trifluoroacetamido-substituted analogues exhibit moderate enhancement of potency compared to the nonfluorinated analogues for tubulin assembly inhibition and cytotoxicity toward two wild type cell lines. The C-ring substituted fluoroethylamides have reduced relative potencies in the same systems due to the strong electron-withdrawing effect of the fluoro derivatives. The fluoro colchicinoids are much more cytotoxic toward drug-resistant cell lines than to the wild type cell lines. Their enhanced potency is probably due to an effect of the fluoro moiety on functions specific to resistant cells and/or their higher hydrophobicity that may result in higher intracellular drug content. This finding may suggest the application of designed fluorinated anticancer drugs to overcome acquired resistance which may develop after several regiments of treatment with a nonfluorinated chemotherapeutic agent.
Ringel
I
I
Department of Pharmacology, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Jaffe
D
D
Alerhand
S
S
Boye
O
O
Muzaffar
A
A
Brossi
A
A
D000818:Animals; D002417:Cattle; D002460:Cell Line; D003078:Colchicine / Q000031:analogs & derivatives*; D003603:Cytotoxins / Q000138:chemical synthesis* / Q000627:therapeutic use; D006845:Hydrocarbons, Fluorinated / Q000138:chemical synthesis* / Q000627:therapeutic use; D007941:Leukemia P388 / Q000188:drug therapy; D051379:Mice; D013329:Structure-Activity Relationship; D050257:Tubulin Modulators
D003603:Cytotoxins; D006845:Hydrocarbons, Fluorinated; D050257:Tubulin Modulators; D003078:Colchicine