1,5-Disubstituted 1,2,3-triazoles as cis-restricted analogues of combretastatin A-4: Synthesis, molecular modeling and evaluation as cytotoxic agents and inhibitors of tubulin.
A series of cis-restricted 1,5-disubstituted 1,2,3-triazole analogues of combretastatin A-4 (1) have been prepared. The triazole 12f, 2-methoxy-5-(1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)aniline, displayed potent cytotoxic activity against several cancer cell lines with IC(50) values in the nanomolar range. The ability of triazoles to inhibit tubulin polymerization has been evaluated, and 12f inhibited tubulin polymerization with IC(50)=4.8microM. Molecular modeling experiments involving 12f and the colchicine binding site of alpha,beta-tubulin showed that the triazole moiety interacts with beta-tubulin via hydrogen bonding with several amino acids.
Odlo
Kristin
K
School of Pharmacy, Department of Pharmaceutical Chemistry, University of Oslo, PO Box 1068, N-0316 Oslo, Norway.
Hentzen
Jean
J
dit Chabert
Jérémie Fournier
JF
Ducki
Sylvie
S
Gani
Osman A B S M
OA
Sylte
Ingebrigt
I
Skrede
Martina
M
Flørenes
Vivi Ann
VA
Hansen
Trond Vidar
TV
D000596:Amino Acids / Q000737:chemistry; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D006860:Hydrogen Bonding; D020128:Inhibitory Concentration 50; D020014:K562 Cells; D008958:Models, Molecular; D015394:Molecular Structure; D013237:Stereoisomerism; D013267:Stilbenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014404:Tubulin / Q000187:drug effects*
D000596:Amino Acids; D000970:Antineoplastic Agents; D013267:Stilbenes; D014230:Triazoles; D014404:Tubulin; C058728:fosbretabulin