Synthesis of C2-C3'N-linked macrocyclic taxoids. Novel docetaxel analogues with high tubulin activity.
Novel C2-C3'N-linked macrocyclic taxoids 4 bearing an aromatic ring at position C2 were synthesized. These compounds, tethered between N3' and the C2-aromatic ring at the ortho, meta, or para position, were constructed by ring-closing metathesis. The para-substituted derivatives were unable to stabilize microtubules, whereas the ortho- and meta-substituted compounds show significant activity in cold-induced microtubule disassembly assay. The meta derivative 4c is the first C2-C3'-linked cyclic analogue to be equipotent to paclitaxel in this assay and to show significant cytotoxicity. Computational studies of the conformational behavior of these compounds indicate that they can adopt several conformations including mainly the "T-shaped" forms. Docking experiments have shown that the "T-shaped" form is preferred for a good interaction of these compounds with the beta-tubulin binding pocket.
Querolle
Olivier
O
Institut de Chimie des Substances Naturelles, CNRS, 91190 Gif sur Yvette, France.
Dubois
Joëlle
J
Thoret
Sylviane
S
Roussi
Fanny
F
Guéritte
Françoise
F
Guénard
Daniel
D
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D000077143:Docetaxel; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007624:KB Cells; D008958:Models, Molecular; D008968:Molecular Conformation; D013329:Structure-Activity Relationship; D043823:Taxoids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014404:Tubulin / Q000737:chemistry*
D000970:Antineoplastic Agents; D043823:Taxoids; D014404:Tubulin; D000077143:Docetaxel