Synthesis of novel macrocyclic docetaxel analogues. Influence of their macrocyclic ring size on tubulin activity.
This work describes the synthesis of a series of novel macrocyclic taxoids 3 and 3(H) designed to mimic the docetaxel solid-state ("nonpolar") conformation. These compounds, bearing 18-, 20-, 21-, and 22-membered rings connecting the C-2 OH and C-3' NH moieties, were constructed by ring-closing olefin metathesis of the taxoid-omega,omega'-dienes 4. Biological evaluation of these new taxoids showed that activity is dependent on the ring size, and only the 22-membered ring taxoid 3d exhibits significant tubulin binding. Synthesis of the open-chain analogues 7 and 7(H) and comparison of their biological activities with macrocyclic taxoids show that the carbon tether between C-2 OH and C-3' NH does not hamper tubulin binding. Computational studies of the conformational behavior of the macrocyclic taxoids 3 indicate that the 18-, 20-, and 21-membered-ring 3a-c adopt mainly conformations that are not recognized by tubulin. The most active taxoid 3d appears to adopt a conformation that is between the "nonpolar" and T-shaped forms.
Querolle
Olivier
O
Institut de Chimie des Substances Naturelles, CNRS, Avenue de la Terrasse, 91198 Gif sur Yvette Cedex, France.
Dubois
Joëlle
J
Thoret
Sylviane
S
Roussi
Fanny
F
Montiel-Smith
Sara
S
Guéritte
Françoise
F
Guénard
Daniel
D
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000077143:Docetaxel; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007624:KB Cells; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012996:Solutions; D013329:Structure-Activity Relationship; D043823:Taxoids; D014404:Tubulin / Q000737:chemistry*
D000970:Antineoplastic Agents; D012996:Solutions; D043823:Taxoids; D014404:Tubulin; D000077143:Docetaxel; D017239:Paclitaxel