期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 46, 期 17, 页码 3623-3630出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm030770w
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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.
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