A Paclitaxel Analogues And Structure-activity Relationship Af-5 New Synthetic Routes

Sinenxan A, which was found from the cell culture of Taxus yunnanensis, has the same skeleton as that of most taxanes and has a unique 14β-hydroxyl group instead of 13-oxygen functionalities. We have designed the synthesis of taxol analogues from this new taxane aiming to find new anticancer drugs and to study the structure-activity relationship. Through two pathways, six analogues were synthesized among which two possess the side chains of taxol and taxotere respectively and the four others possess homologated ones. Unfortunately, these analogues did not show activity at 10μM in the tubulin assembly assay, and showed only marginal activity in MTT assay against tumor cell lines.After comparison of the structure and activity of these compounds with that of taxol, taxotere and Ojima's 14β-side chain taxol, we supposed that 1-OH is one of the necessary pharmacophores for anticancer activity of taxol and taxol analogues.To reveal the SAR contribution of 1-hydroxyl, we attempted two different route to obtain 1-dehydroxy taxol. SmI₂ was used to reductively remove 1-hydroxyl group in its acetate form from 10-DAB when the C-2 oxygen function was changed to ketone to facilitate the reduction. The 1-hydroxyl was reduced but only two A-ring contracted compounds were obtained during the reduction.Starting from taxinine, a natural taxane without 1-hydroxyl, we attempted to convert it into 1-deoxy taxol analogue using our established semisynthesis strategy, but failed because the 13-ketone could not be reduced selectively. The conjugated C-C double bond was reduced with NaBH₄ or both ketone and double bond were reduced.A total 71 compounds were synthesized, 43 of which are unreported. AF-5 is an antianxiety drug under development. We have explored two synthetic pathways in order to find a more practical and more economic method. In the linear one, we started from dihydrocarvone and acrylonitrile, and a mimicry of the key intermediate of compound 6 was obtained. In the convergent one, vinyl pentylketone, the key moiety for Robinson annelation, was synthesized throughα-elongation of heptanone with ethylformate. Direct hydration of dihydrocarvone at the double bond was achieved using formic acid. The final product was obtained by Ronbinson annelation and subsequent reduction and cyclization. This new route avoided the use of most of the hazardous and expensive reagents.A total of 27 compounds were synthesized, 21 of which are unreported.