Bioactive taxoids from the Japanese yew Taxus cuspidata

Abstract

A series of new taxoids, named taxuspines A-H and J-Z (1-25) and taxezopidines A-H and J-L (26-36), have been isolated together with 37 known taxoids (37-73) including paclitaxel (53) from the Japanese yew, Taxus cuspidata Sieb. et Zucc. (Taxaceae). These new taxoids possess various skeletons containing 5/7/6, 6/10/6, 6/5/5/6, 6/8/6, or 6/12-membered ring systems. Among the new taxoids, some non-taxol-type compounds remarkably reduced CaCl(2)-induced depolymerization of microtubules, or increased cellular accumulation of vincristine in multidrug-resistant tumor cells as potent as verapamil. On the other hand, chemical derivatization of taxinine (37), one of major taxoids obtained from this yew, led to the discovery of unusual reactions of taxinine derivatives. Here we describe our recent results on the isolation, structure elucidation, and bioactivity of these new and known taxoids and the formation of unexpected products of the unusual reactions of taxinine.

Two New Taxanes from the Needles and Branches Bark of Taxus cuspidata

“…s), as well as the NOESY correlations of HÀC(3)/HÀC(7), HÀC(5)/H a ÀC(6), HÀC(5)/H b ÀC (6), and H b ÀC(6)/Me (19), indicated that the C-ring adopted a chair conformation. Further, the NOESY crosspeaks between HÀC(2)/HÀC(9), HÀC(2)/Me (19), HÀC(3)/HÀC(7), and HÀC(9)/ Me(19) indicated a trans junction of rings B and C. The b-orientations of HÀC(2), HÀC (9), and HÀC (13) were assigned on the basis of the NOESY correlations of HÀC(2)/HÀC(9), HÀC(2)/Me(17), HÀC(2)/Me (19), HÀC(9)/Me(17), HÀC(9)/ Me(19); and of HÀC(13)/H b ÀC (14), HÀC(13)/Me (16). The b-orientation of HÀC (5) was assumed from its small coupling constants with HÀC(4), H a ÀC (6), and H b ÀC(6) ( Table 1).…”

“…The bb-, b-, and a-orientations of HÀC(2), HÀC(5), HÀC (9), and HÀC(10), respectively, were assumed from a biogenetic viewpoint of taxanes, and were in agreement with the observed coupling constants [14] [15]. Taking all these data into account, the structure of 2 was, therefore, unequivocally established as (2a,5a,9a,10b-)-2,9,10-triacetoxy-5-[(b-d-glucopyranosyl)oxy]-3,11-cyclotax-11-en-13-one.…”

Chemical Studies on Taxus cuspidata

“…3. Structures of 3,11-cyclotaxanes type taxane was markedly different from those of other taxanes, especially with respect to the coupling constants between HÀC(9) and HÀC (10). On the other hand, a set of AB system of H a ÀC (16) Fig.…”

A pharmacophore modeling approach to design new taxol® mimics: towards the synthesis of potential anticancer and MDR-reversing agent

“…The biological data of taxuspine U are not yet published but it is well known that taxuspine X is able to increase accumulation of vincristine in MDR cell lines, so it is interesting for overcoming multi-drug resistance. 17 Interestingly this compound is characterized by a cinnamoyl group at C-5, while lacking both an oxetane ring and a phenylisoserine group at C-13. Once fitted into the tubulin binding site, the closely resemblance of taxuspine U 3D rearrangement to taxol bioactive conformation led us to design few structural modification of 22 ( Figure 6, A), aimed at obtaining interesting molecule, such as 24 ( Figure 5), potentially active as anticancer and/or MDR reversing agents.…”