Hirokazu Hosoyama

Taxuspines A ∼ C, new taxoids from Japanese yew Taxus cuspidata inhibiting drug transport activity of P-glycoprotein in multidrug-resistant cells

Abstract Three new taxoids, taxuspines A ∼ C (1 ∼ 3), possessing different skeletons from usual taxane diterpenoids consisting of a 6/8/6-membered ring system have been isolated together with known taxoids (4 ∼ 12) from stems of the Japanese yew Taxus cuspidata Sieb. et Zucc. and the structures elucidated on the basis of spectroscopic data. Most of the taxoids increased cellular accumulation of vincristine in multidrug-resistant tumor cells, while taxol (12) did not show such an activity. The taxoids (1 ∼ 11) showed no or weak cytotoxicity and among them, 2 and 6 reduced appreciably CaCI2-induced depolymerization of microtubules. These results suggest that some taxoids may be useful for overcoming multidrug resistance in tumor cells.

Effects of taxoids from Taxus cuspidata on microtubule depolymerization and vincristine accumulation in MDR cells

Abstract Among new taxoids, taxuspines A ∼ H and J ∼ T ( 1 ∼ 19 ), and known taxoids 20 ∼ 56 containing taxol ( 56 ) and taxol-type compounds 37 ∼ 44 with an N -acylphenylisoserine group at C-13 and an oxetane ring at C-4 and C-5 isolated from stems and leaves of the Japanese yew Taxus cuspidata Sieb. et Zucc., non-taxol-type compounds 4 and 32 remarkably reduced CaCl 2 -induced depolemerization of microtubules. Furthermore, some non-taxol-type compounds 2 , 3 , 9 , 24 , 25 , 27 , and 28 increased cellular accumulation of vincristine in multidrug-resistant tumor cells as potent as verapamil, while taxol ( 36 ) and taxol-type compounds did not show such an activity. In addition, the non-taxol-type compounds enhancing vincristine accumulation inhibited competitively binding of azidopine to P-glycoprotein. These results suggest that some non-taxol-type taxoids may be useful for overcoming multidrug resistance in tumor cells.

Modulation of multidrug resistance by taxuspine C and other taxoids from Japanese yew

Taxuspine C (1), a new taxoid from the Japanese yew Taxus cuspidata, increasing the cellular accumulation of vincristine (VCR) in multidrug-resistant tumor cells as potent as verapamil enhanced the chemotherapeutic effect of VCR in P388/VCR-bearing mice. When taxuspine C (1) was given i.p. daily at 200 mg/kg with 0.2 mg/kg VCR for 5 days, a treated/control (T/C) value of 138% was obtained. The other new taxoids, taxezopidines G (8) and H (9), from the yew also increased the VCR accumulation as potent as verapamil. These results suggest that some taxoids may be useful for overcoming multidrug resistance in tumor cells.

Taxuspines E ∼ H and J, new taxoids from the Japanese yew Taxus cuspidata

Abstract Five new taxoids, taxuspines E ∼ H and J (1 ∼ 5), have been isolated together with known taxoids (6 ∼ 23) containing a series of taxol-related compounds (15 ∼ 20) from stems and leaves of the Japanese yew Taxus cuspidata Sieb. et Zucc. and the structures elucidated on the basis of spectroscopic data. The structures and cytotoxicity of these taxoids (1 ∼ 23) are described.

Taxuspine D, a new taxane diterpene fromTaxus cuspidata with potent inhibitory activity against Ca2+-induced depolymerization of microtubules

A new taxane diterpenoid, taxuspine D (1), possessing an enolacetate moiety, has been isolated from stems of the Japanese yewTaxus cuspidata Sieb. et Zucc., and the structure elucidated on the basis of spectroscopic data. Taxuspine D (1) markedly inhibited Ca2+-induced depolymerization of microtubules.

Taxuspines U, V, and W, new taxane and related diterpenoids from the Japanese yew Taxus cuspidata

Abstract Three new taxane and related diterpenoids, taxuspines U, V, and W ( 1 ≈ 3 ), have been isolated from stems of the Japanese yew Taxus cuspidata Sieb, et Zucc. and the structures elucidated on the basis of spectroscopic data. Taxuspine U ( 1 ) is a very rare bicyclic taxane related diterpenoid from yew trees of genus Taxus , while taxuspine W ( 3 ) is a rare taxoid having a 2(3→20)-abeotaxane skeleton.

Modulation of multidrug resistance in tumor cells by taxinine derivatives

Among a series of taxinine (1) and its designed derivatives (2-33), two taxoids (29 and 33) increased cellular accumulation of vincristine in multidrug-resistant tumor cells more potently than verapamil, while the activities of eight taxoids (11, 14-16, 22, and 30-32) were comparable with that of verapamil. These results reveal that some taxinine derivatives are good modifiers of multidrug resistance in tumor cells.

STEREOSELECTIVE EPOXIDATION OF 4(20)-EXOMETHYLENE IN TAXININE DERIVATIVES AND ASSIGNMENT OF THE EPOXIDE ORIENTATION BY NMR

Abstract Epoxidation of taxinine (1), taxinine A (2), and taxinine derivative 7 with m-chloroperbenzoic acid afforded the α-4(20)-epoxides selectively (α : β = 99 : 1), while epoxidation of taxinine derivatives 7 and 8 with dimethyldioxirane gave the β-4(20)-epoxides predominantly (α : β = 1 : 4∼5). The epoxide orientation was found to be assignable by magnitude of chemical shift differences between the geminal epoxide protons in the 1H NMR spectra. Relative stereochemistry of 1β-hydroxybaccatin I (9) possessing β-4(20)-epoxide moiety was established by X-ray analysis to provide valid assignment of the epoxide orientation.

Multidrug resistance reversal activity of taxoids from Taxus cuspidata in KB-C2 and 2780AD cells.

Some non‐taxol‐type taxoids having neither an oxetane ring at C‐4 and C‐5 nor an N‐acylphenylisoserine group at C‐13, such as taxuspine C, 2′‐desacetoxyaustrospicatine, and 2‐desacetoxytaxinine J, which were isolated from the Japanese yew Taxus cuspidata, increased cellular accumulation of vincristine (VCR) in multidrug‐resistant 2780AD cells as potently as verapamil, and efficiently inhibited [3H]azidopine photolabeling of P‐glycoprotein (P‐gp). Taxuspine C, 2′‐desacetoxyaustrospicatine, and 2‐desacetoxytaxinine J at 10μM completely reversed the resistance to colchicine, VCR, and taxol in KB‐C2 cells, which overexpress P‐gp, while taxinine and taxinine M showed no effect. Taxuspine C, 2′‐desacetoxyaustrospicatine, and 2‐desacetoxytaxinine J may be candidate pharmaceuticals for reversing multidrug resistance (MDR) and also may be good modifiers of MDR in cancer chemotherapy.

Taxezopidines J, K, and L, new taxoids from Taxus cuspidata inhibiting Ca2+-induced depolymerization of microtubules

Abstract Three new taxoids, taxezopidines J (1), K (2), and L (3), have been isolated from seeds of the Japanese yew Taxus cuspidata Sieb. et Zucc. and the structures were elucidated on the basis of spectroscopic data and chemical means. Taxezopidines K (2) and L (3) markedly inhibited Ca2+-induced depolymerization of microtubules, while taxuspine D (4), a known taxoid from the yew, induced unusual shape change of mitotic spindles like taxol.