Relationships between the structures of taxol and baccatine III derivatives and their in vitro action on the disassembly of mammalian brain and Physarum amoebal microtubules.

Abstract

The in vitro disassembly of microtubules from mammalian brain and Physarum is inhibited by various derivatives of taxol and baccatine III. Structure-activity relationships of the taxol derivatives were identical for both mammalian brain and Physarum microtubules. This observation suggests that the site of action of taxol has been preserved during the evolution of these two different eukaryotic lines. The substituent at C-13 of taxol was required to prevent disassembly of brain microtubules with or without microtubule-associated proteins. In contrast, both taxol and baccatine III prevented the disassembly of Physarum microtubules to the same extent, showing that the substituent at C-13 was not required in the interaction with Physarum tubulin. The different effects of baccatine III and taxol derivatives indicate that measuring the disassembly of microtubules from different organisms could be a useful parameter in the search for derivatives exhibiting antiparasitic activity.Assembly properties of tubulin are highly preserved along the various evolutionary pathways of eukaryotic cells as illustrated by the in vitro coassembly of tubulin from fungi (1-3), ciliates (4), myxomycetes (5), algae (6, 7), and higher plants (8) with mammalian brain tubulin. In contrast, the sensitivity of eukaryotic cells towards microtubule poisons depends on a selective pharmacological specificity of their tubulin (9-11), allowing the use of spindle or microtubular poisons such as griseofulvin (12-14) and methyl 2-benzimidazolecarbamate derivatives (10,15) (36,37). In order to compare the interaction of taxol on tubulin from two distinct evolutionary lines of eukaryotic cells, we have studied the effects of various taxol derivatives, in particular baccatine III (Fig.

Molecular cloning and heterologous expression of the C-13 phenylpropanoid side chain-CoA acyltransferase that functions in Taxol biosynthesis

“…Structure-activity relationship studies have demonstrated that the C-2 benzoxy group, an intact oxetane ring bridged by the C-4(5) bond, and the C-13 O-[N-benzoyl (Bz) phenylisoserine] side chain of Taxol ( Fig. 1 A) are required for the unique tubulin-binding mode of action (6,7).…”

Relationship between the Structures of Taxane Derivatives and Their Microtubule Polymerization Activity

“…1), and these side chains are thought to be essential for stabilization of the microtubules. 12,13) All 18 taxane compounds used in this study lack such hydrophobic substitutions (Supplemental Fig. S3).…”

“…10,11) The N-benzoylphenylisoserine side chain at C-13 and the C-2 benzoyl group are essential for the stabilization of microtubules. 12,13) Chatterjee et al compared the dynamic properties of paclitaxel and those of one of its ''inactive'' analogs, baccatin III (Fig. 1C, 2), and concluded that they behave similarly in their interactions with tubulin.…”

Preparative separation and enrichment of four taxoids from Taxus chinensis needles extracts by macroporous resin column chromatography

“…The resource of yew tree is limited, and the content of paclitaxel is so low in plant materials that it cannot meet the growing demand for paclitaxel for clinical trials [20,21]. However, other taxoids such as 10-DAB III and 7-xyl-10-DAT are presented in much higher quantities than paclitaxel in Taxus species, and pharmacological experiments indicated that 7-xyl-10-DAT exerted strong antitumour activity [22]. These taxoids can be transferred to paclitaxel or its derivatives through the biosynthesis or chemosynthesis methods [10, 12, 23 -26].…”