Taxoids mechanisms

Epothilones are naturally occurring cytotoxic macrolides, which were initially isolated from a mycobacterium. Their antitumor activity is similar to that of the clinically established taxoids (Taxol, Taxotere), by interrupting the dynamic mechanism of microtubule assembly/disassembly via microtubule stabilization. In contrast to taxoids, epothilones are remarkably efficient against multidrug resistant cells. 

VII. FURTHER STUDIES ON THE BIOLOGICAL ACTIVITY OF TAXOIDS ALTERNATIVE MECHANISMS OF ACTION... 

Our SAR study of paclitaxel analogues on their ability to activate macrophage, inducing the production of NO and TNF, has revealed stark differences in the structural requirements for cytotoxicity vs. macrophage activation. The results warrant a great deal of further study on the possible alternative or auxiliary mechanism of action for paclitaxel and taxoids, which might lead to the discovery of a new series of taxoid anticancer agents with unique mechanism of action. 

The attainment of this pocket by quite different structural motifs indicates that the pocket on (3-tubulin may be malleable and its moulding by natural product ligands may be the key to unravelling the mechanisms of tubulin assembly.61 As taxoids and epothilones have proven successful in the clinic,62,63 advancing the understanding as to the mechanisms involved in regulating... 

The conjugate of two molecules with different functions or mechanisms of action often displayed dual functions or enhanced activities. Based on this rationale, Shi et al. prepared five taxoid-epipodophyllotoxin dimers. All dimers showed... 

Most research has focused on the development of paclitaxel analogs or prodrugs with enhanced specificity MDR reversal and orally effective taxoids have also been developed recently. Meanwhile, scientists have gained insights into the mechanism of action of taxoids at molecular level, that is, binding sites on tubulin and dynamics of tubulin polymerization. It is worth pointing out that the SAR results derived from traditional medicinal chemistry have shown the essential... 

Taxol is biosynthesized in 19 steps from GGPP that originates from precursors of the MEP pathway (Fig. 5). The biosynthesis of Taxol begins with the formation of the tricyclic diterpene skeleton of taxa-4(5),ll(12)-diene (17, 39). All genes for the enzymes in this early pathway have been identified in Taxus cuspidata and a taxa-4(5),ll(12)-diene synthase has been identified in several Taxus species. The mechanism of this di-TPS has been explored in detail (39). Taxa-4(5),ll(12)-diene is then hydroxylated by several cytochrome P450 taxoid oxygenases to yield a putative intermediate decorated with seven alcohol... 

Epothilones, isolated from the mycobacterium Sorangium cellulosum in 1996, are a new class of cytotoxic macrolides that are especially effective against drug-resistant tumor cell lines by the same mechanism as the taxoids. The structural feature of epothilones (Fig. 1) includes a 16-membered lactone ring, p-hydroxyl carbonyl units and cw-epoxide on the macrocyclic ring, and a thiazole unit as the side chain. 

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