Tubuline stabilizing agents

1 Kamil,W. M., Dewick, P. M., Biosynthesis of Podophyllum lignans. Part 3. Biosynthesis of the lignans a- and p-peltatin. Phytochemistry 1986, 25, 2089-92. 

Seasonal variation in natural taxoids of north-western Himalaya, 

4 Gragg, G. M., Newman, D. J., Discovery and development of antineoplastic agents from natural sources, Cancer Invest. 1999, 27, 153-163. 

Natural Products in Drug Discovery and Development, J. Nat. Prod. 1997, 67, 52-60. 

6 Harvey, A., Strategies for discovering drugs from previously unexplored natural products, DDT 2000, 5, 294-300. 

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Ramaswamy B, Puhalla S. Docetaxel a tubulin-stabilizing agent approved for the management of several solid tumors. Drugs Today (Bare) 2006 42(4) 265-279. 

Paclitaxel (21), formerly known as taxol , is a nitrogen-containing diterpenoid compound isolated from the bark of Taxus brevifolia Nutt. (Pacific yew). As an anticancer agent, paclitaxel acts as a tubulin stabilizer and leads to cell cycle arrest.Since paclitaxel was originally isolated from the bark of the slow-growing species, 77 brevifolia, sourcing was a major obstacle in the development of this drug and its introduction into the market.However, as described later in this chapter, this has now been overcome. 

Kowalski RJ, Giannakakous P et al (1997) Activities of the microtubule-stabilizing agents epothilones A and B with purified tubulin and in cells resistant to paclitaxel (Taxol). J Biol Chem 272 2534-2541... 

The fourth and fifth chapters review the efforts and achievements made in the characterization of the structure of the complexes of tubulin with microtubules stabilizing agents by NMR (Chapter 4) and EM (Chapter 5). Especially evident is the discrepancy of the results obtained for epothilones, where the two techniques deliver radically different structures of the bound drug. Both NMR and EM models are, however, able to explain a consistent set of SAR data. The authors of the two chapters discuss critically the advantages and limitations of each methodology. 

On the other hand, from a thermodynamical point of view, a common mechanism for assembly induction can be proposed. All microtubule stabilizing agents bind tightly to the assembled form, while they do not bind with a measurable affinity to the dimeric tubulin [33], indicating that the taxane binding pocket is either not formed or not-completely formed in non-microtubular tubulin. 

Peluroside A was the first microtubule stabilizing agent whose conformation has been determined bound to microtubules (those of Paclitaxel and Epothilone were determined in non-microtubular tubulin [5, 12, 38, 91]). In the bound state, the NMR data, assisted by molecular mechanics calculations and docking experiments, indicated that only one (that present in water, B) of the two major conformations existing in water solution is bound to microtubules (a-tubulin). A model of the binding mode to tubulin has also been proposed [27], involving the a-tubulin monomer, in contrast with paclitaxel, which binds to the p-monomcr. 

The similarity of its bioactive and X-ray conformations had been anticipated on the basis of SAR data and of its structural homology to dictyostatin [125], Dictyostatin (Fig. 16) is another MT-stabilizing agent that competes with PTX and has a similar effect on MT dynamics [125], The preferred solution structure of the conformation-ally constrained dictyostatin overlays quite closely the tubulin-bound conformation of DDM, suggesting that they interact in a similar way with MT (Fig. 19). This hypothesis was further supported by the synthesis of a macrocyclic DDM/dictyostatin hybrid, that displays considerable antiproliferative activity [126],... 

The Tubulin Binding Mode of Microtubule Stabilizing Agents Studied by EC... 

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