Microtubule stabilizing agents taxol

Two kinds of resistant biotypes have been noted one is highly-resistant (R) and is unaffected even by saturated solutions of dinitroaniline herbicide, whereas an intermediate-resistant (I) biotype is only 50X resistant to trifluralin and less than 10X resistant to oryzalin compared with the susceptible (S) biotype. Both R and I biotypes are cross-resistant to phosphoric amide herbicides. Tubulin from the R is able to polymerize into microtubules even in the presence of oryzalin, whereas that of the S biotypes cannot. Western blots of tubulin from the R biotype reveal two -tubulin isotypes whereas only one form is noted in the S biotype. Because the R biotype is hypersensitive to the microtubule-stabilizing agent taxol, it is likely that the R biotype is resistant by having hyperstabilized microtubules. The I biotype has no gross alteration in tubulin nor extreme sensitivity to taxol, indicating that this biotype has a different resistance mechanism than the R. 

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... 

Bollag DM, McQueney PA, Zhu J, Hensens O, Koupal L, Liesch J, Goetz M, Lazarides E, Woods CM. Epothilones, a new class of microtubule-stabilizing agents with a taxol-like mechanism of action. Cancer Res. 1995 55 2325-2333. 

Taxol is a potent microtubule-stabilizing agent that has been approved for cancer treatment. Despite taxoTs therapeutic promise, its aqueous insolubility (<0.004mg/mL)... 

Kowalski, R.J., Giannakakou, P., Gunasekera, S.P., Longley, R.E., Day, B.W., and Hamel, E. (1997) The microtubule-stabillizing agent discodermolide competitively inhibits the binding of paditaxd (Taxol) to tubulin polymers, enhances tubulin nudeation reactions more potently than paclitaxel, and inhibits the growth of paditaxel-resistant cells. Mol. Pharmacol. 52,613-622. 

Microtubule filaments are hollow cylinders made of the protein tubulin. The wall of the microtubule is made up of a helical array of alternating a- and 13-tubulin subunits. The mitotic spindle involved in separating the chromosomes during cell division is made of microtubules. Colchicine inhibits microtubule formation, whereas the anticancer agent, taxol, stabilizes microtubules and interferes with mitosis. 

Bogdan, C. and Ding, A. (1992) Taxol, a microtubule-stabilizing antineoplastic agent, induces expression of tumor necrosis factor alpha and interleukin-1 in macrophages. J. Leukocyte Biol. 52,119-121. 

Although ft-keto esters typically undergo -hydroxylation, there are some known cases in which Ca deprotonation may not be kinetically observed, as a consequence of steric or stereoelectronic factors. A notable example can be found in Holton s total synthesis of the microtubule-stabilizing anticancer agent paclitaxel (Taxol, 225, Scheme 3.32) [123]. This striking tour de force showcases a facile y-hydroxylation of 223 to furnish 224 in 88 % yield [123, 124],... 

The novel marine natural product laulimalide (65), a metabolite of various sponges, has received attention as a potential antitumor agent due to its taxol-like ability to stabilize microtubules. There has been considerable synthetic effort toward 65, culminating within not more than 2 years in as many as ten... 

The natural product eleutherobin (1) was isolated in 1994 by Fenical et al. from a marine soft coral from an Eleutherobia species and its structure was elucidated shortly afterwards (Figure 1) [1]. Eleutherobin is a diterpene glycoside that possesses remarkable cytotoxicity against a wide variety of cancer cells, which is likely to be based on binding to tubulin and stabilization of microtubules [2, 3]. Mitosis is interrupted and the cell division cycle is terminated. The mechanism of action of eleutherobin is comparable to that of highly potent cytostatic agents such as paclitaxel (Taxol), nonataxel, epothilones, and discodermolide. 

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