Inhibition microtubule assembly

Similar to paclitaxel, promotes microtubule assembly inhibits depolymerization of tubulin inhibits cell division... 

The classification system is describing not only the chemical family belonging to a specific mode of action but all compounds via their common names counted to each family, as shown in Table 1.2 for the modes of action such as Inhibition of DHP (dihydropteroate) synthase , Microtubule assembly inhibition , Inhibition of mitosis/microtubule organization , Inhibition of VLCFAs (Inhibition of cell division) and Inhibition of cell wall (cellulose) synthesis as examples (not mentioned in other chapters of this book) (for a detailed table see www. plantprotection.org/HRAC/). The scheme The World of Herbicides available under this internet address also shows all chemical structures of the different herbicides belonging to the different chemical families. 

C3c1. Microtubule assembly inhibition (K1) C3c2. Inhibition of mitosis (K2)... 

Estramustine, an oral drug, also inhibits microtubule assembly and has weak estrogenic activity at the estradiol hormone receptors of the cell. Approximately 75% of a dose of estramustine is absorbed.15 The terminal half-life ranges between 20 to 24 hours, with nonrenal excretion as the major route of elimination. This drug is used primarily for the treatment of prostate cancer, but its use is limited by the side effects, which include nausea and vomiting, diarrhea, thromboembolic events, and gynecomastia. 

The answer is d. (Hardman, p 1258. Katzung, pp 935-9.36.) Vinblastine binds to tubulin and blocks the protein from polymerizing to microtubules. The drug-tubulin complex binds to the developing microtubule, resulting in inhibition of microtubule assembly and subsequent depolymerization. 

DMT, TMT, DBT, TBT and DPhT chlorides exhibited in vitro spindle disturbance in V79 Chinese hamster cells of brain tubulin. The V79 cells lose stainable spindles at higher concentration. The cell mitosis activity effect at low concentration increased with the lipophilicity of the OTC, but all compounds showed a concentration dependence on microtubules. The OTC seem to act through two different cooperative mechanisms inhibition of microtubule assembly and interaction with hydrophobic sites. The latter mechanism might involve Cl/OH ion exchange28. 

Triethyllead was suggested to be one of the factors causing progressive damage of European forests144. The toxic effect of triethylleads on cells was attributable to inhibition of microtubule assembly. Triethylleads react with SH groups present in tubulin, whereupon the latter loses its capability for microtubule assembly144. 

The role of microtubules in secretion is more clearly defined. Colchicine and vinblastine inhibit secretion, even in cytochalasin-B-treated cells, and D2O (which promotes tubulin assembly) enhances secretion in cytochalasin-treated cells. Microtubules may also be necessary for the translocation of phagocytic vesicles from the neutrophil periphery into the central region of the cytoplasm. Drugs affecting microtubule assembly may inhibit particle-induced oxidase activation or else increase oxidase activation in response to soluble agents such as fMet-Leu-Phe. 

Fig. 1. Concentration-dependent inhibition of microtubule assembly by VBL ( ), deoxy VBL (O), epideoxy VBL ( ), and deoxydesethyl VBL (A).

The mitotic indices observed after treatment of both cell lines with 10-fold the IC70 concentration of each congener establish that the action of the vinca binary alkaloids with this cellular target in vivo is correlated with the ability of the molecule to inhibit microtubule assembly and not with its high-concentration-dependent activities with MTP or microtubules. Based on the current understanding that neurotoxicity and neuro-ti bule damage are concerted events, the results of our structure-activity studies support the optimistic expectation that the development of a nonneurotoxic vinblastine-vincristine congener can be achieved. 

Partially hydrogenated quinoline cores are also present in some important bioactive compounds. For example, the 4-aza-analogs of Podophyllotoxin, a plant lignan that inhibits microtubule assembly, revealed to be more potent and less toxic anticancer agents. In 2006, Ji s group reported a green multicomponent approach to a new series of these derivatives, consisting of the reaction of either tetronic acid or 1,3-indanedione with various aldehydes and substituted anilines in water under microwave irradiation conditions (Scheme 26) [107]. For this efficient and eco-friendly transformation, the authors proposed a mechanism quite similar to the one that was postulated for the synthesis of tetrahydroquinolines in the precedent section. 

At the cellular level, rotenone inhibits cellular respiration by blocking electron transport between flavoprotein and ubiquinone. It also inhibits spindle microtubule assembly. ... 

Thiabendazole (Mintezol) inhibits fumarate reductase and electron transport-associated phosphorylation in helminths. Interference with ATP generation decreases glucose uptake and affects the energy available for metabolism. Benzimidazole anthelmintics as a class (e.g., thiabendazole, mebendazole, and albendazole), bind selectively to (3-tubulin of nematodes (roundworms), ces-todes (tapeworms), and trematodes (flukes). This inhibits microtubule assembly, which is important in a number of helminth cellular processes, such as mitosis, transport, and motihty. 

Podophyllotoxin is an aryltetralin lignan which has been isoiated from severai plants of the Podophyllum species, it is a potent cytotoxic agent against various cancer celi iines, stopping the cell cycle in metaphase through the inhibition of microtubules assembly by binding the colchicine site of the tubulin [112]. Because of numerous side effects, podophyllotoxin cannot be used as a drug. 

Paclitaxel is an alkaloid ester derived from the Pacific yew (Taxus brevifolia) and the European yew (Taxus baccata). The drug functions as a mitotic spindle poison through high-affinity binding to microtubules with enhancement of tubulin polymerization. This promotion of microtubule assembly by paclitaxel occurs in the absence of microtubule-associated proteins and guanosine triphosphate and results in inhibition of mitosis and cell division. 

Evans, D.B. Rank, K.B. Bhattacharya, K. Thomsen, D.R. Gurney, M.E. Sharma, S.K. t Phosphorylation at serine 396 and serine 404 by human recombinant r protein kinase II inhibits fs ability to promote microtubule assembly. J. Biol. Chem., 275, 24977-24983 (2000)... 

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