Microtubule synthesis

Mebendazole is a broad spectrum anthelmintic and of special use for mixed worm infestations. Its mechanism of action is based on inhibition of microtubule synthesis and decreased transport of vesicles and organelles thus irreversibly blocking glucose uptake. 

Albendazole (9.117), a benzimidazole carbamate, is a broad-spectrum oral antihelminthic used for cysticercosis, ascariasis, pinworm infestation, and hookworm infestation. It is thought to work by blocking microtubule synthesis in the nematode, subsequently impairing glucose uptake. 

Benzimidazoles are thought to act against nematodes by inhibiting microtubule synthesis. Albendazole also has larvicidal effects in hydatid disease, cysticercosis, ascariasis, and hookworm infection and ovicidal effects in ascariasis, ancylostomiasis, and trichuriasis. 

Mebendazole probably acts by inhibiting microtubule synthesis the parent drug appears to be the active form. Efficacy of the drug varies with gastrointestinal transit time, with intensity of infection, and perhaps with the strain of parasite. The drug kills hookworm, ascaris, and trichuris eggs. 

Antimitotics Inhibit microtubule synthesis inhibit cell division (e.g., paclitaxel)... 

Mechanism Mebendazole acts by selectively inhibiting microtubule synthesis and glucose uptake in nematodes. 

Anthelmintic important drug for pinworm and whipworm infections. Inhibits microtubule synthesis and glucose uptake in nematodes. Tox GI distress, caution in pregnancy. Albendazole and thiabendazole are related anthelmintics. 

More recent work from Gross laboratory claims that at least some maternal mRNA s code for microtubule proteins, or, more correctly, for soluble proteins which, after partial purification by vinblastine precipitation, co-migrate on acrylamide gel electrophoresis with known microtubule proteins from sperm tails (Raff et ah, 1971, 1972). Although there is a pool of these microtubule proteins in the unfertilized egg it seems that this pool is maintained or supplemented (for the construction of such things as mitotic spindles and cilia) by continuous synthesis of the monomeric subunits from stored mRNA, starting from the first cleavage cycle. Hopefully, more detailed analysis of the relative rate of microtubule synthesis at different times after fertilization, in the absence of new RNA synthesis, will provide information about the way in which this particular maternal mRNA is utilized during development. 

The influences of herbicides on cell division fall into two classes, ie, dismption of the mitotic sequence and inhibition of mitotic entry from interphase (G, S, G2). If ceU-cycle analyses indicate increases in abnormal mitotic figures, combined with decreases in one or more of the normal mitotic stages, the effect is upon mitosis. Mitotic effects usually involve the microtubules of the spindle apparatus in the form of spindle depolymerization, blocked tubulin synthesis, or inhibited microtubule polymerization (163). Alkaloids such as colchicine [64-86-8J,viahla.stiae [865-21-4] and vincristine [57-22-7] dismpt microtubule function (164). Colchicine prevents microtubule formation and promotes disassembly of those already present. Vinblastine and vincristine also bind to free tubulin molecules, precipitating crystalline tubulin in the cytoplasm. The capacities of these dmgs to interfere with mitotic spindles, blocking cell division, makes them useful in cancer treatment. 

It iaterferes with the synthesis of the hyphal walls, the biosynthesis of nucleic acids, and the synthesis of chitin. The iateraction with microtubules has also been described. The sensitivity of a cell seems to depend particularly on the abiUty to form griseofulvin—nucleic acid complexes. Further information concerning griseofulvin is available (21). 

The ER has a reticular morphology which provides a large surface area, which presumably is required for the synthesis and transport of proteins and lipids and for the storage of calcium. The ER is associated with microtubules, and the two are highly interdependent structures. Terasaki et al. (1986) found that when microtubules in the cell are depolymerized by colchicine, the ER network slowly retracts toward the center of the cell. If the microtubules are repolymerized, the ER network is restored to its original morphology, thereby suggesting that the MTs participate in the formation and maintenance of the ER. 

Chemical Synthesis and Biological Studies of the Epothilones - Microtubule Stabilizing Agents with Enhanced Activity Against Multidrug-Resistant Cell Lines and Tumors. 

The microtubular electrode concept described here also offers another possible advantage. In these concentric tubular electrodes, each particle of the Li intercalation material (the outer tube) has its own current collector (the inner metal microtubule). This could be an important advantage for Li+ intercalation materials with low electrical conductivity. This advantage was not demonstrated here because TiS2 has relatively high electronic conductivity. We have recently shown that electrochemical synthesis can be used to coat the gold microtubular current collector with outer mbes of a... 

While ionophore-stimulated 5-LO product release from neutrophils is often used as an indication of 5-LO inhibition, one must interpret these results cautiously. For example, halothane, an inhalation anaesthetic which may cause membrane perturbation [26], and colchicine, a microtubule disrupter [27], both were active, but presumably not because of 5-LO inhibition. A23187 is assumed to stimulate 5-LO by raising the intracellular calcium level, but this agent causes many other effects which may or may not be related to 5-LO activation, including changes in membrane potential, protein phosphorylation, phospholipid turnover, cyclic nucleotide levels, and DNA and protein synthesis [28]. Also, the effects of some putative 5-LO inhibitors on product release from neutrophils has been shown to vary with the stimulant used [29]. 

The cytosol is the fluid compartment of the cell and contains the enzymes responsible for cellular metabolism together with free ribosomes concerned with local protein synthesis. In addition to these structures which are common to all cell types, the neuron also contains specific organelles which are unique to the nervous system. For example, the neuronal skeleton is responsible for monitoring the shape of the neuron. This is composed of several fibrous proteins that strengthen the axonal process and provide a structure for the location of specific membrane proteins. The axonal cytoskeleton has been divided into the internal cytoskeleton, which consists of microtubules linked to filaments along the length of the axon, which provides a track for the movement of vesicular material by fast axonal transport, and the cortical cytoskeleton. 

Intracellular protein phosphorylation is enhanced by chronic antidepressant treatment. This leads to the increased synthesis of microtubules that form an important feature of the cellular cytoskeleton. Thus antidepressants might change signal transduction with the neurone. 

The structural modification of natural products is useful in several ways. The known pharmacology of bisindole alkaloids is enriched by the diversity of chemical structures that are made available by structure modification and total synthesis. These molecules have served as biochemical probes in several areas of biology, especially in those of microtubule assembly and drug resistance. The most elusive prize, however, has remained the discovery of new compounds with clinical activity. In recent years several compounds have been evaluated in clinical trials, but vinblastine and vincristine remain the only bisindole alkaloids approved for the treatment of cancer in the United States. These compounds are joined by vindesine in Europe, and at least two new derivatives are the subject of ongoing clinical trials. Considering the breadth of chemical research in this area, the overall yield as measured by new compounds with clinical activity has been relatively low, but this observation is not unique in history of analog development in cancer research. Nevertheless, the search continues, and this chapter details the chemical endeavors to discover a new bisindole alkaloid with clinical activity. 

With the exception of the effect on microtubules described in the foregoing paragraph, the bisindole alkaloids have little or no effect on macro-molecular synthesis at subtoxic concentrations (21,22). In experiments utilizing radiolabeled precursors ([ H]leucine, -uridine, or -thymidine) cells cultured in the presence of vinblastine showed no differential incorporation of radioactivity. Furthermore, there is no indication that treatment of cells with vinblastine or vincristine produces alterations in cellular DNA (23,24). 

ACTIN ASSEMBLY KINETICS MICROTUBULE ASSEMBLY KINETICS Triglyceride synthesis kinetics (hepatic), LIRID TRACER KINETICS 2,4,5-Trihydroxyphenylalanine quinone, REDOX-ACTIVE AMINO ACIDS TRIMOLECULAR MOLECUARITY ORDER... 

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. 

Vinblastine and vincristine are alkaloids isolated from plants of the periwinkle family (Vinca rosea). These compounds cause cells to stop at metaphase and inhibit assembly of microtubules, and likewise, failure of mitotic spindle formations. They inhibit synthesis of nucleic acids and proteins. 

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