Microtubulin

Microtubulin Polymerization Inhibitors. The ben2imida2oles were first reported to have systemic fungicidal activity in 1964 (29). Prominent examples include thiabendazole [148-79-8] (42) fuberida2ole [3878-19-1] (43) carbendazim [10605-21-7] (44) benomyl [17804-35-2] (45) and thiophanate methyl [23564-05-8] (46). Benomyl (45), the most widely used member of this group is almost certainly inactive as a fungicide until it is converted in plants and soil to carbendazim (44). Likewise, thiophanate and thiophanate methyl (46) are nonfungitoxic until converted to carbendazin (44). 

Unfortunately, the low aqueous solubility of the DCL components precluded templating studies with the intended target microtubulin. As proof of principle, the proteins albumin and subtilisin were substituted as organic solvent tolerant alternatives. Starting from the homodimeric compounds 45 and 48, the amount of heterodimer 51 formed was shown to be influenced by the presence of the proteins. 

Epothilone B (38) Polyketide macrol- actone Patupilone (Epothilone B, EPO-906) (38) Oncology Microtubulin stabilization Phase 111 (ovarian cancer) Novartis 913,914... 

Paclitaxel (Taxol) is a highly complex, organic compound isolated from the bark of the Pacific yew tree. It binds to tubulin dimers and microtubulin filaments, promoting the assembly of filaments and preventing their depolymerization. This increase in the stability of microfilaments results in disruption of mitosis and cytotoxicity and disrupts other normal microtubular functions, such as axonal transport in nerve fibers. 

Microtubulin Polymerization Inhibitors. The benzimidazoles were first reported to have systemic fungicidal activity in 1964 (29). 

It has been demonstrated by numerous workers that the majority of benzimidazoles inhibit the microtubulin [6-11 ] of tegumental or intestinal cells of nematodes or cestodes through degeneration of these cells. This mechanism is now well accepted as the mode of action for benzimidazole derivatives. 

FIGURE 6.26 Compounds that affect microtubulin polymerization and depolymerization... 

Islam MN, Iskander MN. Microtubulin binding sites as target for developing anticancer agents. Mini-Rev. Med. Chem. 2004 4 1077-1104. 

The length of the microtubule cylinder may measure upto 10,000 A, but the diameter is usually 180-250 A. The polymerisation of tubulins to microtubules takes place at 37°C in presence of Mg ions, endogenous cofactors such as GTP and microtubule-associated proteins (MAPs). The depolymerisation of microtubules occurs at temperatures lower than 37°C and in presence of Ca ions. The assembly and disassembly of microtubules proceeds in a nucleated fashion and is associated with a number of cellular functions. The formation of microtubules are required to control various cell activities such as cytoplasmic movement, cell division, cell shape and substrate and vesicle transport etc. Thus, interruption of the microtubulin assembly by a chemotherapeutic agent would result in several cellular dysfunctions leading to death of the parasites. Several drugs are known to bind with tubulin and block its polymerisation into microtubules. This results in gradual disappearance of microtubules from the cells. Consequently cytoplasmic movement and transport of nutrients are disturbed. These abnormal conditions cause death of the cell [59,60]. 

Podophyllotoxin (1) inhibits the assembly of microtubulin and the activity of topo-isomerase II, and exhibits strong antitumor activity. It is considered as the critical structure of antitumor compounds. Since the 1940s, many podophyllotoxin derivatives have been synthesized. Among them, etoposide (VP-16-213,65) and teniposide (VM-26, 66) exhibit no gastrointestinal toxicity, and have been used with cisplatin (ciY-diaminodichloroplatinum) in human chemotherapy. Compound 66 is more potent than 65 in L-1210 and HeLa tumor cell lines, and shows strong activity in hematological malignancies. 

Environmental Fate of Microtubulin Assembly Inhibitors (Pyridines) 319 7.3... 

Major changes in phosphorylation induced by ischaemia and subsequent reperfusion in rat striatum were observed for a 130-kDa protein, tentatively identified as the Ca "" transport ATPase, and calcium/calmodulin-dependent protein kinase II (Sankaran etal. 1997). A 200-300% increase in [ PjSNjATP photoinsertions was observed in the striatum and hippocampus region of a 43-kDa protein with an isoelectric point of 6.8. This protein was identified as glutamine synthetase and the increase in binding was found to be due to both increased copy number and activation by Mn ". An increase in [ PjSNjATP photoinsertions into a 55-kDa protein, identified as the P-subunit of tubulin, was found only in the striatum and hippocampus indicating the depolymerization of microtubulin in these tissues. 

Protection of the C2 hydroxyl group as an ester results in loss of activity in terms of microtubuline stabilization but not in cytotoxicity. 

AU these compounds, as they affect microtubulin formation and/or depolymerization, can also affect noncancerous cells where microtubulin is involved in other cell functions such as cell movement. Hence, they are potentially cytotoxic. Well, can we find or make compounds that affect only the dividing cells This is the direction... 

Most of the clinically effective antitumor agents were discovered in the 1960s by testing a inst tumor ceU lines the active metabohtes which were too toxic for use as anti-infective drugs. Only recently, a new family of products, active by stabilizing microtubulins, has been discovered by a target-oriented screening. 

Paclitaxel (Taxol 53, Figure 4.16), a complex, polycyclic diterpene, exhibits a unique mode of action on microtubule proteins responsible for the formation of the spindle during cell division and known to inhibit the depol)nnerization process of microtubulin. Paclitaxel is approved by the FDA for the treatment of ovarian cancer and metastatic breast cancers. (] )-54 side chain was required for the preparation of the Paclitaxel 53 [85-88] by a semisynthetic process. The enantioselective enzymatic hydrolysis of racemic acetate ds-3-(acetyloxy) -phenyl-2-azetidinone 55 to the corresponding (S)-alcohol 56 and the xmreacted desired (] )-acetate 57 was demonstrated [89] using lipase PS-30 from Pseudomonas cepacia (Amano Enz)nne Co.) and BMS lipase (extracellular lipase derived from the fermentation of Pseudomonas sp. SC 13856). Reaction 3delds of >48% (theoretical maximum )deld 50%) with ee of >99.5% were obtained for the (R)-acetate. 

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