Microtubule assembly inhibitors

Perez OD, Chang YT, Rosania G, Sutherlin D, Schultz PG. Inhibition and reversal of myogenic differentiation by purine-based microtubule assembly inhibitors. Chem. Biol. 2002 9 475-483. 

Alkaloids are a class of about 3000 nitrogenous compounds made in plants. They include substances, such as morphine (a narcotic) and colchicine (microtubule assembly inhibitor). Many of these substances have potent physiological effects in animals, but their function in plant metabolism is not well understood. Many alkaloids are derived from the aromatic amino acids tyrosine and phenylalanine. 

Microtubule assembly inhibitor reduces mobility and phagocytosis by WBCs in gout-inflamed joints useful in acute gout. Tox GI (often severe), hepatic, renal damage. 

Sharpless has noted that the regiochemical outcome with cinnamyl esters is coupled to the ligand system employed [237]. Thus, when AQN ligands (314), were used, benzylic alcohols were preferentially obtained, rather than the benzylic amines observed with PHAL ligands (311). This selectivity trend was utilized by Joullie in the synthesis of the potent microtubule assembly inhibitor ustiloxin D (356, Scheme 9.45) [238]. Under optimized conditions, cinnamyl ester 354 was converted selectively into the desired benzylic alcohol 355 (58% yield). This constitutes one of the structurally more complex substrates to have successfully been employed in catalytic asymmetric aminohydroxylation [238, 239]. 

C5a and C5a des Arg stimulate aerobic glycolysis, hexose monophosphate shunt activity, glucose uptake and the respiratory burst of human neutrophils. All of these processes are stimulated in neutrophil suspensions incubated in the absence of cytochalasin B, but the responses are considerably enhanced if this inhibitor of microtubule assembly is present. Stimulated rates of oxidative metabolism are maximal within 2 min of addition of peptides, with half-maximal responses obtained at 30-60 nM C5a and 1-3 pM C5a des Arg. 

Paditaxel 1992 Ovarian, breast, small cell lung cancer Inhibitor of microtubule assembly [21]... 

Liu H, Namikoshi M, Meguro S, Nagai H, Kobayashi H, Yao X (2004) Isolation and Characterization of Polybrominated Diphenyl Ethers as Inhibitors of Microtubule Assembly from the Marine Sponge Phyllospongia dendyi Collected at Palau. J Nat Prod 67 472... 

Natural Products and Semi-Synthetics - Several naturally occurring compounds or their derivatives have received considerable attention this past year because of their clinical potential. The epipodophyllotoxins, VP-16,213 (7 ) and VM-26 (8), known to be potent inhibitors of cell division, were found not to be inhibitors of microtubule assembly as are... 

The ability to make unnatural cephalostatins will greatly aid our understanding of the biological potency of these compounds. For example, one half could be kept identical to a natural product, while varying the other with synthetic steroids prepared from commercially available materials. In this sense, the cephalostatins provide a unique opportunity for such experiments, as the steroid skeleton is a readily accessible and well understood scaffold in which the effects of particular substituents can be determined. The situation here is in stark contrast to certain other potent biologically active compounds such as taxol (which promotes microtubule assembly) and bryostatin (a protein kinase C inhibitor). In the latter cases, construction of the skeletal framework is a formidable enterprise, hindering further dissection of the biological activity. 

Thereafter, several compounds closely related to ircinins and variabilin have been isolated [5,6]. Fusetani and co-workers [34] reported the isolation of two compounds, dehydroderivative of ircinin (8) and an isomer of variabilin (9) from the Japanese sponge Cacospongia scalaris. Both compounds inhibited the cell division of fertilised starfish eggs at a concentration of 1.0 pg/ml. This assay is a variation on the test with sea urchin embryos, which can detect DNA and RNA synthesis inhibitors, microtubule assembly and protein synthesis inhibitors, the common leads... 

This drug is an inhibitor of microtubule assembly. It therefore inhibits cell division (spindle formation), cellular movement, and transport of substances within a cell (gel-sol transformations, through microtubule dissolution and reformation). The therapeutic action of the drug lies in the inhibition of microtubule assembly in neutrophils—neutrophil migration into affected areas is inhibited, as is the secretion of inflammatory substances (due to inhibition of gel-sol transformations). Thus, inflammation is reduced. 

Zoxamide (1) [3,5-dichloro-N-(3-chloro-l-ethyl-l-methyl-2-oxopropyl)-4-methyl-benzamide, RH-7281, Fig. 16.1.1] was discovered and commercialized by Rohm and Haas Company in 2001 for control of Oomycete pathogens [1], and is now marketed by Dow AgroSciences LLC. The primary markets for zoxamide are late blight on potatoes and downy mildews on vines and vegetables. Inhibitors of microtubule assembly that have been used as fungicides include the benzimidazole (BZ) and thiophanate fungicides such as carbendazim and thiophanate-methyl, the N-phenylcarbamate (NPC) diethofencarb, and the antibiotic griseofulvin. Zoxamide represents the first inhibitor of microtubule assembly to be used commercially for control of Oomycetes. 

These include rhazinilam (15.4.6) 494), which inhibits the disassembly of microtubules but has a different mechanism of action than taxol, laulimalide (15.4.7) and isolaulimalide (15.4.8) 496), WS9885B (15.4.9) 497), and polyisoprenylated benzophenones such as guttiferone E (15.4.10) 497). The naturally occurring 3(2H)-furanone derivative geiparvin has been found to counteract the microtubule-assembly effects of taxol, suggesting that it is a competitive inhibitor at the taxol-binding site of tubulin 498). 

An important strategy for the treatment of cancer is the modulation of microtubule assembly either by preventing its disassembly or by blocking tnbnlin polymerization, and an excellent review is available that discusses several indole leads [98], For example, Silvestri and colleagues report that arylthioindoles are potent inhibitors of tubuhn polymerization [99-101]. For example, 84 inhibits the... 

Genistein, which is isolated from soy, inactivates Bcl-2 by phosphorylation, delays the G2/M phase of die cell cycle, and induces apoptosis of hiunan breast adenocarcinoma MCF-7 cells and it is also an inhibitor of protein tyrosine kinase and topoisomerase II (42). The natural estrogen metabolite 2-methoxyestradiol (2ME) is anti- angiogenic in vivo, can phosphorylate Bcl-2 and its mechanism of action is independent of die signaling enemies JNK/SAPK (41). The dolastatins are natural peptides, which inhibit microtubule assembly and induce apoptosis and phosphorylate Bcl-2 in small cell lung cancer (SCLC) (43). Beta-Lapachone,... 

Some examples of aromatic derivatives similar to those formd in dendroceratid sponges of the genus Dysidea (see above) and in some Chlorophyceae (see Chapter 12), were isolated from the spedes Phyllospor ia dendyi harvested in Palau (Hattori et al, 2001 liu et al., 2004) and Lamellodysidea herhacea harvested in Indonesia (Hanif et al., 2007). Many of these derivatives are inhibitors of microtubule assembly, with IC50 dose to 4 pM (Liu et al, 2004). 

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