Antitubulin

Fluorescent tubulin, antitubulin antibody, and fluorescent taxol. 

Fig. 3. Immunofluorescence localization of tubulin in microtubules in Swiss 3T3 cultured fibroblasts. Swiss 3T3 cells were fixed in glutaraldehyde followed by treatment with sodium borohydride (4). Tubulin was detected using a rat monoclonal antitubulin antibody (YLl/2), followed by goat antirat IgG conjugated to rhodamine, all steps in the continuous presence of 0.1% saponin. Note the individual microtubules visible under the dark nuclear region (bar = 4 im).

Mahindroo N, Liou J-P, Chang J-Y, Hsieh H-P. (2006) Antitubulin agents for the treatment of cancer — a medicinal chemistry update. Expert Opin Ther Pat 16 647-691. 

Bennouna J, Campone M, Delord JP, Pinel MC. (2005) Vinflunine A novel antitubulin agent in solid malignancies. Expert Opin Invest Drugs 14 1259-1267. 

The thiocarbonyl group is a classic bioisosteric replacement for the carbonyl group which has been widely exploited in medicinal chemistry. This is illustrated with the preparation of thioketones derived from thiocolchicine283 and isothiocolchicine284 which exhibited high antitubulin activity (equation 38). 

Pellegrini F, Budman DR. Review tubulin function, action of antitubulin drugs, and new drug development. Cancer Invest. 2005 23 264-273. 

Alcohol 10, obtained from 7 on reduction with sodium borohydride, and acetate 11, prepared from 10 by acetylation (72), are obviously mixtures of isomers, and as such they are of little value for evaluating their antitubulin effects. Testing of an optically pure isomer of 11, as shown below, which is isosteric to colchicine, would be of interest. 

Anti-Inflammatory Activity and Antitubulin Effects of Selected Colchicinoids"... 

Phenolic colchicines found as plant consituents and as metabolites (1) are less potent antitubulin compounds than their fully methylated analogs (Fig. 26). It can be seen that 10-SCH3 analogs of colchicines (thiocol-chicines) were always more potent inhibitors of tubulin polymerization... 

Antitubulin Activity and Acute Toxicity of Phenolic Colchicinoids and Thio Congeners"... 

Radiolabeled 3-demethyl-3-chloroacetylthiocolchicine with a l4C label in the chloroacetyl moiety (DCTC) was found to be a potent inhibitor of tubulin polymerization and of colchicine binding to tubulin. The reaction was 80-90% inhibited in the presence of saturating, amounts of known antitubulin compounds such as podophyllotoxin, combretastatin A-4, and colchicine itself. The tubulin /3 subunit was labeled 5-6 times faster than the a subunit. Cyanogen bromide digestion of the /3 subunit which had reacted covalently with DCTC indicated that at least three positions in /3-tubulin had reacted with DCTC. Purification and amino acid sequencing of these peptides are in progress (138). 

Finally, one has to mention the work of Levy and co-workers who described the semi-synthesis of D-ring seco-rhazinilam analogues from (-)-tabersonine using an Emde degradation and /nCPBA oxidation [90]. The. veco-analogue 50 is only twice less active than rhazinilam on the inhibition of microtubules disassembly, illustrating that the absence of the D-ring is not strictly deleterious to the antitubulin activity [91,92]. 

Table 1. Antitubulin activity and cytotoxicity of selected steganes [42,43,149]...

Methoxy indole-containing combretastatin derivatives, (I), and prodrugs, (II), prepared by Pinney (2) were found effective as antimitotic and antitubulin polymerization agents and used in the selective destruction of tumor cell vasculature. 

In 2001, several articles revealed a microtubule structure with improved resolu-tion. ° In the refined tubulin structure, the binding pocket of paclitaxel was modified shghtly. ° These structures will provide a good starting point in the construction of the pharmacophores of paclitaxel and other antitubulin dmgs. 

The antiproliferative and antitubulin activities of libraries of pyranopyridones and pyranoquinolones 147 (Scheme 28) derived from aldehydes, malononitrile and pyridones 146 have been examined [65]. The compounds were evaluated for their ability to reduce cell viability by 50% after 48 h of treatment relative to control. The HeLa and MCE-7 cell fines were used as models for human cervical and breast adenocarcinoma, respectively. Numerous compounds exhibited submicromolar antiproliferative activities with the quinolones being more potent than their pyridine counterparts (Eig. 20). Because of the structural similarity of pyranopyridones with chromene scaffolds known to inhibit tubulin polymerization, compounds 149 and 150 were further evaluated in Jurkat cells for their apoptotic... 

Magedov IV, Manpadi M, Ogasawara MA (2008) Stmctural simplification of bioactive natural products with multicomponent synthesis. 2. Antiproliferative and antitubulin activities of pyrano[3, 2-c]pyridones and pyrano[3, 2-c]quionolones. J Med Chem 51 2561-2570... 

Shi Q, Chen K, Brossi A, Verdier-Pinard P, Hamel E, McPhail AT, Lee KH. Antitumor agents 184. Syntheses and antitubulin activity of compounds derived from reaction of thiocolchicone with amines lactams, alcohols, and esters analogs of allothio-colchicinoids. Helv. Chim. Acta 1998 81 1023-1037. 

Chang Z, et al. Biosynthetic pathway and gene cluster analysis of curacin A, an antitubulin natural product from the tropical marine cyanobacterium Lyngbya majuscula. J. Nat. Prod. 2004 67 1356-1367. 

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