Tubulin polymerization inhibitors

The allocolchicine positional isomers 70-73, Fig. (14), were synthesized by Boye and Brossi by cyclization of the open-chain biphenyl carboxylic acid 68 in acid medium [14,100,101], Whereas the allocolchicinol methyl ether analogues 70 and 71 were inactive as tubulin polymerization inhibitors, the deamino analogues 72 and 73 were found to be equipotent with allocolchicine. 

Pettit (6) prepared phenstatin, (VII), and prodrug derivatives, (VIII), which were more effective tubulin polymerization inhibitors than colchicine and more effective as tubulin binder inhibitors than combretastatin. 

Some years ago a benzothiophene that exhibited some activity as a tubulin polymerization inhibitor and appeared to bind weakly to the colchicine binding domain of tubulin was reported. This finding stimulated the synthesis of several benzofuran and indole analogues, Fig. (17). 

Figure 8-14 Enzyme inhibitors (54-59) and tubulin polymerization inhibitors (60 and 61) derived from thalidomide (48).

Prinz, H. Recent advances in the field of tubulin polymerization inhibitors. Expert Rev. Anticancer Then 2002, 2, 695—708. 

Tubulin polymerization inhibitor 1172 Tumor angiogenesis 1278 Tumor associated antigen (TAA) 183 Tumor-associated glycoprotein 72, 1276 Tumor cell, targeting markers on 1276 Tumor growth index 523 Tumor hypoxia, assessment of 1263 Tumor necrosis factor (TN F) 7, 80, 264,... 

The Schmidt rearrangement of a six-membered benzo-fused ketone with sodium azide yielded benzazepinone derivatives en route to the synthesis ofa library of tubulin-polymerization inhibitors (14JME1390).The reaction of N-nitrosoaniUnes 16 with 2-vinyloxirane 17, catalyzed by rhodium (111), followed by Raney-nickel-catalyzed hydrogenation led to a series of benzazepane derivatives 18 via a reductive amination of a proposed aldehyde intermediate (140L1200). 

Fig.l Structure of some tubulin polymerization inhibitors and potentially bioactive diaryl... 

Combretastatins, a series of bioactive stilbenes (combretastatin A series), bibenzyls (B series), phenanthrenes (C series), and macrocycUc lactone (D series), were obtained from the African wiUow tree Combretum caffrum (Combretaceae). Among them, the A series of combretastatins belonging to stilbenes, including combretastatins A-1 to A-6 2—7, are found to be tubulin polymerization inhibitors. 

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