Figure 28 Structures of estradiols.

Figure 28 Structures of estradiols.

varied (Figures 29 and 30). The molecule 66 most resembling colchicine showed the best binding to tubulin. A further improvement was obtained when the methoxy was substituted with a chloride 67.164

Expansion of the B ring and introduction of an acetamide similar to that found in colchicine resulted in a slightly weaker compound 68; however, the epimer 69 was significantly poorer.165 Interestingly, some estrogenic drugs, for example E-diethylstilbestrol 70, also appear to bind to tubulin at the colchicine-binding site.166 Synthetic compounds

Two classes of synthetic compounds that function by destabilizing tubulin have entered human clinical trials. These classes are the sulfonamides and the aryl carbamates. Sulfonamides are a class of compounds that shows a range of biological activity (Figure 31). This made them an interesting class of compounds to screen for antimitotic activity. The sulfonamide 71 was found through the screening.167 This molecule was optimized using in vitro and in vivo assays. It was shown that the methoxy group improved activity over a methyl group, while the in vivo activity was improved by introducing a nitrogen atom into the ring and introducing a hydroxyl group into the anilino ring to generate ABT-751 (formally E7010) 72. The molecule showed good activity against a range of human tumors in vivo, including MDR expressing resistant cell lines,168 and was subsequently shown to inhibit tubulin polymerization by binding to the

Figure 31 Structures of aryl sulfonamides.

Figure 31 Structures of aryl sulfonamides.

Alkyl 1


e-Donating aryl > aryl > alkyl

Spacers between rings LESS active

Imidazole I LESS activel

0 0

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