Oh

Figure 25 Structure of centaureidin.

Figure 26 Centaureidin SAR.

colchicine site, it has been shown to be a competitive inhibitor of colchicine binding, suggesting that it binds to the same site.159 It is assumed that in solution it adopts a conformation that allows it to interact with tubulin. Significantly, screening a range of fatty-acid derivatives resulted in no active compounds. The stereochemistry at the 2-position of the thiazoline ring is important, for the epimer is inactive.160 However, removal of the cyclopropane, 62, or epimerization of the cyclopropane only modestly reduces potency.

The secondary metabolite of estrogen, 2-methoxyestradiol 63, was found while screening for angiogenesis. The molecule is a potent inhibitor of endothelial cell proliferation and migration as well as angiogenesis.161 Further studies showed that this molecule inhibited angiogenesis through its interaction with tubulin and was an effective inhibitor of colchicine binding.162 2-Methoxyestradiol has been shown to suppress tumor growth in vivo without apparent signs of toxicity. Moreover, analyses showed that there was a reduction in tumor vessel density and proliferation rate, suggesting that there is direct inhibition of both endothelial and tumor cell compartments.163 Initial screening showed that 2-hydroxyestriol 64 and 2-methoxyestradiol-3-methyl ether 65 were 50-100-fold weaker in activity (Figure 28).

These results suggested that the A ring was playing a similar role in binding tubulin to that of the C ring of colchicine. To test this theory a collection of tropolone A-ring analogs were synthesized, in which the tropolone ring was

Curacin A (61)

Figure 27 Structures of curacin A and analog

Curacin A (61)

Figure 27 Structures of curacin A and analog

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