In investigating the use of combretastatin as a potential therapeutic, the low solubility of the compound made formulation difficult. To address this issue a number of prodrugs of the B-ring phenol have been synthesized.145 The sodium phosphate compound 52 was stable and increased the water solubility significantly. This prodrug showed similar nanomolar activity to the parent compound. An interesting characteristic of this molecule is its ability to target the vasculature. It has been shown to lower blood flow to tumors, leading to hemorrhage. Although the reason for this unusual activity is unclear, it is thought that cytoskeletal changes take place in the endothelial cells of the new blood vessels due to tubulin binding which results in disruption of the blood flow. This activity was observed in a phase I

Figure 18 Podophyllotoxin and steganicin SAR.

Combrestatin (49)

Figure 19 Structures of combrestatins.

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