Prodrugs Prepared to Improve Water Solubility

Most water-soluble prodrugs were realized by the derivatization of 2 -OH and 7-OH positions, the two most liable positions in paclitaxel. Some prodrugs are as active as the parental drug both in vitro and in vivo. 

Wrasidlo et al. demonstrated the impact of nature and position of different substitutents on the activity with the 2 - and 7-pyridinium and 2 -sulfonate paclitaxel derivatives. They found that the 2 -(A-methyl-pyridinium acetate) paclitaxel (118) behaved more likely as a prodmg, in comparison with 7-pyridinium and 2 -sulfo-nate derivatives, because it showed almost no cytotoxicity and tubulin binding ability in the absence of plasma. However, it exhibited higher in vivo activity and reduced system toxicitiy than those of paclitaxel, whereas 7-pyridinium and 2 -sul-fonate derivatives showed little activities in nude mice although they retained strong cytotoxicities. 

Non-prodrug water-soluble paclitaxel analogs were also reported. Because their C-10 positions were covalently attached to secondary amines instead of acetate in paclitaxel, they cannot convert into paclitaxel under physiological conditions. 

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