Phosphate Ester and other Prodrugs

On the other hand, the derivatives 10.2.3 and 10.2.4, prepared by logical extensions of previously used methodology, underwent much faster hydrolysis by phosphatase enzymes (which are present in more than normal amounts in cancer cells), and both were found to be much more soluble in water than taxol. The 7-substituted derivative 10.2.4 was found to be as active as taxol in the murine Ml09 tumor model (361), and the carbonate derivative 10.2.5 also had comparable activity to taxol in the Ml09 model (362). 

Continued investigation by the Bristol-Myers Squibb group led to the development of the phosphonooxymethyl analogs 10.2.6, 10.2.7, and 

These analogs had improved water-solubility and comparable Ml09 in vivo activity to taxol, and were thus stated to be suitable prodrugs of taxol the carbonate 10.2.8 was especially promising in this regard (363), and a radioactive derivative of it was prepared (364). 

Hwu et al. synthesized taxol-containing aminophosphates as protaxols. Treatment of taxol with MeOPCl2 and collidine in THF and then with (monomethoxy)tritylated amino alcohols, I2 and water produced zwitter-ionic taxol-containing aminophosphates such as 10.2.9 (365). 

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