propionate Benorylate30

that may provide dual therapeutic benefits against cancer, e.g., accelerating tumor cell death while protecting normal tissues from damage. However, D609 contains a dithiocarbonate (xanthate) group [O—C(=S)S(-)/O—C(=S)SH] that is chemically unstable, being readily

oxidized to form a disulfide bond with subsequent loss of all biological activities. A series of S-(alkoxyacyl)-D609 prodrugs that connect the xanthate group of D609 to an ester via a self-immolative methyleneoxyl group was designed recently. These S-(alkoxylacyl)-D609 prodrugs release D609 in two steps: esterase-catalyzed hydrolysis of the acyl ester bond followed by conversion of the resulting hydroxymethyl D609 to formaldehyde and D609. The prodrugs are stable at ambient conditions but are readily hydrolyzed by esterases to liberate D609 in a controlled manner.

An interesting variation of the ester-prodrug approach is creation of a double prodrug, where two functional groups are modified simultaneously to achieve the combined physicochemical properties that would maximize permeability enhancement. A double prodrug of the direct platelet and thrombin aggregation inhibitor Melagatran was developed by converting the carboxylic acid to an ester and hydroxylating the imi-dine moiety to reduce its basicity.30 Melagatran (Fig. 3.4) originally exhibited a low oral bioavailability of 5 percent, which was attributed

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