1

11.24 cl

I Bacterial I

2H ZD-2767 ZD-2767P

FIGURE 11.23 ADEPT approaches to chemotherapy with nitrogen mustards.

O-SO2-CH3

The first example of a locally activated prodrug using and ADEPT approach that reached clinical trials was the mustard prodrug CMDA in combination with bacterial carboxypeptidase G and cyclosporin to counteract the immune response to the conjugate.25 The activity of 11.23 is probably associated with its ionized form 11.24, where the electron density of the nitrogen atom is increased. It is also relevant to note that 11.23 shows a higher activity than its bischloroethyl analogue (compound 5.13, Section 2.3 of Chapter 5), which can be ascribed to the higher ability of the mesylate unit to act as a leaving group. A related carbamate prodrug is ZD-2767P, which releases the corresponding iodo nitrogen mustard and has also undergone Phase I clinical trials26 (Fig. 11.23).

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