Spiromustine analogues. Relationships between structure, plasma stability, and antitumor activity.

Spiromustine is a hydantoin-containing nitrogen mustard currently in Phase I clinical trial. Since the in vitro plasma half-life of this compound (6.4 min, 37 degrees C, pH 7.4) appeared to be influenced by the hydantoin ring, analogues containing 2-5 methylene spacer groups between this ring and the nitrogen mustard moiety were prepared and evaluated for hydrolytic stability and antitumor activity. Stability correlated with structure and pKa values. The proximity of the hydantoin ring to the mustard function was a stabilizing factor. Activity against murine P-388 leukemia was demonstrated and a gradual decrease in this activity was observed as the hydrolytic instability increased. A relationship between analogue structure and a mass spectral rearrangement ion was identified.