Syntheses and Biological Activities of a Novel Group of Steroidal Derived Inhibitors for Human CDC25A Protein Phosphatase<SUP>1</SUP><BBR RID="jm0004401b00001">

Silica gel supported pyrolysis of an azido-homo-oxa steroid led to rearrangement, presumably by a mechanism similar to that of solution phase Schmidt fragmentation, to produce a group of novel inhibitors for the oncogenic cell cycle regulator Cdc25A phosphatase. Cyano-containing acid <BO>17</BO>, one of the best inhibitors in this group, inhibited the activity of Cdc25A protein phosphatase reversibly and noncompetitively with an IC<INF>50</INF> value of 2.2 μM. Structure−activity relationships revealed that a phosphate surrogate such as a carboxyl or a xanthate group is required for inhibitory activity, and a hydrophobic alkyl chain, such as the cholesteryl side chain, contributes greatly to the potency. Without the cyano group, acid <BO>26</BO> and xanthate <BO>27</BO> were found to be more selective over Cdc25A (IC<INF>50</INF> = 5.1 μM and 1.1 μM, respectively) than toward CD45 (IC<INF>50</INF> > 100 μM, in each case), a receptor protein tyrosine phosphatase. Several of these inhibitors showed antiproliferative activities in the NCI 60-human tumor cell line screen. These steroidal derived Cdc25 inhibitors provide unique leads for the development of dual-specificity protein phosphatase inhibitors.