Thirty-eight antileukemic steroidal esters possessing conformationally flexible nitrogen mustards were studied,
and the 3D QSAR/CoMFA and CoMSIA methodologies were applied in order to derive the correlation
between their structure and the in ViVo antileukemic activity. These compounds show significantly reduced
toxicity and possibly increased bioavailability compared to free nitrogen mustards and therefore constitute
potent antileukemic drugs. Both the CoMFA and CoMSIA studies gave similar results indicating that the
steric effect and the hydrophobic/hydrophilic balance especially in the steroidal part of the molecules probably
determined their bioactivity. Of paramount interest is the observation that the orientation of the alkylating
part of the SMEs toward the surface of ring B of the steroidal skeleton was related with increased activity.
Concerning the steroidal part, the presence of hydrophobic groups in rings B and D was found to be important
for enhanced activity. Enhancement of antileukemic potency is further observed if hydrophilic/H-bond acceptor
groups are present at the positions 7 and 17 of the steroidal skeleton. Leapfrog simulations provided novel
compounds which lead our future synthetic endeavor for obtaining SMEs with optimum bioactivity