Comparison of the structural parameters of mitindomide and the bisdioxopiperazines dexrazoxane (ICRF-187) and ICRF-193
| Parameter | Mitindomide | Dexrazoxane | ICRF-193 |
|---|---|---|---|
| ImideN-to-imide N distance (Å) | 7.8 | 9.0 | 9.2 |
| Coplanarity of imide rings (°) | 7.3 | 1.3 | 2.9 |
| N-to-plane distance (Å) | 3.0 | 3.7 | 2.8 |
| Nonpolar surface area (Å2) | 127 | 135 | 153 |
| Polar surface area (Å2) | 135 | 141 | 144 |
| Total surface area (Å2) | 262 | 276 | 297 |
| Molecular volume (Å3) | 326 | 351 | 374 |
| Human p170 topoisomerase II inhibition, IC50(μm) | 200 | 9.3 | 0.62-a |
The molecular parameters were derived from molecular modeling and X-ray structures of dexrazoxane and an analog of mitindomide. ImideN-to-imide N distance, coplanarity of imide rings, and N-to-plane distance were derived from X-ray crystal structures from an N-substituted derivative of mitindomide (32) and dexrazoxane (31) and molecular modeling for ICRF-193. The imide ring plane was defined by the nitrogen imide atom and the two adjacent carbonyl carbon atoms. The coplanarity was measured by calculating the angle of the normals of the two planes to each other. Area and volume were calculated from the van der Waals surfaces by molecular modeling. Nonpolar surface area includes contributions from both unsaturated (mitindomide only) and saturated areas.
↵2-a From Ref. 12.