Conformational Analysis using 2D NMR Spectroscopy Coupled with Computational Analysis as an Aid in the Alignment Procedure of 3DQSAR Studies

The alignment of molecules in 3D-QSAR studies is an important step that affects considerably the outcome and the quality of CoMFA and CoMSIA models and subsequently the drug design and synthesis. Several applications will be reviewed with regard to the flexibility of the structures involved and the alignment procedures applied. Emphasis will be given to the contribution of NMR spectroscopy coupled with theoretical calculations to provide bioactive conformers in environments, which mimic the biological site of action. The aim of this review article is to inform medicinal chemists involved in the design and synthesis of novel drugs about the existing weaponry, which can be of aid in their research work

Synthesis and 3D QSAR/CoMFA and CoMSIA Studies on Antileukemic Steroidal Esters coupled with Conformationally Flexible Nitrogen Mustards

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