3D QSAR Studies of 3, 16 and 17 Position Modifications in Steroidal Derivatives for CNS Anticancer Activity

Sonal Dubey, M.R. Suraj, Tilak Goni, Tilak Gulalkai, S. Shankar, Sumanth Gowda and Prashant Tiwari

Background and Objective: The role of steroids in cancer is well established in reducing inflammation, immune response and sickness while undergoing chemotherapy and improving appetite. However, these steroidal agents have been seldom tested as direct inhibitors for the enzymes associated with cancer. This study was undertaken to establish a 3D QSAR model of 16-(substituted) dehydroepiandrosterone derivatives, which can help in designing novel compounds in the series. Materials and Methods: For this study, some novel steroidal derivatives exhibiting CNS anti-cancer activity were taken and tried to understand their SAR and quantify it using 3D QSAR to know the requirement for future development in the area. About 56 novels 16-(substituted) dehydroepiandrosterone derivatives which were previously synthesized in our lab and evaluated for CNS anticancer activity were taken for this study. After energy minimization, these compounds were aligned over each other to determine the pharmacophore and then subjected to CoMFA analysis. Results: Eight CoMFA models were generated, the most optimum model was the one with r² = 0.892, q² = 0.02 and the lowest STD deviation error correction. The introduction of electropositive groups at positions 11 and 14 and electro negative groups at positions 3 and 16 in the steroidal ring can lead to potentially active compounds. Conclusion: The 3D CoMFA model generated gave us an insight that the introduction of electropositive groups at positions 11 and 14 and electro-negative groups at positions 3 and 16 in the steroidal ring will give us compounds with better CNS anticancer activity.

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