Pyrimido[4,5-b]indole Derivatives Bearing 1,2,4-oxadiazole Moiety As MDM2 Inhibitor Candidates in Cancer Treatment

Abstract

Aim: In this study, novel hybrid structures of pyrimido-indole-oxadiazole were developed as MDM2 inhibitors for restoring the regular function of the p53. Materials & methods: A multistep chemical pathway was used to synthesize the derivatives. Nutlin-3a was used as a standard lead in molecular docking and molecular dynamics simulations. Finally, cytotoxicity was evaluated against MCF-7 cancer cells versus Doxorubicin. Results: The most promising candidate was 12c, which had an NO₂ group in the para position of the oxadiazole ring (IC₅₀: 1.1 μM). A satisfactory result was obtained with the combined application of 12c and Doxorubicin (IC₅₀ decreased to 0.63 μM), which could be potentially attributed to MDM2 inhibition. Conclusion: These hybrid structures can be further investigated as potential MDM2 inhibitors.

Keywords:

• cytotoxicity
• MDM2 inhibitor
• MD simulation
• oxadiazole
• pyrimidoindole

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at:www.tandfonline.com/doi/full/10.2217/epi-2016-0184

Acknowledgments

The authors wish to thank A Fassihi for final editing of this manuscript.

Financial & competing interests disclosure

This work was supported by the Pharmaceutical Sciences Research Center at Isfahan University of Medical Sciences (grant no. 299008). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.