Pharmaceutical Research

, Volume 27, Issue 6, pp 1146–1158 | Cite as

Structure-Activity Studies on Therapeutic Potential of Thymoquinone Analogs in Pancreatic Cancer

  • Sanjeev Banerjee
  • Asfar S. Azmi
  • Subhash Padhye
  • Marjit W. Singh
  • Jubaraj B. Baruah
  • Philip A. Philip
  • Fazlul H. Sarkar
  • Ramzi M. Mohammad
Research Paper

ABSTRACT

Purpose

Pancreatic cancer (PC) is one of the deadliest of all tumors. Previously, we were the first to show that Thymoquinone (TQ) derived from black seed (Nigella sativa) oil has anti-tumor activity against PC. However, the concentration of TQ required was considered to be high to show this efficacy. Therefore, novel analogs of TQ with lower IC50 are highly desirable.

Methods

We have synthesized a series of 27 new analogs of TQ by modifications at the carbonyl sites or the benzenoid sites using single pot synthesis and tested their biological activity in PC cells.

Results

Among these compounds, TQ-2G, TQ-4A1 and TQ-5A1 (patent pending) were found to be more potent than TQ in terms of inhibition of cell growth, induction of apoptosis and modulation of transcription factor-NF-κB. We also found that our novel analogs were able to sensitize gemcitabine and oxaliplatin-induced apoptosis in MiaPaCa-2 (gemcitabine resistant) PC cells, which was associated with down-regulation of Bcl-2, Bcl-xL, survivin, XIAP, COX-2 and the associated Prostaglandin E2.

Conclusion

From our results, we conclude that three of our novel TQ analogs warrant further investigation against PC, especially in combination with conventional chemotherapeutic agents.

KEY WORDS

apoptosis pancreatic cancer thymoquinone thymoquinone analogs 

Notes

ACKNOWLEDGEMENTS

The authors express their sincere appreciation to Ms.Christine Wojewoda for her editorial assistance. Grant support from the National Institutes of Health RO1CA109389 (RM Mohammad) and NIH R01CA083695, R01CA131151, and R01CA132794 awarded to FHS is gratefully acknowledged. The authors also acknowledge the financial contribution of Guido Foundation.

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Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Sanjeev Banerjee
    • 1
  • Asfar S. Azmi
    • 1
  • Subhash Padhye
    • 4
  • Marjit W. Singh
    • 3
  • Jubaraj B. Baruah
    • 3
  • Philip A. Philip
    • 2
  • Fazlul H. Sarkar
    • 1
  • Ramzi M. Mohammad
    • 2
  1. 1.Department of Pathology Barbara Ann Karmanos Cancer InstituteWayne State University School of MedicineDetroitUSA
  2. 2.Division of Hematology and Oncology, Barbara Ann Karmanos Cancer InstituteWayne State University School of MedicineDetroitUSA
  3. 3.Department of ChemistryIndian Institute of TechnologyGuwahatiIndia
  4. 4.D.Y.Patil UniversityPuneIndia

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