Research Paper

Pharmaceutical Research

, Volume 27, Issue 6, pp 1146-1158

First online:

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

  • Sanjeev BanerjeeAffiliated withDepartment of Pathology Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine
  • , Asfar S. AzmiAffiliated withDepartment of Pathology Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine
  • , Subhash PadhyeAffiliated withD.Y.Patil University
  • , Marjit W. SinghAffiliated withDepartment of Chemistry, Indian Institute of Technology
  • , Jubaraj B. BaruahAffiliated withDepartment of Chemistry, Indian Institute of Technology
  • , Philip A. PhilipAffiliated withDivision of Hematology and Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine
  • , Fazlul H. SarkarAffiliated withDepartment of Pathology Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine
  • , Ramzi M. MohammadAffiliated withDivision of Hematology and Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine Email author 

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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