2. Academic Validation
  3. Pyrrolizines: Design, synthesis, anticancer evaluation and investigation of the potential mechanism of action

Pyrrolizines: Design, synthesis, anticancer evaluation and investigation of the potential mechanism of action

  • Bioorg Med Chem. 2017 Oct 15;25(20):5637-5651. doi: 10.1016/j.bmc.2017.08.039.
Ahmed M Gouda 1,  Ahmed H Abdelazeem 2,  Hany A Omar 3,  Ashraf N Abdalla 4,  Mohammed A S Abourehab 5,  Hamed I Ali 6
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Umm Al-Qura University, Makkah 21955, Saudi Arabia; Department of Medicinal Chemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt. Electronic address: ahmed.gouda@pharm.bsu.edu.eg.
  • 2 Department of Medicinal Chemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt.
  • 3 Sharjah Institute for Medical Research and College of Pharmacy, University of Sharjah, Sharjah 27272, United Arab Emirates; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt.
  • 4 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Umm Al-Qura University, Makkah 21955, Saudi Arabia; Department of Pharmacology, Medicinal and Aromatic Plants Research Institute, National Center for Research, Khartoum 2404, Sudan.
  • 5 Department of Pharmaceutics, Faculty of Pharmacy, Umm Al-Qura University, Makkah 21955, Saudi Arabia.
  • 6 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Helwan University, Cairo, Egypt; Rangel College of Pharmacy, Health Science Center, Texas A&M University, Kingsville, TX 78363, United States. Electronic address: alyismail@pharmacy.tamhsc.edu.
PMID: 28916158 DOI: 10.1016/j.bmc.2017.08.039
Abstract

A novel set of pyrrolizine-5-carboxamides has been synthesized and evaluated for their Anticancer potential against human breast MCF-7, lung carcinoma A549 and hepatoma Hep3B Cancer cell lines. Compound 10c was the most active against MCF-7 with IC50 value of 4.72µM, while compound 12b was the most active against A549 and Hep3B cell lines. Moreover, kinases/COXs inhibition and Apoptosis induction were suggested as potential molecular mechanisms for the Anticancer activity of the novel pyrrolizines based on their structural features. The new compounds significantly inhibited COX-1 and COX-2 with IC50 values in the ranges of 5.78-11.96µM and 0.1-0.78µM, respectively with high COX-2 selectivity over COX-1. Interestingly, the most potent compound in MTT assay, compound 12b, exhibited high inhibitory activity against COX-2 with selectivity index (COX-1/COX-2)>100. Meanwhile, compound 12b displayed weak to moderate inhibition of six kinases with inhibition% (7-20%) compared to imatinib (inhibition%=1-38%). The results of cell cycle analysis, annexin V PI/FITC Apoptosis assay and Caspase-3/7 assay revealed that compound 12b has the ability to induce Apoptosis. The docking results of compound 12b into the active sites of COXs, ALK1 and Aurora kinases indicated that it fits nicely inside their active sites. Overall, the current study highlighted the significant Anticancer activity of the newly synthesized pyrrolizines with a potential multi-targeted mechanism which could serve as a base for future studies and further structural optimization into potential Anticancer agents.

Keywords

Annexin V; Anticancer; Apoptosis; COX-2; Caspase-3/7; Cell cycle; Kinase; Pyrrolizine.

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