Elaborating piperazinyl-furopyrimidine based scaffolds as phosphoinositol-3-kinase enzyme alpha (PI3Kα) inhibitors to combat pancreatic cancer |
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| Authors: | Mai A Mansour Deena S Lasheen Hatem M Gaber Khaled A M Abouzid |
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| Institution: | Pharmaceutical Chemistry Department, Faculty of Pharmacy, Badr University in Cairo, Egypt.; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo 11566 Egypt.; National Organization for Drug Control and Research, Egypt ; Department of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Sadat City, Sadat City Menoufia Egypt |
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| Abstract: | Phosphoinositol-3-kinase enzyme (PI3K) plays a crucial role in driving oncogenic growth in various mammalian cells, particularly pancreatic cells. In the current study a series of novel furo2,3-d]pyrimidine based-compounds were designed and synthesized as potential PI3K-α inhibitors. In accordance to the structure–activity relationship (SAR) studies of known PI3K-α inhibitors, different linkers including amide, urea and ether were attached to a piperazinyl furo2,3-d]pyrimidine core. The synthesized compounds that revealed moderate PI3K-α inhibitory activity were tested for their anti-proliferative activities against pancreatic carcinoma on the PANC-1 cell line. Compounds 7b and 8a showed the highest anti-proliferative activity with IC50 values of 4.5 μM and 6 μM, respectively and relatively, the best in vitro PI3K inhibition ability within the newly synthesized compounds. Additionally, all the newly synthesized final compounds were tested on 60 human cancer cell lines. A docking study was carried out on the PI3K-α active site showing a comparable binding mode to that of FDA approved PI3K-α inhibitors. These newly discovered lipid kinase inhibitors could be considered as potential candidates for the development of new targeted anticancer agents.Phosphoinositol-3-kinase alpha (PI3K-α) enzyme inhibition to combat pancreatic cancer. |
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