Discovery of anilino-furo[2,3-d]pyrimidine derivatives as dual inhibitors of EGFR/HER2 tyrosine kinase and their anticancer activity
- Eur J Med Chem. 2018 Jan 20:144:330-348. doi: 10.1016/j.ejmech.2017.12.022.
- 1. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abassia, Cairo 11566, Egypt; Center for Drug Discovery and Development Research, Faculty of Pharmacy, Ain Shams University, Abassia, Cairo 11566, Egypt. Electronic address: [email protected].
- 2. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abassia, Cairo 11566, Egypt; Center for Drug Discovery and Development Research, Faculty of Pharmacy, Ain Shams University, Abassia, Cairo 11566, Egypt.
- 3. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abassia, Cairo 11566, Egypt.
- 4. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Abassia, Cairo 11566, Egypt; Center for Drug Discovery and Development Research, Faculty of Pharmacy, Ain Shams University, Abassia, Cairo 11566, Egypt.
- 5. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Nasr City, Cairo, Egypt.
- 6. Pharmacognosy Department, Faculty of Pharmacy, Ain Shams University, Abassia, Cairo 11566, Egypt; Center for Drug Discovery and Development Research, Faculty of Pharmacy, Ain Shams University, Abassia, Cairo 11566, Egypt.
- 7. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abassia, Cairo 11566, Egypt; Center for Drug Discovery and Development Research, Faculty of Pharmacy, Ain Shams University, Abassia, Cairo 11566, Egypt. Electronic address: [email protected].
Being responsible for the development of many Cancer types, EGFR (Epidermal Growth Factor Receptor) and HER2 (Human Epidermal growth factor Receptor 2) were the focus of this study where a series of novel 4-anilino-furo[2,3-d]pyrimidine derivatives was designed, synthesized and biologically evaluated. Modification of the solvent accessible 5-position side chain greatly affected the in-vitro EGFR/HER2 inhibitory activity. Three derivatives bearing 5-carboxylic acid side chain, namely the 3-chloroanilino derivative (8c), the 3-bromoaniline (8d) and the lapatinib analogue (10) demonstrated the most significant submicromolar EGFR inhibition. Surprisingly, the in-vitro assay of the ester 7h and its acid analogue 10 showed a significant variation of results between the antiproliferative activity against A549 cell line (IC50 0.5 and 21.4 μM) respectively and EGFR inhibitory activity (18% and 100%) respectively, suggesting that 7h might be a prodrug for 10. This assumption was also affirmed by the in-vivo results, where the in-vivo antitumor assessment against EAC (Ehrlich Ascites Carcinoma) solid tumor model revealed that 7h and 8d (10 mg/kg dose) exhibited antitumor activity comparable to that of gefitinib at the same dose, exhibiting TGI% of 67%, 71% and 70%, respectively. This effect could be explained, at least partly, via activation of Apoptosis, where 7h and 8d caused more than 2-fold increase of Caspase 3 and cytochrome c expression than the control group which is comparable to that of gefitinib-treated group. Finally, 7h was the most effective apoptotic inducer, resulting in a significant elevation in annexin V-FITC-positive apoptotic cells (both early and late Apoptosis) by 25 and 79-folds, respectively, compared to control, which is higher than that of gefitinib (22 and 61-folds, respectively).