| Autor: |
Taghour MS; Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt., Elkady H; Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt., Eldehna WM; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt., El-Deeb N; Biopharmaceutical Products Research Department, Genetic Engineering and Biotechnology Research Institute, City of Scientific Research and Technological Applications (SRTA-City), Alexandria, Egypt.; Pharmaceutical and Fermentation Industries Development Center, City of Scientific Research and Technological Applications (SRTA city), Alexandria, Egypt., Kenawy AM; Nucleic Acids Research Department, Genetic Engineering and Biotechnology Research Institute. City of Scientific Research and Technological Applications (SRTA-City), Alexandria, Egypt., Abd El-Wahab AE; Pharmaceutical and Fermentation Industries Development Center, City of Scientific Research and Technological Applications (SRTA city), Alexandria, Egypt.; Medical Biotechnology Department, Genetic Engineering and Biotechnology Research Institute, City of Scientific Research and Technological Applications (SRTA-City), Alexandria, Egypt., Elkaeed EB; Department of Pharmaceutical Sciences, College of Pharmacy, AlMaarefa University, Riyadh, Saudi Arabia., Alsfouk BA; Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia., Metwaly AM; Biopharmaceutical Products Research Department, Genetic Engineering and Biotechnology Research Institute, City of Scientific Research and Technological Applications (SRTA-City), Alexandria, Egypt.; Pharmacognosy and Medicinal Plants Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt., Eissa IH; Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt. |
| Abstrakt: |
A new set of quinoline and isatine derivatives were synthesized as antiangiogenic VEGFR-2 inhibitors. On a biological level, the in vitro ability of the obtained candidates to inhibit VEGFR-2 was found to be strong with IC 50 values in the range of 76.64-175.50 nM. To investigate the cytotoxicity and safety, all compounds were tested against a panel of four cancer cell lines (A549, Caco2, HepG2 and MDA) as well as two normal cell lines (Vero and WI-38). Interestingly, compound 12 exhibited noticeable cytotoxicity against A549, Caco2 and MDA with IC 50 values of 5.40, 0.58 and 0.94 µM, respectively. These results were better and comparable to that of doxorubicin (0.70, 0.82 and 0.90 µM, respectively) with more than three folds higher selectivity index against the Caco2 cell lines. Compound 9 prevented the healing of the cancer cells at a low concentration. Also, the compound's potential to induce programmed cell death in Caco-2 was proved through the significant down regulating of the expression of Bcl2, Bcl-xl and Survivin in addition to the slight upregulation of the TGF-β gene. The cell cycle analysis indicated that compound 9 arrested the Caco-2 cells in the G2/M phase. Interestingly, the molecular docking studies against VEGFR-2 revealed the correct binding of the targeted compounds similar to sorafenib. Furthermore, MD experiments validated the binding of compound 12 with VEGFR-2 over 100 ns, as well as MM-PBSA analysis that confirmed the precise binding with optimum energy. Finally, ADMET analysis showed the general drug-likeness and confirmed the safety of the tested compounds.Communicated by Ramaswamy H. Sarma. |
