1. Discovery of new pyridine-quinoline hybrids as competitive and non-competitive PIM-1 kinase inhibitors with apoptosis induction and caspase 3/7 activation capabilities.
- Author
-
El-Miligy, Mostafa M. M., Abdelaziz, Marwa E., Fahmy, Salwa M., Ibrahim, Tamer M., Abu-Serie, Marwa M., Mahran, Mona A., and Hazzaa, Aly A.
- Subjects
- *
KINASE inhibitors , *CASPASES , *MYELOID leukemia , *APOPTOSIS , *IMIDAZOPYRIDINES , *MOLECULAR docking , *QUINOLINE - Abstract
New quinoline-pyridine hybrids were designed and synthesised as PIM-1/2 kinase inhibitors. Compounds 5b, 5c, 6e, 13a, 13c, and 14a showed in-vitro low cytotoxicity against normal human lung fibroblast Wi-38 cell line and potent in-vitro anticancer activity against myeloid leukaemia (NFS-60), liver (HepG-2), prostate (PC-3), and colon (Caco-2) cancer cell lines. In addition, 6e, 13a, and 13c significantly induced apoptosis with percentage more than 66%. Moreover, 6e, 13a, and 13c significantly induced caspase 3/7 activation in HepG-2 cell line. Furthermore, 5c, 6e, and 14a showed potent in-vitro PIM-1 kinase inhibitory activity. While, 5b showed potent in-vitro PIM-2 kinase inhibitory activity. Kinetic studies using Lineweaver–Burk double-reciprocal plot indicated that 5b, 5c, 6e, and 14a behaved as competitive inhibitors while 13a behaved as both competitive and non-competitive inhibitor of PIM-1 kinase enzyme. Molecular docking studies indicated that, in-silico affinity came in coherence with the observed in-vitro inhibitory activities against PIM-1/2 kinases. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF