Harnessing molecular hybridization approach to discover novel quinoline EGFR-TK inhibitors for cancer treatment
Aim: Using molecular hybridization approach, novel 18 quinoline derivatives (6a–11) were designed and synthesized as EGFR-TK inhibitors. Materials & methods: The antiproliferative activity was assessed against breast (MCF-7), leukemia (HL-60) and lung (A549) cancer cell lines. Moreover, the most active quinoline derivatives (6d and 8b) were further investigated for their potential as EGFR-TK inhibitors. In addition, cell cycle analysis and apoptosis induction activity were conducted. Results: A considerable cytotoxic activity was attained with IC50 values spanning from 0.06 to 1.12 μM. Besides, the quinoline derivatives 6d and 8b displayed potent inhibitory activity against EFGR with IC50 values of 0.18 and 0.08 μM, respectively. Conclusion: Accordingly, the afforded quinoline derivatives can be used as promising lead anticancer candidates for future optimization.
Tyrosine kinases (TK) play a pivotal role in cellular signaling pathways, making them key targets for therapeutic interventions.
Molecular hybridization approach was utilized to design and synthesize novel eighteen quinoline derivatives (6a–11) as EGFR-TK inhibitors.
The antiproliferative activity of the synthesized quinoline derivatives (6a–11) was assessed against breast (MCF-7), leukemia (HL-60) and lung (A549) cancer cell lines.
A considerable cytotoxic activity was attained against the investigated cancer cell lines with IC50 values spanning from 0.06 to 1.12 μM in comparison to 5-FU (0.18 to 0.51 μM).
The quinoline derivatives 6d and 8b could display potent inhibitory activity against EFGR with IC50 values of 0.18 and 0.08 μM, respectively in comparison to Lapatinib (0.05 μM).
Additionally, cell cycle analysis displayed that quinoline derivatives 6d and 8b could significantly prompt S phase arrest in A549 cancer cells.
The flow cytometry analysis revealed that the treatment of A549 cells with quinoline compounds 6d and 8b resulted in 34.88 and 31.41% cellular apoptosis, respectively, whereas non-treated cells showed 0.63%.
The conducted in silico studies showed eligible binding pattern for the synthesized quinoline derivatives to EGFR-TK with acceptable pharmacokinetics and toxicity profiles.
The afforded quinoline derivatives can be used as promising lead anticancer candidates for future optimization.
