Abstract
Epidermal growth factor receptor (EGFR) regulates several cell functions which include cell growth, survival, multiplication, differentiation, and apoptosis. Currently, EGFR kinase inhibitors are of increasing interest as promising targeted antitumor therapeutic agents.
Different thiazolyl-pyrazoline derivatives (
) were synthesized and were first tested for anti-proliferative effect towards the A549 lung cancer cell line and the T-47D breast cancer cell line in MTT assay. Thereafter, thiazolyl-pyrazolines (
, and
) were subsequently evaluated for their PK inhibition for EGFR. Moreover, representative promising derivatives (
and
) in cytotoxic and PK inhibition assays were tested to investigate their impact on the apoptosis and cell cycle phases in T-47D cells in order to explore more insights into the antitumor actions of the target thiazolyl-pyrazolines. Furthermore, docking studies were accomplished to evaluate the patterns of binding of thiazolyl-pyrazolines
, and
in the EGFR active pocket (PDB ID: 1M17).
Testing the thiazolyl pyrazoline compounds
on A549 and T-47D cell lines showed IC
arrays between 3.92 and 89.03 µM, and between 0.75 and 77.10 µM, respectively. Also, the tested thiazolyl-pyrazolines (
, and
) demonstrated significant sub-micromolar EGFR inhibitory actions with IC
values 83, 262, 171 and 305 nM, respectively, in comparison to erlotinib (IC
=57 nM).
Generally, it was observed that the tested thiazolyl pyrazolines showed more potent antiproliferative activity toward breast cancer cells T-47D than toward lung cancer cell lines A549. In particular, thiazolyl pyrazolines
and
showed the best activity against A549 cells (IC
= 3.92 and 6.53 µM) and T-47D cells (IC
= 0.88 and 0.75 µM). Compounds
and
provoked a sub-G1 phase arrest and cell apoptosis which are in agreement with the expected outcome of EGFR inhibition. Finally, the molecular docking of
and
in the active site of EGFR revealed a common binding pattern similar to that of erlotinib which involves the accommodation of the 1,3 thiazol-4-one ring and pyrazoline ring of target compounds in the binding region of erlotinib's quinazoline ring and anilino moiety.