Department of Chemistry, College of Science, Princess Nourah Bint Abdulrahman University, Riyadh, Saudi Arabia.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
Drug Des Devel Ther. 2022 May 16;16:1457-1471. doi: 10.2147/DDDT.S356988. eCollection 2022.
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.
表皮生长因子受体（EGFR）调节多种细胞功能，包括细胞生长、存活、增殖、分化和凋亡。目前，EGFR 激酶抑制剂作为有前途的靶向抗肿瘤治疗药物越来越受到关注。
合成了不同的噻唑基-吡唑啉衍生物（），并首先在 MTT 测定中测试它们对 A549 肺癌细胞系和 T-47D 乳腺癌细胞系的抗增殖作用。此后，噻唑基-吡唑啉（、和）随后评估了它们对 EGFR 的 PK 抑制作用。此外，在细胞毒性和 PK 抑制测定中对有前途的代表性衍生物（和）进行了测试，以研究它们对 T-47D 细胞中细胞凋亡和细胞周期相的影响，以深入了解目标噻唑基-吡唑啉的抗肿瘤作用。此外，还进行了对接研究，以评估噻唑基-吡唑啉、和在 EGFR 活性口袋（PDB ID：1M17）中的结合模式。
在 A549 和 T-47D 细胞系上测试噻唑基吡唑啉化合物显示 IC 数组分别为 3.92 和 89.03 μM，以及 0.75 和 77.10 μM。此外，测试的噻唑基-吡唑啉（、和）在 EGFR 中显示出显著的亚微摩尔抑制作用，IC 值分别为 83、262、171 和 305 nM，而厄洛替尼（IC =57 nM）。
一般来说，观察到测试的噻唑基吡唑啉对乳腺癌细胞 T-47D 的增殖活性比对肺癌细胞系 A549 更强。特别是噻唑基吡唑啉和显示出对 A549 细胞（IC = 3.92 和 6.53 μM）和 T-47D 细胞（IC = 0.88 和 0.75 μM）的最佳活性。化合物和导致 G1 期阻滞和细胞凋亡，这与 EGFR 抑制的预期结果一致。最后，和在 EGFR 活性位点的分子对接揭示了一种与厄洛替尼相似的共同结合模式，涉及将 1,3 噻唑-4-酮环和吡唑啉环容纳在目标化合物的喹唑啉环和苯胺部分的结合区域中。
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