Zeidan Mohamed A, Ashour Heba F, Yassen Asmaa S A, Abo Elmaaty Ayman, Farag Ayman B, Sharaky Marwa, Abdullah Alzahrani Abdullah Yahya, Mughram Mohammed H Al, Al-Karmalawy Ahmed A
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Horus University-Egypt New Damietta 34518 Egypt
Department of Medicinal Chemistry, Faculty of Pharmacy, Galala University New Galala New Galala 43713 Egypt.
RSC Med Chem. 2024 Dec 19. doi: 10.1039/d4md00750f.
Many cancers have displayed resistance to chemotherapeutic drugs over the past few decades. EGFR has emerged as a leading target for cancer therapy inhibiting tumor angiogenesis. Besides, studies strongly suggest that blocking telomerase activity could be an effective way to control the growth of certain cancer cells. Based on the fact that multi-target design rationale can afford candidates with greater treatment effectiveness. Besides, it was evidenced that inhibition of human telomerase enhances the effect of some tyrosine kinase inhibitors. So, in the current work, we aimed to design and synthesize novel 1,2,3-triazole-tethered Schiff bases (5a-l) to act as dual EGFR and telomerase inhibitors. Growth inhibition (GI)% was conducted for the synthesized compounds using a panel of eleven cancer cell lines as well as two normal cell lines. Interestingly, compound 5e displayed the highest mean GI% (76.78%) among the investigated compounds surpassing the mean GI% of the reference drug doxorubicin (65.79%). In addition, compound 5g displayed notably the lowest IC values (13.31, 13.31, 12.62, and 31.19 μM) for the four utilized cancer cell lines HNO97, HCT116, A375, and HEPG2, respectively. Interestingly, the investigated compounds exhibited significant inhibitory potential to EGFR and telomerase protein expression; in particular, compound 5g recorded inhibitory potentials of 3.45 and 1.31 ng mL, respectively. Hence, protein expression of the apoptosis-related proteins was carried out for compound 5g. Pro-apoptotic proteins (caspases 3, 8, and 9) were upregulated by 1.35, 1.55, and 1.51-fold change, respectively. Meanwhile, the anti-apoptotic proteins (CDK-2, CDK-4, and CDK-6) were downregulated by 2.91, 2.01, and 9.15-fold change, respectively, ensuring the apoptotic potential of compound 5g. Accordingly, compound 5g was selected for further investigation of its effects on cell cycle progression in A375 cancer cells. Obviously, compound 5g prompted cell cycle arrest at the G0-G1 phase. Additionally, the investigated compounds showed eligible pharmacokinetic profiles with feasible oral bioavailability. Consequently, the synthesized compounds can be treated as lead multi-target anticancer ligands for future optimization.
在过去几十年中，许多癌症已对化疗药物产生耐药性。表皮生长因子受体（EGFR）已成为癌症治疗中抑制肿瘤血管生成的主要靶点。此外，研究强烈表明，阻断端粒酶活性可能是控制某些癌细胞生长的有效方法。基于多靶点设计原理能够提供具有更高治疗效果的候选药物这一事实。此外，有证据表明抑制人端粒酶可增强某些酪氨酸激酶抑制剂的效果。因此，在当前工作中，我们旨在设计并合成新型的1,2,3 - 三唑连接的席夫碱（5a - l），使其作为EGFR和端粒酶的双重抑制剂。使用一组11种癌细胞系以及两种正常细胞系对合成的化合物进行生长抑制（GI）%测定。有趣的是，在研究的化合物中，化合物5e表现出最高的平均GI%（76.78%），超过了参考药物阿霉素的平均GI%（65.79%）。此外，化合物5g对所使用的四种癌细胞系HNO97、HCT116、A375和HEPG2分别显示出显著最低的IC值（13.31、13.31、12.62和31.19 μM）。有趣的是，所研究的化合物对EGFR和端粒酶蛋白表达表现出显著的抑制潜力；特别是，化合物5g的抑制潜力分别为3.45和1.31 ng/mL。因此，对化合物5g进行了凋亡相关蛋白的蛋白表达研究。促凋亡蛋白（半胱天冬酶3、8和9）分别上调了1.35、1.55和1.51倍。同时，抗凋亡蛋白（细胞周期蛋白依赖性激酶 - 2、4和6）分别下调了2.91、2.01和9.15倍，证实了化合物5g的凋亡潜力。因此，选择化合物5g进一步研究其对A375癌细胞细胞周期进程的影响。显然，化合物5g促使细胞周期停滞在G0 - G1期。此外，所研究的化合物显示出符合要求的药代动力学特征以及可行的口服生物利用度。因此，合成的化合物可被视为未来优化的潜在多靶点抗癌配体。
