Srour Aladdin M, El-Bayaa Mohamed N, Temirak Ahmed, Alanzy Asmaa L, Awad Hanem M, Saleh Asmaa, Saleh Mahmoud G, El-Sayed Wael A
Department of Therapeutic Chemistry, Pharmaceutical and Drug Industries Research Institute, National Research Centre, Dokki, Giza, 12622, Egypt.
Department of Chemistry, College of Science, Qassim University, Buraidah, 51452, Saudi Arabia.
Sci Rep. 2025 Jul 15;15(1):25514. doi: 10.1038/s41598-025-96675-3.
A new series of glycosyl heterocyclic scaffolds, 5a-10b with N-glycosidic linkage, were synthesized, starting with 2-acetyl-1H-benzimidazole as a precursor of the propargyl-derived substrates (2) and (3), which were then converted to the target 1,2,3-triazole glycosides (8a-10b) bearing unprotected hydroxyl groups. The new chemical entities have been assessed for their cytotoxic properties on diverse human cancer cell lines, namely HepG-2 (human liver cancer), HCT-116 (human colorectal), and MCF-7 (human breast cancer), in addition to a human normal cell line (BJ-1), following the LDH assay and with erlotinib and doxorubicin as the standard references. Most of the tested compounds demonstrated potent activity, particularly the triazole glycosides 6b, 7b, 8b, 9a, 9b, 10a, and 10b. Compound 9a was the best against all targeted cell lines, particularly HepG-2 and HCT-116, by IC values of 1.64 ± 0.11 and 5.00 ± 0.51 µM, superior to that of erlotinib, IC = 2.07 ± 0.07 and 5.14 ± 0.33 µM, respectively. Furthermore, it showed a safe profile against the tested normal cell line BJ-1. The triazole glycosides 8a-10b were investigated to assess their capability to inhibit EGFR. Remarkably, 9a and 9b exhibited noteworthy inhibitory activity against EGFR (IC = 0.069 ± 0.003 and 0.075 ± 0.003 µM, respectively) in comparison with erlotinib, the reference drug (0.048 ± 0.002 µM). Molecular docking confirmed these findings, suggesting that the incorporation of the α,β-unsaturated ketone function enhances compounds' stability within the EGFR active site. Thus, these results indicate that compounds 9a and 9b disclosed potential anti-cancer agents targeting EGFR kinase.
以2-乙酰基-1H-苯并咪唑作为炔丙基衍生底物（2）和（3）的前体，合成了一系列新的具有N-糖苷键的糖基杂环支架5a - 10b，然后将其转化为带有未保护羟基的目标1,2,3-三唑糖苷（8a - 10b）。采用LDH测定法，以厄洛替尼和多柔比星作为标准对照，对这些新的化学实体在多种人类癌细胞系（即HepG-2（人类肝癌细胞系）、HCT-116（人类结肠癌细胞系）和MCF-7（人类乳腺癌细胞系））以及一种人类正常细胞系（BJ-1）上的细胞毒性特性进行了评估。大多数测试化合物表现出较强的活性，特别是三唑糖苷6b、7b、8b、9a、9b、10a和10b。化合物9a对所有靶向细胞系的活性最佳，对HepG-2和HCT-116的IC值分别为1.64±0.11和5.00±0.51 μM，优于厄洛替尼，其IC值分别为2.07±0.07和5.14±0.33 μM。此外，它对测试的正常细胞系BJ-1显示出安全的特性。对三唑糖苷8a - 10b进行了研究，以评估它们抑制EGFR的能力。值得注意的是，与参考药物厄洛替尼（0.048±0.002 μM）相比，9a和9b对EGFR表现出显著的抑制活性（IC值分别为0.069±0.003和0.075±0.003 μM）。分子对接证实了这些发现，表明α,β-不饱和酮官能团的引入增强了化合物在EGFR活性位点内的稳定性。因此，这些结果表明化合物9a和9b是靶向EGFR激酶的潜在抗癌药物。
