Reheim M A M Abdel, Elgammal Walid E, Bashandy Mahmoud S, Hamed Mohammed I A, AboulMagd Asmaa M, Khalil Mona G, Abdou Amr M, Hassan Rasha A
Department of Chemistry, Faculty of Science, Arish University Arish 45511 Egypt.
Chemistry Department, Faculty of Science, Al-Azhar University Nasr City Cairo Egypt.
RSC Med Chem. 2025 Jun 17. doi: 10.1039/d5md00139k.
The current study aimed to synthesize a series of innovative improved anticancer chemical entities by combining the unique advantages of 1,3,4-thiadiazole as an established anticancer pharmacophore with the furopyrimidine scaffold which is a key component of many reported cytotoxic agents. Sixteen furopyrimidine derivatives were designed and evaluated by several biological tests including antiproliferative activity against 60 human cancer cell lines, measurement of GI, TGI, and LC values, MTT and selectivity index (SI) calculation, enzymatic PI3Kα/β and AKT inhibitory assay, cell cycle analysis and apoptosis evaluation. The results indicated that the designed compound 10b revealed potent anticancer activity with a mean GI of 108.32%, remarkable anticancer activity with GI values ranging from 0.91 to 16.7 μM and strong cytostatic action (TGI range: 2.32-15.0 μM) against 38 cancer cell lines. It also exhibited a potent and selective antiproliferative activity against the breast cancer HS 578T cell line (GI = 1.51 μM and TGI = 4.96 μM). Furthermore, compound 10b demonstrated the highest inhibitory activity against PI3Kα/β and AKT enzymes with IC = 0.175 ± 0.007, 0.071 ± 0.003 and 0.411 ± 0.02 μM, respectively. Additionally, it could strongly induce cell cycle arrest in breast cancer HS 578T cells at the G0-G1 phase and trigger apoptosis. Molecular docking and dynamics were also performed in this study which revealed that compound 10b provided an improved binding pattern with the key amino acids in the PI3K and AKT-1 binding sites. According to the findings, the designed compound 10b has potent antiproliferative and apoptotic activities with a wide therapeutic index particularly against breast cancer.
本研究旨在通过将1,3,4-噻二唑作为一种成熟的抗癌药效基团的独特优势与作为许多已报道细胞毒性药物关键成分的呋喃嘧啶支架相结合，合成一系列创新的改良抗癌化学实体。设计了16种呋喃嘧啶衍生物，并通过多种生物学测试进行评估，包括对60种人类癌细胞系的抗增殖活性、GI、TGI和LC值的测定、MTT和选择性指数（SI）计算、酶促PI3Kα/β和AKT抑制测定、细胞周期分析和凋亡评估。结果表明，设计的化合物10b显示出强效抗癌活性，平均GI为108.32%，对38种癌细胞系具有显著抗癌活性，GI值范围为0.91至16.7μM，具有较强的细胞生长抑制作用（TGI范围：2.32 - 15.0μM）。它还对乳腺癌HS 578T细胞系表现出强效且选择性的抗增殖活性（GI = 1.51μM，TGI = 4.96μM）。此外，化合物10b对PI3Kα/β和AKT酶表现出最高的抑制活性，IC值分别为0.175±0.007、0.071±0.003和0.411±0.02μM。此外，它可强烈诱导乳腺癌HS 578T细胞在G0 - G1期发生细胞周期阻滞并引发凋亡。本研究还进行了分子对接和动力学研究，结果表明化合物10b与PI3K和AKT - 1结合位点中的关键氨基酸提供了改进的结合模式。根据研究结果，设计的化合物10b具有强效的抗增殖和凋亡活性，具有广泛的治疗指数，尤其对乳腺癌有效。
