Bioorganic chemistry. 2025 Jun 6:163:108672. doi: 10.1016/j.bioorg.2025.108672 Q24.52024

Discovery of novel thiazolopyrimidine derivatives targeting topoisomerase II: Design, synthesis, antiproliferative evaluation, molecular docking and apoptosis inducing activity

新型噻唑并吡啶衍生物靶向拓扑异构酶II的发现：设计、合成、抗增殖评价、分子对接及诱导凋亡活性研究翻译改进

Sara Y Ewieda¹, Mo'men Salem², Ahmed Elshewy³, Mohnad Abdalla⁴, May El-Manawaty⁵, Hoda Khalifa Abdelhady⁶, Haredy Hassan Haredy⁶, Wael A A Fadaly⁷, Mamdouh F A Mohamed⁸, Mohamed T M Nemr⁹

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作者单位

¹ Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr El-Eini street, 11562 Cairo, Egypt. Electronic address: sara.eweda@pharma.cu.edu.eg.

² Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Sinai University - Arish branch, Arish 45511, Egypt.

³ Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr El-Eini street, 11562 Cairo, Egypt; Department of Natural and Applied Sciences, College of Arts and Sciences, The American University of Iraq-Baghdad (AUIB), Baghdad, Iraq.

⁴ Pediatric Research Institute, Children's Hospital Affiliated to Shandong University, Jinan, Shandong 250022, PR China.

⁵ Pharmacognosy Department, National Research Centre, Egypt.

⁶ Pharmacology Department, Faculty of Medicine, Al-Azhar University, Assuit, Egypt.

⁷ Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt.

⁸ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Sohag University, 82524 Sohag, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, New Valley University, New Valley 72511, Egypt.

⁹ Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr El-Eini street, 11562 Cairo, Egypt.

DOI: 10.1016/j.bioorg.2025.108672 PMID: 40482357

摘要中英对照阅读

Two new sets of thiazolopyrimidines IIa-h, IVa-d were designed, synthesized, and screened for their anticancer activity against MCF-7 breast cancer adenocarcinoma, HCT116 colorectal cancer, and HepG2 hepatic cancer. The safety of the newly synthesized compounds was tested using normal cells (BJ). Compounds IIa, IId, and IVa showed exceptional cytotoxic activity against both MCF-7 and HepG2, with IC₅₀ ranges of (24.52-30.22 & 21.49-34.09 μM), respectively, compared to Doxorubicin IC₅₀ (32.36 & 50.29 μM), respectively. Furthermore, they exhibited significant selectivity towards the tested cancer cells (SI values 1.7-4.4) compared to doxorubicin (SI values 0.8-1.8). Additionally, thiazolopyrimidines IIa, IId, and IVa showed potent topoisomerase II inhibitory activity (IC₅₀ 1.23, 0.94, and 1.72 μM, respectively) in comparison with reference compound doxorubicin (IC₅₀ 3.08 μM). Cell cycle analysis showed that the most potent derivative IId induces cell cycle arrest at the G1 phase, leading to inhibition of cell proliferation and apoptosis. Docking study of thiazolopyrimidines IIa, IId, and IVa showed that they could fit well in the pocket in a similar pattern to etoposide, which accounts for their high potency.

Keywords: Antiproliferative; Apoptosis; Molecular docking; Thiazolopyrimidines; Topoisomerase II.

Keywords：thiazolopyrimidine derivatives; topoisomerase II; antiproliferative evaluation; molecular docking; apoptosis inducing activity

设计、合成了两组新的噻唑嘧啶类化合物IIa-h和IVa-d，并对其抗乳腺癌细胞系MCF-7（腺癌）、结直肠癌细胞系HCT116以及肝癌细胞系HepG2的抗癌活性进行了筛选。使用正常细胞（BJ）测试了新合成化合物的安全性。化合物IIa、IId和IVa在对抗MCF-7和HepG2时表现出优异的细胞毒性，IC₅₀值范围分别为(24.52-30.22 & 21.49-34.09 μM)，与阿霉素（Doxorubicin）相比分别为(32.36 & 50.29 μM)。此外，它们对测试的癌细胞表现出显著的选择性(SI值为1.7-4.4)，而阿霉素的SI值则为0.8-1.8。另外，噻唑嘧啶类化合物IIa、IId和IVa显示出强大的拓扑异构酶II抑制活性（IC₅₀分别为1.23、0.94和1.72 μM），与参考化合物阿霉素(3.08 μM)相比效果更佳。细胞周期分析表明，最强效的衍生物IId在G1期诱导了细胞周期停滞，从而抑制了细胞增殖并促发了细胞凋亡。噻唑嘧啶类化合物IIa、IId和IVa的分子对接研究显示它们能够以与依托泊苷相似的方式很好地结合到口袋中，这解释了其高活性的原因。

关键词： 抗增殖；细胞凋亡；分子对接；噻唑嘧啶类；拓扑异构酶II

关键词：噻唑并嘧啶衍生物; 拓扑异构酶II; 抗增殖评价; 分子对接; 诱导凋亡活性

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期刊名：Bioorganic chemistry

缩写：BIOORG CHEM

ISSN：0045-2068

e-ISSN：1090-2120

IF/分区：4.5/Q2

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Discovery of novel thiazolopyrimidine derivatives targeting topoisomerase II: Design, synthesis, antiproliferative evaluation, molecular docking and apoptosis inducing activity

新型噻唑并吡啶衍生物靶向拓扑异构酶II的发现：设计、合成、抗增殖评价、分子对接及诱导凋亡活性研究翻译改进

Novel inhibitors of oncogenic Wnt/TCF-4/β-catenin signaling pathway: Design, synthesis, molecular docking studies and apoptosis inducing activity of pyrimidothiazino-, dihydropyrimidotriazepino- and 1,3,4-thiadiazolopyrimido-indole hybrids

新型的抗肿瘤Wnt/TCF-4/β-连环蛋白信号通路抑制剂：嘧啶并噻嗪诺、二氢嘧啶三氮杂环氧-和1,3,4-噻二唑嘧啶并吲哚杂合物的设计、合成、分子对接研究及诱导凋亡活性

The Assessment of Cytotoxicity, Apoptosis Inducing Activity and Molecular Docking of a new Ciprofloxacin Derivative in Human Leukemic Cells

新型环丙沙星衍生物在人白血病细胞中细胞毒性和诱导凋亡及分子对接的评价研究

Synthesis, evaluation and molecular docking of thiazolopyrimidine derivatives as dipeptidyl peptidase IV inhibitors

噻唑并嘧啶衍生物作为二肽基肽酶Ⅳ抑制剂的合成、评价及分子对接研究

Molecular docking studies on thirteen fluoroquinolines with human topoisomerase II a and b

13种氟喹诺酮类化合物的人拓扑异构酶IIA和IIB分子对接研究

Antiproliferative Evaluation of Some 2-[2-(2-Phenylethenyl)-cyclopent-3-en-1-yl]-1,3-benzothiazoles: DFT and Molecular Docking Study

二苯并噻唑类衍生物的抗增殖活性评价：DFT及分子对接研究

New [1,2,4]triazolo[4,3-c]quinazoline derivatives as vascular endothelial growth factor receptor-2 inhibitors and apoptosis inducers: Design, synthesis, docking, and antiproliferative evaluation

设计、合成、对接和抗增殖评价新型[1,2,4]三氮唑并[4,3-c]喹唑啉衍生物作为血管内皮生长因子受体-2抑制剂和促凋亡诱导剂

Design and synthesis of new 1,6-dihydropyrimidin-2-thio derivatives targeting VEGFR-2: Molecular docking and antiproliferative evaluation

设计和合成新的1,6-二氢嘧啶-2-硫衍生物以靶向VEGFR-2：分子对接与抗增殖评价

Synthesis, cytotoxicity, apoptosis-inducing activity and molecular docking studies of novel isatin-podophyllotoxin hybrids

新型吲哚酸鬼臼毒素衍生物的合成、细胞毒性、促凋亡活性及分子对接研究

Antiproliferative, apoptosis-inducing activity and molecular docking studies of sydnones compounds

三氮氧类化合物的抗增殖和促凋亡活性及分子对接研究

Discovery of novel thiazolopyrimidine derivatives targeting topoisomerase II: Design, synthesis, antiproliferative evaluation, molecular docking and apoptosis inducing activity

新型噻唑并吡啶衍生物靶向拓扑异构酶II的发现：设计、合成、抗增殖评价、分子对接及诱导凋亡活性研究 翻译改进

Novel inhibitors of oncogenic Wnt/TCF-4/β-catenin signaling pathway: Design, synthesis, molecular docking studies and apoptosis inducing activity of pyrimidothiazino-, dihydropyrimidotriazepino- and 1,3,4-thiadiazolopyrimido-indole hybrids

新型的抗肿瘤Wnt/TCF-4/β-连环蛋白信号通路抑制剂：嘧啶并噻嗪诺、二氢嘧啶三氮杂环氧-和1,3,4-噻二唑嘧啶并吲哚杂合物的设计、合成、分子对接研究及诱导凋亡活性

The Assessment of Cytotoxicity, Apoptosis Inducing Activity and Molecular Docking of a new Ciprofloxacin Derivative in Human Leukemic Cells

新型环丙沙星衍生物在人白血病细胞中细胞毒性和诱导凋亡及分子对接的评价研究

Synthesis, evaluation and molecular docking of thiazolopyrimidine derivatives as dipeptidyl peptidase IV inhibitors

噻唑并嘧啶衍生物作为二肽基肽酶Ⅳ抑制剂的合成、评价及分子对接研究

Molecular docking studies on thirteen fluoroquinolines with human topoisomerase II a and b

13种氟喹诺酮类化合物的人拓扑异构酶IIA和IIB分子对接研究

Antiproliferative Evaluation of Some 2-[2-(2-Phenylethenyl)-cyclopent-3-en-1-yl]-1,3-benzothiazoles: DFT and Molecular Docking Study

二苯并噻唑类衍生物的抗增殖活性评价：DFT及分子对接研究

New [1,2,4]triazolo[4,3-c]quinazoline derivatives as vascular endothelial growth factor receptor-2 inhibitors and apoptosis inducers: Design, synthesis, docking, and antiproliferative evaluation

设计、合成、对接和抗增殖评价新型[1,2,4]三氮唑并[4,3-c]喹唑啉衍生物作为血管内皮生长因子受体-2抑制剂和促凋亡诱导剂

Design and synthesis of new 1,6-dihydropyrimidin-2-thio derivatives targeting VEGFR-2: Molecular docking and antiproliferative evaluation

设计和合成新的1,6-二氢嘧啶-2-硫衍生物以靶向VEGFR-2：分子对接与抗增殖评价

Synthesis, cytotoxicity, apoptosis-inducing activity and molecular docking studies of novel isatin-podophyllotoxin hybrids

新型吲哚酸鬼臼毒素衍生物的合成、细胞毒性、促凋亡活性及分子对接研究

Antiproliferative, apoptosis-inducing activity and molecular docking studies of sydnones compounds

三氮氧类化合物的抗增殖和促凋亡活性及分子对接研究

新型噻唑并吡啶衍生物靶向拓扑异构酶II的发现：设计、合成、抗增殖评价、分子对接及诱导凋亡活性研究翻译改进