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新型 2-硫代尿嘧啶-5-磺胺衍生物的合成及其作为细胞周期阻滞和 CDK2A 抑制剂的潜力：基于分子对接的研究。

Synthesis of Novel 2-Thiouracil-5-Sulfonamide Derivatives as Potent Inducers of Cell Cycle Arrest and CDK2A Inhibition Supported by Molecular Docking.

机构信息

Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Helwan University, Helwan 11795, Egypt.

Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Helwan University, Helwan 11795, Egypt.

出版信息

Int J Mol Sci. 2021 Nov 4;22(21):11957. doi: 10.3390/ijms222111957.

DOI:10.3390/ijms222111957
PMID:34769385
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8584424/
Abstract

In an effort to discover potent anticancer agents, 2-thiouracil-5-sulfonamides derivatives were designed and synthesized. The cytotoxic activity of all synthesized compounds was investigated against four human cancer cell lines viz A-2780 (ovarian), HT-29 (colon), MCF-7 (breast), and HepG2 (liver). Compounds -, and showed promising anticancer activity and significant inhibition of CDK2A. Moreover, they were all safe when tested on WI38 normal cells with high selectivity index for cancer cells. Flow cytometric analysis for the most active compound displayed induction of cell growth arrest at G1/S phase (A-2780 cells), S phase (HT-29 and MCF-7 cells), and G2/M phase (HepG2 cells) and stimulated the apoptotic death of all cancer cells. Moreover, was able to cause cycle arrest indirectly through enhanced expression of cell cycle inhibitors p21 and p27. Finally, molecular docking of compound endorsed its proper binding to CDK2A, which clarifies its potent anticancer activity.

摘要

为了发现有效的抗癌剂，设计并合成了 2-硫代尿嘧啶-5-磺酰胺衍生物。对所有合成化合物的细胞毒性活性进行了研究，针对四种人类癌细胞系 A-2780（卵巢）、HT-29（结肠）、MCF-7（乳腺）和 HepG2（肝脏）进行了测试。化合物 - 、 和 表现出有希望的抗癌活性和对 CDK2A 的显著抑制作用。此外，在 WI38 正常细胞上进行测试时，它们都很安全，对癌细胞具有高选择性指数。对最活跃的化合物 的流式细胞术分析显示，在 G1/S 期（A-2780 细胞）、S 期（HT-29 和 MCF-7 细胞）和 G2/M 期（HepG2 细胞）诱导细胞生长停滞，并刺激所有癌细胞的凋亡死亡。此外， 通过增强细胞周期抑制剂 p21 和 p27 的表达，能够间接引起细胞周期停滞。最后，化合物 的分子对接证实了它与 CDK2A 的适当结合，这阐明了它强大的抗癌活性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba45/8584424/ff3593f0e757/ijms-22-11957-g008.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba45/8584424/66f69b9f4f95/ijms-22-11957-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba45/8584424/ff3593f0e757/ijms-22-11957-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba45/8584424/564e234fadc2/ijms-22-11957-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba45/8584424/3f9cbb41d4e3/ijms-22-11957-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba45/8584424/7fac4eef7754/ijms-22-11957-sch001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba45/8584424/eb8f5f38815b/ijms-22-11957-sch002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba45/8584424/0d7d00d62ccd/ijms-22-11957-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba45/8584424/5e05d8a8cdf5/ijms-22-11957-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba45/8584424/eeb06db70cff/ijms-22-11957-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba45/8584424/a97180b3535f/ijms-22-11957-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba45/8584424/66f69b9f4f95/ijms-22-11957-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba45/8584424/ff3593f0e757/ijms-22-11957-g008.jpg

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