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设计、合成及评估 STAT3 抑制作用的 BP-1-102 类似物，这些类似物的疏水片段经过了修饰。

Design, synthesis, and evaluation of BP-1-102 analogs with modified hydrophobic fragments for STAT3 inhibition.

机构信息

Department of Chemistry, Faculty of Science, University of Hradec Kralove, Hradec Kralove, Czech Republic.

Department of Genome Integrity, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic.

出版信息

J Enzyme Inhib Med Chem. 2021 Dec;36(1):410-424. doi: 10.1080/14756366.2020.1871336.

DOI:10.1080/14756366.2020.1871336
PMID:33440995
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7808747/
Abstract

Twelve novel analogs of STAT3 inhibitor BP-1-102 were designed and synthesised with the aim to modify hydrophobic fragments of the molecules that are important for interaction with the STAT3 SH2 domain. The cytotoxic activity of the reference and novel compounds was evaluated using several human and two mouse cancer cell lines. BP-1-102 and its two analogs emerged as effective cytotoxic agents and were further tested in additional six human and two murine cancer cell lines, in all of which they manifested the cytotoxic effect in a micromolar range. Reference compound S3I-201.1066 was found ineffective in all tested cell lines, in contrast to formerly published data. The ability of selected BP-1-102 analogs to induce apoptosis and inhibition of STAT3 receptor-mediated phosphorylation was confirmed. The structure-activity relationship confirmed a demand for two hydrophobic substituents, i.e. the pentafluorophenyl moiety and another spatially bulky moiety, for effective cytotoxic activity and STAT3 inhibition.

摘要

设计并合成了 12 种新型 STAT3 抑制剂 BP-1-102 类似物，旨在修饰对与 STAT3 SH2 结构域相互作用很重要的分子的疏水片段。使用几种人源和两种鼠源癌细胞系评估了参考化合物和新型化合物的细胞毒性。BP-1-102 及其两种类似物作为有效的细胞毒性剂出现，并在另外六个人类和两个鼠类癌细胞系中进一步进行了测试，在所有这些细胞系中，它们在微摩尔范围内表现出细胞毒性作用。与以前发表的数据相反，参考化合物 S3I-201.1066 在所有测试的细胞系中均无效。证实了选定的 BP-1-102 类似物诱导细胞凋亡和抑制 STAT3 受体介导的磷酸化的能力。构效关系证实，需要两个疏水取代基，即五氟苯基部分和另一个空间较大的部分，以实现有效的细胞毒性和 STAT3 抑制作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfca/7808747/860a6dd1ee94/IENZ_A_1871336_F0005_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfca/7808747/7507c0d4bd55/IENZ_A_1871336_SCH0001_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfca/7808747/527a6920f30c/IENZ_A_1871336_SCH0002_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfca/7808747/f6f0411dd6a0/IENZ_A_1871336_SCH0003_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfca/7808747/328c0869aa19/IENZ_A_1871336_F0001_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfca/7808747/049293cb53fa/IENZ_A_1871336_F0002_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfca/7808747/fede21972782/IENZ_A_1871336_F0003_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfca/7808747/bfb4119303b9/IENZ_A_1871336_F0004_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfca/7808747/860a6dd1ee94/IENZ_A_1871336_F0005_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfca/7808747/7507c0d4bd55/IENZ_A_1871336_SCH0001_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfca/7808747/527a6920f30c/IENZ_A_1871336_SCH0002_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfca/7808747/f6f0411dd6a0/IENZ_A_1871336_SCH0003_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfca/7808747/328c0869aa19/IENZ_A_1871336_F0001_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfca/7808747/049293cb53fa/IENZ_A_1871336_F0002_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfca/7808747/fede21972782/IENZ_A_1871336_F0003_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfca/7808747/bfb4119303b9/IENZ_A_1871336_F0004_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cfca/7808747/860a6dd1ee94/IENZ_A_1871336_F0005_C.jpg

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