Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Rm 338 Parks Hall, 500 West 12th Avenue, Columbus, OH 43210-1291, United States.
Bioorg Med Chem Lett. 2013 Dec 15;23(24):6864-7. doi: 10.1016/j.bmcl.2013.09.098. Epub 2013 Oct 9.
STAT3 is constitutively active in a large variety of cancers. The search for STAT3 inhibitors led to the discoveries of LLLs 3 and 12, which are substituted anthraquinones. LLL12 is an extremely potent compound that exhibits high levels of antiproliferative activity. Herein the synthesis and evaluation of compounds containing either an anthraquinone or 1,4-naphthoquinone moiety are reported. Analogs were evaluated in several cancer cell lines. Interestingly, it was found that the anthraquinones did not follow the same trends as the 1,4-naphthoquinones in regards to potency. LLL12, which contains a sulfonamide at position 1, was found to be the most potent of the anthraquinones. In contrast, the methyl ketone and methyl ester derivatives (LLLs 3.1 and 5.1) were found to be the most potent of the 1,4-naphthoquinones. Selected 1,4-naphthoquinones were also evaluated in the STAT3 fluorescence polarization assay in order to evaluate their abilities to bind to the STAT3 SH2 domain. They were found to have similar affinities, and their activities suggest that STAT3 is one of their molecular targets.
STAT3 在多种癌症中持续激活。对 STAT3 抑制剂的研究导致了 LLLs3 和 12 的发现，它们是取代的蒽醌。LLL12 是一种极其有效的化合物，具有高水平的抗增殖活性。本文报道了含有蒽醌或 1,4-萘醌部分的化合物的合成和评价。在几种癌细胞系中对类似物进行了评估。有趣的是，发现蒽醌在效力方面并没有遵循与 1,4-萘醌相同的趋势。在位置 1 含有磺酰胺的 LLL12 被发现是最有效的蒽醌。相比之下，甲基酮和甲酯衍生物（LLLs3.1 和 5.1）是最有效的 1,4-萘醌。还评估了选定的 1,4-萘醌在 STAT3 荧光偏振测定法中的能力，以评估它们与 STAT3 SH2 结构域结合的能力。发现它们具有相似的亲和力，其活性表明 STAT3 是它们的一个分子靶标。
