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能够在不损害健康角质形成细胞活力的情况下对抗黑色素瘤细胞存活的三唑-咪唑并[1,2-]吡唑类化合物。

Triazole-imidazo[1,2-]pyrazoles Able to Counteract Melanoma Cell Survival Without Compromising the Viability of Healthy Keratinocytes.

作者信息

Brullo Chiara, Marengo Barbara, Domenicotti Cinzia, Lusardi Matteo, Cichero Elena, Salis Annalisa, Caviglia Debora, Russo Eleonora, Spallarossa Andrea

机构信息

Department of Pharmacy, University of Genoa, Viale Benedetto XV 3, 16132 Genova, Italy.

Department of Experimental Medicine (DIMES), University of Genova, Via Leon Battista Alberti 2, 16132 Genoa, Italy.

出版信息

Int J Mol Sci. 2025 Jun 30;26(13):6312. doi: 10.3390/ijms26136312.

DOI:10.3390/ijms26136312
PMID:40650091
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12249857/
Abstract

To further extend the structure-activity relationships on previously identified anti-proliferative imidazo-pyrazoles, a novel series of compounds was designed and synthesized. In the obtained derivatives (), the imidazo-pyrazole scaffold was formally condensed with a substituted triazole moiety, known for its biological properties. All derivatives were tested for anti-proliferative activity on a panel of 60 different cancer cell lines and compound was identified as the most promising derivative, being highly effective against melanoma cells. Additional investigations demonstrated a cytotoxic and pro-oxidant action of the compound on human metastatic melanoma cell lines (MeOV and MeTA) but not on healthy keratinocytes (HaCAT), confirming the selective activity of the compound. In silico calculations predicted favorable drug-like and pharmacokinetic properties and pre-formulation studies evaluated the effect of Tween 80 on solubility. Overall, the collected data confirmed the pharmacological potential of the imidazo-pyrazole scaffold and indicated as an interesting lead structure for the development of novel anti-melanoma agents.

摘要

为了进一步拓展先前鉴定的抗增殖咪唑并吡唑类化合物的构效关系,设计并合成了一系列新型化合物。在所得到的衍生物中,咪唑并吡唑骨架与具有生物活性的取代三唑部分进行了形式上的缩合。所有衍生物均在60种不同癌细胞系的面板上测试了抗增殖活性,化合物被鉴定为最有前景的衍生物,对黑色素瘤细胞具有高效活性。进一步的研究表明,化合物对人转移性黑色素瘤细胞系(MeOV和MeTA)具有细胞毒性和促氧化作用,但对健康角质形成细胞(HaCAT)无此作用,证实了该化合物的选择性活性。计算机模拟计算预测了良好的类药性质和药代动力学性质,制剂前研究评估了吐温80对溶解度的影响。总体而言,所收集的数据证实了咪唑并吡唑骨架的药理潜力,并表明该化合物是开发新型抗黑色素瘤药物的一个有趣的先导结构。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09d6/12249857/8c1461265e7b/ijms-26-06312-g007.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09d6/12249857/7e2cb1a4e74e/ijms-26-06312-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09d6/12249857/31a4dee18d42/ijms-26-06312-sch001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09d6/12249857/872bdf091e48/ijms-26-06312-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/09d6/12249857/ebbcc0414596/ijms-26-06312-g004.jpg
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