Synthesis and biological evaluation of a new class of azole urea compounds as Akt inhibitors with promising anticancer activity in pancreatic cancer models.

IF 4.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Camilla Pecoraro, Fabio Scianò, Daniela Carbone, Geng Xu, Juan Deng, Stella Cascioferro, Elisa Giovannetti, Patrizia Diana, Barbara Parrino
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引用次数: 0

Abstract

The PI3K/Akt pathway is crucial in numerous cellular functions such as cell growth, survival proliferation and movement in both normal and cancer cells. It plays also a key role in epithelial-mesenchymal transitions and angiogenesis during the tumorigenesis processes. Since many transformative events in cancer are driven by increased PI3K/Akt pathway signaling, Akt is considered a valuable target for developing new therapies against various tumor types, including pancreatic cancer. This is because the PI3K/AKT/mTOR pathway is a key downstream effector of RAS, and RAS activation is the most prominent genetic alteration in pancreatic cancer. Herein we report the synthesis and the biological evaluation of a new series of azole urea compounds that exhibited promising antiproliferative and antimigratory activities against pancreatic cancer cells through an Akt inhibition mechanism. These effects were demonstrated using a variety of assays, including Sulforhodamine B, cell-cycle, wound-healing, and kinase activity, apotposis and ELISA assays. Additionally, the anticancer properties of the most active compound in the series were confirmed in the 3D spheroid model of PATU-T cells.

一类新型唑脲化合物的合成和生物学评价,作为 Akt 抑制剂在胰腺癌模型中具有良好的抗癌活性。
PI3K/Akt 通路对许多细胞功能至关重要,如正常细胞和癌细胞的细胞生长、存活、增殖和运动。在肿瘤发生过程中,它在上皮-间质转化和血管生成中也起着关键作用。由于癌症中的许多转化事件都是由 PI3K/Akt 通路信号的增加所驱动的,因此 Akt 被认为是开发针对包括胰腺癌在内的各种肿瘤类型的新疗法的重要靶点。这是因为 PI3K/AKT/mTOR 通路是 RAS 的一个关键下游效应器,而 RAS 激活是胰腺癌最显著的基因改变。在此,我们报告了一系列新的唑类脲化合物的合成和生物学评价,这些化合物通过 Akt 抑制机制对胰腺癌细胞表现出良好的抗增殖和抗移行活性。研究人员使用了多种检测方法,包括磺基罗丹明 B、细胞周期、伤口愈合、激酶活性、细胞凋亡和酶联免疫吸附试验,证明了这些作用。此外,该系列中活性最强的化合物的抗癌特性在 PATU-T 细胞的三维球形模型中得到了证实。
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来源期刊
Bioorganic Chemistry
Bioorganic Chemistry 生物-生化与分子生物学
CiteScore
9.70
自引率
3.90%
发文量
679
审稿时长
31 days
期刊介绍: Bioorganic Chemistry publishes research that addresses biological questions at the molecular level, using organic chemistry and principles of physical organic chemistry. The scope of the journal covers a range of topics at the organic chemistry-biology interface, including: enzyme catalysis, biotransformation and enzyme inhibition; nucleic acids chemistry; medicinal chemistry; natural product chemistry, natural product synthesis and natural product biosynthesis; antimicrobial agents; lipid and peptide chemistry; biophysical chemistry; biological probes; bio-orthogonal chemistry and biomimetic chemistry. For manuscripts dealing with synthetic bioactive compounds, the Journal requires that the molecular target of the compounds described must be known, and must be demonstrated experimentally in the manuscript. For studies involving natural products, if the molecular target is unknown, some data beyond simple cell-based toxicity studies to provide insight into the mechanism of action is required. Studies supported by molecular docking are welcome, but must be supported by experimental data. The Journal does not consider manuscripts that are purely theoretical or computational in nature. The Journal publishes regular articles, short communications and reviews. Reviews are normally invited by Editors or Editorial Board members. Authors of unsolicited reviews should first contact an Editor or Editorial Board member to determine whether the proposed article is within the scope of the Journal.
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