Characterizing New Oncology Drugs with NMR

Cancer is the second-leading cause of death globally, with about 1 in every 6 deaths occurring around the world being due to cancer. In 2018, cancer caused an estimated 9.6 million deaths.

随着新的更有效治疗的发展，癌症死亡率率下降。但是，癌症正在不断发展，这可能导致癌症对可用疗法具有抵抗力。一旦癌症发展出耐药性，它可能会继续不受限制地增加，从而导致复发和更严重的疾病。

因此，持续寻找具有多种作用方式的新型抗癌剂。

Many of the vital processes needed for cancer cells to grow and multiply have been targeted by pharmaceuticals. It was found that tumor development is closely related to angiogenesis (the creation of new blood vessels) and so this became a key therapeutic target.

Inhibition of Angiogenesis

The inhibition of abnormal angiogenesis can prevent the proliferation, migration, and invasion of cancer cells.

实际上，一大种抗癌药物，例如靶向血管内皮生长因子（VEGF）的药物，通过干扰血管生成来发挥其治疗作用。这使肿瘤无法扩展其脉管系统，从而通过防止氧气和新癌细胞的必需营养素的供应来限制肿瘤的生长。

Many agents that disrupt the tumor’s ability to extend its network of blood vessels have shown efficacy in clinical trials of many different cancers.

寻找具有抑制肿瘤血管生成能力的新药物的搜索表明，从干燥根部提取的提取物S. Baicalensisknown as baicalein has a disruptive effect on tumor vasculature.⁷然而，由于化合物的非理想物理特性，例如口服生物利用度较差和水溶性较低，因此黄氨基林的临床应用受到限制。

The potential of baicalein as an effective anti-cancer agent prompted the creation of baicalein derivatives with more favorable characteristics. Studies have demonstrated a range of desirable anticancer activities of baicalein derivatives.Most recently, baicalein derivatives have been evaluated as inhibitors of angiogenesis.

Evaluation of Baicalein Derivatives as Anticancer Agents

Researchers recently evaluated the体内转基因斑马鱼模型中一系列贝莱辛衍生物的抗血管生成作用。

Zebrafish was chosen for the research due to the high level of gene conservation between zebrafish and mammals and these ease with which drugs effects can be studied due to their transparency.

The zebrafish used in this study had also been engineered to exhibit vasculature-specific expression of enhanced green fluorescent protein (EGFP) during embryonic and larval development. This enables visualization of endothelial cells using a fluorescence microscope, which means that anti-angiogenic effects can be studied directly.

合成了一系列的黄胶衍生物，并通过Bruker Avance 300 MHz光谱仪确认其结构。

The baicalein derivatives with alkyl alcohol side chains demonstrated anti-angiogenic effects. In particular, a derivative with a piperazine acetamide group at position 6 (compound 42) had potent in vivo anti-angiogenic activity and low toxicity in a transgenic zebrafish model.

体外评估of compound 42 revealed that it inhibited cell proliferation in a dose-dependent manner in human umbilical vein endothelial cells (HUVECs), human lung cancer A549 cells and, to a lesser extent, human normal fibroblast L929 cells. Compound 42 achieved an IC50 value of 4.73 μM for the inhibition of A549 cell growth.

使用膜联蛋白V-FITC/PI双标记流式细胞术，证明细胞抑制是通过晚期凋亡的显着增加（使用8μM浓度的62％）实现的。

与媒介物对照相比，对转基因斑马鱼中化合物42的进一步评估显示，剂量依赖性抑制了段段血管（ISV）形成。化合物42至后期胚胎的给药并未引起血管形态的明显变化。这证实了化合物42通过抑制血管生成（而不是破坏现有的脉管系统）来实现这种作用，因为在此阶段ISV的形成已经完成。

Using NMR spectroscopy, this latest research identified the structural modifications to baicalein that provide significant anti-angiogenic and anticancer effects without associated toxicity. In particular, compound 42 with a piperazine acetamide group added at position 6 was shown to represent a novel potential compound for further evaluation as a cancer therapy.

参考

• WHO Cancer Fact sheet. September 2018.https://www.who.int/betway捕鱼游戏下载news-room/fact-sheets/detail/cancer
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