Design and discovery of carboxamide-based pyrazole conjugates with multifaceted potential against Triple-Negative Breast cancer MDA-MB-231 cells

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-09-16 DOI:10.1016/j.bmcl.2024.129960

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Abstract

We report the design, synthesis, and validation of carboxamide-based pyrazole and isoxazole conjugates with a multifaceted activity against Breast Cancer Cell Line MDA-MB-231. The study established that amongst the series, N-(3,5-bis(trifluoromethyl)benzyl)-3-(3,4,5-trimethoxyphenyl)-1H-pyrazole-5-carboxamide (5g) exhibits the highest potency in inhibiting Breast Cancer Cell Line MDA-MB-231 with an IC₅₀ value of 15.08 ± 0.04 µM. The MDA‐MB‐231 cells, upon treatment with compound 5g, exhibited characteristic apoptotic specific activities such as nuclear fragmentation, phosphatidylserine translocation to the outer plasma membrane, release of lactate dehydrogenase (LDH), and upregulation of caspase 3 and caspase 9 activities. Also, the modulation of pro and antiapoptotic proteins in 5g treated MDA-MB-231 cells was revealed by membrane array analysis. More importantly, the combination of paclitaxel and compound 5g has exhibited improved activity by several folds via their synergistic effects.

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设计和发现具有抗三阴性乳腺癌 MDA-MB-231 细胞多方面潜力的羧酰胺基吡唑共轭物

我们报告了对乳腺癌细胞株 MDA-MB-231 具有多方面活性的羧酰胺基吡唑和异噁唑共轭物的设计、合成和验证。研究发现，在这一系列化合物中，N-(3,5-双(三氟甲基)苄基)-3-(3,4,5-三甲氧基苯基)-1H-吡唑-5-甲酰胺（5g）对乳腺癌细胞株 MDA-MB-231 的抑制作用最强，IC50 值为 15.08 ± 0.04 µM。用化合物 5g 处理 MDA-MB-231 细胞后，细胞表现出特有的凋亡活性，如核破碎、磷脂酰丝氨酸转位到外质膜、乳酸脱氢酶（LDH）释放以及 caspase 3 和 caspase 9 活性上调。此外，膜阵列分析还揭示了 5g 处理的 MDA-MB-231 细胞中促凋亡蛋白和抗凋亡蛋白的变化。更重要的是，紫杉醇和化合物 5g 的组合通过协同效应提高了数倍的活性。

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来源期刊

Bioorganic & Medicinal Chemistry Letters 医学-医药化学

CiteScore

5.70

自引率

3.70%

发文量

463

审稿时长

27 days

期刊介绍： Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.