Thiophene Carboxamide Analogs with Long Alkyl Chains Comprising Ethylene Glycol Units Inhibit Glioblastoma Cell Proliferation by Activating AMPK,Journal of Medicinal Chemistry

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Thiophene Carboxamide Analogs with Long Alkyl Chains Comprising Ethylene Glycol Units Inhibit Glioblastoma Cell Proliferation by Activating AMPK
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-04-28 , DOI: 10.1021/acs.jmedchem.3c00474
Kaito Ohta ₁ , Hiromi Ii ₂ , Chiami Moyama ₂ , Shota Ando ₂ , Hisanori Nambu ₁ , Susumu Nakata ₂ , Naoto Kojima ₁

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Glioblastoma is a refractory malignant tumor that requires novel therapeutic strategies for effective treatment. We have previously reported that JCI-20679 (1), an analog of annonaceous acetogenins, shows potent antitumor activity against glioblastomas. However, the synthesis of 1 requires 23 steps, including 16 steps for the preparation of a tetrahydrofuran (THF) moiety. This study reports the design and synthesis of 11 analogs with a triethylene glycol moiety in place of the THF moiety in 1. Among these, the analog 2k with an n-decyl chain exhibited potent inhibitory activity against the growth of glioblastoma stem cells by inhibiting mitochondrial function and synergistically enhancing the effect of temozolomide (TMZ). Furthermore, 2k significantly suppressed tumor growth without critical toxicity in vivo. Hence, this study presents novel potential anticancer agents and a strategy for the development of these agents that can be produced easily.

中文翻译：

包含乙二醇单元的具有长烷基链的噻吩甲酰胺类似物通过激活 AMPK 抑制胶质母细胞瘤细胞增殖

胶质母细胞瘤是一种难治性恶性肿瘤，需要新的治疗策略才能有效治疗。我们之前曾报道过 JCI-20679 ( 1 ) 是番荔枝苷类似物，对胶质母细胞瘤显示出有效的抗肿瘤活性。然而， 1的合成需要23个步骤，其中包括16个四氢呋喃(THF)部分的制备步骤。本研究报道了 11 种类似物的设计和合成，其中三甘醇部分取代了1中的 THF 部分。其中，带有n的模拟2k-癸基链通过抑制线粒体功能并协同增强替莫唑胺（TMZ）的作用，对胶质母细胞瘤干细胞的生长表现出有效的抑制活性。此外，2k显着抑制肿瘤生长，且体内没有严重毒性。因此，这项研究提出了新型潜在的抗癌药物以及开发这些易于生产的药物的策略。

更新日期：2023-04-28

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