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Design and SAR of Withangulatin A Analogues that Act as Covalent TrxR Inhibitors through the Michael Addition Reaction Showing Potential in Cancer Treatment.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-09-04 , DOI: 10.1021/acs.jmedchem.0c01128 Cheng Wang 1 , Shang Li 1 , Jinhua Zhao 1 , Huali Yang 1 , Fucheng Yin 1 , Ming Ding 1 , Jianguang Luo 1 , Xiaobing Wang 1 , Lingyi Kong 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-09-04 , DOI: 10.1021/acs.jmedchem.0c01128 Cheng Wang 1 , Shang Li 1 , Jinhua Zhao 1 , Huali Yang 1 , Fucheng Yin 1 , Ming Ding 1 , Jianguang Luo 1 , Xiaobing Wang 1 , Lingyi Kong 1
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The thioredoxin system plays an important role in cancer cells. Inhibiting thioredoxin reductase (TrxR) has emerged as an effective strategy to selectively target cancer cells. Withangulatin A (WA), a natural product extracted from the whole herb of Physalis angulata L. (Solanaceae), exhibits potent anticancer activity and other diverse pharmacological activities. To improve activity and targeting, we designed and prepared 41 semisynthetic analogues of WA. Biological evaluation indicated that the most promising compound 13a displayed the most significant effect on HT-29 cells (human colon cancer cells) (IC50 = 0.08 μM). A structure–activity relationship study indicated that α,β-unsaturated ketones and ester are necessary groups, allowing 13a to undergo Michael addition reactions with mercaptan and selenol. Liquid chromatography–mass spectrometry (LC-MS) analysis confirmed that 13a modified selenocysteine 498 (U) residues in the redox centers of TrxR, resulting in enzyme inhibition. Therefore, compound 13a acts as a novel TrxR inhibitor and may be a promising candidate for cancer intervention.
中文翻译：
通过迈克尔加成反应充当共价TrxR抑制剂的Withangulatin A类似物的设计和SAR，显示出在癌症治疗中的潜力。
硫氧还蛋白系统在癌细胞中起重要作用。抑制硫氧还蛋白还原酶（TrxR）已经成为选择性靶向癌细胞的有效策略。Withangulatin A（WA）是从酸浆（Solanaceae）整个草药中提取的天然产物，具有强大的抗癌活性和其他多种药理活性。为了提高活性和针对性，我们设计并制备了WA的41种半合成类似物。生物学评估表明，最有前途的化合物13a对HT-29细胞（人结肠癌细胞）显示出最显着的作用（IC 50= 0.08μM）。构效关系研究表明，α，β-不饱和酮和酯是必需基团，使13a与硫醇和硒醇进行迈克尔加成反应。液相色谱-质谱（LC-MS）分析证实，TrxR氧化还原中心的13a修饰的硒代半胱氨酸498（U）残基导致酶抑制。因此，化合物13a充当新型TrxR抑制剂，可能是有希望的癌症干预候选药物。
更新日期：2020-10-08
中文翻译：
通过迈克尔加成反应充当共价TrxR抑制剂的Withangulatin A类似物的设计和SAR，显示出在癌症治疗中的潜力。
硫氧还蛋白系统在癌细胞中起重要作用。抑制硫氧还蛋白还原酶（TrxR）已经成为选择性靶向癌细胞的有效策略。Withangulatin A（WA）是从酸浆（Solanaceae）整个草药中提取的天然产物，具有强大的抗癌活性和其他多种药理活性。为了提高活性和针对性，我们设计并制备了WA的41种半合成类似物。生物学评估表明，最有前途的化合物13a对HT-29细胞（人结肠癌细胞）显示出最显着的作用（IC 50= 0.08μM）。构效关系研究表明，α，β-不饱和酮和酯是必需基团，使13a与硫醇和硒醇进行迈克尔加成反应。液相色谱-质谱（LC-MS）分析证实，TrxR氧化还原中心的13a修饰的硒代半胱氨酸498（U）残基导致酶抑制。因此，化合物13a充当新型TrxR抑制剂，可能是有希望的癌症干预候选药物。
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