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Synthetic Peroxides Promote Apoptosis of Cancer Cells by Inhibiting P-Glycoprotein ABCB5.
ChemMedChem ( IF 3.6 ) Pub Date : 2020-03-10 , DOI: 10.1002/cmdc.202000042 Ivan A Yaremenko 1 , Paolo Coghi 2 , Parichat Prommana 3 , Congling Qiu 4 , Peter S Radulov 1 , Yuanqing Qu 4 , Yulia Yu Belyakova 1 , Enrico Zanforlin 5 , Vladimir A Kokorekin 1 , Yuki Yu Jun Wu 4 , Fabrice Fleury 6 , Chairat Uthaipibull 3 , Vincent Kam Wai Wong 4 , Alexander O Terent'ev 1
ChemMedChem ( IF 3.6 ) Pub Date : 2020-03-10 , DOI: 10.1002/cmdc.202000042 Ivan A Yaremenko 1 , Paolo Coghi 2 , Parichat Prommana 3 , Congling Qiu 4 , Peter S Radulov 1 , Yuanqing Qu 4 , Yulia Yu Belyakova 1 , Enrico Zanforlin 5 , Vladimir A Kokorekin 1 , Yuki Yu Jun Wu 4 , Fabrice Fleury 6 , Chairat Uthaipibull 3 , Vincent Kam Wai Wong 4 , Alexander O Terent'ev 1
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This article discloses a new horizon for the application of peroxides in medical chemistry. Stable cyclic peroxides are demonstrated to have cytotoxic activity against cancer cells; in addition a mechanism of cytotoxic action is proposed. Synthetic bridged 1,2,4,5‐tetraoxanes and ozonides were effective against HepG2 cancer cells and some ozonides selectively targeted liver cancer cells (the selectivity indexes for compounds 11 b and 12 a are 8 and 5, respectively). In some cases, tetraoxanes and ozonides were more selective than paclitaxel, artemisinin, and artesunic acid. Annexin V flow‐cytometry analysis revealed that the active ozonides 22 a and 23 a induced cell death of HepG2 by apoptosis. Further study showed that compounds 22 a and 23 a exhibited a strong inhibitory effect on P‐glycoprotein (P‐gp/ABCB5)‐overexpressing HepG2 cancer cells. ABCB5 is a key player in the multidrug‐resistant phenotype of liver cancer. Peroxides failed to demonstrate a direct correlation between oxidative potential and their biological activity. To our knowledge this is the first time that peroxide diastereoisomers have been found to show stereospecific antimalarial action against the chloroquine‐sensitive 3D7 strain of Plasmodium falciparum . Stereoisomeric ozonide 12 b is 11 times more active than stereoisomeric ozonide 12 a (IC50=5.81 vs 65.18 μm ). Current findings mean that ozonides merit further investigation as potential therapeutic agents for drug‐resistant hepatocellular carcinoma.
中文翻译：
合成过氧化物通过抑制P-糖蛋白ABCB5促进癌细胞的凋亡。
本文揭示了过氧化物在医学化学中的应用新前景。稳定的环状过氧化物被证明对癌细胞具有细胞毒活性。另外，提出了细胞毒性作用的机制。合成桥接1,2,4,5- tetraoxanes和（对于化合物的选择性指标臭氧化物反对的HepG2肿瘤细胞和一些臭氧化物选择性地靶向肝癌细胞有效部11b和12是图8和5，分别地）。在某些情况下，四恶烷和臭氧化物比紫杉醇，青蒿素和青蒿琥酯更具选择性。Annexin V流式细胞仪分析发现活性臭氧化物22a和23a通过凋亡诱导HepG2细胞死亡。进一步的研究表明，化合物22a和23a对过表达P-糖蛋白（P-gp / ABCB5）的HepG2癌细胞具有强烈的抑制作用。ABCB5是肝癌多药耐药表型的关键因素。过氧化物未能证明氧化电位与其生物学活性之间存在直接关系。据我们所知，这是首次发现过氧化物非对映异构体对恶性疟原虫的氯喹敏感3D7菌株具有立体定向的抗疟作用。立体异构体的臭氧化物12b中是11倍以上的立体异构体臭氧化物多种活性12（IC 50= 5.81 VS 65.18μ米）。目前的发现表明，臭氧化物类药物作为耐药性肝细胞癌的潜在治疗剂值得进一步研究。
更新日期：2020-03-10
中文翻译：
合成过氧化物通过抑制P-糖蛋白ABCB5促进癌细胞的凋亡。
本文揭示了过氧化物在医学化学中的应用新前景。稳定的环状过氧化物被证明对癌细胞具有细胞毒活性。另外，提出了细胞毒性作用的机制。合成桥接1,2,4,5- tetraoxanes和（对于化合物的选择性指标臭氧化物反对的HepG2肿瘤细胞和一些臭氧化物选择性地靶向肝癌细胞有效部11b和12是图8和5，分别地）。在某些情况下，四恶烷和臭氧化物比紫杉醇，青蒿素和青蒿琥酯更具选择性。Annexin V流式细胞仪分析发现活性臭氧化物22a和23a通过凋亡诱导HepG2细胞死亡。进一步的研究表明，化合物22a和23a对过表达P-糖蛋白（P-gp / ABCB5）的HepG2癌细胞具有强烈的抑制作用。ABCB5是肝癌多药耐药表型的关键因素。过氧化物未能证明氧化电位与其生物学活性之间存在直接关系。据我们所知，这是首次发现过氧化物非对映异构体对恶性疟原虫的氯喹敏感3D7菌株具有立体定向的抗疟作用。立体异构体的臭氧化物12b中是11倍以上的立体异构体臭氧化物多种活性12（IC 50= 5.81 VS 65.18μ米）。目前的发现表明，臭氧化物类药物作为耐药性肝细胞癌的潜在治疗剂值得进一步研究。
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