Mitochondria-targeted betulinic and ursolic acid derivatives: synthesis and anticancer activity,RSC Medicinal Chemistry

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Mitochondria-targeted betulinic and ursolic acid derivatives: synthesis and anticancer activity
RSC Medicinal Chemistry ( IF 4.1 ) Pub Date : 2017-09-13 00:00:00 , DOI: 10.1039/c7md00248c
Darya A. Nedopekina _{1,

2,

3,

4} , Rinat R. Gubaidullin _{1,

2,

3,

4} , Victor N. Odinokov _{1,

2,

3,

4} , Polina V. Maximchik _{5,

6,

7,

8} , Boris Zhivotovsky _{5,

6,

7,

8,

9} , Yuriy P. Bel'skii _{4,

10,

11} , Veniamin A. Khazanov _{4,

10,

11} , Arina V. Manuylova _{4,

10,

11} , Vladimir Gogvadze _{5,

6,

7,

8,

9} , Anna Yu. Spivak _{1,

2,

3,

4}

Affiliation

A series of new betulinic and ursolic acid conjugates with a lipophilic triphenylphosphonium cation, meant to enhance the bioavailability and mitochondriotropic action of natural triterpenes, have been synthesized. The in vitro experiments on three human cancer cell lines (MCF-7, HCT-116 and TET21N) revealed that all the obtained triphenylphosphonium triterpene acid derivatives not only showed higher cytotoxicity as compared to betulinic acid but were also markedly superior in triggering mitochondria-dependent apoptosis, as assessed using a range of apoptosis markers such as cytochrome c release, stimulation of caspase-3 activity, and cleavage of poly(ADP-ribose) polymerase, which is one of the targets of caspase 3. The IC₅₀ was much lower for all triphenylphosphonium derivatives when compared to betulinic acid. Out of the tested group of conjugates, the most potent toxicity was exhibited by the betulinic acid conjugate 9 (for 9, the IC₅₀ values against MCF-7 and TET21N cells were 0.70 μM and 0.74 μM; for betulinic acid (BA), IC₅₀ > 25 μM against MCF-7 cells).

中文翻译：

线粒体靶向的桦木和熊果酸衍生物：合成和抗癌活性

已经合成了一系列具有亲脂性三苯基tri阳离子的新的桦木酸和熊果酸共轭物，意在增强天然三萜的生物利用度和线粒体作用。在体外对三种人癌细胞系的实验（MCF-7，HCT-116和TET21N）揭示相比，桦木酸，但也分别在触发显着优于线粒体依赖性所有获得的三苯基三萜酸衍生物不仅表现出较高的细胞毒性细胞凋亡，作为使用范围的细胞凋亡标记物的评估，如细胞色素c ^释放，胱天蛋白酶-3活性的刺激，和聚（ADP核糖）聚合酶，其是胱天蛋白酶的靶标之一3. IC的裂解₅₀与桦木酸相比，所有三苯基phosph衍生物的含量都低得多。在测试的结合物组中，桦木酸结合物9表现出最强的毒性（对于9，针对MCF-7和TET21N细胞的IC ₅₀值为0.70μM和0.74μM；对于桦木酸（BA），IC ₅₀ > 25μM（针对MCF-7细胞）。

更新日期：2017-10-18

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