Tsepaeva Olga V, Nemtarev Andrey V, Pashirova Tatiana N, Khokhlachev Michail V, Lyubina Anna P, Amerkhanova Syumbelya K, Voloshina Alexandra D, Mironov Vladimir F
Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of RAS Arbuzov Str. 8 420088 Kazan Russian Federation
Kazan (Volga Region) Federal University Kremlevskaya Str. 18 420008 Kazan Russian Federation.
RSC Med Chem. 2023 Jan 11;14(3):454-469. doi: 10.1039/d2md00363e. eCollection 2023 Mar 22.
This work deals with the creation of new cationic triphenylphosphonium amphiphilic conjugates of glycerolipid type (TPP-conjugates), bearing a pharmacophore terpenoid fragment (abietic acid and betulin) and a fatty acid residue in one hybrid molecule as a new generation of antitumor agents with high activity and selectivity. The TPP-conjugates showed high mitochondriotropy leading to the development of mitochondriotropic delivery systems such as TPP-pharmacosomes and TPP-solid lipid particles. Introducing the betulin fragment into the structure of a TPP-conjugate (compound 10) increases the cytotoxicity 3 times towards tumor cells of prostate adenocarcinoma DU-145 and 4 times towards breast carcinoma MCF-7 compared to TPP-conjugate 4a in the absence of betulin. TPP-hybrid conjugate 10 with two pharmacophore fragments, betulin and oleic acid, has significant cytotoxicity toward a wide range of tumor cells. The lowest IC of 10 is 0.3 μM toward HuTu-80. This is at the level of the reference drug doxorubicin. TPP-pharmacosomes (10/PC) increased the cytotoxic effect approximately 3 times toward HuTu-80 cells, providing high selectivity (SI = 480) compared to the normal liver cell line Chang liver.
这项工作致力于合成新型甘油脂质型阳离子三苯基鏻两亲性共轭物（TPP共轭物），在一个杂合分子中带有药效基团萜类片段（枞酸和桦木醇）和脂肪酸残基，作为新一代具有高活性和选择性的抗肿瘤药物。TPP共轭物表现出高线粒体靶向性，从而促使了线粒体靶向递送系统的发展，如TPP药物体和TPP固体脂质颗粒。与不含桦木醇的TPP共轭物4a相比，将桦木醇片段引入TPP共轭物（化合物10）的结构中，对前列腺腺癌DU - 145肿瘤细胞的细胞毒性增加了3倍，对乳腺癌MCF - 7细胞的细胞毒性增加了4倍。具有桦木醇和油酸两个药效基团片段的TPP杂合共轭物10对多种肿瘤细胞具有显著的细胞毒性。10对HuTu - 80的最低半数抑制浓度（IC）为0.3 μM。这与参考药物阿霉素处于同一水平。TPP药物体（10/PC）对HuTu - 80细胞的细胞毒性作用提高了约3倍，与正常肝细胞系Chang liver相比具有高选择性（选择性指数SI = 480）。
