State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou, Gansu 730000, China.
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou, Gansu 730000, China.
Free Radic Biol Med. 2019 Apr;134:406-418. doi: 10.1016/j.freeradbiomed.2019.01.033. Epub 2019 Jan 29.
Developing concise theranostic prodrugs is highly desirable for personalized and precision cancer therapy. Herein we used the glutathione (GSH)-mediated conversion of 2,4-dinitrobenzenesulfonates to phenols to protect a catechol moiety and developed stable pro-catechol-type diphenylpolyenes as small molecule-based prooxidative anticancer theranostic prodrugs. These molecules were synthesized via a modular route allowing creation of various pro-catechol-type diphenylpolyenes. As a typical representative, PDHH demonstrated three unique advantages: (1) capable of exploiting increased levels of GSH in cancer cells to in situ release a catechol moiety followed by its in situ oxidation to o-quinone, leading to preferential redox imbalance (including generation of HO and depletion of GSH) and final selective killing of cancer cells over normal cells, and is also superior to 5-fluorouracil and doxorubicin, the widely used chemotherapy drugs, in terms of its ability to kill preferentially human colon cancer SW620 cells (IC = 4.3 μM) over human normal liver L02 cells (IC = 42.3 μM) with a favourable in vitro selectivity index of 9.8; (2) permitting a turn-on fluorescent monitoring for its release, targeting mitochondria and therapeutic efficacy without the need of introducing additional fluorophores after its activation by GSH in cancer cells; (3) efficiently targeting mitochondria without the need of introducing additional mitochondria-directed groups.
开发简洁的治疗药物前体是实现个性化和精准癌症治疗的迫切需求。在此，我们利用谷胱甘肽（GSH）介导的 2,4-二硝基苯磺酸盐转化为酚类来保护儿茶酚部分，并开发了稳定的邻苯二酚型二苯基多烯作为基于小分子的促氧化抗癌治疗药物前体。这些分子通过模块化途径合成，允许创建各种邻苯二酚型二苯基多烯。以 PDHH 为例，它具有三个独特的优势：（1）能够利用癌细胞中增加的 GSH 水平原位释放儿茶酚部分，随后原位氧化为邻醌，导致优先的氧化还原失衡（包括产生 HO 和耗尽 GSH），最终选择性杀死癌细胞而不杀死正常细胞，并且在杀死优先人类结肠癌 SW620 细胞（IC=4.3 μM）方面优于广泛使用的化疗药物 5-氟尿嘧啶和阿霉素，对人正常肝 L02 细胞（IC=42.3 μM）的选择性指数为 9.8；（2）允许通过 GSH 在癌细胞中的激活来进行荧光监测，靶向线粒体和治疗效果，而无需在其激活后引入额外的荧光团；（3）无需引入额外的线粒体靶向基团即可有效地靶向线粒体。
