Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, 610041, China.
Department of Chemistry and RCMI Cancer Research Center, Xavier University of Louisiana, New Orleans, LA, 70125, USA.
Eur J Med Chem. 2022 Jul 5;237:114375. doi: 10.1016/j.ejmech.2022.114375. Epub 2022 Apr 16.
Breast cancer is one of the most common cancers in the world, and pro-apototic drugs activating the apoptotic pathway are a strategy for anticancer therapy. To explore new antineoplastic agents, a series of novel mono-indolylbenzoquinone derivatives have been designed and synthesized. Compared with the lead bis-indolylbenzoquinones, most of the novel mono-indolylbenzoquinone derivatives have significantly increased their activity against A549, HeLa, and especially, MDA-MB-231 cell lines. Among them, 10d has the lowest IC value of 70 nM on MDA-MB-231 cells. Moreover, its oral toxicity is extremely low with an LD value of 374 mg/kg and no obvious liver and kidney damage to mice. 10d down-regulated Bcl-2, up-regulated Bax, and increased the release of cytochrome C, caspase3 and 9. 10d also up-regulated the expression of p53, catalase, and HTRA2/Omi. Therefore, 10d may exert its anticancer activity by activating apoptotic pathway and p53 expression. In vivo, 10d suppressed breast cancer 4T1 tumor growth with 36% inhibition ratio of tumor by intraperitoneal injection in mice. Furthermore, a cross-linked cyanoacrylate (CA)-based local sustained-release drug delivery systems (LSRDDSs) improved 10d anticancer activity to 49.8% inhibition of tumor growth. Taken together, 10d could be a promising drug candidate for clinical development to treat metastatic breast cancer.
乳腺癌是世界上最常见的癌症之一，促凋亡药物激活凋亡途径是抗癌治疗的一种策略。为了探索新的抗肿瘤药物，设计并合成了一系列新型单吲哚苯醌衍生物。与先导双吲哚苯醌相比，大多数新型单吲哚苯醌衍生物对 A549、HeLa 细胞系，特别是 MDA-MB-231 细胞系的活性显著提高。其中，10d 对 MDA-MB-231 细胞的 IC 值最低，为 70 nM。此外，其口服毒性极低，LD 值为 374 mg/kg，对小鼠无明显肝肾功能损害。10d 下调 Bcl-2，上调 Bax，并增加细胞色素 C、caspase3 和 caspase9 的释放。10d 还上调了 p53、过氧化氢酶和 HTRA2/Omi 的表达。因此，10d 可能通过激活凋亡途径和 p53 表达发挥其抗癌活性。在体内，10d 通过腹腔注射在小鼠中抑制乳腺癌 4T1 肿瘤生长，抑制率为 36%。此外，交联氰基丙烯酸酯（CA）基局部缓释药物递送系统（LSRDDS）将 10d 的抗癌活性提高至抑制肿瘤生长 49.8%。综上所述，10d 可能成为一种有前途的候选药物，用于临床开发以治疗转移性乳腺癌。
