Design, synthesis, and evaluation of a novel series of mono-indolylbenzoquinones derivatives for the potential treatment of breast cancer

  • Eur J Med Chem. 2022 Jul 5;237:114375. doi: 10.1016/j.ejmech.2022.114375.
Jingjing Jia  1 ,  Honglu Yin  1 ,  Chen Chen  1 ,  Mingli Hu  1 ,  Qiu Zhong  2 ,  Shilong Zheng  2 ,  Wei Zhang  3 ,  Haibo Li  4 ,  Liang Xu  3 ,  Guangdi Wang  5 ,  Ling He  6
Affiliations
  • 1. 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.
  • 2. Department of Chemistry and RCMI Cancer Research Center, Xavier University of Louisiana, New Orleans, LA, 70125, USA.
  • 3. State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing, 100850, China.
  • 4. Department of Microbiology and Biochemical Pharmacy, National Engineering Research Center of Immunological Products, College of Pharmacy, Third Military Medical University, Chongqing, China.
  • 5. Department of Chemistry and RCMI Cancer Research Center, Xavier University of Louisiana, New Orleans, LA, 70125, USA. Electronic address: [email protected].
  • 6. 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. Electronic address: [email protected].
PMID: 35477142 DOI: 10.1016/j.ejmech.2022.114375
Abstract

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 IC50 value of 70 nM on MDA-MB-231 cells. Moreover, its oral toxicity is extremely low with an LD50 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.

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