2. Academic Validation
  3. Design, synthesis, and evaluation of a novel series of mono-indolylbenzoquinones derivatives for the potential treatment of breast cancer

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

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: gwang@xula.edu.
  • 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: heling2012@scu.edu.cn.
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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