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  3. Natural products fragment-based design and synthesis of a novel pentacyclic ring system as potential MAPK inhibitor

Natural products fragment-based design and synthesis of a novel pentacyclic ring system as potential MAPK inhibitor

  • Bioorg Med Chem Lett. 2023 Dec 31:99:129598. doi: 10.1016/j.bmcl.2023.129598.
Bao-Long Hou 1,  Kenan Wu 1,  Rongrong Liu 2,  Jianli Liu 3,  Jinrui Wang 2,  Cuiling Wang 4,  Yanni Liang 5,  Zheng Wang 6
Affiliations

Affiliations

  • 1 Collaborative Innovation Center of Chinese Medicine Resources Industrialization, State Key Laboratory of Research & Development of Characteristic Qin Medicine Resources (Cultivation), Shaanxi Innovative Drug Research Center, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi 712046, China.
  • 2 Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, College of Life Science, Northwest University, Xi'an 710069, China.
  • 3 Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, College of Life Science, Northwest University, Xi'an 710069, China; Xi'an Peihua University, Xi'an 710125, China.
  • 4 Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, College of Life Science, Northwest University, Xi'an 710069, China. Electronic address: wangcl@nwu.edu.cn.
  • 5 Collaborative Innovation Center of Chinese Medicine Resources Industrialization, State Key Laboratory of Research & Development of Characteristic Qin Medicine Resources (Cultivation), Shaanxi Innovative Drug Research Center, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi 712046, China. Electronic address: aiziji_2005@126.com.
  • 6 Collaborative Innovation Center of Chinese Medicine Resources Industrialization, State Key Laboratory of Research & Development of Characteristic Qin Medicine Resources (Cultivation), Shaanxi Innovative Drug Research Center, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi 712046, China. Electronic address: wazh0405@126.com.
PMID: 38169246 DOI: 10.1016/j.bmcl.2023.129598
Abstract

The synthesis of compounds based on fragments derived from Natural Products (NPs) serves as a source of inspiration for the design of pseudo-natural products (PNPs), to identify bioactive molecules that exhibit similar characteristics to NPs. These novel molecular scaffolds exhibit previously unexplored biological activities as well. This study reports the development and synthesis of a novel pentacyclic ring system, the indole-pyrimidine-quinoline (IPQ) scaffold. The design of this scaffold was based on the structural characteristics of four Natural Products, namely tryptanthrin, luotonin A, rutaecarpine, and camptothecin. Several successive steps accomplished the effective synthesis of the IPQ scaffold. The constituent components of the pentacycle, containing the indole, quinazolinone, pyrimidone, and quinoline units, possess significant biological significance. Compound 1a demonstrated noteworthy anti-tumor activity efficacy against A549 cell lines among the tested compounds. The compound 1a was observed to elicit cell cycle arrest in both the G2/M and S phases, as well as trigger Apoptosis in A549 cells. These effects were attributed to its ability to modulate the activation of mitochondrial-related mitogen-activated protein kinase (MAPK) signaling pathways.

Keywords

Anti-tumor activity; Indole-pyrimidine-quinoline; MAPK signaling pathways; Natural products; Pentacyclic ring system.

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