Novel anti-cancer agents: design, synthesis, biological activity, molecular docking, and MD simulations of 2, 3, 4, 5-tetrahydro-1H-pyrido-[4,3-b]indole derivatives

  • Yu Feng
  • Xingxing Teng
  • Jinhua Gu
  • Bangwei Yu
  • Yan Luo
  • Lianbao Ye
Original Research


In the previous research, our group designed and synthesized 2,3,4,5-tetrahydro-1H-pyrido-[4,3-b] indoles, which showed high anti-tumor activity. In this study, a series of novel 2,3,4,5-tetrahydro-1H-pyrido-[4,3-b] indole derivatives were designed by introducing an alkyl or aralkyl and a sulfonyl group, which are considered as the pharmacophores of some antitumor drugs based on the combination principles, and synthesized. The antiproliferative activity of all the target compounds were evaluated against Hela, A549, HepG2, and MCF-7 cell lines using the MTT assay in vitro. The results were represented by IC50 values. All compounds showed moderate to excellent antiproliferative activity with IC50 values between 0 μM and 100 μM against cancer cells. The proliferations of Hela, A549, HepG2, and MCF-7 cell lines were inhibited in a dose-dependent manner, and the cytolytic activity was markedly inhibited at the same time. The IC50 values of intermediate 3 inhibited against Hela, A549, HepG2, and MCF-7 cell lines were 52.75, 50.30, 60.31, and 54.39 μM, respectively, which were higher than the new compounds that we expected. The compounds 4a4d bearing sulfonyl, substituted by electron donating group, showed moderate to significant antiproliferative activity, in which compound 4c was the best with the IC50 values of 13.71, 9.42, 15.06, and 14.77 μM, and these results suggested that the introduction of sulfonyl could increase the antiproliferative activity of 2,3,4,5-tetrahydro-1H-pyrido-[4,3-b]indole. Compounds 4e4g bearing alkyl, phenyl, and arylated alkyl produced good antiproliferative activity and the IC50 value of 4g was lower than 30 μM. The target compounds were more potent against A549 compared to the other three cell lines. Molecular docking studies revealed the binding orientations of all the synthesized compounds in the active site of c-Met. Moreover, molecular dynamics simulations have been performed to evaluate the binding stabilities between the synthesized compounds and their receptors.


2,3,4,5-Tetrahydro-1H-pyrido-[4,3-b]indole derivatives Design and synthesis Biological activities Molecular docking Molecular dynamics simulations 



The work was supported by the Special Innovation Project of Guangdong Education Department (Natural Science) (2017KTSCX107), Guangdong Natural Science Foundation (2015A03031356), Science and Technology Planning Project of Guangdong Province (2017ZC0199), Guangdong Provincial Applied Scientific and Technological Project (2015B020234009), National Scientific and Technological Project of Traditional Chinese Medicine Industry (201507004), Guangdong Pharmaceutical University’ School Powered by Innovation Foundation of China (2016KZDXM039), and Guangdong special training fund for university students’ scientific and technological innovation (51328004). The authors are grateful to Mr. Tan and Sun Yet-Sen University for molecular docking experiment.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

44_2018_2271_MOESM1_ESM.docx (1.1 mb)
Supplementary Information


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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Yu Feng
    • 1
  • Xingxing Teng
    • 1
  • Jinhua Gu
    • 1
  • Bangwei Yu
    • 2
  • Yan Luo
    • 1
  • Lianbao Ye
    • 1
    • 3
  1. 1.School of PharmacyGuangdong Pharmaceutical UniversityGuangzhouChina
  2. 2.Institute of Traditional Chinese MedicineGuangdong Pharmaceutical UniversityGuangzhouChina
  3. 3.Key Laboratory of New Drug Discovery and Evaluation of Ordinary Universities of Guangdong Province, Guangzhou Key Laboratory of Construction and Application of New Drug Screening Model Systems, Guangzhou Key Laboratory of Construction and Application of New Drug Screening Model Systems and Guangdong Province Engineering Technology Center for Molecular Probes & Biomedical ImagingGuangdong Pharmaceutical UniversityGuangdongChina

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