Toward chelerythrine optimization: Analogues designed by molecular simplification exhibit selective growth inhibition in non-small-cell lung cancer cells

  • Bioorg Med Chem. 2016 Oct 1;24(19):4600-4610. doi: 10.1016/j.bmc.2016.07.065.
Rosania Yang  1 ,  Maurício T Tavares  1 ,  Sarah F Teixeira  2 ,  Ricardo A Azevedo  2 ,  Diego C Pietro  1 ,  Thais B Fernandes  1 ,  Adilson K Ferreira  2 ,  Gustavo H G Trossini  3 ,  José A M Barbuto  4 ,  Roberto Parise-Filho  5
Affiliations
  • 1. Laboratory of Design and Synthesis of Bioactive Substances (LAPESSB), Department of Pharmacy, Faculty of Pharmaceutical Science, University of São Paulo, Av. Prof. Lineu Prestes, 580, São Paulo, SP 5508-000, Brazil.
  • 2. Laboratory of Tumor Immunology, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes, 1730, São Paulo, SP 05508-900, Brazil.
  • 3. Laboratory of Experimental and Computational Integrated Techniques (LITEC), Department of Pharmacy, Faculty of Pharmaceutical Science, University of São Paulo, Av. Prof. Lineu Prestes, 580, São Paulo, SP 5508-000, Brazil.
  • 4. Laboratory of Tumor Immunology, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes, 1730, São Paulo, SP 05508-900, Brazil; Cell and Molecular Therapy Center NUCEL/NETCEM, Faculty of Medicine, University of São Paulo, Rua Pangaré, São Paulo, SP 05360-120, Brazil.
  • 5. Laboratory of Design and Synthesis of Bioactive Substances (LAPESSB), Department of Pharmacy, Faculty of Pharmaceutical Science, University of São Paulo, Av. Prof. Lineu Prestes, 580, São Paulo, SP 5508-000, Brazil. Electronic address: [email protected].
PMID: 27561984 DOI: 10.1016/j.bmc.2016.07.065
Abstract

A series of novel chelerythrine analogues was designed and synthesized. Antitumor activity was evaluated against A549, NCI-H1299, NCI-H292, and NCI-H460 non-small-cell lung Cancer (NSCLC) cell lines in vitro. The selectivity of the most active analogues and chelerythrine was also evaluated, and we compared their cytotoxicity in NSCLC cells and non-tumorigenic cell lines, including human umbilical vein endothelial cells (HUVECs) and LL24 human lung fibroblasts. In silico studies were performed to establish structure-activity relationships between chelerythrine and the analogues. The results showed that analogue compound 3f induced significant dose-dependent G0/G1 cell cycle arrest in A549 and NCI-H1299 cells. Theoretical studies indicated that the molecular arrangement and electron characteristics of compound 3f were closely related to the profile of chelerythrine, supporting its activity. The present study presents a new and simplified chelerythrinoid scaffold with enhanced selectivity against NSCLC tumor cells for further optimization.

Keywords
Chelerythrine; Chelerythrine analogues; Molecular simplification; NSCLC.