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

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

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: roberto.parise@usp.br.
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.

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