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

Rosania Yang; Maurício T Tavares; Sarah F Teixeira; Ricardo A Azevedo; Diego C Pietro; Thais B Fernandes; Adilson K Ferreira; Gustavo H G Trossini; José A M Barbuto; Roberto Parise-Filho

doi:10.1016/j.bmc.2016.07.065

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. Epub 2016 Jul 30.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemistry*
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Benzophenanthridines / chemistry*
Benzophenanthridines / pharmacology*
Carcinoma, Non-Small-Cell Lung / drug therapy*
Carcinoma, Non-Small-Cell Lung / pathology
Cell Line, Tumor
Cell Proliferation / drug effects
G1 Phase Cell Cycle Checkpoints / drug effects
Human Umbilical Vein Endothelial Cells
Humans
Lung / drug effects
Lung / pathology
Lung Neoplasms / drug therapy*
Lung Neoplasms / pathology
Models, Molecular
Structure-Activity Relationship

Substances

Antineoplastic Agents
Benzophenanthridines
chelerythrine