title: Toward chelerythrine optimization: Analogues designed by molecular simplification exhibit selective growth inhibition in non-small-cell lung cancer cells.
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.
authors: 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.
authors: Rosania
authors: R
authors: Yang
authors: 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.
authors: Maurício T
authors: MT
authors: Tavares
authors: 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.
authors: Sarah F
authors: SF
authors: Teixeira
authors: 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.
authors: Ricardo A
authors: RA
authors: Azevedo
authors: 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.
authors: Diego
authors: D
authors: C Pietro
authors: 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.
authors: Thais B
authors: TB
authors: Fernandes
authors: 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.
authors: Adilson K
authors: AK
authors: Ferreira
authors: 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.
authors: Gustavo H G
authors: GHG
authors: Trossini
authors: 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.
authors: José A M
authors: JAM
authors: Barbuto
authors: 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.
authors: Roberto
authors: R
authors: Parise-Filho
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053119:Benzophenanthridines / Q000737:chemistry* / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008958:Models, Molecular; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D053119:Benzophenanthridines; C016299:chelerythrine
keywords: Chelerythrine; Chelerythrine analogues; Molecular simplification; NSCLC