Synthetic Analogue of the Natural Product Piperlongumine as a Potent Inhibitor of Breast Cancer Cell Line Migration

Authors:

Marilia Valli¹, Wanessa Alte², Ricardo N. dos Santos², Emilio C. de Lucca Jr.³, Marco A. Dessoy³, Renan M. Pioli¹ , Fernando Cotinguiba⁴, Xavier Cachet⁵, Sylvie Michel⁵, Maysa Furlan¹, Luiz C. Dias³, Adriano D. Andricopulo², Vanderlan S. Bolzani¹

Abstract:

Piperlongumine is a natural amide alkaloid isolated from several species of Piper and is described in the literature as selectively cytotoxic to several cancer cell lines. Inhibiting cell migration has gained considerable interest as an approach for discovering antimetastatic agents because this process is fundamental to metastasis. Piperlongumine, selected from cell-based assay screening of NuBBE Database, inhibited the migration of MDA-MB-231 breast cancer cells with an EC₅₀ of 3.0 ± 1.0 µM by the Boyden chamber assay. A series of five analogous compounds based on the structure of piperlongumine were designed, synthesized and evaluated in cell migration and cytotoxicity assays. The analogue designed by molecular simplification ((E)-N-acryloyl-3-(3,4,5-trimethoxyphenyl)acrylamide) was the most active of the series, with an EC₅₀ of 1.5 ± 1 µM. Additionally, this compound was selectively cytotoxic, with a selectivity index (SI) of 4.4.

¹Núcleo de Bioensaios, Biossíntese e Ecofisiologia de Produtos Naturais (NuBBE), Departamento de Química Orgânica, Instituto de Química, Universidade Estadual Paulista (UNESP), 14800-060 Araraquara-SP, Brazil

²Laboratório de Química Medicinal e Computacional, Centro de Pesquisa e Inovação em Biodiversidade e Fármacos, Instituto de Física de São Carlos, Universidade de São Paulo (USP), 13563-120 São Carlos-SP, Brazil

³Laboratório de Química Orgânica Sintética, Instituto de Química, Universidade Estadual de Campinas (UNICAMP), 13083-970 Campinas-SP, Brazil

⁴Instituto de Pesquisas de Produtos Naturais (IPPN), Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro (UFRJ), 21941-902 Rio de Janeiro-RJ, Brazil

⁵Laboratoire de Pharmacognosie, UMR 8638 COMETE CNRS, Faculté de Pharmacie de Paris, Université Paris Descartes, Sorbonne Paris Cité, Paris, France

Link to full article:

http://www.scielo.br/scielo.php?pid=S0103-50532017000300475&script=sci_arttext