title: A new goniothalamin N-acylated aza-derivative strongly downregulates mediators of signaling transduction associated with pancreatic cancer aggressiveness.
abstract: In this study, a novel concise series of molecules based on the structure of goniothalamin (1) was synthesized and evaluated against a highly metastatic human pancreatic cancer cell line (Panc-1). Among them, derivative 8 displayed a low IC50 value (2.7 μM) and its concentration for decreasing colony formation was 20-fold lower than goniothalamin (1). Both compounds reduced the levels of the receptor tyrosine kinase (AXL) and cyclin D1 which are known to be overexpressed in pancreatic cancer cells. Importantly, despite the fact that goniothalamin (1) and derivative 8 caused pancreatic cancer cell cycle arrest and cell death, only derivative 8 was able to downregulate pro-survival and proliferation pathways mediated by mitogen activated protein kinase ERK1/2. Another interesting finding was that Panc-1 cells treated with derivative 8 displayed a strong decrease in the transcription factor (c-Myc), hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) protein levels. Notably, the molecular effects caused by derivative 8 might not be related to ROS generation, since no significant production of ROS was observed in low concentrations of this compound (from 1.5 up to 3 μM). Therefore, the downregulation of important mediators of pancreatic cancer aggressiveness by derivative 8 reveals its great potential for the development of new chemotherapeutic agents for pancreatic cancer treatment.
authors.affiliation: Department of Organic Chemistry, Chemistry Institute, University of Campinas, CP 6154, 13083-970, Campinas, SP, Brazil.
authors.forename: Rosimeire Coura
authors.initials: RC
authors.lastname: Barcelos
authors.affiliation: Department of Biochemistry, Biology Institute, University of Campinas, 13083-862, Campinas, São Paulo, Brazil.
authors.forename: Karin Juliane
authors.initials: KJ
authors.lastname: Pelizzaro-Rocha
authors.affiliation: Department of Organic Chemistry, Chemistry Institute, University of Campinas, CP 6154, 13083-970, Campinas, SP, Brazil.
authors.forename: Julio Cezar
authors.initials: JC
authors.lastname: Pastre
authors.affiliation: Department of Biochemistry, Biology Institute, University of Campinas, 13083-862, Campinas, São Paulo, Brazil.
authors.forename: Marina Pereira
authors.initials: MP
authors.lastname: Dias
authors.affiliation: Department of Biochemistry, Biology Institute, University of Campinas, 13083-862, Campinas, São Paulo, Brazil.
authors.forename: Carmen Veríssima
authors.initials: CV
authors.lastname: Ferreira-Halder
authors.affiliation: Department of Organic Chemistry, Chemistry Institute, University of Campinas, CP 6154, 13083-970, Campinas, SP, Brazil. Electronic address: pilli@iqm.unicamp.br.
authors.forename: Ronaldo Aloise
authors.initials: RA
authors.lastname: Pilli
mesh_terms: D000215:Acylation; D000818:Animals; D001372:Aza Compounds / Q000737:chemistry*; D002460:Cell Line; D015536:Down-Regulation / Q000187:drug effects*; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D011753:Pyrones / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D001372:Aza Compounds; D011753:Pyrones; C103280:goniothalamin
keywords: AXL kinase; Goniothalamin; HIF-1α; N-acylated aza-derivatives; Panc-1 cells; Pancreatic cancer