A new goniothalamin N-acylated aza-derivative strongly downregulates mediators of signaling transduction associated with pancreatic cancer aggressiveness

• Published in: European journal of medicinal chemistry Vol. 87; pp. 745 - 758
• Main Authors: Barcelos, Rosimeire Coura, Pelizzaro-Rocha, Karin Juliane, Pastre, Julio Cezar, Dias, Marina Pereira, Ferreira-Halder, Carmen Veríssima, Pilli, Ronaldo Aloise
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 24.11.2014; Elsevier
• Subjects: Acylation; Animals; AXL kinase; Aza Compounds - chemistry; Cell Line; Chemistry, Medicinal; Down-Regulation - drug effects; Goniothalamin; HIF-1α; Life Sciences & Biomedicine; N-acylated aza-derivatives; Panc-1 cells; Pancreatic cancer; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Pharmacology & Pharmacy; Pyrones - chemistry; Pyrones - pharmacology; Science & Technology; Signal Transduction - drug effects; HIF-1α; MTT; Panc-1 cells; BCL-2; DMEM; FSB; GSH; Goniothalamin; BCL-xl; VEGF; STAT3; PARP-1; AXL kinase; RB; Mcl-1; ERK1/2; CDK6; AXL; CDK4; PMSF; Pancreatic cancer; ROS; N-acylated aza-derivatives; BAX; IAP; GAS6; GAPDH; HF; INDUCED CELL-DEATH; APOPTOSIS; STYRYL-LACTONE GONIOTHALAMIN; HIF-1 alpha; INDUCIBLE FACTOR-I; C-MYC; HYPOXIA; CYTOTOXIC ACTIVITY; HALOENOL LACTONE; SESQUITERPENE LACTONES; IN-VITRO EVALUATION
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2014.09.085

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. [Display omitted] •N-acylated aza-goniothalamin derivatives are more potent than goniothalamin against Panc-1 cells.•Derivative 8 acts in concentrations 20-fold lower than goniothalamin.•Derivative 8 downregulates pro-survival and proliferation pathways mediated by ERK1/2.•Derivative 8 downregulates mediators of pancreatic cancer aggressiveness, such as AXL, HIF-1α and VEGF.•N-acylated aza-goniothalamin derivatives can be considered for pancreatic cancer treatment.