Acaricidal activity of synthetic spilanthol derivative against ticks of medical and veterinary importance.

The ANESPSAT, a synthetic spilanthol derivative, and its nanoformulation were evaluated against Rhipicephalus microplus and Amblyomma sculptum ticks. ANESPSAT activity was compared with spilanthol and derivatives (ANESPE and others). The compound was synthesized in a gram-scale by a 2-step process, comprising a direct ester amidation and a Horner-Wadsworth- Emmons reaction. The nanoemulsions were produced by coarse homogenization followed by high-energy ultrasonication, in which hydrodynamic diameter, polydispersity index, and zeta potential remained stable. The spilanthol-eugenol hybrid derivatives did not show significant acaricidal activity. ANESPE killed 83% of the R. microplus larvae at 30 mg.mL-1, while ANESPSAT killed 97% at 0.5 mg.mL-1, showing to be the most active compound. Spilanthol and ANESPSAT had similar high mortality rates for tick larvae, with LC50 values of 0.10 and 0.14 mg.mL-1 for R. microplus larvae, and 0.04 and 0.48 mg.mL-1 for A. sculptum larvae, respectively. The efficacy of spilanthol was lower against R. microplus engorged females when compared with ANESPSAT, which was highly effective (>98%) against R. microplus engorged females. The nanoemulsion with ANESPSAT was effective against tick females, preventing egg laying and achieving 100% efficacy at 2.5 mg.mL-1. Spilanthol had only 59% efficacy at 10 mg.mL-1. The results suggest that ANESPSAT, a natural product derivative, could be used in novel formulations for tick management that might be safer and environmentally friendly.

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

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.

Synthesis of methoxylated goniothalamin, aza-goniothalamin and γ-pyrones and their in vitro evaluation against human cancer cells.

The present work describes the preparation of three novel series of compounds based on the structure of goniothalamin, a natural styryl lactone which has been found to display cytotoxic and antiproliferative activities against a variety of cancer cell lines. A focused library of 29 novel goniothalamin analogues was prepared and evaluated against seven human cancer cell lines. While the γ-pyrones and the aza-goniothalamin analogues were less potent than the lead compound, 2,4-dimethoxy analogue 88 has shown to be more potent in vitro than goniothalamin against all cancer cell lines evaluated. Furthermore, it was more potent than doxorubicin against NCI-ADR/RES, OVCAR-03 and HT-29 while being less toxic to human keratinocytes (HaCat). The 3,5-dimethoxy analogue 90 and 2,4,5-trimethoxy analogue 92 also displayed promising antiproliferative activity when compared to goniothalamin (1). These results provide new elements for the design and synthesis of novel representatives of this family of natural compounds.

Efficient Heck arylations of cyclic and acyclic acrylate derivatives using arenediazonium tetrafluoroborates. A new synthesis of the antidepressant drug (+/-)-paroxetine.

[reaction: see text] The Heck arylation of acyclic- and cyclic-substituted acrylates using several arenediazonium tetrafluoroborates was investigated. Arylations were carried out under aerobic, ligand-free conditions to provide the corresponding substituted acrylates in moderate to high isolated yields. Heck arylations were usually completed in less than 2 h in refluxing methanol. The aza-endocyclic acrylate derivative 11a was converted into the antidepressant drug (+/-)-paroxetine in a concise new route in good overall yield.