Semisynthetic Esters of 17-Hydroxycativic Acid with in Vitro Cytotoxic Activity against Leukemia Cell Lines.

A collection of sixteen semisynthetic 17-hydroxycativic acid esters with alcohols containing a tertiary amine group was evaluated for their in vitro cytotoxicity against two human cancer cell lines, THP-1 and U937, and for their effects on the cell cycle and cell death. While 17-hydroxycativic acid itself is not cytotoxic, all the esters displayed cytotoxic activity, with 50% growth inhibition (GI50) values ranging between 3.2 and 23.1 µM. In general, the most potent compounds in both cell lines were esters with four carbon long alcohol residues. There was no clear relationship between the identity of the terminal secondary amine and the activity of the compound. Experiments using the 6-(pyrrolidin-1-yl)pentyl ester, 2c, revealed that this compound activates caspases-3/7 and causes poly(ADP-ribose)polymerase 1 (PARP-1) fragmentation in THP-1 and U937 cells, indicating the induction of apoptotic cell death. These results suggest that further investigation into the anticancer activity of diterpene derivatives and other labdane diterpenes may be fruitful.

Phosphoinositides: Two-Path Signaling in Neuronal Response to Oligomeric Amyloid ß Peptide.

We have previously demonstrated that oligomeric amyloid ß peptide (oAß) together with iron overload generates synaptic injury and activation of several signaling cascades. In this work, we characterized hippocampal neuronal response to oAß. HT22 neurons exposed to 500 nM oAß showed neither increased lipid peroxidation nor altered mitochondrial function. In addition, biophysical studies showed that oAß did not perturb the lipid order of the membrane. Interestingly, although no neuronal damage could be demonstrated, oAß was found to trigger bifurcated phosphoinositide-dependent signaling in the neuron, on one hand, the phosphorylation of insulin receptor, the phosphatidylinositol 3-kinase (PI3K)-dependent activation of Akt, its translocation to the nucleus and the concomitant phosphorylation, inactivation, and nuclear exclusion of the transcription factor Forkhead Box O3a (FoxO3a), and on the other, phosphoinositide-phospholipase C (PI-PLC)-dependent extracellular signal-regulated kinase 1/2 (ERK1/2) activation. Pharmacological manipulation of the signaling cascades was used in order to better characterize the role of oAß-activated signals, and mitochondrial function was determined as a measure of neuronal viability. The inhibition of PI3K, PI-PLC, and general phosphoinositide metabolism impaired neuronal mitochondrial function. Furthermore, increased oAß-induced cell death was observed in the presence of phosphoinositide metabolism inhibition. Our results allow us to conclude that oAß triggers the activation of phosphoinositide-dependent signaling, which results in the subsequent activation of neuroprotective mechanisms that could be involved in the determination of neuronal fate.

Natural AChE Inhibitors from Plants and their Contribution to Alzheimer's Disease Therapy.

As acetylcholinesterase (AChE) inhibitors are an important therapeutic strategy in Alzheimer's disease, efforts are being made in search of new molecules with anti-AChE activity. The fact that naturally-occurring compounds from plants are considered to be a potential source of new inhibitors has led to the discovery of an important number of secondary metabolites and plant extracts with the ability of inhibiting the enzyme AChE, which, according to the cholinergic hypothesis, increases the levels of the neurotransmitter acetylcholine in the brain, thus improving cholinergic functions in patients with Alzheimer's disease and alleviating the symptoms of this neurological disorder. This review summarizes a total of 128 studies which correspond to the most relevant research work published during 2006-2012 (1st semester) on plant-derived compounds, plant extracts and essential oils found to elicit AChE inhibition.