No abstract

Flurbiprofen, a nonsteroidal antiinflammatory drug (NSAID), has been recently described to selectively inhibit beta-amyloid(1)(-)(42) (Abeta42) secretion, the most toxic component of the senile plaques present in the brain of Alzheimer patients. The use of this NSAID in Alzheimer's disease (AD) is hampered by a significant gastrointestinal toxicity associated with cyclooxygenase (COX) inhibition. New flurbiprofen analogues were synthesized, with the aim of increasing Abeta42 inhibitory potency while removing anti-COX activity. In vitro ADME developability parameters were taken into account in order to identify optimized compounds at an early stage of the project. Appropriate substitution patterns at the alpha position of flurbiprofen allowed for the complete removal of anti-COX activity, while modifications at the terminal phenyl ring resulted in increased inhibitory potency on Abeta42 secretion. In rats, some of the compounds appeared to be well absorbed after oral administration and to penetrate into the central nervous system. Studies in a transgenic mice model of AD showed that selected compounds significantly decreased plasma Abeta42 concentrations. These new flurbiprofen analogues represent potential drug candidates to be developed for the treatment of AD.

We describe 1,3,4-oxadiazole-containing hydroxamates (2) and 2-aminoanilides (3) as histone deacetylase inhibitors. Among them, 2t, 2x, and 3i were the most potent and selective against HDAC1. In U937 leukemia cells, 2t was more potent than SAHA in inducing apoptosis, and 3i displayed cell differentiation with a potency similar to MS-275. In several acute myeloid leukemia (AML) cell lines, as well as in U937 cells in combination with doxorubicin, 3i showed higher antiproliferative effects than SAHA.

The Chlorophyte Parietochloris incisa comb. nov (Trebuxiophyceae) was found to be the richest plant source of the pharmaceutically valuable long‐chain polyunsaturated fatty acid (PUFA), arachidonic acid (20:4ω6, AA). Over 90% of total AA are deposited in triacylglycerols (TAG). Under nitrogen starvation, the fatty acid content constituted over 35% of dry weight and the proportion of AA exceeded 60% of total fatty acids. Consequently, we obtained an AA content of over 20%. This is, to the best of our knowledge, the highest reported content of any PUFA in algae. Increasing the biomass concentration resulted in an enhancement of both the proportion of AA and the fatty acid content. We hypothesize that one of the roles of TAG in P. incisa is to serve as a reservoir of AA that can be used for the construction of membranal lipids.