BODIPY-Based Analogue of the TREM2-Binding Molecular Adjuvant Sulfavant A, a Chemical Tool for Imaging and Tracking Biological Systems.

Recently, we described synthetic sulfolipids named Sulfavants as a novel class of molecular adjuvants based on the sulfoquinovosyl-diacylglycerol skeleton. The members of this family, Sulfavant A (1), Sulfavant R (2), and Sulfavant S (3), showed important effects on triggering receptor expressed on myeloid cells 2 (TREM2)-induced differentiation and maturation of human dendritic cells (hDC), through a novel cell mechanism underlying the regulation of the immune response. As these molecules are involved in biological TREM2-mediated processes crucial for cell survival, here, we report the synthesis and application of a fluorescent analogue of Sulfavant A bearing the 4,4-difluoro-1,3,5,7-tetramethyl-4-bora-3a,4a-diaza-s-indacene moiety (Me4-BODIPY). The fluorescent derivative, named PB-SULF A (4), preserving the biological activity of Sulfavants, opens the way to chemical biology and cell biology experiments to better understand the interactions with cellular and in vivo organ targets and to improve our comprehension of complex molecular mechanisms underlying the not fully understood ligand-induced TREM2 activity.

Butanolides and Butenolides from a Marine-Derived Streptomyces sp. Exert Neuroprotective Activity through Activation of the TrkB Neurotrophin Receptor.

Neurodegenerative diseases are incurable and debilitating conditions, characterized by progressive loss and degeneration of vulnerable neuronal populations. Currently, there are no effective therapies available for the treatment of most neurodegenerative disorders. A panel of extracts exhibiting interesting chemical profiles among a high number of bacterial strains isolated from East Mediterranean marine sediments and macroorganisms were evaluated for their activity on TrkB-expressing cells. Among them, the actinobacterial strain Streptomyces sp. BI0788, exhibiting neuroprotective activity in vitro, was selected and cultivated in large-scale. The chemical analysis of its organic extract resulted in the isolation of four new butanolides (1, 4-6), along with two previously reported butanolides (2 and 3) and eight previously reported butenolides (7-14). Compounds 2-4 and 7-14 were evaluated for their neuroprotective effects on TrkB-expressing NIH-3T3 cells. Among them, metabolites 3, 4, 7, 10, 11, 13 and 14 exhibited significant protective activity on the aforementioned cells through the activation of TrkB, the high-affinity receptor for the Brain-Derived Neurotrophic Factor (BDNF), which is well known to play a crucial role in neuronal cell survival and maintenance.