Background:The guanine exchange factor Epac is a cAMP sensor. Results: We have identified a tetrahydroquinoline analog named CE3F4 that blocks Epac activation in response to cAMP in vitro and in living cultured cells. Conclusion: CE3F4 behaves as an uncompetitive antagonist of Epac with respect to cAMP. Significance: CE3F4 may serve as a basis for the development of new therapeutic drugs.

Drug screening for antimalarials uses heme biocrystallization inhibition methods as an alternative to parasite cultures, but they involve complex processes and cannot detect artemisinin-like molecules. The described method detects heme-binding compounds by mass spectrometry, using dissociation of the drug-heme adducts to evaluate putative antiplasmodial activity. Applied to a chemical library, it showed a good hit-to-lead ratio and is an efficient early stage screening for complex mixtures like natural extracts.

Three new monoterpene indole alkaloids (1-3) have been isolated from the bark of Geissospermum laeve, together with the known alkaloids (-)-leuconolam (4), geissolosimine (5), and geissospermine (6). The structures of 1-3 were elucidated by analysis of their HRMS and NMR spectroscopic data. The absolute configuration of geissolaevine (1) was deduced from the comparison of experimental and theoretically calculated ECD spectra. The isolation workflow was guided by a molecular networking-based dereplication strategy using an in-house database of monoterpene indole alkaloids. In addition, five known compounds previously undescribed in the Geissospermum genus were dereplicated from the G. laeve alkaloid extract network and were assigned with various levels of identification confidence. The antiparasitic activities against Plasmodium falciparum and Leishmania donovani as well as the cytotoxic activity against the MRC-5 cell line were determined for compounds 1-5.

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Vielfältige 1,2‐Dihydroisochinolin‐Derivate 3 wurden durch die AgOTf‐katalysierte Reaktion von ortho‐Alkinylarylaldiminen 1 mit verschiedenen Pronucleophilen 2 in guten Ausbeuten erhalten (siehe Schema). Bei der Umsetzung von 1 mit einer stöchiometrischen Menge AgOTf und der Protonierung mit TfOH entstand 4. Demnach sollte die gezeigte direkte Addition über eine Isochinolinium‐Zwischenstufe verlaufen. Tf=Trifluormethansulfonyl.

BackgroundMitochondrial function is dramatically altered in heart failure (HF). This is associated with a decrease in the expression of the transcriptional coactivator PGC-1α, which plays a key role in the coordination of energy metabolism. Identification of compounds able to activate PGC-1α transcription could be of future therapeutic significance.Methodology/Principal FindingsWe thus developed a robotized cellular assay to screen molecules in order to identify new activators of PGC-1α in a cardiac-like cell line. This screening assay was based on both the assessment of activity and gene expression of a secreted luciferase under the control of the human PGC-1α promoter, stably expressed in H9c2 cells. We screened part of a library of human endogenous ligands and steroid hormones, B vitamins and fatty acids were identified as activators of PGC-1α expression. The most responsive compounds of these families were then tested for PGC-1α gene expression in adult rat cardiomyocytes. These data highly confirmed the primary screening, and the increase in PGC-1α mRNA correlated with an increase in several downstream markers of mitochondrial biogenesis. Moreover, respiration rates of H9c2 cells treated with these compounds were increased evidencing their effectiveness on mitochondrial biogenesis.Conclusions/SignificanceUsing our cellular reporter assay we could identify three original families, able to activate mitochondrial biogenesis both in cell line and adult cardiomyocytes. This first screening can be extended to chemical libraries in order to increase our knowledge on PGC-1α regulation in the heart and to identify potential therapeutic compounds able to improve mitochondrial function in HF.

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