Insights on the vasorelaxant mode of action of malbrancheamide

Abstract

Experimental evidence revealed that malbrancheamides induced both endothelium-independent and endothelium-dependent relaxant effects. According to theoretical studies, it is feasible that the endothelium-independent relaxation exerted by malbrancheamide could be mediated by its calmodulin inhibitory properties throughout an interference with myosin light chain phosphorylation and a positive modulation of eNOS.

Enzyme evolution in fungal indole alkaloid biosynthesis

“…A unique aspect of these systems is that A. protuberus and A. amoenus produce antipodal versions of these molecules. While A. protuberus produces exo-products (+)stephacidin A (10)/(-)-notoamide B (12) and endoproducts (+)-6-epi-stephacidin A (9)/(+)-versicoloamide B (8), A. amoenus produces (-)-stephacidin A (13)/(+)-notoamide B (14), where in both systems the exometabolites are favored ( Fig. 3) [49].…”

“…Racemic 6-epi-notoamide T (33/34) was converted to 6-epi-stephacidin A (9/35) and (+)-versicolamide B (8) in A. protuberus [49]. The isolation and incorporation of notoamide S (5) into notoamides C (19), D (20), (-)-stephacidin A (13), (+)-notoamide B (14), and (+)versicolamide B (8) in A. amoenus [62,65] indicated that the FMO can also accept (+)-6-epi-stephacidin A (9). The observation of an enantiomeric mixture of 6epi-stephacidin A (9/35) enriched with the (-)-isomer from A. amoenus indicated that the enzymes upstream of the FMO were not selective.…”

“…Our work has focused on the families of monoketopiperazines (MKPs) such as the paraherquamides (Phq) [2,3] and malbrancheamides (Mal) [4], and diketopiperazines (DKP) such as the stephacidins [5], notoamides (Not) [6‐8], and brevianamides (Bvn) (Figs 1–3) [9]. These molecules display significant biological activities with potential therapeutic value such as anthelmintics [10‐13], vasodilators [14], and anticancer agents [15]. All bear a similar core scaffold, but vary structurally based on key functionalities including oxidation, halogenation, and additional ring systems.…”

Halogenase engineering and its utility in medicinal chemistry

“…Many of the over 4,000 known halogenated natural products have therapeutic potential. The antitumor agent rebeccamycin, 11 antibiotic vancomycin, 12,13 and vasorelaxant malbrancheamide 14,15 are structurally complex compounds, and strategies toward their synthesis would benefit from new halogenation methods (Fig. 1).…”

Insights in Fungal Bioprospecting in Mexico

“…Furthermore, docking studies carried out with two crystallized eNOS domains, namely, oxygenase (PDB code 3NOS) and a CaM-binding peptide bound to CaM (PDB code 1NIW), predicted that the endothelium-independent relaxation exerted by 75 could be mediated by its CaM inhibitory properties throughout a positive modulation of eNOS. In addition, in a fluorescent-based experiment using the hCaM M124C-mBBr biosensor, it was demonstrated that 75 (K d = 0.55 µM) induced a perturbation of the Ca 2+ -hCaM-MLCK complex, which could also account for its vasorelaxant effect [60].…”