ABSTRACT
The structural complexity and diversity of natural products make them attractive sources for potential drug discovery, with their characteristics being derived from the multi-step combination of enzymatic and non-enzymatic conversions of intermediates in each biosynthetic pathway. Intermediates that exhibit multipotent behaviour have great potential for use as starting points in diversity-oriented synthesis. Inspired by the biosynthetic pathways that form complex metabolites from simple intermediates, we developed a semi-synthetic process that combines heterologous biosynthesis and artificial diversification. The heterologous biosynthesis of fungal polyketide intermediates led to the isolation of novel oligomers and provided evidence for ortho-quinonemethide equivalency in their isochromene form. The intrinsic reactivity of the isochromene polyketide enabled us to access various new chemical entities by modifying and remodelling the polyketide core and through coupling with indole molecules. We thus succeeded in generating exceptionally diverse pseudo-natural polyketides through this process and demonstrated an advanced method of using biosynthetic intermediates.
Subject(s)
Biological Products/chemistry , Fungi/metabolism , Polyketides/chemistry , Aspergillus oryzae/enzymology , Benzopyrans/chemistry , Biological Products/metabolism , Chaetomium/metabolism , Indolequinones/biosynthesis , Indolequinones/chemistry , Indoles/chemistry , Indoles/metabolism , Pigments, Biological/chemistry , Polyketide Synthases/genetics , Polyketide Synthases/metabolism , Polyketides/metabolismABSTRACT
Inhibition of the amyloid ß aggregation process could possibly prevent the onset of Alzheimer's disease. In this article, we report a structure-activity relationship study of curcumin analogues for anti amyloid ß aggregation activity. Compound 7, the ideal amyloid ß aggregation inhibitor in vitro among synthesized curcumin analogues, has not only potent anti amyloid ß aggregation effects, but also water solubility more than 160 times that of curcumin. In addition, new approaches to improve water solubility of curcumin-type compounds are proposed.
Subject(s)
Amyloid beta-Peptides/antagonists & inhibitors , Curcumin/chemistry , Amyloid beta-Peptides/metabolism , Curcumin/chemical synthesis , Humans , Kinetics , Molecular Conformation , Protein Binding , Quantum Theory , Solubility , Structure-Activity RelationshipABSTRACT
To research a new non-peptidyl inhibitor of beta-site amyloid precursor protein cleaving enzyme 1, we focused on the curcumin framework, two phenolic groups combined with an sp2 carbon spacer for low-molecular and high lipophilicity. The structure-activity relationship study of curcumin derivatives is described. Our results indicate that phenolic hydroxy groups and an alkenyl spacer are important structural factors for the inhibition of beta-site amyloid precursor protein cleaving enzyme 1 and, furthermore, non-competitive inhibition of enzyme activity is anticipated from an inhibitory kinetics experiment and docking simulation.
