Short synthesis of skeletally and stereochemically diverse small molecules by coupling petasis condensation reactions to cyclization reactions.

Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138, USA.
Angewandte Chemie International Edition (Impact Factor: 13.73). 06/2006; 45(22):3635-8. DOI:10.1002/anie.200600497
Source: PubMed
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    ABSTRACT: The Petasis reaction is the multi-component reaction of a carbonyl compound, amine, and arylboronic acid to form an α-amino acid or a β-aminoalcohol. In this work, as the first analytical application of the Petasis reaction, a high-performance liquid chromatographic (HPLC) method with fluorescence detection was developed for determination of glyoxylic acid. The glyoxylic acid was derivatized with 1-pyreneboronic acid, as fluorescent arylboronic acid, in the presence of N-methylbutylamine, as amine, to give a fluorescent α-amino acid. HPLC separation of the fluorescent derivative was performed within 30 min on an octyl column eluted with a gradient prepared from acetonitrile and 50 mmol L(-1) acetate buffer (pH 4.0). The detection limit (S/N=3) for glyoxylic acid was 5.0 nmol L(-1) (20 fmol/injection). The method can be used to determine the concentration of glyoxylic acid in human urine without interference from biological components.
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    ABSTRACT: Efforts to discover new drugs for Alzheimer's disease emphasizing multiple targets was conducted seeking to inhibit amyloid oligomer formation and to prevent radical formation. The tryptoline and tryptamine cores of BACE1 inhibitors previously identified by virtual screening were modified in silico for additional modes of action. These core structures were readily linked to different side chains using 1,2,3-triazole rings as bridges by copper catalyzed azide-alkyne cycloaddition reactions. Three compounds among the sixteen designed compounds exerted multifunctional activities including β-secretase inhibitory action, anti-amyloid aggregation, metal chelating and antioxidant effects at micromolar levels. The neuroprotective effects of the multifunctional compounds 6h, 12c and 12h on Aβ₁₋₄₂ induced neuronal cell death at 1 μM were significantly greater than those of the potent single target compound, BACE1 inhibitor IV and were comparable to curcumin. The observed synergistic effect resulting from the reduction of the Aβ₁₋₄₂ neurotoxicity cascade substantiates the validity of our multifunctional strategy in drug discovery for Alzheimer's disease.
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    ABSTRACT: By emulating the universal biosynthetic strategy, which employs modular assembly and divergent cyclizations, we have developed a four-step synthetic process to yield a collection of natural-product-inspired scaffolds. Modular assembly of building blocks onto a piperidine-based manifold 6, having a carboxylic acid group, was achieved through Ugi condensation, N-acetoacetylation and diazotransfer, leading to cyclization precursors. The rhodium-catalyzed tandem cyclization and divergent cycloaddition gave rise to tetracyclic and hexacyclic scaffolds by the appropriate choice of dipolarophiles installed at modules 3 and 4. A different piperidine-based manifold 15 bearing an amino group was successfully applied to demonstrate the flexibility and scope of the unified four-step process for the generation of structural diversity in the fused scaffolds. Evaluation of in vitro antitrypanosomal activities of the collections and preliminary structure-activity relationship (SAR) studies were also undertaken.
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Naoya Kumagai