Piperazine-derived diazabicycles are privileged structures found in natural products and synthetic chemical entities, including therapeutic agents. Herein, we deciphered the biosynthesis of two unique classes of diazabicyclic alkaloids, fischerazines A-C. Notably, we characterized a multifunctional P450 monooxygenase NfiC that installs -dihydroxyl groups on the dibenzyl-piperazines, in turn triggering a range of NfiC-catalyzed and spontaneous cyclization events.
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Biosynthesis of Piperazine-Derived Diazabicyclic Alkaloids Involves a Nonribosomal Peptide Synthetase and Subsequent Tailoring by a Multifunctional Cytochrome P450 Enzyme.
Org Lett
June 2022
Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan R.O.C.
Piperazine-derived diazabicycles are privileged structures found in natural products and synthetic chemical entities, including therapeutic agents. Herein, we deciphered the biosynthesis of two unique classes of diazabicyclic alkaloids, fischerazines A-C. Notably, we characterized a multifunctional P450 monooxygenase NfiC that installs -dihydroxyl groups on the dibenzyl-piperazines, in turn triggering a range of NfiC-catalyzed and spontaneous cyclization events.
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J Org Chem
December 2017
Department of Chemistry, The College of William & Mary, P.O. Box 8795, Williamsburg, Virginia 23187, United States.
The convergent synthesis of bicyclo[2.2.2]diazaoctane structures using an intermolecular Diels-Alder cycloaddition between a pyrazinone and commercially available fumarate or maleate precursors is reported.
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Department of Chemistry, The College of William & Mary, P.O. Box 8795, Williamsburg, Virginia 23187, United States.
A stereoselective intermolecular Diels-Alder cycloaddition of an intermediate pyrazinone with both achiral and chiral acrylate-derived dienophiles provides rapid access to the bicyclo[2.2.2]diazaoctane core shared among several prenylated indole alkaloids.
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Eur J Med Chem
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Department of Neuroscience, Psychology, Drug Research and Child's Health, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy.
As a continuation of previous work on quinoline derivatives, which showed some preference (2-3 times) for the α7 with respect to α4β2 acetylcholine nicotinic receptors (nAChRs), we synthesized a series of novel azabicyclic or diazabicyclic compounds carrying a quinoline or isoquinoline ring, with the aim of searching for more selective α7 nAChR compounds. Radioligand binding studies on α7* and α4β2* nAChRs (rat brain homogenate) revealed one compound (7) with a 2-fold higher affinity for the α4β2*-subtype, and four compounds (11, 13, 14 and 16) with at least 3-fold higher affinity for α7* nAChR. The most promising was 11, showing Ki∼100 nM and over 10-fold selectivity for α7* nAChR.
View Article and Find Full Text PDFEnantioselective synthesis of (+)-malbrancheamide B.
J Org Chem
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Department of Chemistry, The College of William & Mary, P.O. Box 8795, Williamsburg, Virginia 23187, United States.
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