2. Academic Validation
  3. Chemoenzymatic approach towards the synthesis of the antitumor and antileishmanial marine metabolite (+)-Harzialactone A via the stereoselective, biocatalyzed reduction of a prochiral ketone

Chemoenzymatic approach towards the synthesis of the antitumor and antileishmanial marine metabolite (+)-Harzialactone A via the stereoselective, biocatalyzed reduction of a prochiral ketone

  • Bioorg Chem. 2023 Sep:138:106675. doi: 10.1016/j.bioorg.2023.106675.
Angelica Artasensi 1,  Ivan Bassanini 2,  E E Ferrandi 3,  Lucia Feni 4,  Giulio Vistoli 5,  Laura Fumagalli 6,  Raffaella Gandolfi 7
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, Università degli Studi di Milano, 20133, Milan, Italy. Electronic address: angelica.artasensi@unimi.it.
  • 2 Istituto di Scienze e Tecnologie Chimiche ''Giulio Natta'', Consiglio Nazionale delle Ricerche, Via Mario Bianco 9, 20131, Milan, Italy. Electronic address: ivan.bassanini@scitec.cnr.it.
  • 3 Istituto di Scienze e Tecnologie Chimiche ''Giulio Natta'', Consiglio Nazionale delle Ricerche, Via Mario Bianco 9, 20131, Milan, Italy. Electronic address: erica.ferrandi@scitec.cnr.it.
  • 4 Department of Pharmaceutical Sciences, Università degli Studi di Milano, 20133, Milan, Italy. Electronic address: lucia.feni@unimi.it.
  • 5 Department of Pharmaceutical Sciences, Università degli Studi di Milano, 20133, Milan, Italy. Electronic address: giulio.vistoli@unimi.it.
  • 6 Department of Pharmaceutical Sciences, Università degli Studi di Milano, 20133, Milan, Italy. Electronic address: laura.fumagalli@unimi.it.
  • 7 Department of Pharmaceutical Sciences, Università degli Studi di Milano, 20133, Milan, Italy. Electronic address: raffaella.gandolfi@unimi.it.
PMID: 37329813 DOI: 10.1016/j.bioorg.2023.106675
Abstract

As a rich source of biological active compounds, Marine natural products have been increasingly screened as candidates for developing new drugs. Among the several marine products and metabolites, (+)-Harzialactone A has drawn considerable attention for its antitumor and antileishmanial activity. In this work a chemoenzymatic approach has been implemented for the preparation of the marine metabolite (+)-Harzialactone A. The synthesis involved a stereoselective, biocatalyzed reduction of the prochiral ketone 4-oxo-5-phenylpentanoic acid or the corresponding esters, all generated by chemical reactions. A collection of different promiscuous oxidoreductases (both wild-type and engineered) and diverse microorganism strains were investigated to mediate the bioconversions. After co-solvent and co-substrate investigation in order to enhance the bioreduction performance, T. molischiana in presence of NADES (choline hydrochloride-glucose) and ADH442 were identified as the most promising biocatalysts, allowing the obtainment of the (S)-enantiomer with excellent ee (97% to > 99% respectively) and good to excellent conversion (88% to 80% respectively). The successful attempt in this study provides a new chemoenzymatic approach for the synthesis of (+)-Harzialactone A.

Keywords

Biocatalysis; Harzialactone A; Marine metabolite; Oxidoreductases; Prochiral ketones; Stereoselective reduction; Whole cell bioreactor.

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