Biocatalytic synthesis of two pharmacologically active compounds: (S)-pramipexole and its enantiomer, dexpramipexole Samuele Ciceri,a,* Patrizia Ferraboschi,a Paride Grisenti,b Matteo Moric and Fiorella Meneghettic a Department of Medical Biotechnology and Translational Medicine, University of Milan, Via C. Saldini 50, 20133 Milano, Italy b Chemical-Pharmaceutical Consulting and IP Management, Viale G. da Cermenate 58, 20141 Milano, Italy c Department of Pharmaceutical Sciences, University of Milan, Via L. Mangiagalli 25, 20133 Milano, Italy *samuele.ciceri@guest.unimi.it Many pharmaceutically active compounds contain a chiral core inside their structure. Therefore, compounds formed highly selectively are valuable products. The chemo-, regio-, and stereo-selectivity required could be achieved using biocatalysts (enzymes or microorganisms), which can work on a wide range of substrates, in mild reaction conditions and not only in aqueous solutions, but also in organic solvents. Moreover, biocatalysis meets the green chemistry principles. Our research work focuses on the biocatalytic synthesis of key building blocks affording to pharmaceutically active compounds, currently used in therapy [1, 2]. Following this approach, we were able to synthetize the enantiopure key intermediates of (S)-pramipexole, a synthetic dopaminergic agonist utilized as anti-Parkinson drug, and (R)-pramipexole, which has been studied as therapeutic agent against Amyotrophic Lateral Sclerosis (ALS) and now it has found new interest for the potential treatment of Eosinophilic Asthma and Hypereosinophilic Syndrome. Two different biocatalytic approach allowed us to stereoselectively synthesize these compounds: 1) After the investigation of the activity and selectivity of different microorganisms (especially yeasts), we obtained the enantiomerically pure synthons for the preparation of (S)- and (R)-pramipexole by means of Saccharomyces cerevisiae, the common baker’s yeast, a cheap and easy to handle microorganism. 2) The two enantiomerically pure synthons were achieved by means of a double kinetic resolution catalized by a commercially available purified enzyme, Lipase A from Candida antarctica, under irreversible transesterification conditions. The definition of the stereochemistry of the two enantiomers was also carried out by means of single crystal X-ray analysis. References [1] Ciceri, S.; Ciuffreda, P.; Grisenti, P. and Ferraboschi, P. Synthesis of the antitumoral nucleoside capecitabine through a chemo-enzymatic approach Tetrahedron Lett. 2015, 56, 5909-5913. [2] Ciceri, S.; Grisenti, P.; Reza Elahi, S. and Ferraboschi, P. A New Chemoenzymatic Synthesis of the Chiral Key Intermediate of the Antiepileptic Brivaracetam Molecules 2018, 23, 2206.

Biocatalytic synthesis of two pharmacologically active compounds: (S)-pramipexole and its enantiomer, dexpramipexole / S. Ciceri, P. Ferraboschi, P. Grisenti, M. Mori, F. Meneghetti. ((Intervento presentato al convegno Italian Young Medicinal Chemistry Virtual Meeting tenutosi a online nel 2020.

Biocatalytic synthesis of two pharmacologically active compounds: (S)-pramipexole and its enantiomer, dexpramipexole.

S. Ciceri;P. Ferraboschi
Secondo
;
M. Mori;F. Meneghetti
2020

Abstract

Biocatalytic synthesis of two pharmacologically active compounds: (S)-pramipexole and its enantiomer, dexpramipexole Samuele Ciceri,a,* Patrizia Ferraboschi,a Paride Grisenti,b Matteo Moric and Fiorella Meneghettic a Department of Medical Biotechnology and Translational Medicine, University of Milan, Via C. Saldini 50, 20133 Milano, Italy b Chemical-Pharmaceutical Consulting and IP Management, Viale G. da Cermenate 58, 20141 Milano, Italy c Department of Pharmaceutical Sciences, University of Milan, Via L. Mangiagalli 25, 20133 Milano, Italy *samuele.ciceri@guest.unimi.it Many pharmaceutically active compounds contain a chiral core inside their structure. Therefore, compounds formed highly selectively are valuable products. The chemo-, regio-, and stereo-selectivity required could be achieved using biocatalysts (enzymes or microorganisms), which can work on a wide range of substrates, in mild reaction conditions and not only in aqueous solutions, but also in organic solvents. Moreover, biocatalysis meets the green chemistry principles. Our research work focuses on the biocatalytic synthesis of key building blocks affording to pharmaceutically active compounds, currently used in therapy [1, 2]. Following this approach, we were able to synthetize the enantiopure key intermediates of (S)-pramipexole, a synthetic dopaminergic agonist utilized as anti-Parkinson drug, and (R)-pramipexole, which has been studied as therapeutic agent against Amyotrophic Lateral Sclerosis (ALS) and now it has found new interest for the potential treatment of Eosinophilic Asthma and Hypereosinophilic Syndrome. Two different biocatalytic approach allowed us to stereoselectively synthesize these compounds: 1) After the investigation of the activity and selectivity of different microorganisms (especially yeasts), we obtained the enantiomerically pure synthons for the preparation of (S)- and (R)-pramipexole by means of Saccharomyces cerevisiae, the common baker’s yeast, a cheap and easy to handle microorganism. 2) The two enantiomerically pure synthons were achieved by means of a double kinetic resolution catalized by a commercially available purified enzyme, Lipase A from Candida antarctica, under irreversible transesterification conditions. The definition of the stereochemistry of the two enantiomers was also carried out by means of single crystal X-ray analysis. References [1] Ciceri, S.; Ciuffreda, P.; Grisenti, P. and Ferraboschi, P. Synthesis of the antitumoral nucleoside capecitabine through a chemo-enzymatic approach Tetrahedron Lett. 2015, 56, 5909-5913. [2] Ciceri, S.; Grisenti, P.; Reza Elahi, S. and Ferraboschi, P. A New Chemoenzymatic Synthesis of the Chiral Key Intermediate of the Antiepileptic Brivaracetam Molecules 2018, 23, 2206.
Settore CHIM/08 - Chimica Farmaceutica
Settore BIO/10 - Biochimica
Società Chimica Italiana Divisione di Chimica Farmaceutica
European Federation for Medicinal Chemistry
https://www.i-ymc-vmeet.it/
Biocatalytic synthesis of two pharmacologically active compounds: (S)-pramipexole and its enantiomer, dexpramipexole / S. Ciceri, P. Ferraboschi, P. Grisenti, M. Mori, F. Meneghetti. ((Intervento presentato al convegno Italian Young Medicinal Chemistry Virtual Meeting tenutosi a online nel 2020.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/761930
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