Human Dihydroorotate Dehydrogenase (hDHODH), a mitochondrial enzyme that plays a pivotal role in the de novo pyrimidine biosynthesis, has been associated to Acute Myelogenous Leukemia (AML), as hDHODH inhibitors are able to restore myeloid differentiation (1). In recent years, we designed potent hDHODH inhibitors applying a scaffold-hopping approach to brequinar’s structure (2). By investigating the lead compound’s SAR, we recently discovered compound 1 (Figure), a candidate superior to brequinar in terms of in vitro potency. Unfortunately, compound 1 showed in vitro metabolic instability, as it soon undergoes to hydroxylation on alkoxy side chain by microsomal enzymes (3). In this occasion, we investigated on the metabolic hydroxylation site through the synthesis of the possible products of microsomal metabolism according to literature (4) and their comparison to compound 1’ s own metabolite in high resolution mass spectrometry (HR-MS); then we designed a new generation of hDHODH inhibitors protected from metabolic oxidation on the alkoxy side chain. Design, synthesis, in vitrometabolism and biological characterization of the new developed compounds are here described and discussed

Targeting myeloid leukemias using human Dihydroorotate Dehydrogenase inhibitors based on 2-hydroxypyrazolo[1,5-a]pyridine scaffold: overcoming of metabolic issues

Chiara Vigato;Stefano Sainas;Marta Giorgis;Paola Circosta;Agnese Chiara Pippione;Giuseppe Saglio;Donatella Boschi;Marco Lucio Lolli.
2021

Abstract

Human Dihydroorotate Dehydrogenase (hDHODH), a mitochondrial enzyme that plays a pivotal role in the de novo pyrimidine biosynthesis, has been associated to Acute Myelogenous Leukemia (AML), as hDHODH inhibitors are able to restore myeloid differentiation (1). In recent years, we designed potent hDHODH inhibitors applying a scaffold-hopping approach to brequinar’s structure (2). By investigating the lead compound’s SAR, we recently discovered compound 1 (Figure), a candidate superior to brequinar in terms of in vitro potency. Unfortunately, compound 1 showed in vitro metabolic instability, as it soon undergoes to hydroxylation on alkoxy side chain by microsomal enzymes (3). In this occasion, we investigated on the metabolic hydroxylation site through the synthesis of the possible products of microsomal metabolism according to literature (4) and their comparison to compound 1’ s own metabolite in high resolution mass spectrometry (HR-MS); then we designed a new generation of hDHODH inhibitors protected from metabolic oxidation on the alkoxy side chain. Design, synthesis, in vitrometabolism and biological characterization of the new developed compounds are here described and discussed
EFMC-YMCS 2021 8th EFMC Young Medicinal Chemists’ Symposium
Virtual Event
9 - 10 Settembre 2021
EFMC-YMCS 2021 8th EFMC Young Medicinal Chemists’ Symposium
63
63
Chiara Vigato, Stefano Sainas, Marta Giorgis, Paola Circosta, Alice Passoni, Agnese Chiara Pippione, Renzo Bagnati, Giuseppe Saglio, Donatella Boschi, Marco Lucio Lolli.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2318/1852966
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