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 differentiation1. In recent years, we designed potent hDHODH inhibitors applying a scaffold-hopping approach to brequinar’s structure2. By investigating the lead compound’s SAR, we recently discovered compound 12, 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 enzymes3. In this occasion, we investigated on the metabolic hydroxylation site through the synthesis of the possible products of cytochrome metabolism according to literature4 and their comparison to microsome-incubated compound 1 in high-resolution mass spectrometry; then we developed new hDHODH inhibitors protected from metabolic oxidation on the alkoxy side chain. Design, synthesis, in vitro metabolism and biological characterization of the new compounds are here described and discussed. 1. Sykes, D. B. et al. Inhibition of Dihydroorotate Dehydrogenase Overcomes Differentiation Blockade in Acute Myeloid Leukemia. Cell 2016, 167(1), 171-186 2. Sainas, S. et al. Targeting Myeloid Differentiation Using Potent 2-Hydroxypyrazolo[1,5- a]pyridine Scaffold-Based Human Dihydroorotate Dehydrogenase Inhibitors. J. Med. Chem. 2018, 61, 6034-6055. 3. Sainas, S. et al. Targeting Acute Myelogenous Leukemia using potent human dihydroorotate dehydrogenase inhibitors based on the 2-hydroxypyrazolo[1,5- a]pyridine scaffold: SAR of the biphenyl moiety. J. Med. Chem. 2021, 64, 5404-5428 4. Testa, B. and Clement, B. Biotransformation Reactions and Their Enzymes. The Practice of Medicinal Chemistry: Fourth Ed. Academic Press. 2015, 561-584.

Improvement of Metabolic Weakness of New Dihydroorotate Dehydrogenase Inhibitors Based on 2-Hydroxypyrazolo[1,5-a]pyridine Scaffold to Target Myeloid Leukemias

Chiara Vigato
First
;
Stefano Sainas;Marta Giorgis;Paola Circosta;Agnese Chiara Pippione;Giuseppe Saglio;Donatella Boschi;Marco Lucio Lolli
Last
2021-01-01

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 differentiation1. In recent years, we designed potent hDHODH inhibitors applying a scaffold-hopping approach to brequinar’s structure2. By investigating the lead compound’s SAR, we recently discovered compound 12, 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 enzymes3. In this occasion, we investigated on the metabolic hydroxylation site through the synthesis of the possible products of cytochrome metabolism according to literature4 and their comparison to microsome-incubated compound 1 in high-resolution mass spectrometry; then we developed new hDHODH inhibitors protected from metabolic oxidation on the alkoxy side chain. Design, synthesis, in vitro metabolism and biological characterization of the new compounds are here described and discussed. 1. Sykes, D. B. et al. Inhibition of Dihydroorotate Dehydrogenase Overcomes Differentiation Blockade in Acute Myeloid Leukemia. Cell 2016, 167(1), 171-186 2. Sainas, S. et al. Targeting Myeloid Differentiation Using Potent 2-Hydroxypyrazolo[1,5- a]pyridine Scaffold-Based Human Dihydroorotate Dehydrogenase Inhibitors. J. Med. Chem. 2018, 61, 6034-6055. 3. Sainas, S. et al. Targeting Acute Myelogenous Leukemia using potent human dihydroorotate dehydrogenase inhibitors based on the 2-hydroxypyrazolo[1,5- a]pyridine scaffold: SAR of the biphenyl moiety. J. Med. Chem. 2021, 64, 5404-5428 4. Testa, B. and Clement, B. Biotransformation Reactions and Their Enzymes. The Practice of Medicinal Chemistry: Fourth Ed. Academic Press. 2015, 561-584.
2021
Bringing Chemical Biology to Cancer Research
Virtual Event
02-03 December 2021
-
46
46
Chiara Vigato, Stefano Sainas, Marta Giorgis, Paola Circosta, Alice Passoni, Marta Alberti, Agnese Chiara Pippione, Riccardo Miggiano, Davide Ferraris...espandi
File in questo prodotto:
File Dimensione Formato  
Bringing Chemical Biology to Cancer Research 2-3 Dec 2021_Final.pdf

Accesso riservato

Descrizione: Program and Book of Abstract
Tipo di file: MATERIALE NON BIBLIOGRAFICO
Dimensione 1.73 MB
Formato Adobe PDF
1.73 MB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1882161
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus ND
  • ???jsp.display-item.citation.isi??? ND
social impact