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Targeting myeloid d...
Targeting myeloid differentiation using potent 2-hydroxypyrazolo[1,5-a]pyridine scaffold-based human dihydroorotate dehydrogenase (hDHODH) inhibitors.
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Sainas, Stefano (author)
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Pippione, Agnese Chiara (author)
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Lupino, Elisa (author)
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Giorgis, Marta (author)
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Circosta, Paola (author)
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Gaidano, Valentina (author)
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- Goyal, Parveen, 1984 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för kemi och molekylärbiologi,Department of Chemistry and Molecular Biology
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Bonanni, Davide (author)
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Rolando, Barbara (author)
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Cignetti, Alessandro (author)
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Ducime, Alex (author)
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- Andersson, Mikael (author)
- Gothenburg University,Göteborgs universitet,Institutionen för kemi och molekylärbiologi,Department of Chemistry and Molecular Biology
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Järvå, Michael (author)
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- Friemann, Rosmarie, 1975 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för kemi och molekylärbiologi,Department of Chemistry and Molecular Biology
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Piccinini, Marco (author)
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Ramondetti, Cristina (author)
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Buccinnà, Barbara (author)
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Al-Karadaghi, Salam (author)
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Boschi, Donatella (author)
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Saglio, Giuseppe (author)
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Lolli, Marco L (author)
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(creator_code:org_t)
- 2018-06-25
- 2018
- English.
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In: Journal of medicinal chemistry. - : American Chemical Society (ACS). - 1520-4804 .- 0022-2623. ; 61:14, s. 6034-6055
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Abstract
Subject headings
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- Human dihydroorotate dehydrogenase (hDHODH) catalyzes the rate-limiting step in de novo pyrimidine biosynthesis, the conversion of dihydroorotate to orotate. hDHODH has recently been found to be associated with acute myelogenous leukemia, a disease for which the standard of intensive care has not changed over decades. This work presents a novel class of hDHODH inhibitors, which are based on an unusual carboxylic group bioisostere 2-hydroxypyrazolo[1,5-a]pyridine, that has been designed starting from brequinar, one of the most potent hDHODH inhibitors. A combination of structure-based and ligand-based strategies produced compound 4, which shows brequinar-like hDHODH potency in vitro and is superior in terms of cytotoxicity and immunosuppression. Compound 4 also restores myeloid differentiation in leukemia cell lines at concentrations that are one log digit lower than those achieved in experiments with brequinar. This paper reports the design, synthesis, SAR, X-ray crystallography, biological assays and physicochemical characterization of the new class of hDHODH inhibitors.
Subject headings
- NATURVETENSKAP -- Biologi -- Strukturbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Structural Biology (hsv//eng)
- NATURVETENSKAP -- Kemi -- Organisk kemi (hsv//swe)
- NATURAL SCIENCES -- Chemical Sciences -- Organic Chemistry (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Läkemedelskemi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medicinal Chemistry (hsv//eng)
Publication and Content Type
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- art (subject category)
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- By the author/editor
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Sainas, Stefano
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Pippione, Agnese ...
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Lupino, Elisa
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Giorgis, Marta
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Circosta, Paola
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Gaidano, Valenti ...
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show more...
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Goyal, Parveen, ...
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Bonanni, Davide
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Rolando, Barbara
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Cignetti, Alessa ...
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Ducime, Alex
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Andersson, Mikae ...
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Järvå, Michael
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Friemann, Rosmar ...
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Piccinini, Marco
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Ramondetti, Cris ...
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Buccinnà, Barbar ...
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Al-Karadaghi, Sa ...
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Boschi, Donatell ...
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Saglio, Giuseppe
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Lolli, Marco L
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show less...
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Biological Scien ...
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and Structural Biolo ...
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Chemical Science ...
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and Organic Chemistr ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Medicinal Chemis ...
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Journal of medic ...
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University of Gothenburg