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3,4-Dihydropyrimidi...
3,4-Dihydropyrimidin-2(1H)-ones as Antagonists of the Human A2B Adenosine Receptor : Optimization, Structure–Activity Relationship Studies, and Enantiospecific Recognition
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Majellaro, María (author)
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- Jespers, Willem (author)
- Uppsala universitet,Beräkningsbiologi och bioinformatik
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Crespo, Abel (author)
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Núñez, María J. (author)
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Novio, Silvia (author)
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Azuaje, Jhonny (author)
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Prieto-Diaz, Ruben (author)
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Gioé, Claudia (author)
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- Alispahic, Belma (author)
- Uppsala universitet,Institutionen för cell- och molekylärbiologi
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Brea, José (author)
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Loza, María I. (author)
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Freire-Garabal, Manuel (author)
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Garcia-Santiago, Carlota (author)
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Rodriguez-Garcia, Carlos (author)
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García-Mera, Xerardo (author)
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Caamaño, Olga (author)
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Fernandez-Masaguer, Christian (author)
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Sardina, Javier F. (author)
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Stefanachi, Angela (author)
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El Maatougui, Abdelaziz (author)
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Mallo-Abreu, Ana (author)
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- Åqvist, Johan (author)
- Uppsala universitet,Beräkningsbiologi och bioinformatik
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- Gutiérrez-de-Terán, Hugo (author)
- Uppsala universitet,Beräkningsbiologi och bioinformatik
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Sotelo, Eddy (author)
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(creator_code:org_t)
- 2020-12-29
- 2021
- English.
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In: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 64:1, s. 458-480
- Related links:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
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- We present and thoroughly characterize a large collection of 3,4-dihydropyrimidin-2(1H)-ones as A2BAR antagonists, an emerging strategy in cancer (immuno) therapy. Most compounds selectively bind A2BAR, with a number of potent and selective antagonists further confirmed by functional cyclic adenosine monophosphate experiments. The series was analyzed with one of the most exhaustive free energy perturbation studies on a GPCR, obtaining an accurate model of the structure–activity relationship of this chemotype. The stereospecific binding modeled for this scaffold was confirmed by resolving the two most potent ligands [(±)-47, and (±)-38Ki = 10.20 and 23.6 nM, respectively] into their two enantiomers, isolating the affinity on the corresponding (S)-eutomers (Ki = 6.30 and 11.10 nM, respectively). The assessment of the effect in representative cytochromes (CYP3A4 and CYP2D6) demonstrated insignificant inhibitory activity, while in vitro experiments in three prostate cancer cells demonstrated that this pair of compounds exhibits a pronounced antimetastatic effect.
Subject headings
- NATURVETENSKAP -- Kemi -- Organisk kemi (hsv//swe)
- NATURAL SCIENCES -- Chemical Sciences -- Organic Chemistry (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Majellaro, María
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Jespers, Willem
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Crespo, Abel
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Núñez, María J.
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Novio, Silvia
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Azuaje, Jhonny
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show more...
-
Prieto-Diaz, Rub ...
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Gioé, Claudia
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Alispahic, Belma
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Brea, José
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Loza, María I.
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Freire-Garabal, ...
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Garcia-Santiago, ...
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Rodriguez-Garcia ...
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García-Mera, Xer ...
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Caamaño, Olga
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Fernandez-Masagu ...
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Sardina, Javier ...
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Stefanachi, Ange ...
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El Maatougui, Ab ...
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Mallo-Abreu, Ana
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Åqvist, Johan
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Gutiérrez-de-Ter ...
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Sotelo, Eddy
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show less...
- About the subject
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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 Pharmacology and ...
- Articles in the publication
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Journal of Medic ...
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Uppsala University