Novel selective IDO1 inhibitors with isoxazolo[5,4-d]pyrimidin-4(5H)-one scaffold

Dolšak, Ana (avtor), Bratkovič, Tomaž (avtor), Mlinarič, Larisa (avtor), Ogorevc, Eva (avtor), Švajger, Urban (avtor), Gobec, Stanislav (avtor), Sova, Matej (avtor)

Indoleamine 2,3-dioxygenase 1 (IDO1) is a promising target in immunomodulation of several pathological conditions, especially cancers. Here we present the synthesis of a series of IDO1 inhibitors with the novel isoxazolo[5,4-d]pyrimidin-4(5H)-one scaffold. A focused library was prepared using a 6- or 7-step synthetic procedure to allow a systematic investigation of the structure-activity relationships of the described scaffold. Chemistry-driven modifications lead us to the discovery of our best-in-class inhibitors possessing p-trifluoromethyl (23), p-cyclohexyl (32), or p-methoxycarbonyl (20, 39) substituted aniline moieties with IC$_{50}$ values in the low micromolar range. In addition to hIDO1, compounds were tested for their inhibition of indoleamine 2,3-dioxygenase 2 and tryptophan dioxygenase, and found to be selective for hIDO1. Our results thus demonstrate a successful study on IDO1-selective isoxazolo[5,4-d]pyrimidin-4(5H)-one inhibitors, defining promising chemical probes with a novel scaffold for further development of potent small-molecule immunomodulators.

• Jezik: Angleški jezik
• Ključne besede: indoleamine 2, 3-dioxygenase 1, selective inhibitors, isoxazolo[5, 4-d]pyrimidin-4(5H)-one, immunomodulation, cancer
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: FFA - Fakulteta za farmacijo
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2021
• Št. strani: 18 str.
• Številčenje: Vol. 14, iss. 3, art. 265
• PID: 20.500.12556/RUL-135216
• UDK: 616-097+616-006
• ISSN pri članku: 1424-8247
• DOI: 10.3390/ph14030265
• COBISS.SI-ID: 57316099
• Datum objave v RUL: 01.03.2022

Gradivo je del revije

• Naslov: Pharmaceuticals
• Skrajšan naslov: Pharmaceuticals
• Založnik: MDPI
• ISSN: 1424-8247
• COBISS.SI-ID: 517582617

Licence

• Licenca: CC BY 4.0, Creative Commons Priznanje avtorstva 4.0 Mednarodna
• Povezava: http://creativecommons.org/licenses/by/4.0/deed.sl
• Opis: To je standardna licenca Creative Commons, ki daje uporabnikom največ možnosti za nadaljnjo uporabo dela, pri čemer morajo navesti avtorja.
• Začetek licenciranja: 15.03.2021

Sekundarni jezik

• Jezik: Slovenski jezik
• Ključne besede: selektivni zaviralci, rak, imunomodulacija

Projekti

• Financer: ARRS - Agencija za raziskovalno dejavnost Republike Slovenije
• Številka projekta: P1-0208
• Naslov: Farmacevtska kemija: načrtovanje, sinteza in vrednotenje učinkovin

• Financer: ARRS - Agencija za raziskovalno dejavnost Republike Slovenije
• Program financ.: Junior Researcher