Novel electrophilic amides amenable by the Ugi reaction perturb thioredoxin system via thioredoxin reductase 1 (TrxR1) inhibition: Identification of DVD-445 as a new lead compound for anticancer therapy.
2019
Аутори:
Jovanović, MirnaZhukovsky, Daniil
Podolski-Renić, Ana
Domračeva, Ilona
Žalubovskis, Raivis
Senćanski, Milan
Glišić, Sanja
Sharoyko, Vladimir
Tennikova, Tatiana
Dar'in, Dmitry
Pešić, Milica
Krasavin, Mikhail
Тип документа:
Чланак у часопису (Објављена верзија)
,
© 2019 Elsevier Masson SAS.
Метаподаци
Приказ свих података о документуАпстракт:
A series of peptidomimetic compounds incorporating an electrophilic moiety was synthesized using the Ugi reaction. These compounds (termed the Ugi Michael acceptors or UMAs) were designed to target the selenocysteine catalytic residue of thioredoxin reductase 1 (TrxR1), a promising cancer target. The compounds were assessed for their potential to inhibit TrxR1 using human neuroblastoma (SH-SY5Y) cell lysate. Based on this initial screening, six compounds were selected for testing against recombinant rat TrxR1 and in the insulin assay to reveal low-micromolar to submicromolar potency of these inhibitors. The same frontrunner compounds were evaluated for their ability to exert antiproliferative activity and induce cell death and this activity was compared to the UMA effects on the levels of reactive oxygen and nitrogen species (RONS). Collectively, the UMA compounds class presented itself as a rich source of leads for TrxR1 inhibitor discovery for anticancer application. Compound 7 (DVD-445) was nominated a lead for further optimization.
Извор:
European Journal of Medicinal Chemistry, 2019, 181, 111580-Финансирање / пројекти:
- Идентификација молекуларних маркера за предикцију прогресије тумора, одговора на терапију и исхода болести (RS-MESTD-Integrated and Interdisciplinary Research (IIR or III)-41031)
- Russian Foundation for Basic Research (project grant 18–515-76001)
- ERA.Net RUS plus joint program grant RUS_ST2017-309
- State Education Development Agency of Republic of Latvia (“THIOREDIN”)
- COST Action CA17104
DOI: 10.1016/j.ejmech.2019.111580
PubMed: 31400708
WoS: 000493211900034
Scopus: 2-s2.0-85073183701
URI
https://www.sciencedirect.com/science/article/pii/S0223523419307147?via%3Dihubhttps://radar.ibiss.bg.ac.rs/handle/123456789/3488