7-Azaindole, 2,7-diazaindole, and 1H-pyrazole as core structures for novel anticancer agents with potential chemosensitizing properties

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00179906%3A_____%2F22%3A10445938" target="_blank" >RIV/00179906:_____/22:10445938 - isvavai.cz</a>

Alternative codes found

RIV/68378050:_____/22:00559439 RIV/60162694:G44__/23:00558179 RIV/00216208:11150/22:10445938 RIV/00216208:11160/22:10445938

Result on the web

<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=LTgMyvgV6e" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=LTgMyvgV6e</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.ejmech.2022.114580" target="_blank" >10.1016/j.ejmech.2022.114580</a>

Result language

angličtina

Original language name

7-Azaindole, 2,7-diazaindole, and 1H-pyrazole as core structures for novel anticancer agents with potential chemosensitizing properties

Original language description

Chemoresistance of cancer cells is a hallmark of treatment failure and the poor patient prognosis. The mechanism of resistance is often connected to the overexpression of specific kinases involved in DNA damage response cascade. Contrary, selected kinase inhibition can augment cancer cell sensitization to conventional therapy, enabling more efficient treatment. Among those kinases, ataxia-telangiectasia and Rad3-related kinase (ATR), the major responder to replication stress, stands out as one of the most attractive targets. Inspired by clinical candidates targeting ATR, we designed and prepared a small, focused library of 40 novel compounds building on 7-azaindoles, 2,7-diazaindoles, and 1H-pyrazoles as core structures. All the compounds alone or combined with cisplatin (CDDP) were screened against a panel of nine cancer cell lines and one healthy cell line. Three highlighted compounds (3, 22, and 29) were selected for broad oncology panel screening containing 104 kinases. Only compound 29, the 2,7-diazaindole representative, showed ATR inhibitory efficacy with the IC50 around 10 μM. In contrast, the compound 22, 7-azaindole congener with the most pronounced cytotoxicity profile exceeding CDDP alone or in combination with CDDP, expressed the multi-kinase activity. Highlighted representatives, including compound 29, were also effective alone against primary glioblastoma. Overall, we showed that 7-azaindole, and 2,7-diazaindole scaffolds could be considered novel pharmacophores delivering anticancer activity.

Czech name

—

Czech description

—

Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

30104 - Pharmacology and pharmacy

Project

<a href="/en/project/EF18_069%2F0010046" target="_blank" >EF18_069/0010046: Pre-application research into innovative medicines and medical technologies</a><br>

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2022

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

European Journal of Medicinal Chemistry

ISSN

0223-5234

e-ISSN

1768-3254

Volume of the periodical

240

Issue of the periodical within the volume

OCT

Country of publishing house

FR - FRANCE

Number of pages

20

Pages from-to

114580

UT code for WoS article

000826524000002

EID of the result in the Scopus database

2-s2.0-85133161716