Synthesis and biological activity evaluation of novel 2,6,9-trisubstituted purine conjugates as potential protein kinases inhibitors

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61989592%3A15310%2F22%3A73616116" target="_blank" >RIV/61989592:15310/22:73616116 - isvavai.cz</a>

Výsledek na webu

<a href="https://www.sciencedirect.com/science/article/pii/S0960894X22000798" target="_blank" >https://www.sciencedirect.com/science/article/pii/S0960894X22000798</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.bmcl.2022.128603" target="_blank" >10.1016/j.bmcl.2022.128603</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Synthesis and biological activity evaluation of novel 2,6,9-trisubstituted purine conjugates as potential protein kinases inhibitors

Popis výsledku v původním jazyce

Deregulation of protein kinases is often associated with uncontrolled cell proliferation in various tumours and the inhibition of kinase activity remains an important target for anti-tumour drug development. Here, we report a novel series of 2-aminocyclohexylamino-6-(substituted benzylamino/anilino)-9-cyclopentylpurine derivatives conjugated with putrescine, spermidine or spermine moiety in an effort to expand library of highly potent 2,6,9-trisubstituted purine kinase inhibitors. Presented aniline-type conjugates exhibit significant cytotoxic activity in MV4-11 and EOL-1 cell lines which correlates with FLT3-ITD and PDGFRα inhibition. Furthermore, 6-anilinopurines affected MAPK and STAT pathways in the treated MV4-11 cells and induced cell cycle arrest in the G1 phase. 6-Benzylaminopurines showed comparable CDK2 inhibitory activity to 6-anilinopurines, however, the PDGFRα and FLT3-ITD inhibition was strongly suppressed. Our results show that novel compounds containing aniline in the structure can be involved in the development of potent tyrosine kinase inhibitors with strong activity toward acute myeloid leukemia or chronic eosinophilic leukemia.

Název v anglickém jazyce

Synthesis and biological activity evaluation of novel 2,6,9-trisubstituted purine conjugates as potential protein kinases inhibitors

Popis výsledku anglicky

Deregulation of protein kinases is often associated with uncontrolled cell proliferation in various tumours and the inhibition of kinase activity remains an important target for anti-tumour drug development. Here, we report a novel series of 2-aminocyclohexylamino-6-(substituted benzylamino/anilino)-9-cyclopentylpurine derivatives conjugated with putrescine, spermidine or spermine moiety in an effort to expand library of highly potent 2,6,9-trisubstituted purine kinase inhibitors. Presented aniline-type conjugates exhibit significant cytotoxic activity in MV4-11 and EOL-1 cell lines which correlates with FLT3-ITD and PDGFRα inhibition. Furthermore, 6-anilinopurines affected MAPK and STAT pathways in the treated MV4-11 cells and induced cell cycle arrest in the G1 phase. 6-Benzylaminopurines showed comparable CDK2 inhibitory activity to 6-anilinopurines, however, the PDGFRα and FLT3-ITD inhibition was strongly suppressed. Our results show that novel compounds containing aniline in the structure can be involved in the development of potent tyrosine kinase inhibitors with strong activity toward acute myeloid leukemia or chronic eosinophilic leukemia.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10401 - Organic chemistry

Projekt

<a href="/cs/project/GA19-09086S" target="_blank" >GA19-09086S: Duální inhibice FLT3/CDK9 jako možný terapeutický přístup v léčbě akutních leukémií s přestavbou genu MLL</a><br>

Návaznosti

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

Rok uplatnění

2022

Kód důvěrnosti údajů

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

Název periodika

BIOORGANIC &amp; MEDICINAL CHEMISTRY LETTERS

ISSN

0960-894X

e-ISSN

1464-3405

Svazek periodika

60

Číslo periodika v rámci svazku

MAR

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

7

Strana od-do

"128603-1"-"128603-7"

Kód UT WoS článku

000783559000005

EID výsledku v databázi Scopus

2-s2.0-85124034241