Development of New Pyrazolo [3,4-b]Pyridine Derivatives as Potent Anti-Leukemic Agents and Topoisomerase IIα Inhibitors with Broad-Spectrum Cytotoxicity

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61989592%3A15110%2F25%3A73632510" target="_blank" >RIV/61989592:15110/25:73632510 - isvavai.cz</a>

Alternative codes found

RIV/61989592:15310/25:73632510

Result on the web

<a href="https://www.mdpi.com/1424-8247/18/11/1770" target="_blank" >https://www.mdpi.com/1424-8247/18/11/1770</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.3390/ph18111770" target="_blank" >10.3390/ph18111770</a>

Result language

angličtina

Original language name

Development of New Pyrazolo [3,4-b]Pyridine Derivatives as Potent Anti-Leukemic Agents and Topoisomerase IIα Inhibitors with Broad-Spectrum Cytotoxicity

Original language description

Background/Objectives: In the current medical era, Topoisomerase II is recognized as an essential enzyme that regulates DNA topology during critical biological processes such as DNA replication, transcription, and repair. This study aimed to design, synthesize, and biologically evaluate a new series of pyrazolo[3,4-b]pyridines (8a–g, 10a–g, and 12) as potential anticancer agents and Topoisomerase II inhibitors. Methods: The synthesized compounds were subjected to in vitro anticancer screening at the National Cancer Institute (NCI, USA). Active derivatives were further evaluated through a five-dose screening to determine their antiproliferative potency. Selected compounds were examined for their effects on leukemia cell lines (K562 and MV4-11), and mechanistic studies were performed to assess DNA damage, cell cycle distribution, and apoptosis-related protein modulation. Additionally, enzyme inhibition assays were conducted to determine Topoisomerase IIα (TOPIIα) inhibition. Results: Initial single-dose screening identified several active compounds, notably 8b, 8c, 8e, 8f, 10b, 10c, 10e, and 10f. Among these, compound 8c exhibited potent and broad-spectrum antiproliferative activity across the NCI cancer cell line panel, with a GI50 MG-MID value of 1.33 µM (range: 0.54–2.08 µM). The synthesized molecules showed moderate to good anti-leukemic efficacy against K562 and MV4-11 cells. Mechanistic investigations revealed that compound 8c induced DNA damage and S-phase cell cycle arrest, leading to apoptosis as evidenced by the modulation of PARP-1, Bax, XIAP, and Caspases. Furthermore, target-based assays confirmed that compound 8c significantly inhibited the DNA relaxation activity of TOPIIα in a dose-dependent manner, comparable to etoposide. Conclusions: The study highlights compound 8c as a promising pyrazolo[3,4-b]pyridine derivative with potent antiproliferative activity and effective inhibition of Topoisomerase IIα. These findings suggest its potential as a lead scaffold for further optimization in anticancer drug development.

Czech name

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Czech description

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Type

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

CEP classification

—

OECD FORD branch

30107 - Medicinal chemistry

Project

<a href="/en/project/LX22NPO5102" target="_blank" >LX22NPO5102: National institute for cancer research</a><br>

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)<br>S - Specificky vyzkum na vysokych skolach

Publication year

2025

Confidentiality

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

Name of the periodical

Pharmaceuticals

ISSN

1424-8247

e-ISSN

—

Volume of the periodical

18

Issue of the periodical within the volume

11

Country of publishing house

CH - SWITZERLAND

Number of pages

26

Pages from-to

"1770-1"-"1770-26"

UT code for WoS article

001623724700001

EID of the result in the Scopus database

2-s2.0-105023482483