One-pot three-component synthesis of novel pyrazolo[3,4-b]pyridines as potent antileukemic agents

被引：39

作者：

Barghash, Reham F. ^{[1
]}

Eldehna, Wagdy M. ^{[2
]}

Kovalova, Marketa ^{[3
]}

Vojatkova, Veronika ^{[3
]}

Krystof, Vladimir ^{[3
]}

Abdel-Aziz, Hatem A. ^{[4
]}

机构：

[1] Natl Res Ctr, Inst Chem Ind Res, POB 12622, Giza, Egypt

[2] Kafrelsheikh Univ, Fac Pharm, Dept Pharmaceut Chem, Kafrelsheikh 33516, Egypt

[3] Palacky Univ, Dept Expt Biol, Slechtitelu 27, Olomouc 78371, Czech Republic

[4] Natl Res Ctr, Dept Appl Organ Chem, POB 12622, Giza, Egypt

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2022年 / 227卷

关键词：

Pyrazolopyridine; One-pot synthesis; Cell cycle arrest; Anticancer agents; HOXA9; protein; MEIS1; BIOLOGICAL EVALUATION; PYRAZOLOPYRIDINE DERIVATIVES; ANTIPROLIFERATIVE AGENTS; INHIBITORS; DISCOVERY; DESIGN; APOPTOSIS; ANTITUMOR; IDENTIFICATION; OPTIMIZATION;

D O I：

10.1016/j.ejmech.2021.113952

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

In the current study, we report on the development of novel series of pyrazolo[3,4-b]pyridine derivatives (8a-u, 11a-n, and 14a,b) as potential anticancer agents. The prepared pyrazolo[3,4-b]pyridines have been screened for their antitumor activity in vitro at NCI-DTP. Thereafter, compound 8a was qualified by NCI for full panel five-dose assay to assess its GI(50), TGI and LC50 values. Compound 8a showed broadspectrum anti-proliferative activities over the whole NCI panel, with outstanding growth inhibition full panel GI(50) (MG-MID) value equals 2.16 mu M and subpanel GI(50) (MG-MID) range: 1.92-2.86 mu M. Furthermore, pyrazolo[3,4-b]pyridines 8a, 8e-h, 8o, 8u, 11a, 11e, 11h, 11l and 14a-b were assayed for their antiproliferative effect against a panel of leukemia cell lines (K562, MV4-11, CEM, RS4;11, ML-2 and KOPN-8) where they possessed moderate to excellent anti-leukemic activity. Moreover, pyrazolo[3,4-b] pyridines 8o, 8u, 14a and 14b were further explored for their effect on cell cycle on RS4;11 cells, in which they dose-dependently increased populations of cells in G2/M phases. Finally we analyzed the changes of selected proteins (HOXA9, MEIS1, PARP, BcL-2 and McL-1) related to cell death and viability in RS4;11 cells via Western blotting. Collectively, the obtained results suggested pyrazolo[3,4-b]pyridines 8o, 8u, 14a and 14b as promising lead molecules for further optimization to develop more potent and efficient anticancer candidates. (C) 2021 Elsevier Masson SAS. All rights reserved.

引用

页数：16

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