Design, synthesis and biological evaluation of N-alkyl or aryl substituted isoindigo derivatives as potential dual cyclin-dependent kinase 2 (CDK2)/glycogen synthase kinase 3β (GSK-3β) phosphorylation inhibitors

Zhao, Ping; Li, Yanzhong; Guang-wei, Gao; Wang, Shuai; Yan, Yun; Zhan, Xiaoping; Liu, Zenglu; Mao, Zhuo; Chen, Shaoxiong; Wang, Liqun

doi:10.1016/j.ejmech.2014.08.049

Cited by 43 publications

(19 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The antitumor properties of some of these compounds have been studied with respect to apoptosis and cell cycle arrest. Indirubin and several of its analogues exhibit their anticancer activity through modulating CDKs, which will arrest cell cycle progression leading to cell death by apoptosis [17,18,19,20,22,23,25,26,27,28]. Multiple indirubin derivatives have been shown to arrest cell cycle at G0/G1 phase at low micromolar concentrations (up to 1 µM), while higher concentrations, ≥ 5 µM, inhibit cell cycle at G2/M phase [23].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

The Anticancer Activity of the Substituted Pyridone-Annelated Isoindigo (5'-Cl) Involves G0/G1 Cell Cycle Arrest and Inactivation of CDKs in the Promyelocytic Leukemia Cell Line HL-60

Saleh

Aljada

El‐Abadelah

et al. 2015

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims:The antileukemic potential of isoindigos make them desired candidates for understanding their mechanism of action. We have recently synthesized a novel group of pyridone-annelated isoindigos and identified the derivative 5'-Cl that is cytotoxic to various cancer cell lines. In the present study, we analyzed the effect of this compound on cell cycle of the promyelocytic leukemia cell line HL-60. Methods:HL-60 cells were treated with 5'-Cl and its effect on cell cycle stages were determined by flow cytometry. Expression of cyclins, cyclin dependent kinases (CDKs) and cyclin kinase inhibitors (CKIs) were determined by Western blotting, and activation of CDKs was studied using kinase assays. Results:5'-Cl remarkably arrested cell cycle in HL-60 cells at the G0/G1 phase in a dose and time-dependent manner. Furthermore, 5'-Cl treatment significantly inhibited expression of D-cyclins, CDK2 and CDK4 and suppressed phosphorylation of the retinoblastoma protein Rb, whereas it increased the level of CKI p21. Molecular modelling experiments show that 5'-Cl may compete with ATP for binding to the catalytic subunit of CDK2 and CDK4 that could lead to inhibition of these enzymes. Indeed, 5'-Cl inhibited the kinase activity of CDK2 and CDK4 both in cell free systems and in treated cells. 5'-Cl also inhibited cell cycle progression in several other tumor cell lines. Conclusion:We demonstrate the potent inhibitory effects of 5'-Cl on HL-60 cells could be mediated by arresting cells in the G0/G1 phase.

show abstract

Section: Discussionmentioning

confidence: 99%

“…Several of these compounds have been shown to inhibit CDKs and glycogen-synthase kinase (GSK-3β) and induce apoptosis in leukemic cells with varying degrees of potency [17,18,19,20,22,23,25,26,27,28]. In spite of extensive investigations on the mode of action of isoindigos in various malignancies, comprehensive study is yet to be done.…”

Section: Introductionmentioning

confidence: 99%

The Anticancer Activity of the Substituted Pyridone-Annelated Isoindigo (5'-Cl) Involves G0/G1 Cell Cycle Arrest and Inactivation of CDKs in the Promyelocytic Leukemia Cell Line HL-60

Saleh

Aljada

El‐Abadelah

et al. 2015

Cell Physiol Biochem

View full text Add to dashboard Cite

show abstract

“…The FDA approval of sunitinib paved the way to design and synthesis of various isatin-based molecules with diverse activities against cancer. In this context, many synthetic isatin-based derivatives were developed to inhibit diverse tyrosine and serine/threonine kinases, to name just a few, c-Met kinase [10], c-Src kinase [11], RET kinase [12], FLT3 kinase [13], cyclin-dependent kinases (CDKs) [14], glycogen synthase kinase 3β (GSK-3β) [15], Aurora B kinase [16], p38α MAP kinase [17], JNK3 MAP kinase [18], p90 ribosomal S6 protein kinase 2 (RSK2) [19] and Polo-like kinase 4 (PLK4) [20,21].…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis and QSAR study of certain isatin-pyridine hybrids as potential anti-proliferative agents

Eldehna

Altoukhy

Mahrous

et al. 2015

European Journal of Medicinal Chemistry

View full text Add to dashboard Cite

“…Cell cycle analysis was carried out as previously described 29 . The cells were harvested with trypsin 24 h after BHX treatment.…”

Section: Methodsmentioning

confidence: 99%

BHX, a novel pyrazoline derivative, inhibits breast cancer cell invasion by reversing the epithelial-mesenchymal transition and down-regulating Wnt/β-catenin signalling

Bao

Zhang

Zhu

et al. 2017

Sci Rep

View full text Add to dashboard Cite

The novel pyrazoline derivative, BHX, has recently been shown to exhibit potent anti-tumour activity by blocking the Wnt/β-catenin signalling pathway. However, its effect on breast cancer growth and invasion are unknown. Our results show that BHX suppresses MDA-MB-231 cell viability and colony formation in a dose-dependent manner, and induces apoptosis and G0/G1 phase arrest. BHX-treated breast cancer cells showed morphological characteristics of cells undergoing apoptosis. Furthermore, BHX inhibited cell migration and invasion, which was associated with increased E-cadherin mRNA and protein expression, and down-regulation of SNAIL and vimentin. In addition, BHX induced the generation of intracellular ROS and decreased β-catenin protein and mRNA expression. We used a mouse xenograft model to investigate the effects of BHX in vivo, where the growth of MDA-MB-231 xenografted tumours was suppressed in nude mice treated continuously with BHX for 21 days. Finally, the rat plasma concentration of BHX was measured by ultra-performance liquid-chromatography tandem mass spectrometry and the pharmacokinetic parameters of BHX were processed by non-compartmental analysis. In conclusion, BHX merits further study as a novel therapeutic small molecule for the treatment of breast cancer.

show abstract

Design, synthesis and biological evaluation of N-alkyl or aryl substituted isoindigo derivatives as potential dual cyclin-dependent kinase 2 (CDK2)/glycogen synthase kinase 3β (GSK-3β) phosphorylation inhibitors

Cited by 43 publications

References 25 publications

The Anticancer Activity of the Substituted Pyridone-Annelated Isoindigo (5'-Cl) Involves G0/G1 Cell Cycle Arrest and Inactivation of CDKs in the Promyelocytic Leukemia Cell Line HL-60

The Anticancer Activity of the Substituted Pyridone-Annelated Isoindigo (5'-Cl) Involves G0/G1 Cell Cycle Arrest and Inactivation of CDKs in the Promyelocytic Leukemia Cell Line HL-60

Design, synthesis and QSAR study of certain isatin-pyridine hybrids as potential anti-proliferative agents

BHX, a novel pyrazoline derivative, inhibits breast cancer cell invasion by reversing the epithelial-mesenchymal transition and down-regulating Wnt/β-catenin signalling

Contact Info

Product

Resources

About