Novel pyrazolo[3,4‐d]pyrimidine derivatives inhibit human cancer cell proliferation and induce apoptosis by ROS generation
- 19 February 2020
- journal article
- research article
- Published by Wiley in Archiv der Pharmazie
- Vol. 353 (4), e1900296
- https://doi.org/10.1002/ardp.201900296
Abstract
The paucity of effective anticancer drugs for successful treatment is a major concern, indicating the strong need for novel therapeutic compounds. In the quest of new molecules, the present study aimed to explore the potential of pyrazolo[3,4‐d]pyrimidine derivatives as antiproliferative agents. In vitro anticancer screening of selected compounds was done by the National Cancer Institute's Developmental Therapeutics Programme against a panel of 60 cancer cell lines. The lead compound PP‐31d considerably inhibited the growth of cancer cells, such as NCI‐H460 (non‐small‐cell lung cancer), OVCAR‐4 (ovarian cancer), 786‐0 (renal cancer), A549 (non‐small‐cell lung cancer), and ACHN (renal cancer), showing strong anticancer potential, among other derivatives. Kinetic studies of PP‐31d on NCI‐H460 cells revealed a dose‐dependent effect with an IC50 of 2 µM. The observed inhibition by PP‐31d is attributed to the generation of reactive oxygen species and the subsequent induction of cellular apoptosis, as evidenced by the increase in the hypodiploid (subG1) population, the early apoptotic cell population, and caspase‐3/7 activity, the loss of the mitochondrial membrane potential, and the degradation of nuclear DNA. Collectively, our results demonstrated that pyrazolo[3,4‐d]pyrimidine derivatives inhibit cancer cell proliferation by inducing apoptosis and, thus, have the potential to be further explored for anticancer properties.Keywords
This publication has 36 references indexed in Scilit:
- 2-Hydroxypropyl-β-cyclodextrin strongly improves water solubility and anti-proliferative activity of pyrazolo[3,4-d]pyrimidines Src-Abl dual inhibitorsEuropean Journal of Medicinal Chemistry, 2010
- Synthesis of some new pyrazolo[3,4-d]pyrimidine derivatives of expected anticancer and radioprotective activityEuropean Journal of Medicinal Chemistry, 2010
- Discovery of Potent and Selective Inhibitors of the Mammalian Target of Rapamycin (mTOR) KinaseJournal of Medicinal Chemistry, 2009
- Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach?Nature Reviews Drug Discovery, 2009
- OLEX2: a complete structure solution, refinement and analysis programJournal of Applied Crystallography, 2009
- A short history of SHELXActa Crystallographica Section A Foundations of Crystallography, 2007
- Methods for the assessment of mitochondrial membrane permeabilization in apoptosisApoptosis, 2007
- In vitro measurement of cell death with the annexin A5 affinity assayNature Protocols, 2006
- Mechanism of apoptosis induced by doxorubicin through the generation of hydrogen peroxideLife Sciences, 2005
- A New Method for the Cytofluorometric Analysis of Mitochondrial Membrane Potential Using the J-Aggregate Forming Lipophilic Cation 5,5′,6,6′-Tetrachloro-1,1′,3,3′-tetraethylbenzimidazolcarbocyanine Iodide (JC-1)Biochemical and Biophysical Research Communications, 1993