Details

Autor(en) / Beteiligte

• Ayaz, Shahid
• Gupta, Shankar
• Singh, Rajveer
• Kurmi, Balak Das
• Almehizia, Abdulrahman A.
• Asati, Vivek

Titel

Combined computational and synthetic strategies for the development of potent pyrazolo-pyridine derivatives as anticancer agents

Ist Teil von

• Journal of molecular structure, 2024-09, Vol.1311, p.138301, Article 138301

Ort / Verlag

Elsevier B.V

Erscheinungsjahr

2024

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• •Targeting class IA PI3K mutations in cancer, this research leveraged computational techniques to discover promising anti-cancer candidates.•Computationally designed pyrazolo-pyridines (MSA6 & MSA7) bind strongly to PI3K kinase (−9.03 & −9.0 kcal/mol).•MSA6 in lung cancer cells: boosts ROS, triggers caspase cleavage, modulates PI3K, reduces migration & colony formation (dose-dependently).•Specific structural features of MSA6 contribute to its potent anti-cancer activity (IC50 49.23 μM).•Pyrazolo-pyridines have potential for further development as PI3K kinase inhibitors. PI3K comprise a group of lipid kinases mainly made up of three classes and have a particular role in signal transduction. The aberration of class IA PI3K is most frequently shown in cancer. The computation techniques have been applied for the identification of potent compounds. This involved the generation of a library of novel compounds (2700) through R-group enumeration study. The screening process utilized a combination of pharmacophore-based virtual screening and various docking algorithms, leading to the discovery of ten novel compounds. The docking studies against PI3K kinase highlighted MSA6 and MSA7 as the most promising compounds, with docking scores of -9.03 and -9.0 kcal/mol, respectively. Results of docking studies of all derivatives confirmed satisfactory binding mode of the compounds within the active site of the target protein PI3K kinase. The screened pyrazolo-pyridine derivatives (MSA1-MSA10) were synthesized and evaluated as anti-cancer agents against NSCLC using A549 cell line. MSA6 showed the dose dependent enhancement in ROS production at concentration of 10 and 20 µM in A549 cells. MSA6 triggered caspase 3 cleavage in lung cancer cells in a dose-dependent manner. MSA6 treatment at 10 and 20 µM levels boosted NF-κβ expression in the cytoplasm while decreasing it in the nucleus, as demonstrated by flow cytometry with an anti-NF-κβ antibody. The modulation of PI3K activity have been observed at 10 µM and 20 µM concentration of MSA6. A549 cells treated with MSA6 with 20 µM showed significant reduction in wound healing in cancerous cell. A549 cells treated with 20 µM showed significantly reduction in number of colonies compared to control group. Compound MSA6 having a methyl group at the para position of phenyl ring at imine carbon and phenyl ring substitution at nitrogen of pyrazole ring exhibited remarkable growth inhibitory activity with IC50 value of 49.23 μM. Based on the above results, pyrazolo-pyridine derivatives can be used for the further development of novel PI3K kinase inhibitors as anticancer agents.