Design, synthesis, and cytotoxicity screening of novel pyrazolopyrimidines over renal cell carcinoma (UO-31 cells) as p38α inhibitors, and apoptotic cells inducing activities

Sara Y Ewieda; Amr Sonousi; Aliaa M Kamal; Mohamed K Abdelhamid

doi:10.1016/j.ejmech.2024.117005

Design, synthesis, and cytotoxicity screening of novel pyrazolopyrimidines over renal cell carcinoma (UO-31 cells) as p38α inhibitors, and apoptotic cells inducing activities

Eur J Med Chem. 2025 Jan 5:281:117005. doi: 10.1016/j.ejmech.2024.117005. Epub 2024 Nov 5.

Authors

Sara Y Ewieda¹, Amr Sonousi², Aliaa M Kamal³, Mohamed K Abdelhamid⁴

Affiliations

¹ Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt.
² Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt; University of Hertfordshire hosted by Global Academic Foundation, New Administrative Capital, Cairo, Egypt.
³ Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt; Organic Chemistry Department, Faculty of Pharmacy, October University for Modern Science and Arts (MSA), Giza, Egypt.
⁴ Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt. Electronic address: [email protected].

PMID: 39527892
DOI: 10.1016/j.ejmech.2024.117005

Abstract

A series of novel molecules with pyrazolopyrimidine-4-amine core were designed and synthesized as potential cytotoxic agents over Renal Cell Carcinoma cells (UO-31). Results of cytotoxic activity against UO-31 cells showed that pyrazolopyrimidines 19 and 31 were found to be more cytotoxic than sorafenib (SOR). The cytotoxic activity of these compounds appeared to correlate with their ability to inhibit p38α MAPK which are 2.53- and 2.27- folds more potent than SOR. Moreover, results of the cell cycle analysis as well as the results of annexin-V on the (UO-31) cells showed that pyrazolopyrimidines 19 and 31 had a pro-apoptotic activity higher than SOR by 1.42- and 1.20- folds, respectively. Furthermore, compounds 19 and 31 were found to be effective in arresting the cell cycle throughout the accumulation of the cells at G2/M phase. Finally, the tested compounds decreased the TNF concentration as well as increased the expression of tumor suppressor gene p53, Bax/BCL-2 ratio and caspase 3/7.

Keywords: Anticancer activity; Pyrazolopyrimidines; UO-31 cells; p38α inhibitors.

MeSH terms

Antineoplastic Agents* / chemical synthesis
Antineoplastic Agents* / chemistry
Antineoplastic Agents* / pharmacology
Apoptosis* / drug effects
Carcinoma, Renal Cell* / drug therapy
Carcinoma, Renal Cell* / pathology
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor*
Humans
Kidney Neoplasms* / drug therapy
Kidney Neoplasms* / pathology
Mitogen-Activated Protein Kinase 14 / antagonists & inhibitors
Mitogen-Activated Protein Kinase 14 / metabolism
Molecular Structure
Protein Kinase Inhibitors* / chemical synthesis
Protein Kinase Inhibitors* / chemistry
Protein Kinase Inhibitors* / pharmacology
Pyrazoles* / chemical synthesis
Pyrazoles* / chemistry
Pyrazoles* / pharmacology
Pyrimidines* / chemical synthesis
Pyrimidines* / chemistry
Pyrimidines* / pharmacology
Structure-Activity Relationship

Substances

Antineoplastic Agents
Pyrimidines
Pyrazoles
Protein Kinase Inhibitors
Mitogen-Activated Protein Kinase 14