A1 Journal article (refereed)
Triggering Breast Cancer Apoptosis via Cyclin-Dependent Kinase Inhibition and DNA Damage by Novel Pyrimidinone and 1,2,4-Triazolo[4,3-a]pyrimidinone Derivatives (2024)

Abd Al Moaty, M. N., El Kilany, Y., Awad, L. F., Soliman, S. M., Barakat, A., Ibrahim, N. A., Abu-Serie, M. M., Haukka, M., El-Yazbi, A., & Teleb, M. (2024). Triggering Breast Cancer Apoptosis via Cyclin-Dependent Kinase Inhibition and DNA Damage by Novel Pyrimidinone and 1,2,4-Triazolo[4,3-a]pyrimidinone Derivatives. ACS Omega, Early online. https://doi.org/10.1021/acsomega.4c00466

JYU authors or editors

Publication details

All authors or editors: Abd Al Moaty, Mohamed N.; El Kilany, Yeldez; Awad, Laila F.; Soliman, Saied M.; Barakat, Assem; Ibrahim, Nihal A.; Abu-Serie, Marwa M.; Haukka, Matti; El-Yazbi, Amira; Teleb, Mohamed

Journal or series: ACS Omega

ISSN: 2470-1343

eISSN: 2470-1343

Publication year: 2024

Publication date: 06/05/2024

Volume: Early online

Publisher: American Chemical Society (ACS)

Publication country: United States

Publication language: English

DOI: https://doi.org/10.1021/acsomega.4c00466

Publication open access: Openly available

Publication channel open access: Partially open access channel

Publication is parallel published (JYX): https://jyx.jyu.fi/handle/123456789/95096

Abstract

Combinations of apoptotic inducers are common clinical practice in breast cancer. However, their efficacy is limited by the heterogeneous pharmacokinetic profiles. An advantageous alternative is merging their molecular entities in hybrid multitargeted scaffolds exhibiting synergistic activities and uniform distribution. Herein, we report apoptotic inducers simultaneously targeting DNA and CDK-2 (cyclin-dependent kinase-2) inspired by studies revealing that CDK-2 inhibition sensitizes breast cancer to DNA-damaging agents. Accordingly, rationally substituted pyrimidines and triazolopyrimidines were synthesized and assayed by MTT against MCF-7, MDA-MB231, and Wi-38 cells compared to doxorubicin. The N-(4-amino-2-((2-hydrazinyl-2-oxoethyl)thio)-6-oxo-1,6-dihydropyrimidin-5-yl)acetamide 5 and its p-nitrophenylhydrazone 8 were the study hits against MCF-7 (IC50 = 0.050 and 0.146 μM) and MDA-MB231 (IC50 = 0.826 and 0.583 μM), induced DNA damage at 10.64 and 30.03 nM, and inhibited CDK-2 (IC50 = 0.172 and 0.189 μM). 5 induced MCF-7 apoptosis by 46.75% and disrupted cell cycle during S phase. Docking and MD simulations postulated their stable key interactions.

Keywords: fluorescence; genetics; mixtures; cancerous diseases

Free keywords: apoptosis; cancer; fluorescence; genetics; mixtures

Contributing organizations

Ministry reporting: Yes

Reporting Year: 2024

Preliminary JUFO rating: 1