2. Academic Validation
  3. Pyrimidine-5-carbonitrile based potential anticancer agents as apoptosis inducers through PI3K/AKT axis inhibition in leukaemia K562

Pyrimidine-5-carbonitrile based potential anticancer agents as apoptosis inducers through PI3K/AKT axis inhibition in leukaemia K562

  • J Enzyme Inhib Med Chem. 2022 Dec;37(1):895-911. doi: 10.1080/14756366.2022.2051022.
Nehad M El-Dydamony 1,  Rana M Abdelnaby 2,  Rasha Abdelhady 3,  Omaima Ali 4,  Mohamed I Fahmy 5,  Rasha R Fakhr Eldeen 6,  Amira A Helwa 7
Affiliations

Affiliations

  • 1 Pharmaceutical Chemistry Department, College of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology, 6th of October City, Egypt.
  • 2 Pharmaceutical Chemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo, Egypt.
  • 3 Pharmacology and Toxicology Department, Faculty of Pharmacy, Fayoum University, Fayoum, Egypt.
  • 4 Cell Line Unit, Egyptian Drug Authority (EDA), Cairo, Egypt.
  • 5 Pharmacology and Toxicology Department, Faculty of Pharmacy, Heliopolis University, Cairo, Egypt.
  • 6 Biochemistry Department, College of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology, 6th of October City, Egypt.
  • 7 Pharmaceutical Organic Chemistry Department, College of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology, 6th of October City, Egypt.
PMID: 35345960 DOI: 10.1080/14756366.2022.2051022
Abstract

A novel series of 4-(4-Methoxyphenyl)-2-(methylthio)pyrimidine-5-carbonitrile was developed linked to an aromatic moiety via N-containing bridge and then evaluated for their cytotoxic activity against MCF-7 and K562 cell lines. Seven compounds exhibited the highest activity against both cell lines where compounds 4d and 7f were the most active against K562 cell line. Exploring their molecular mechanisms by Enzyme inhibition assay on PI3Kδ/γ and AKT-1 showed that compound 7f was promising more than 4d with IC50 = 6.99 ± 0.36, 4.01 ± 0.55, and 3.36 ± 0.17 uM, respectively. Also, flowcytometric analysis revealed that 7f caused cell cycle arrest at S-phase followed by Caspase 3 dependent Apoptosis induction. Mechanistically, compound 7f proved to modulate the expression of PI3K, p-PI3K, Akt, p-AKT, Cyclin D1, and NFΚβ. Furthermore, in-vivo toxicity study indicated good safety profile for 7f. These findings suggest that the trimethoxy derivative 7f has strong potential as a multi-acting inhibitor on PI3K/Akt axis targeting breast Cancer and leukaemia.

Keywords

PI3K/AKT pathway; Pyrimidine-5-carbonitrile; apoptosis; breast cancer (MCF-7); leukaemia (K562).

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