Pyrimidine-5-carbonitrile based potential anticancer agents as apoptosis inducers through PI3K/AKT axis inhibition in leukaemia K562
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 w...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2022-12-01
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| Series: | Journal of Enzyme Inhibition and Medicinal Chemistry |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/14756366.2022.2051022 |
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| author | Nehad M. El-Dydamony Rana M. Abdelnaby Rasha Abdelhady Omaima Ali Mohamed I. Fahmy Rasha R. Fakhr Eldeen Amira A. Helwa |
| author_facet | Nehad M. El-Dydamony Rana M. Abdelnaby Rasha Abdelhady Omaima Ali Mohamed I. Fahmy Rasha R. Fakhr Eldeen Amira A. Helwa |
| author_sort | Nehad M. El-Dydamony |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-18T02:49:12Z |
| format | Article |
| id | doaj.art-f13f7a6bc3734aa3a3614d7d68524661 |
| institution | Directory Open Access Journal |
| issn | 1475-6366 1475-6374 |
| language | English |
| last_indexed | 2024-12-18T02:49:12Z |
| publishDate | 2022-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Journal of Enzyme Inhibition and Medicinal Chemistry |
| spelling | doaj.art-f13f7a6bc3734aa3a3614d7d685246612022-12-21T21:23:30ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742022-12-0137189591110.1080/14756366.2022.2051022Pyrimidine-5-carbonitrile based potential anticancer agents as apoptosis inducers through PI3K/AKT axis inhibition in leukaemia K562Nehad M. El-Dydamony0Rana M. Abdelnaby1Rasha Abdelhady2Omaima Ali3Mohamed I. Fahmy4Rasha R. Fakhr Eldeen5Amira A. Helwa6Pharmaceutical Chemistry Department, College of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology, 6th of October City, EgyptPharmaceutical Chemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo, EgyptPharmacology and Toxicology Department, Faculty of Pharmacy, Fayoum University, Fayoum, EgyptCell Line Unit, Egyptian Drug Authority (EDA), Cairo, EgyptPharmacology and Toxicology Department, Faculty of Pharmacy, Heliopolis University, Cairo, EgyptBiochemistry Department, College of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology, 6th of October City, EgyptPharmaceutical Organic Chemistry Department, College of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology, 6th of October City, EgyptA 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.https://www.tandfonline.com/doi/10.1080/14756366.2022.2051022Pyrimidine-5-carbonitrileleukaemia (K562)breast cancer (MCF-7)PI3K/AKT pathwayapoptosis |
| spellingShingle | Nehad M. El-Dydamony Rana M. Abdelnaby Rasha Abdelhady Omaima Ali Mohamed I. Fahmy Rasha R. Fakhr Eldeen Amira A. Helwa Pyrimidine-5-carbonitrile based potential anticancer agents as apoptosis inducers through PI3K/AKT axis inhibition in leukaemia K562 Journal of Enzyme Inhibition and Medicinal Chemistry Pyrimidine-5-carbonitrile leukaemia (K562) breast cancer (MCF-7) PI3K/AKT pathway apoptosis |
| title | Pyrimidine-5-carbonitrile based potential anticancer agents as apoptosis inducers through PI3K/AKT axis inhibition in leukaemia K562 |
| title_full | Pyrimidine-5-carbonitrile based potential anticancer agents as apoptosis inducers through PI3K/AKT axis inhibition in leukaemia K562 |
| title_fullStr | Pyrimidine-5-carbonitrile based potential anticancer agents as apoptosis inducers through PI3K/AKT axis inhibition in leukaemia K562 |
| title_full_unstemmed | Pyrimidine-5-carbonitrile based potential anticancer agents as apoptosis inducers through PI3K/AKT axis inhibition in leukaemia K562 |
| title_short | Pyrimidine-5-carbonitrile based potential anticancer agents as apoptosis inducers through PI3K/AKT axis inhibition in leukaemia K562 |
| title_sort | pyrimidine 5 carbonitrile based potential anticancer agents as apoptosis inducers through pi3k akt axis inhibition in leukaemia k562 |
| topic | Pyrimidine-5-carbonitrile leukaemia (K562) breast cancer (MCF-7) PI3K/AKT pathway apoptosis |
| url | https://www.tandfonline.com/doi/10.1080/14756366.2022.2051022 |
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