Design, synthesis and biological evaluation of novel pyrazolochalcones as potential modulators of PI3K/Akt/mTOR pathway and inducers of apoptosis in breast cancer cells
| Autor: | Garikapati Koteswara Rao, Ahmed Kamal, Sunitha Rani Routhu, Aarti Juvekar, Vangala Santhosh Reddy, Immadi Veena, Shailesh Jadhav, Madan Barkume, Nibedita Patel, Anver Basha Shaik, Irfan Khan, Kunta Chandra Shekar, C. Ganesh Kumar, Manika Pal-Bhadra, G. Bharath Kumar, Jyoti Kode |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Cell cycle checkpoint Antineoplastic Agents Apoptosis Breast Neoplasms Pharmacology 03 medical and health sciences chemistry.chemical_compound Phosphatidylinositol 3-Kinases Structure-Activity Relationship 0302 clinical medicine Chalcones Drug Discovery medicine PTEN Humans Protein kinase B Protein Kinase Inhibitors PI3K/AKT/mTOR pathway Phosphoinositide-3 Kinase Inhibitors biology Dose-Response Relationship Drug Molecular Structure TOR Serine-Threonine Kinases Organic Chemistry RPTOR Cancer General Medicine medicine.disease 030104 developmental biology chemistry 030220 oncology & carcinogenesis Drug Design biology.protein MCF-7 Cells Pyrazoles Female Growth inhibition Proto-Oncogene Proteins c-akt |
| Zdroj: | European journal of medicinal chemistry. 139 |
| ISSN: | 1768-3254 |
| Popis: | Cancer has been established as the "Emperor of all maladies". In recent years, medicinal chemistry has focused on identifying novel anti-cancer compounds; though discovery of these compounds appears to be a herculean task. In present study, we synthesized forty pyrazolochalcone conjugates and explored their cytotoxic activity against a panel of sixty cancer cell lines. Fifteen conjugates of the series showed excellent growth inhibition (13b-e, 13h-j, 14c-d, 15 a, 15 c-d, 16b, 16d and 18f; GI50 for MCF-7: 0.4-20 μM). Conjugates 13b, 13c, 13d, 16b and 14d were also evaluated for their cytotoxic activity in human breast cancer cell line (MCF-7). The promising candidates induced cell cycle arrest, mitochondrial membrane depolarization and apoptosis in MCF-7 cells at a 2 μM concentration. Furthermore, inhibition of PI3K/Akt/mTOR pathway-regulators such as PI3K, p-PI3K, p-AKT, and mTOR were observed; as well as upregulation of p-GSK3β and tumor-suppressor protein, PTEN. Our study indicates that pyrazolochalcone conjugates could serve as potential leads in the development of tailored cancer therapeutics. |
| Databáze: | OpenAIRE |
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