Molecular Docking and Biophysical Studies for Antiproliferative Assessment of Synthetic Pyrazolo-Pyrimidinones Tethered with Hydrazide-Hydrazones
Chemotherapy represents the most applied approach to cancer treatment. Owing to the frequent onset of chemoresistance and tumor relapses, there is an urgent need to discover novel and more effective anticancer drugs. In the search for therapeutic alternatives to treat the cancer disease, a series of...
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MDPI AG
2021-03-01
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| Series: | International Journal of Molecular Sciences |
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| author | Mabrouk Horchani Gerardo Della Sala Alessia Caso Federica D’Aria Germana Esposito Ilaria Laurenzana Concetta Giancola Valeria Costantino Hichem Ben Jannet Anis Romdhane |
| author_facet | Mabrouk Horchani Gerardo Della Sala Alessia Caso Federica D’Aria Germana Esposito Ilaria Laurenzana Concetta Giancola Valeria Costantino Hichem Ben Jannet Anis Romdhane |
| author_sort | Mabrouk Horchani |
| collection | DOAJ |
| description | Chemotherapy represents the most applied approach to cancer treatment. Owing to the frequent onset of chemoresistance and tumor relapses, there is an urgent need to discover novel and more effective anticancer drugs. In the search for therapeutic alternatives to treat the cancer disease, a series of hybrid pyrazolo[3,4-<i>d</i>]pyrimidin-4(<i>5H</i>)-ones tethered with hydrazide-hydrazones, <b>5a</b>–<b>h</b>, was synthesized from condensation reaction of pyrazolopyrimidinone-hydrazide <b>4</b> with a series of arylaldehydes in ethanol, in acid catalysis. In vitro assessment of antiproliferative effects against MCF-7 breast cancer cells, unveiled that <b>5a</b>, <b>5e</b>, <b>5g</b>, and <b>5h</b> were the most effective compounds of the series and exerted their cytotoxic activity through apoptosis induction and G0/G1 phase cell-cycle arrest. To explore their mechanism at a molecular level, <b>5a</b>, <b>5e</b>, <b>5g</b>, and <b>5h</b> were evaluated for their binding interactions with two well-known anticancer targets, namely the epidermal growth factor receptor (EGFR) and the G-quadruplex DNA structures. Molecular docking simulations highlighted high binding affinity of <b>5a</b>, <b>5e</b>, <b>5g</b>, and <b>5h</b> towards EGFR. Circular dichroism (CD) experiments suggested <b>5a</b> as a stabilizer agent of the G-quadruplex from the <i>Kirsten ras</i> (KRAS) oncogene promoter. In the light of these findings, we propose the pyrazolo-pyrimidinone scaffold bearing a hydrazide-hydrazone moiety as a lead skeleton for designing novel anticancer compounds. |
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| format | Article |
| id | doaj.art-2203faf61a6449a39e59ce870d0fdfac |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T13:25:50Z |
| publishDate | 2021-03-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-2203faf61a6449a39e59ce870d0fdfac2023-11-21T09:38:47ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-03-01225274210.3390/ijms22052742Molecular Docking and Biophysical Studies for Antiproliferative Assessment of Synthetic Pyrazolo-Pyrimidinones Tethered with Hydrazide-HydrazonesMabrouk Horchani0Gerardo Della Sala1Alessia Caso2Federica D’Aria3Germana Esposito4Ilaria Laurenzana5Concetta Giancola6Valeria Costantino7Hichem Ben Jannet8Anis Romdhane9Laboratory of Heterocyclic Chemistry, Natural Products and Reactivity, Medicinal Chemistry and Natural Products (LR11ES39), Faculty of Sciences of Monastir, University of Monastir, 5000 Monastir, TunisiaDepartment of Marine Biotechnology, Stazione Zoologica Anton Dohrn, Villa Comunale, 80125 Naples, ItalyThe Blue Chemistry Lab, Department of Pharmacy, University of Naples Federico II, Via D. Montesano 49, 80131 Naples, ItalyDepartment of Pharmacy, University of Naples Federico II, Via D. Montesano 49, 80131 Naples, ItalyThe Blue Chemistry Lab, Department of Pharmacy, University of Naples Federico II, Via D. Montesano 49, 80131 Naples, ItalyLaboratory of Pre-Clinical and Translational Research, IRCCS-CROB, Referral Cancer Center of Basilicata, 85028 Rionero in Vulture, ItalyDepartment of Pharmacy, University of Naples Federico II, Via D. Montesano 49, 80131 Naples, ItalyThe Blue Chemistry Lab, Department of Pharmacy, University of Naples Federico II, Via D. Montesano 49, 80131 Naples, ItalyLaboratory of Heterocyclic Chemistry, Natural Products and Reactivity, Medicinal Chemistry and Natural Products (LR11ES39), Faculty of Sciences of Monastir, University of Monastir, 5000 Monastir, TunisiaLaboratory of Heterocyclic Chemistry, Natural Products and Reactivity, Medicinal Chemistry and Natural Products (LR11ES39), Faculty of Sciences of Monastir, University of Monastir, 5000 Monastir, TunisiaChemotherapy represents the most applied approach to cancer treatment. Owing to the frequent onset of chemoresistance and tumor relapses, there is an urgent need to discover novel and more effective anticancer drugs. In the search for therapeutic alternatives to treat the cancer disease, a series of hybrid pyrazolo[3,4-<i>d</i>]pyrimidin-4(<i>5H</i>)-ones tethered with hydrazide-hydrazones, <b>5a</b>–<b>h</b>, was synthesized from condensation reaction of pyrazolopyrimidinone-hydrazide <b>4</b> with a series of arylaldehydes in ethanol, in acid catalysis. In vitro assessment of antiproliferative effects against MCF-7 breast cancer cells, unveiled that <b>5a</b>, <b>5e</b>, <b>5g</b>, and <b>5h</b> were the most effective compounds of the series and exerted their cytotoxic activity through apoptosis induction and G0/G1 phase cell-cycle arrest. To explore their mechanism at a molecular level, <b>5a</b>, <b>5e</b>, <b>5g</b>, and <b>5h</b> were evaluated for their binding interactions with two well-known anticancer targets, namely the epidermal growth factor receptor (EGFR) and the G-quadruplex DNA structures. Molecular docking simulations highlighted high binding affinity of <b>5a</b>, <b>5e</b>, <b>5g</b>, and <b>5h</b> towards EGFR. Circular dichroism (CD) experiments suggested <b>5a</b> as a stabilizer agent of the G-quadruplex from the <i>Kirsten ras</i> (KRAS) oncogene promoter. In the light of these findings, we propose the pyrazolo-pyrimidinone scaffold bearing a hydrazide-hydrazone moiety as a lead skeleton for designing novel anticancer compounds.https://www.mdpi.com/1422-0067/22/5/2742pyrazolopyrimidinonehydrazide-hydrazoneantitumor lead compoundcytotoxic activityantiproliferative activitymolecular docking |
| spellingShingle | Mabrouk Horchani Gerardo Della Sala Alessia Caso Federica D’Aria Germana Esposito Ilaria Laurenzana Concetta Giancola Valeria Costantino Hichem Ben Jannet Anis Romdhane Molecular Docking and Biophysical Studies for Antiproliferative Assessment of Synthetic Pyrazolo-Pyrimidinones Tethered with Hydrazide-Hydrazones International Journal of Molecular Sciences pyrazolopyrimidinone hydrazide-hydrazone antitumor lead compound cytotoxic activity antiproliferative activity molecular docking |
| title | Molecular Docking and Biophysical Studies for Antiproliferative Assessment of Synthetic Pyrazolo-Pyrimidinones Tethered with Hydrazide-Hydrazones |
| title_full | Molecular Docking and Biophysical Studies for Antiproliferative Assessment of Synthetic Pyrazolo-Pyrimidinones Tethered with Hydrazide-Hydrazones |
| title_fullStr | Molecular Docking and Biophysical Studies for Antiproliferative Assessment of Synthetic Pyrazolo-Pyrimidinones Tethered with Hydrazide-Hydrazones |
| title_full_unstemmed | Molecular Docking and Biophysical Studies for Antiproliferative Assessment of Synthetic Pyrazolo-Pyrimidinones Tethered with Hydrazide-Hydrazones |
| title_short | Molecular Docking and Biophysical Studies for Antiproliferative Assessment of Synthetic Pyrazolo-Pyrimidinones Tethered with Hydrazide-Hydrazones |
| title_sort | molecular docking and biophysical studies for antiproliferative assessment of synthetic pyrazolo pyrimidinones tethered with hydrazide hydrazones |
| topic | pyrazolopyrimidinone hydrazide-hydrazone antitumor lead compound cytotoxic activity antiproliferative activity molecular docking |
| url | https://www.mdpi.com/1422-0067/22/5/2742 |
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