New Quinoxaline-Based Derivatives as PARP-1 Inhibitors: Design, Synthesis, Antiproliferative, and Computational Studies
Herein, 2,3-dioxo-1,2,3,4-tetrahydroquinoxaline was used as a bio-isosteric scaffold to the phthalazinone motif of the standard drug Olaparib to design and synthesize new derivatives of potential PARP-1 inhibitory activity using the 6-sulfonohydrazide analog <b>3</b> as the key intermedi...
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MDPI AG
2022-08-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/27/15/4924 |
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| author | Yasmin M. Syam Manal M. Anwar Somaia S. Abd El-Karim Khaled M. Elokely Sameh H. Abdelwahed |
| author_facet | Yasmin M. Syam Manal M. Anwar Somaia S. Abd El-Karim Khaled M. Elokely Sameh H. Abdelwahed |
| author_sort | Yasmin M. Syam |
| collection | DOAJ |
| description | Herein, 2,3-dioxo-1,2,3,4-tetrahydroquinoxaline was used as a bio-isosteric scaffold to the phthalazinone motif of the standard drug Olaparib to design and synthesize new derivatives of potential PARP-1 inhibitory activity using the 6-sulfonohydrazide analog <b>3</b> as the key intermediate. Although the new compounds represented the PARP-1 suppression impact of IC<sub>50</sub> values in the nanomolar range, compounds <b>8a</b>, <b>5</b> were the most promising suppressors, producing IC<sub>50</sub> values of 2.31 and 3.05 nM compared to Olaparib with IC<sub>50</sub> of 4.40 nM. Compounds <b>4</b>, <b>10b</b>, and <b>11b</b> showed a mild decrease in the potency of the IC<sub>50</sub> range of 6.35–8.73 nM. Furthermore, compounds <b>4</b>, <b>5</b>, <b>8a</b>, <b>10b</b>, and <b>11b</b> were evaluated as in vitro antiproliferative agents against the mutant BRCA1 (MDA-MB-436, breast cancer) compared to Olaparib as a positive control. Compound <b>5</b> exhibited the most significant potency of IC<sub>50</sub>; 2.57 µM, whereas the IC<sub>50</sub> value of Olaparib was 8.90 µM. In addition, the examined derivatives displayed a promising safety profile against the normal WI-38 cell line. Cell cycle, apoptosis, and autophagy analyses were carried out in the MDA-MB-436 cell line for compound <b>5,</b> which exhibited cell growth arrest at the G2/M phase, in addition to induction of programmed apoptosis and an increase in the autophagic process. Molecular docking of the compounds <b>4</b>, <b>5</b>, <b>8a</b>, <b>10b</b>, and <b>11b</b> into the active site of PARP-1 was carried out to determine their modes of interaction. In addition, an in silico ADMET study was performed. The results evidenced that compound <b>5</b> could serve as a new framework for discovering new potent anticancer agents targeting the PARP-1 enzyme. |
| first_indexed | 2024-03-09T05:10:22Z |
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| last_indexed | 2024-03-09T05:10:22Z |
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| spelling | doaj.art-bb43890996e44af8bc37aa2d8e5e274d2023-12-03T12:50:31ZengMDPI AGMolecules1420-30492022-08-012715492410.3390/molecules27154924New Quinoxaline-Based Derivatives as PARP-1 Inhibitors: Design, Synthesis, Antiproliferative, and Computational StudiesYasmin M. Syam0Manal M. Anwar1Somaia S. Abd El-Karim2Khaled M. Elokely3Sameh H. Abdelwahed4Department of Therapeutic Chemistry, National Research Center, Dokki, Cairo 12622, EgyptDepartment of Therapeutic Chemistry, National Research Center, Dokki, Cairo 12622, EgyptDepartment of Therapeutic Chemistry, National Research Center, Dokki, Cairo 12622, EgyptInstitute for Computational Molecular Science, Department of Chemistry, Temple University, Philadelphia, PA 19122, USADepartment of Chemistry, Prairie View A&M University, Prairie View, TX 77446, USAHerein, 2,3-dioxo-1,2,3,4-tetrahydroquinoxaline was used as a bio-isosteric scaffold to the phthalazinone motif of the standard drug Olaparib to design and synthesize new derivatives of potential PARP-1 inhibitory activity using the 6-sulfonohydrazide analog <b>3</b> as the key intermediate. Although the new compounds represented the PARP-1 suppression impact of IC<sub>50</sub> values in the nanomolar range, compounds <b>8a</b>, <b>5</b> were the most promising suppressors, producing IC<sub>50</sub> values of 2.31 and 3.05 nM compared to Olaparib with IC<sub>50</sub> of 4.40 nM. Compounds <b>4</b>, <b>10b</b>, and <b>11b</b> showed a mild decrease in the potency of the IC<sub>50</sub> range of 6.35–8.73 nM. Furthermore, compounds <b>4</b>, <b>5</b>, <b>8a</b>, <b>10b</b>, and <b>11b</b> were evaluated as in vitro antiproliferative agents against the mutant BRCA1 (MDA-MB-436, breast cancer) compared to Olaparib as a positive control. Compound <b>5</b> exhibited the most significant potency of IC<sub>50</sub>; 2.57 µM, whereas the IC<sub>50</sub> value of Olaparib was 8.90 µM. In addition, the examined derivatives displayed a promising safety profile against the normal WI-38 cell line. Cell cycle, apoptosis, and autophagy analyses were carried out in the MDA-MB-436 cell line for compound <b>5,</b> which exhibited cell growth arrest at the G2/M phase, in addition to induction of programmed apoptosis and an increase in the autophagic process. Molecular docking of the compounds <b>4</b>, <b>5</b>, <b>8a</b>, <b>10b</b>, and <b>11b</b> into the active site of PARP-1 was carried out to determine their modes of interaction. In addition, an in silico ADMET study was performed. The results evidenced that compound <b>5</b> could serve as a new framework for discovering new potent anticancer agents targeting the PARP-1 enzyme.https://www.mdpi.com/1420-3049/27/15/4924quinoxalinePARP-1 inhibitorantiproliferativeMDA-MB-436WI-38cell cycle |
| spellingShingle | Yasmin M. Syam Manal M. Anwar Somaia S. Abd El-Karim Khaled M. Elokely Sameh H. Abdelwahed New Quinoxaline-Based Derivatives as PARP-1 Inhibitors: Design, Synthesis, Antiproliferative, and Computational Studies Molecules quinoxaline PARP-1 inhibitor antiproliferative MDA-MB-436 WI-38 cell cycle |
| title | New Quinoxaline-Based Derivatives as PARP-1 Inhibitors: Design, Synthesis, Antiproliferative, and Computational Studies |
| title_full | New Quinoxaline-Based Derivatives as PARP-1 Inhibitors: Design, Synthesis, Antiproliferative, and Computational Studies |
| title_fullStr | New Quinoxaline-Based Derivatives as PARP-1 Inhibitors: Design, Synthesis, Antiproliferative, and Computational Studies |
| title_full_unstemmed | New Quinoxaline-Based Derivatives as PARP-1 Inhibitors: Design, Synthesis, Antiproliferative, and Computational Studies |
| title_short | New Quinoxaline-Based Derivatives as PARP-1 Inhibitors: Design, Synthesis, Antiproliferative, and Computational Studies |
| title_sort | new quinoxaline based derivatives as parp 1 inhibitors design synthesis antiproliferative and computational studies |
| topic | quinoxaline PARP-1 inhibitor antiproliferative MDA-MB-436 WI-38 cell cycle |
| url | https://www.mdpi.com/1420-3049/27/15/4924 |
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