Synthesis, In Vitro Antiproliferative Activity, and In Silico Evaluation of Novel Oxiranyl-Quinoxaline Derivatives
The quinoxaline core is a promising scaffold in medicinal chemistry. Multiple quinoxaline derivatives, such as the topoisomerase IIβ inhibitor XK-469 and the tissue transglutaminase 2 inhibitor GK-13, have been evaluated for their antiproliferative activity. Previous work reported that quinoxaline d...
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MDPI AG
2022-06-01
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| Online Access: | https://www.mdpi.com/1424-8247/15/7/781 |
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| author | Vincent Montero Marc Montana Omar Khoumeri Florian Correard Marie-Anne Estève Patrice Vanelle |
| author_facet | Vincent Montero Marc Montana Omar Khoumeri Florian Correard Marie-Anne Estève Patrice Vanelle |
| author_sort | Vincent Montero |
| collection | DOAJ |
| description | The quinoxaline core is a promising scaffold in medicinal chemistry. Multiple quinoxaline derivatives, such as the topoisomerase IIβ inhibitor XK-469 and the tissue transglutaminase 2 inhibitor GK-13, have been evaluated for their antiproliferative activity. Previous work reported that quinoxaline derivatives bearing an oxirane ring present antiproliferative properties against neuroblastoma cell lines SK-N-SH and IMR-32. Likewise, quinoxalines with an arylethynyl group displayed promising antineoplastic properties against glioblastoma and lung cancer cell lines, U87-MG and A549 respectively. Here, 40 new quinoxaline derivatives bearing an oxirane ring were synthesized using a tetrakis(dimethylamino)ethylene (TDAE) strategy and a Sonogashira cross-coupling reaction. Each reaction with TDAE furnished a pair of diastereoisomers <i>cis</i> and <i>trans</i>. These new compounds formed two series according to the substitution of position 2 on the quinoxaline core, with chlorine or phenylacetylene respectively. Each of these isomers was evaluated for antiproliferative activity against neuroblastoma cell lines SK-N-SH and IMR-32 by MTT assay. All cell viability assay results were analyzed using R programming, as well as a statistical comparison between groups of compounds. Our evaluation showed no difference in drug sensitivity between the two neuroblastoma cell lines. Moreover, <i>trans</i> derivatives were observed to display better activities than <i>cis</i> derivatives, leading us to conclude that stereochemistry plays an important role in the antiproliferative activity of these compounds. Further support for this hypothesis is provided by the lack of improvement in antineoplastic activity following the addition of the phenylacetylene moiety, probably due to steric hindrance. As a result, compounds with nitrofuran substituents from the TDAE series demonstrated the highest antiproliferative activity with IC<sub>50</sub> = 2.49 ± 1.33 μM and IC<sub>50</sub> = 3.96 ± 2.03 μM for compound <b>11a</b> and IC<sub>50</sub> = 5.3 ± 2.12 μM and IC<sub>50</sub> = 7.12 ± 1.59 μM for compound <b>11b</b> against SK-N-SH and IMR-32, respectively. Furthermore, an in silico study was carried out to evaluate the mechanism of action of our lead compounds and predict their pharmacokinetic properties. |
| first_indexed | 2024-03-09T10:13:58Z |
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| id | doaj.art-f1879b366f0e4117bf052ba3612655ba |
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| language | English |
| last_indexed | 2024-03-09T10:13:58Z |
| publishDate | 2022-06-01 |
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| spelling | doaj.art-f1879b366f0e4117bf052ba3612655ba2023-12-01T22:33:08ZengMDPI AGPharmaceuticals1424-82472022-06-0115778110.3390/ph15070781Synthesis, In Vitro Antiproliferative Activity, and In Silico Evaluation of Novel Oxiranyl-Quinoxaline DerivativesVincent Montero0Marc Montana1Omar Khoumeri2Florian Correard3Marie-Anne Estève4Patrice Vanelle5Aix Marseille Univ, CNRS, ICR UMR 7273, Equipe Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, CEDEX 05, 13385 Marseille, FranceAix Marseille Univ, CNRS, ICR UMR 7273, Equipe Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, CEDEX 05, 13385 Marseille, FranceAix Marseille Univ, CNRS, ICR UMR 7273, Equipe Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, CEDEX 05, 13385 Marseille, FranceAix Marseille Univ, CNRS, INP, Inst Neurophysiopathol, CEDEX 05, 13385 Marseille, FranceAix Marseille Univ, CNRS, INP, Inst Neurophysiopathol, CEDEX 05, 13385 Marseille, FranceAix Marseille Univ, CNRS, ICR UMR 7273, Equipe Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, CEDEX 05, 13385 Marseille, FranceThe quinoxaline core is a promising scaffold in medicinal chemistry. Multiple quinoxaline derivatives, such as the topoisomerase IIβ inhibitor XK-469 and the tissue transglutaminase 2 inhibitor GK-13, have been evaluated for their antiproliferative activity. Previous work reported that quinoxaline derivatives bearing an oxirane ring present antiproliferative properties against neuroblastoma cell lines SK-N-SH and IMR-32. Likewise, quinoxalines with an arylethynyl group displayed promising antineoplastic properties against glioblastoma and lung cancer cell lines, U87-MG and A549 respectively. Here, 40 new quinoxaline derivatives bearing an oxirane ring were synthesized using a tetrakis(dimethylamino)ethylene (TDAE) strategy and a Sonogashira cross-coupling reaction. Each reaction with TDAE furnished a pair of diastereoisomers <i>cis</i> and <i>trans</i>. These new compounds formed two series according to the substitution of position 2 on the quinoxaline core, with chlorine or phenylacetylene respectively. Each of these isomers was evaluated for antiproliferative activity against neuroblastoma cell lines SK-N-SH and IMR-32 by MTT assay. All cell viability assay results were analyzed using R programming, as well as a statistical comparison between groups of compounds. Our evaluation showed no difference in drug sensitivity between the two neuroblastoma cell lines. Moreover, <i>trans</i> derivatives were observed to display better activities than <i>cis</i> derivatives, leading us to conclude that stereochemistry plays an important role in the antiproliferative activity of these compounds. Further support for this hypothesis is provided by the lack of improvement in antineoplastic activity following the addition of the phenylacetylene moiety, probably due to steric hindrance. As a result, compounds with nitrofuran substituents from the TDAE series demonstrated the highest antiproliferative activity with IC<sub>50</sub> = 2.49 ± 1.33 μM and IC<sub>50</sub> = 3.96 ± 2.03 μM for compound <b>11a</b> and IC<sub>50</sub> = 5.3 ± 2.12 μM and IC<sub>50</sub> = 7.12 ± 1.59 μM for compound <b>11b</b> against SK-N-SH and IMR-32, respectively. Furthermore, an in silico study was carried out to evaluate the mechanism of action of our lead compounds and predict their pharmacokinetic properties.https://www.mdpi.com/1424-8247/15/7/781ligand-based drug designantiproliferative activityanticancer drugneuroblastomaquinoxalinediastereoisomer |
| spellingShingle | Vincent Montero Marc Montana Omar Khoumeri Florian Correard Marie-Anne Estève Patrice Vanelle Synthesis, In Vitro Antiproliferative Activity, and In Silico Evaluation of Novel Oxiranyl-Quinoxaline Derivatives Pharmaceuticals ligand-based drug design antiproliferative activity anticancer drug neuroblastoma quinoxaline diastereoisomer |
| title | Synthesis, In Vitro Antiproliferative Activity, and In Silico Evaluation of Novel Oxiranyl-Quinoxaline Derivatives |
| title_full | Synthesis, In Vitro Antiproliferative Activity, and In Silico Evaluation of Novel Oxiranyl-Quinoxaline Derivatives |
| title_fullStr | Synthesis, In Vitro Antiproliferative Activity, and In Silico Evaluation of Novel Oxiranyl-Quinoxaline Derivatives |
| title_full_unstemmed | Synthesis, In Vitro Antiproliferative Activity, and In Silico Evaluation of Novel Oxiranyl-Quinoxaline Derivatives |
| title_short | Synthesis, In Vitro Antiproliferative Activity, and In Silico Evaluation of Novel Oxiranyl-Quinoxaline Derivatives |
| title_sort | synthesis in vitro antiproliferative activity and in silico evaluation of novel oxiranyl quinoxaline derivatives |
| topic | ligand-based drug design antiproliferative activity anticancer drug neuroblastoma quinoxaline diastereoisomer |
| url | https://www.mdpi.com/1424-8247/15/7/781 |
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