Activity of New Synthetic (2-Chloroethylthio)-1,4-naphthoquinones in Prostate Cancer Cells
Development of resistance to currently available standard therapies in advanced prostate cancer (PCa) emphasizes the need for novel therapeutic options. Here, we report the synthesis of new hybrid molecules consisting of 2-chloroethylthio and 1,4-naphthoquinone pharmacophores and describe their acti...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-09-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/14/10/949 |
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| author | Sergey A. Dyshlovoy Dmitry N. Pelageev Lea S. Jakob Ksenia L. Borisova Jessica Hauschild Tobias Busenbender Moritz Kaune Ekaterina A. Khmelevskaya Markus Graefen Carsten Bokemeyer Victor Ph. Anufriev Gunhild von Amsberg |
| author_facet | Sergey A. Dyshlovoy Dmitry N. Pelageev Lea S. Jakob Ksenia L. Borisova Jessica Hauschild Tobias Busenbender Moritz Kaune Ekaterina A. Khmelevskaya Markus Graefen Carsten Bokemeyer Victor Ph. Anufriev Gunhild von Amsberg |
| author_sort | Sergey A. Dyshlovoy |
| collection | DOAJ |
| description | Development of resistance to currently available standard therapies in advanced prostate cancer (PCa) emphasizes the need for novel therapeutic options. Here, we report the synthesis of new hybrid molecules consisting of 2-chloroethylthio and 1,4-naphthoquinone pharmacophores and describe their activity in PCa. In screening analyses, the introduction of one 2-chloroethylthio group improved the anticancer properties of 1,4-naphthoquinones, whereas the introduction of a second 2-chloroethylthio moiety rather decreased activity. Two most promising of the synthesized compounds, <b>30</b> and <b>32</b>, were highly active in different human PCa cell lines harboring varying resistance profiles at nanomolar concentrations. The generated data suggest that the compounds are capable of mitochondria targeting, cytotoxic ROS induction, and DNA damage, which resulted in apoptosis presumably executed in a caspase-dependent manner. The substances synergized with the clinically approved PARP inhibitor olaparib and resensitized AR-V7-expressing PCa cells to antiandrogen enzalutamide, as well as to a combination of enzalutamide and an AKT inhibitor. This was at least in part exerted via down-regulation of AR-V7 expression and inhibition of AR signaling. Mild antagonism was observed in combination with platinum- or taxane-based chemotherapy, which was putatively related to treatment-induced activation of p38, JNK1/2, ERK1/2, MEK1/2, and AKT, functioning as potential pro-survival factors. Thus, the synthesized (2-chloroethylthio)-1,4-naphthoquinone derivatives exhibit promising anticancer properties in vitro, suggesting their further development as potential therapeutics for the treatment of castration-resistant PCa. |
| first_indexed | 2024-03-10T06:17:15Z |
| format | Article |
| id | doaj.art-72851b83bf614af68fb86216a3d6a4f8 |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-10T06:17:15Z |
| publishDate | 2021-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-72851b83bf614af68fb86216a3d6a4f82023-11-22T19:34:55ZengMDPI AGPharmaceuticals1424-82472021-09-01141094910.3390/ph14100949Activity of New Synthetic (2-Chloroethylthio)-1,4-naphthoquinones in Prostate Cancer CellsSergey A. Dyshlovoy0Dmitry N. Pelageev1Lea S. Jakob2Ksenia L. Borisova3Jessica Hauschild4Tobias Busenbender5Moritz Kaune6Ekaterina A. Khmelevskaya7Markus Graefen8Carsten Bokemeyer9Victor Ph. Anufriev10Gunhild von Amsberg11Laboratory of Experimental Oncology, Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald-Tumorzentrum, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20251 Hamburg, GermanySchool of Natural Sciences, FEFU Campus, Far Eastern Federal University, Ajax Bay 10, Russky Island, 690922 Vladivostok, RussiaLaboratory of Experimental Oncology, Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald-Tumorzentrum, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20251 Hamburg, GermanyG.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far-East Branch, Russian Academy of Sciences, 690022 Vladivostok, RussiaLaboratory of Experimental Oncology, Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald-Tumorzentrum, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20251 Hamburg, GermanyLaboratory of Experimental Oncology, Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald-Tumorzentrum, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20251 Hamburg, GermanyLaboratory of Experimental Oncology, Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald-Tumorzentrum, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20251 Hamburg, GermanySchool of Natural Sciences, FEFU Campus, Far Eastern Federal University, Ajax Bay 10, Russky Island, 690922 Vladivostok, RussiaMartini-Klinik, Prostate Cancer Center, University Hospital Hamburg-Eppendorf, Martinistrasse 52, 20251 Hamburg, GermanyLaboratory of Experimental Oncology, Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald-Tumorzentrum, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20251 Hamburg, GermanyG.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far-East Branch, Russian Academy of Sciences, 690022 Vladivostok, RussiaLaboratory of Experimental Oncology, Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald-Tumorzentrum, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20251 Hamburg, GermanyDevelopment of resistance to currently available standard therapies in advanced prostate cancer (PCa) emphasizes the need for novel therapeutic options. Here, we report the synthesis of new hybrid molecules consisting of 2-chloroethylthio and 1,4-naphthoquinone pharmacophores and describe their activity in PCa. In screening analyses, the introduction of one 2-chloroethylthio group improved the anticancer properties of 1,4-naphthoquinones, whereas the introduction of a second 2-chloroethylthio moiety rather decreased activity. Two most promising of the synthesized compounds, <b>30</b> and <b>32</b>, were highly active in different human PCa cell lines harboring varying resistance profiles at nanomolar concentrations. The generated data suggest that the compounds are capable of mitochondria targeting, cytotoxic ROS induction, and DNA damage, which resulted in apoptosis presumably executed in a caspase-dependent manner. The substances synergized with the clinically approved PARP inhibitor olaparib and resensitized AR-V7-expressing PCa cells to antiandrogen enzalutamide, as well as to a combination of enzalutamide and an AKT inhibitor. This was at least in part exerted via down-regulation of AR-V7 expression and inhibition of AR signaling. Mild antagonism was observed in combination with platinum- or taxane-based chemotherapy, which was putatively related to treatment-induced activation of p38, JNK1/2, ERK1/2, MEK1/2, and AKT, functioning as potential pro-survival factors. Thus, the synthesized (2-chloroethylthio)-1,4-naphthoquinone derivatives exhibit promising anticancer properties in vitro, suggesting their further development as potential therapeutics for the treatment of castration-resistant PCa.https://www.mdpi.com/1424-8247/14/10/9491,4-naphthoquinone2-chloroethylthiocastration-resistant prostate cancerROSapoptosismitochondria |
| spellingShingle | Sergey A. Dyshlovoy Dmitry N. Pelageev Lea S. Jakob Ksenia L. Borisova Jessica Hauschild Tobias Busenbender Moritz Kaune Ekaterina A. Khmelevskaya Markus Graefen Carsten Bokemeyer Victor Ph. Anufriev Gunhild von Amsberg Activity of New Synthetic (2-Chloroethylthio)-1,4-naphthoquinones in Prostate Cancer Cells Pharmaceuticals 1,4-naphthoquinone 2-chloroethylthio castration-resistant prostate cancer ROS apoptosis mitochondria |
| title | Activity of New Synthetic (2-Chloroethylthio)-1,4-naphthoquinones in Prostate Cancer Cells |
| title_full | Activity of New Synthetic (2-Chloroethylthio)-1,4-naphthoquinones in Prostate Cancer Cells |
| title_fullStr | Activity of New Synthetic (2-Chloroethylthio)-1,4-naphthoquinones in Prostate Cancer Cells |
| title_full_unstemmed | Activity of New Synthetic (2-Chloroethylthio)-1,4-naphthoquinones in Prostate Cancer Cells |
| title_short | Activity of New Synthetic (2-Chloroethylthio)-1,4-naphthoquinones in Prostate Cancer Cells |
| title_sort | activity of new synthetic 2 chloroethylthio 1 4 naphthoquinones in prostate cancer cells |
| topic | 1,4-naphthoquinone 2-chloroethylthio castration-resistant prostate cancer ROS apoptosis mitochondria |
| url | https://www.mdpi.com/1424-8247/14/10/949 |
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