Synthesis and Structure–Activity Relationships of Novel Non-Steroidal CYP17A1 Inhibitors as Potential Prostate Cancer Agents
Twenty new compounds, targeting CYP17A1, were synthesized, based on our previous work on a benzimidazole scaffold, and their biological activity evaluated. Inhibition of CYP17A1 is an important modality in the treatment of prostate cancer, which remains the most abundant cancer type in men. The biol...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-01-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/12/2/165 |
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| author | Tomasz M. Wróbel Oksana Rogova Katyayani Sharma Maria Natalia Rojas Velazquez Amit V. Pandey Flemming Steen Jørgensen Frederic S. Arendrup Kasper L. Andersen Fredrik Björkling |
| author_facet | Tomasz M. Wróbel Oksana Rogova Katyayani Sharma Maria Natalia Rojas Velazquez Amit V. Pandey Flemming Steen Jørgensen Frederic S. Arendrup Kasper L. Andersen Fredrik Björkling |
| author_sort | Tomasz M. Wróbel |
| collection | DOAJ |
| description | Twenty new compounds, targeting CYP17A1, were synthesized, based on our previous work on a benzimidazole scaffold, and their biological activity evaluated. Inhibition of CYP17A1 is an important modality in the treatment of prostate cancer, which remains the most abundant cancer type in men. The biological assessment included CYP17A1 hydroxylase and lyase inhibition, CYP3A4 and P450 oxidoreductase (POR) inhibition, as well as antiproliferative activity in PC3 prostate cancer cells. The most potent compounds were selected for further analyses including in silico modeling. This combined effort resulted in a compound (comp <b>2</b>, IC<sub>50</sub> 1.2 µM, in CYP17A1) with a potency comparable to abiraterone and selectivity towards the other targets tested. In addition, the data provided an understanding of the structure–activity relationship of this novel non-steroidal compound class. |
| first_indexed | 2024-03-09T22:30:52Z |
| format | Article |
| id | doaj.art-6056628f75504571a6d1428b90bed8b1 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-09T22:30:52Z |
| publishDate | 2022-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-6056628f75504571a6d1428b90bed8b12023-11-23T18:57:07ZengMDPI AGBiomolecules2218-273X2022-01-0112216510.3390/biom12020165Synthesis and Structure–Activity Relationships of Novel Non-Steroidal CYP17A1 Inhibitors as Potential Prostate Cancer AgentsTomasz M. Wróbel0Oksana Rogova1Katyayani Sharma2Maria Natalia Rojas Velazquez3Amit V. Pandey4Flemming Steen Jørgensen5Frederic S. Arendrup6Kasper L. Andersen7Fredrik Björkling8Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, DenmarkDepartment of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, DenmarkDivision of Pediatric Endocrinology, Department of Pediatrics, University Children’s Hospital Bern, 3010 Bern, SwitzerlandDivision of Pediatric Endocrinology, Department of Pediatrics, University Children’s Hospital Bern, 3010 Bern, SwitzerlandDivision of Pediatric Endocrinology, Department of Pediatrics, University Children’s Hospital Bern, 3010 Bern, SwitzerlandDepartment of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, DenmarkBiotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, DK-2200 Copenhagen, DenmarkBiotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, DK-2200 Copenhagen, DenmarkDepartment of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, DenmarkTwenty new compounds, targeting CYP17A1, were synthesized, based on our previous work on a benzimidazole scaffold, and their biological activity evaluated. Inhibition of CYP17A1 is an important modality in the treatment of prostate cancer, which remains the most abundant cancer type in men. The biological assessment included CYP17A1 hydroxylase and lyase inhibition, CYP3A4 and P450 oxidoreductase (POR) inhibition, as well as antiproliferative activity in PC3 prostate cancer cells. The most potent compounds were selected for further analyses including in silico modeling. This combined effort resulted in a compound (comp <b>2</b>, IC<sub>50</sub> 1.2 µM, in CYP17A1) with a potency comparable to abiraterone and selectivity towards the other targets tested. In addition, the data provided an understanding of the structure–activity relationship of this novel non-steroidal compound class.https://www.mdpi.com/2218-273X/12/2/165cytochrome P450 17A1CYP17A1prostate cancerenzyme inhibition |
| spellingShingle | Tomasz M. Wróbel Oksana Rogova Katyayani Sharma Maria Natalia Rojas Velazquez Amit V. Pandey Flemming Steen Jørgensen Frederic S. Arendrup Kasper L. Andersen Fredrik Björkling Synthesis and Structure–Activity Relationships of Novel Non-Steroidal CYP17A1 Inhibitors as Potential Prostate Cancer Agents Biomolecules cytochrome P450 17A1 CYP17A1 prostate cancer enzyme inhibition |
| title | Synthesis and Structure–Activity Relationships of Novel Non-Steroidal CYP17A1 Inhibitors as Potential Prostate Cancer Agents |
| title_full | Synthesis and Structure–Activity Relationships of Novel Non-Steroidal CYP17A1 Inhibitors as Potential Prostate Cancer Agents |
| title_fullStr | Synthesis and Structure–Activity Relationships of Novel Non-Steroidal CYP17A1 Inhibitors as Potential Prostate Cancer Agents |
| title_full_unstemmed | Synthesis and Structure–Activity Relationships of Novel Non-Steroidal CYP17A1 Inhibitors as Potential Prostate Cancer Agents |
| title_short | Synthesis and Structure–Activity Relationships of Novel Non-Steroidal CYP17A1 Inhibitors as Potential Prostate Cancer Agents |
| title_sort | synthesis and structure activity relationships of novel non steroidal cyp17a1 inhibitors as potential prostate cancer agents |
| topic | cytochrome P450 17A1 CYP17A1 prostate cancer enzyme inhibition |
| url | https://www.mdpi.com/2218-273X/12/2/165 |
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