Synthesis and Structure–Activity Relationships of Novel Non-Steroidal CYP17A1 Inhibitors as Potential Prostate Cancer Agents

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

doi:10.3390/biom12020165

Synthesis and Structure–Activity Relationships of Novel Non-Steroidal CYP17A1 Inhibitors as Potential Prostate Cancer Agents

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

^*Corresponding author for this work

Research output: Contribution to journal › Journal article › Research › peer-review

7 Citations (Scopus)

24 Downloads (Pure)

Abstract

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 2, IC₅₀ 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.

Original language	English
Article number	165
Journal	Biomolecules
Volume	12
Issue number	2
ISSN	2218-273X
DOIs	https://doi.org/10.3390/biom12020165
Publication status	Published - 2022

Bibliographical note

Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

CYP17A1
Cytochrome P450 17A1
Enzyme inhibition
Prostate cancer

Access to Document

10.3390/biom12020165Licence: CC BY

FulltextFinal published version, 5.23 MBLicence: CC BY

Cite this

Synthesis and Structure–Activity Relationships of Novel Non-Steroidal CYP17A1 Inhibitors as Potential Prostate Cancer Agents. / Wróbel, Tomasz M.; Rogova, Oksana; Sharma, Katyayani; Velazquez, Maria Natalia Rojas; Pandey, Amit V.; Jørgensen, Flemming Steen ; Arendrup, Frederic S.; Andersen, Kasper L.; Björkling, Fredrik.

In: Biomolecules, Vol. 12, No. 2, 165, 2022.

Research output: Contribution to journal › Journal article › Research › peer-review

Wróbel, Tomasz M. ; Rogova, Oksana ; Sharma, Katyayani ; Velazquez, Maria Natalia Rojas ; Pandey, Amit V. ; Jørgensen, Flemming Steen ; Arendrup, Frederic S. ; Andersen, Kasper L. ; Björkling, Fredrik. / Synthesis and Structure–Activity Relationships of Novel Non-Steroidal CYP17A1 Inhibitors as Potential Prostate Cancer Agents. In: Biomolecules. 2022 ; Vol. 12, No. 2.

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title = "Synthesis and Structure–Activity Relationships of Novel Non-Steroidal CYP17A1 Inhibitors as Potential Prostate Cancer Agents",

abstract = "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 2, IC50 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.",

keywords = "CYP17A1, Cytochrome P450 17A1, Enzyme inhibition, Prostate cancer",

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AU - Pandey, Amit V.

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AB - 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 2, IC50 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.

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