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. 2022 Jan 20;12(2):165.
doi: 10.3390/biom12020165.

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

Tomasz M Wróbel  1   2 , Oksana Rogova  1 , Katyayani Sharma  3   4 , Maria Natalia Rojas Velazquez  3   4 , Amit V Pandey  3   4 , Flemming Steen Jørgensen  1 , Frederic S Arendrup  5 , Kasper L Andersen  5 , Fredrik Björkling  1
Affiliations

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

Tomasz M Wróbel et al. Biomolecules. .

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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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Early hit compounds identified in the previous study.
Scheme 1
Scheme 1
Synthesis of compounds 1–8. Reaction conditions: (a) 1-bromo-4-fluorobenzene, K3PO4, DMF, 150–160 °C, 53–78%; (b) amine, precatalyst Pd G1 or G3, tBuXPhos, NaOtBu, THF or tBuOH, 21–73%.
Scheme 2
Scheme 2
Synthesis of compounds 9–11. Reaction conditions: (a) 1-fluoro-4-nitrobenzene, K3PO4, DMF 150 °C, 66% or 2-fluoro-5-nitropyridine, K3PO4, DMSO, rt, 74%; (b) 10% Pd/C, MeOH, rt, 82%; (c) bromide, precatalyst Pd G3, tBuBrettPhos, LHMDS, THF, 60 °C, 4–15%.
Scheme 3
Scheme 3
Synthesis of compound 12. Reaction conditions: (a) 4-hydroxyphenylboronic acid, O2, Cu2S, TMEDA, MeOH, rt, 71%; (b) 4-bromopyridine hydrochloride, NaOtBu, DMF, 150 °C, 32%.
Scheme 4
Scheme 4
Synthesis of compounds 13–16. Reaction conditions: (a) 1-bromo-4-fluorobenzene, K3PO4, DMF, 160 °C, 5–44%; (b) Boc2O, TEA, tBuOH, 40 °C, 74–90%; (c) 4-aminopyridine, precatalyst Pd G1, tBuXPhos, NaOtBu, tBuOH, 70 °C, 11–50%; (d) TFA, DCM, 23–50% (over two steps, c and d).
Scheme 5
Scheme 5
Synthesis of compounds 17–20. Reaction conditions: (a) 1-fluoro-4-nitrobenzene or fluoronitrotoluene, K3PO4, DMF, 160 °C, 18–93%; (b) 10% Pd/C, MeOH, rt, 91–96%; (c) 2- or 4-aminopyridine, precatalyst Pd G3, tBuXPhos, NaOtBu, THF, MW 100 °C, 23–32%.
Figure 2
Figure 2
Inhibition of CYP17A1 17α-hydroxylase activity by compounds 1–20 at 10 µM concentration.
Figure 3
Figure 3
Determination of IC50 of compounds 2, 12, and 20 for inhibition of the 17α-hydroxylase activity of CYP17A1.
Figure 4
Figure 4
The activity of compounds 2, 12, and 20 towards POR (A) and CYP3A4 (B).
Figure 5
Figure 5
Inhibition of CYP17A1 lyase reaction by compounds 2, 12, and 20.
Figure 6
Figure 6
Growth rate inhibition (GR) of compounds 1–20. All compounds were tested at 25 µM, with DMSO as a control and 5-fluorouracil (5-FU) and abiraterone (ABT) as reference compounds. The sign of the GR value relates directly to response phenotype: Values between 0 and 1 show partial growth inhibition, a value of 0 equals cytostasis, and values between 0 and −1 show that compounds are cytotoxic. Significant differences of growth in presence of compounds compared to DMSO were determined by the T-test and indicated by asterisks: ** p < 0.01, **** p < 0.0001.
Figure 7
Figure 7
Heat map showing the docking scores for cross-docking of substrates into the experimentally determined CYP17A1 structures.
Figure 8
Figure 8
Preferred binding mode predicted by the GOLD docking program of compound 2 (green) (A), 20 (green) in comparison with abiraterone (cyan) (B) and 12 in two docking poses (pose #1 green and pose #2 cyan) (C). Coloring: protein is beige; heme is yellow; and all heteroatoms are colored based on type.
Figure 9
Figure 9
Fe···N distances for the four CYP17A1–ligand complexes during the 100 ns molecular dynamics simulations.
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