Description of Chemical Synthesis, Nuclear Magnetic Resonance Characterization and Biological Activity of Estrane-Based Inhibitors/Activators of Steroidogenesis
Abstract
:1. Introduction
2. Chemical Synthesis of Inhibitors 1–7 and Activator 8
3. NMR Characterization of Inhibitors 1–7 and Activator 8
4. Biological Activity of Inhibitors 1–7 and Activator 8
Cpd | Type | Enzyme | IC50 (Ki) in nM | EC50 in nM | Other 1 | Ref |
---|---|---|---|---|---|---|
1 | Inh | STS | 0.024 2 | -- | Irreversible Inh; Not estrogenic and not androgenic in mice and rats; Blocks E1S, E2S, and DHEAS transformations in cells and mouse/rat tissues | [27,52,53] |
2 | Inh | 17β-HSD1 | 27–44 3 (0.9) | -- | Reversible Inh; Weakly estrogenic in cells and mice | [29,57] |
3 | Inh | 17β-HSD1 | 68–83 3 (368) | -- | Irreversible Inh (Kinact = 0.087 min−1); Not estrogenic in cells and mice; Blocks E1- and DHEA-tumor growth in mice; Orally active | [58,59,60,61,62,63] |
4 | Inh | 17β-HSD2 | 63 4 (29) | -- | Reversible Inh; Potentially estrogenic; NTAM | [35] |
5 | Inh | 17β-HSD5 (AKR1C3) | 2.9 5 | -- | Not androgenic and weakly estrogenic in cells; NTAM | [36] |
6 | Inh | 17β-HSD3 | 100–110 6 | -- | Reduces androgen (AR+)-dependent cells; NTAM | [38] |
7 | Inh | 17β-HSD12 | 560 7 | -- | NTAM | [75] |
8 | Act | 17β-HSD12 | -- | 7500 8 | NTAM | [42] |
5. Conclusions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Sample Availability
References
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E2 [41] 1 | E2 [42] 2 | E2 [42] 2 | 1 3 | 1 3 | 2 4 | 2 4 | 3 4 | 3 4 | |
---|---|---|---|---|---|---|---|---|---|
C/H | 13C | 13C | 1H | 13C | 1H | 13C | 1H | 13C | 1H |
1 | 126.9 | 126.0 | 7.00d | 110.4 | 7.06s | 127.1 | 7.07d | 126.4 | 7.22d |
2 | 113.5 | 112.7 | 6.47dd | 148.9 | -- | 113.7 | 6.52dd | 127.2 | 6.97d |
3 | 155.6 | 154.8 | -- | 140.4 | -- | 155.8 | -- | 137.4 | -- |
4 | 115.9 | 114.9 | 6.39d | 124.1 | 6.96s | 116.0 | 6.45d | 130.1 | 6.91s |
5 | 138.4 | 137.1 | -- | 130.2 | -- | 138.7 | -- | 137.8 | -- |
6 | 30.2 | 29.1 | 2.67m | 28.6 | 2.82m | 33.0 | 2.72m | 33.0 | 2.82m |
7 | 28.7 | 26.9 | na | 26.4 | na | 28.6 | na | 28.5 | na |
8 | 39.8 | 38.7 | na | 39.1 | na | 39.8 | na | 39.6 | na |
9 | 44.8 | 43.5 | na | 44.3 | na | 45.3 | na | 45.7 | na |
10 | 132.3 | 130.4 | -- | 136.8 | -- | 132.6 | -- | 140.0 | -- |
11 | 27.1 | 26.0 | na | 27.3 | na | 27.5 | na | 27.3 | na |
12 | 37.6 | 36.5 | na | 31.4 | na | 38.9 | na | 38.9 | na |
13 | 43.9 | 42.8 | -- | 46.7 | -- | 45.4 | -- | 45.4 | -- |
14 | 50.8 | 49.5 | na | 49.5 | na | 49.8 | na | 50.0 | na |
15 | 23.7 | 22.7 | na | 23.3 | na | 30.6 | na | 30.5 | na |
16 | 31.0 | 29.8 | na | 33.7 | na | 43.3 | 3.14d | 43.3 | 3.17m |
17 | 81.9 | 80.0 | 3.48 | 83.0 | -- | 83.0 | 3.81d | 83.0 | 3.84d |
18 | 11.5 | 11.2 | 0.63s | 14.4 | 0.98s | 13.3 | 0.89s | 13.3 | 0.91s |
1′ | -- | -- | -- | 42.3 | 2.68d/ 2.94d | 38.8 | na | 38.8 | na |
1″ | -- | -- | -- | 138.1 | -- | 144.3 | -- | 144.3 | -- |
2″ | -- | -- | -- | 131.0 | 7.33m | 129.1 | 7.73s | 129.1 | 7.75s |
3″ | -- | -- | -- | 128.1 | 7.33m | 134.7 | -- | 134.8 | -- |
4″ | -- | -- | -- | 126.4 | 7.33m | 125.9 | 7.67m | 126.0 | 7.69d |
5″ | -- | -- | -- | 128.1 | 7.33m | 129.4 | 7.37m | 129.4 | 7.40m |
6″ | -- | -- | -- | 131.0 | 7.33m | 133.5 | 7.37m | 133.5 | 7.40m |
CH3O | -- | -- | -- | 56.4 | 3.89s | -- | -- | -- | -- |
CH2Ar | -- | -- | -- | -- | -- | -- | -- | 40.1 | 3.06t |
BrCH2 | -- | -- | -- | -- | -- | -- | -- | 33.9 | 3.55t |
NH2 | -- | -- | -- | -- | 4.96s | -- | -- | -- | -- |
CONH2 | -- | -- | -- | -- | -- | 172.7 | -- | 172.7 | -- |
4 1 | 4 1 | 5 2 | 5 2 | 6 2 | 6 2 | 7 2 | 7 2 | 8 3 | 8 3 | |
---|---|---|---|---|---|---|---|---|---|---|
C/H | 13C | 1H | 13C | 1H | 13C | 1H | 13C | 1H | 13C | 1H |
1 | 126.0 | 7.06d | 125.6 | 7.13m | 125.5 | 7.28m | 125.6 | 7.15m | 126.9 | 7.04d |
2 | 112.7 | 6.52dd | 125.5 | 7.13m | 124.0 | 7.06m | 125.6 | 7.15m | 113.6 | 6.56dd |
3 | 154.9 | -- | 125.2 | 7.13m | 141.5 | -- | 125.3 | 7.15m | 156.0 | -- |
4 | 114.9 | 6.44d | 129.0 | 7.30d | 126.9 | 7.06m | 129.0 | 7.35m | 115.9 | 6.48d |
5 | 137.1 | -- | 139.9 | -- | 137.0 | -- | 140.2 | -- | 138.2 | -- |
6 | 29.5 | 2.73m | 29.4 | 2.88m | 29.2 | 2.91m | 29.6 | 2.93m | 30.7 | 2.68m |
7 | 27.2 | na | 27.4 | na | 26.2 | na | 27.5 | na | 28.5 | na |
8 | ~38 4 | na | 38.9 | na | 37.9 | na | 39.4 | na | 38.2 | na |
9 | 43.0 | na | 44.2 | na | 44.3 | na | 44.4 | na | 44.6 | na |
10 | 130.1 | -- | 135.5 | -- | 136.4 | -- | 136.7 | -- | 131.5 | -- |
11 | 25.8 | na | 25.8 | na | 25.6 | na | 26.1 | na | 27.1 | na |
12 | 31.4 | na | 31.5 | na | 31.5 | na | 31.5 | na | 38.6 | na |
13 | 46.7 | -- | 47.3 | -- | 47.9 | na | 46.9 | -- | 45.1 | -- |
14 | 47.8 | na | 48.8 | na | 50.4 | na | 49.7 | na | 48.4 | ma |
15 | 23.0 | na | 23.3 | na | 21.5 | na | 23.3 | na | 38.6 | ma |
16 | 33.3 | na | 32.0 | na | 35.8 | na | 33.9 | na | 82.8 | -- |
17 | 92.4 | -- | 93.6 | -- | 220.6 | -- | 83.2 | -- | 97.9 | 4.12s |
18 | 14.1 | 0.90s | 14.4 | 1.02s | 13.8 | 0.91s | 14.4 | 0.99s | 12.5 | 0.39s |
1′ | -- | -- | -- | -- | 171.5 | -- | 42.3 | 2.72d/2.99d | 72.0 | 4.77s |
1″ | 27.0 | na | 25.6 | na | -- | -- | 140.2 | -- | 139.6 | -- |
2″ | 15.3 | na | 34.8 | na | 43.5/50.0 | 3.98m/ 4.95m | 126.9 | 7.39d | 127.5 | 7.88d |
3″ | 29.0 | na | 37.8 | na | 46.9 | 3.30m/ 3.40m | 131.0 | 7.39d | 134.0/ 135.2 | -- |
4″ | 171.1 | -- | 177.8 | -- | -- | -- | 134.3 | -- | 127.5 | 7.88d |
5″ | -- | -- | -- | -- | 48.6 | 4.06m/ 4.19m | 131.0 | 7.39d | 129.1 | 7.48t |
6″ | -- | -- | -- | -- | 40.5/44.0 | 3.50m/ 4.90m | 126.9 | 7.39 | 129.1 | 7.40d |
OCON/ CH3 | -- | -- | 27.5 | 1.28s | 14.4/14.6 | 1.06d | 35.4w | 3.05s | 156.4 | -- |
CONH2/ CH3 | -- | -- | 27.8 | 1.28s | 15.8 | 1.12m/ 1.19m | 39.7w | 3.13s | 167.1/ 168.7 | 6.76s 7.55s |
1‴ | -- | -- | -- | 138.8 | -- | 171.7 | -- | 49.2 | 2.90m/3.68m | |
2‴ | -- | -- | -- | 127.2q | -- | -- | -- | 30.1 | na | |
3‴ | -- | -- | -- | 128.6q | 7.89m | -- | -- | 20.5 | na | |
4‴ | -- | -- | -- | 132.8 | 7.70m | -- | -- | 14.1 | 0.84t | |
5‴ | -- | -- | -- | 132.2 | 7.70m | -- | -- | -- | -- | |
6‴ | -- | -- | -- | 132.1 | 8.18m | -- | -- | -- | -- | |
CF3/OH | -- | 9.01s | -- | -- | 122.5q | -- | -- | -- | -- | -- |
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Poirier, D. Description of Chemical Synthesis, Nuclear Magnetic Resonance Characterization and Biological Activity of Estrane-Based Inhibitors/Activators of Steroidogenesis. Molecules 2023, 28, 3499. https://doi.org/10.3390/molecules28083499
Poirier D. Description of Chemical Synthesis, Nuclear Magnetic Resonance Characterization and Biological Activity of Estrane-Based Inhibitors/Activators of Steroidogenesis. Molecules. 2023; 28(8):3499. https://doi.org/10.3390/molecules28083499
Chicago/Turabian StylePoirier, Donald. 2023. "Description of Chemical Synthesis, Nuclear Magnetic Resonance Characterization and Biological Activity of Estrane-Based Inhibitors/Activators of Steroidogenesis" Molecules 28, no. 8: 3499. https://doi.org/10.3390/molecules28083499