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Journal of Medicinal Chemistry
cyclopenta[a]phenanthren-3-ol (42). 1H NMR (400 MHz, (s, 3H); HRMS calcd for C26H43O [M+H-H2O]+ 371.3308,
1
2
3
4
5
6
7
8
CDCl3) δ 5.31-5.30 (m, 1H), 2.44-2.41 (m, 1H), 2.05-1.95 (m,
3H), 1.91-1.81 (m, 3H), 1.77-1.66 (m, 7H), 1.55-1.41 (m, 7H),
1.32-1.25 (m, 3H), 1.20-1.16 (m, 6H), 1.14-0.99 (m, 8H), 0.94-
0.89 (m, 4H), 0.68 (s, 3H); HRMS calcd for C27H43 [M+H-
found 371.3314.
(3S,8S,9S,10R,13R,14S,17R)-17-((2R,5R)-5-
hydroxyheptan-2-yl)-3,10,13-trimethyl-
2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-
2H2O]+ 367.3359, found 367.3364. Optical rotation: [α]22
-247.895 (c = 0.1, THF).
=
589
cyclopenta[a]phenanthren-3-ol
(50).
Synthesis
was
1
analogous to that of compound 14. H NMR (400 MHz, CDCl3)
δH 5.35-5.26 (m, 1H), 3.50-3.45 (m, 1H), 2.42 (d, J = 12Hz,
1H), 2.05-1.92 (m, 3H), 1.87-1.67 (m, 3H), 1.64-1.58 (m, 3H),
1.54-1.35 (m, 9H), 1.33-1.24 (m, 3H), 1.19-1.07 (m, 7H), 1.04-
0.98 (m, 5H), 0.97-0.90 (m, 7H), 0.68 (s, 3H); LC-ELSD/MS
purity 99.26%, MS ESI calcd. for C27H43 [M-2H2O+H]+ 367,
found 367; HRMS calcd for C27H45O [M+H-H2O]+ 385.3465,
found 385.3471.
(3S,8S,9S,10R,13R,14S)-17-((R)-4-(1-
hydroxycyclopropyl)butan-2-yl)-3,10,13-trimethyl-
2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-
9
cyclopenta[a]phenanthren-3-ol (43). 1H NMR (400 MHz,
CDCl3) δ 5.30 (d, J=5.2 Hz, 1H), 2.42 (d, J=13.6 Hz, 1 H), 2.05-
1.92 (m, 3 H), 1.92-1.62 (m, 7 H), 1.51-1.21 (m, 11 H), 1.19-
1.14 (m, 2H), 1.11 (s, 3 H), 1.50 (s, 3H), 0.94 (d, J=6.8 Hz ,3
H), 0.90-0.75 (m, 3H), 0.74-0.70 (m, 2 H), 0.58 (s, 3 H), 0.42
(m, 2 H); HRMS calcd for C27H43O [M+H-H2O]+ 383.3308,
found 383.3314.
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11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(3S,8S,9S,10R,13R,14S,17R)-17-((2R,5S)-5-
hydroxyheptan-2-yl)-3,10,13-trimethyl-
2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-
(3S,8S,9S,10R,13R,14S,17S)-17-(4-hydroxy-4-
methylpentyl)-3,10,13-trimethyl-
cyclopenta[a]phenanthren-3-ol (51).
Synthesis was
analogous to that of compound 14. 1H NMR (400 MHz,
CDCl3) δH 5.33-5.28 (m, 1H), 3.54-3.45 (m, 1H), 2.42 (d, J =
16Hz, 1H), 2.05-1.92 (m, 3H), 1.87-1.67 (m, 3H), 1.53-1.24 (m,
14H), 1.20-1.05 (m, 8H), 1.04-0.89 (m, 12H), 0.68 (s, 3H); LC-
ELSD/MS purity 97.49%, MS ESI calcd. for C27H43 [M-
2H2O+H]+ 367, found 367; HRMS calcd for C27H45O [M+H-
H2O]+ 385.3465, found 385.3469.
2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-
cyclopenta[a]phenanthren-3-ol (44). 1H NMR (400 MHz,
CDCl3) δ 5.31 (d, J=5.6Hz, 1H), 2.43 (d, J=13.2 Hz, 1H), 2.05-
1.95 (m, 2H), 1.90-1.60 (m, 6H), 1.21 (s, 6H), 1.12 (s, 3H),
1.11-1.04 (m, 1H), 1.03 (s, 3H), 1.01-0.92 (m, 2H), 0.58 (s, 3H);
HRMS calcd for C26H41 [M+H-2H2O]+ 353.3203, found
353.3206.
(3S,8S,9S,10R,13R,14S,17R)-17-((2R,5S)-5-cyclopropyl-
5-hydroxypentan-2-yl)-3,10,13-trimethyl-
2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-
(3S,8S,9S,10R,13R,14S,17R)-17-((R)-5-methoxy-5-
methylhexan-2-yl)-3,10,13-trimethyl-
2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-
cyclopenta[a]phenanthren-3-ol (46). 1H NMR (400 MHz,
CDCl3) δ 5.31-5.29 (m, 1H), 3.17 (s, 3H), 2.44-2.40 (m, 1H),
2.05-1.66 (m, 6H), 1.63-1.57 (m, 1H), 1.53-1.21 (m, 10H),
1.20-1.04 (m, 14H), 1.03-0.89 (m, 9H), 0.68 (s, 3H). LC-
ELSD/MS purity 99%, MS ESI calcd. For C27H43 [M+H-
CH3OH-H2O]+ 367.3, found 367.3; HRMS calcd for C28H47O
[M+H-H2O]+ 399.3621, found 399.3616.
cyclopenta[a]phenanthren-3-ol
(52).
Synthesis
was
analogous to that of compound 21/22. 1H NMR (400 MHz,
CDCl3) δ 5.30-5.29 (m, 1H), 2.82-2.79 (m, 1H), 2.43-2.40 (m,
1H), 2.05-0.80 (m, 36H), 0.67 (s, 3H), 0.55-0.40 (m, 2H), 0.30-
0.15 (m, 2H); LC-ELSD/MS purity 99%, MS ESI calcd. for
C28H46O2 [M+H-2H2O]+ 379, found 379; HRMS calcd for
C28H45O [M+H-H2O]+ 397.3465, found 397.3470.
(3S,8S,9S,10R,13R,14S,17R)-17-((2R,5R)-5-cyclopropyl-
5-hydroxypentan-2-yl)-3,10,13-trimethyl-
2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-
(3S,8S,9S,10R,13R,14S,17R)-17-((S)-5-hydroxy-5-
methylhexan-2-yl)-3,10,13-trimethyl-
2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-
cyclopenta[a]phenanthren-3-ol
(53).
Synthesis
was
cyclopenta[a]phenanthren-3-ol
(47).
Synthesis
was
analogous to that of compound 21/22. 1H NMR (400 MHz,
CDCl3) δ 5.30-5.29 (m, 1H), 2.82-2.79 (m, 1H), 2.43-2.40 (m,
1H), 2.05-0.80 (m, 36H), 0.68 (s, 3H), 0.55-0.40 (m, 2H), 0.30-
0.15 (m, 2H); LC-ELSD/MS purity 99%, MS ESI calcd. for
C28H46O2 [M+H-2H2O]+ 379, found 379; HRMS calcd for
C28H45O [M+H-H2O]+ 397.3465, found 397.3470.
1
analogous to that of compound 14. H NMR (400 MHz, CDCl3)
δ 5.36-5.26 (m, 1H), 2.49-2.37 (m, 1H), 2.08-1.91 (m, 3H),
1.87-1.40 (m, 15H), 1.37-1.09 (m, 15H), 1.06-0.91 (m, 5H),
0.89-0.80 (m, 3H), 0.69 (s, 3H); LC-ELSD/MS purity 99%, MS
ESI calcd. for C27H43 [M+H-2H2O]+ 367, found 367; HRMS
calcd for C27H45O [M+H-H2O]+ 385.3465, found 385.3469.
(3S,8S,9S,10R,13R,14S,17R)-3,10,13-trimethyl-17-
((2R,5S)-6,6,6-trifluoro-5-hydroxyhexan-2-yl)-
(3S,8S,9S,10R,13R,14S,17R)-17-((2R,5R)-5-
hydroxyhexan-2-yl)-3,10,13-trimethyl-
2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-
cyclopenta[a]phenanthren-3-ol (54). 1H NMR (400 MHz,
acetone-d6) δ 5.30-5.26 (m, 1H), 4.00-3.90 (m, 1H), 2.42 (d,
J=13.2 Hz, 1H), 2.02-1.29 (m, 18H), 1.28-1.08 (m, 6H), 1.03
(s, 3H), 1.02 (s, 3H), 0.97 (d, J=6.8 Hz, 3H), 0.73 (s, 3H); LC-
ELSD/MS purity 99%, MS ESI calcd. for C26H40F3O [M-
H2O+H]+ 425, found 425; HRMS calcd for C26H40F3O [M+H-
H2O]+ 425.3026, found 425.3030.
2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-
cyclopenta[a]phenanthren-3-ol (48). 1H NMR (400 MHz,
CDCl3) δ 5.31 (d, J=5.2 Hz, 1H), 3.77-3.73 (m, 1H), 2.45-2.40
(m, 1H), 2.03-1.94 (m, 2H), 1.87-1.70 (m, 2H), 1.68-1.62 (m,
1H), 1.55-1.23 (m, 12H), 1.19 (d, J=6.4 Hz, 3H), 1.11 (s, 3H),
1.03 (s, 3H), 0.95 (d, J=6.4 Hz, 3H), 0.68 (s, 3H); HRMS calcd
for C26H43O [M+H-H2O]+ 371.3308, found 371.3313.
(3S,8S,9S,10R,13R,14S,17R)-17-((2R,5S)-5-
hydroxyhexan-2-yl)-3,10,13-trimethyl-
In vitro IWB methods:
2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-
cyclopenta[a]phenanthren-3-ol (49). 1H NMR (400 MHz,
CDCl3) δ 5.31 (d, J=5.2 Hz, 1H), 3.76-3.70 (m, 1H), 2.45-2.40
(m, 1H), 2.03-1.61 (m, 10H), 1.50-1.22 (m, 12H), 1.18 (d, J=6.4
Hz, 3H), 1.11 (s, 3H), 1.07 (s, 3H), 0.95 (d, J=6.8 Hz, 3H), 0.63
Modulation of NMDA receptors was assessed using
electrophyiological recordings of recombinant human
GluN1/GluN2a and GluN1/GluN2b receptors stably expressed
in HEK cells. Whole cell patch clamp recordings were made
using
the
Ionworks
barracuda
high
throughput
21
ACS Paragon Plus Environment