Synthesis of Δ3-2-hydroxybakuchiol analogues and their growth inhibitory activity against rat UMR106 cells

Article abstract of DOI:10.3390/molecules19022213

A series of Δ³-2-hydroxybakuchiol analogues have been synthesized and tested for their growth inhibitory activity against rat UMR106 cells by using the MTT method. Some of them exhibit enhanced activities compared with the natural product, and the preliminary SAR profile shows that the chain tail on the natural product could be subtly modified to enhance the activity and the aromatic moiety or the terminal olefin on the main chain can also be modified without any evident loss of activity. The stereo-configuration of the quaternary chiral center has an important influence on the activity.

Full text of DOI:10.3390/molecules19022213

Molecules 2014, 19, 2213-2225; doi:10.3390/molecules19022213
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Synthesis of ∆3-2-Hydroxybakuchiol Analogues and Their
Growth Inhibitory Activity against Rat UMR106 Cells
Qun Zhao 1, Qianqian Xu 1, Guangsheng Shan 1, Chao Dong 1, Hong Zhang 2,* and
Xinsheng Lei 1,3,
*
1
School of Pharmacy, Fudan University, Shanghai 201203, China
Department of Pharmaceutical Botany, School of Pharmacy, Second Military Medical University,
Shanghai 200433, China
2
3
Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
* Author to whom correspondence should be addressed; E-Mails: zhanghong@smmu.edu.cn (H.Z.);
leixs@fudan.edu.cn (X.L.); Tel./Fax: +86-021-5198-0128 (X.L.).
Received: 17 January 2014; in revised form: 9 February 2014 / Accepted: 11 February 2014 /
Published: 20 February 2014
Abstract: A series of ∆3-2-hydroxybakuchiol analogues have been synthesized and tested
for their growth inhibitory activity against rat UMR106 cells by using the MTT method.
Some of them exhibit enhanced activities compared with the natural product, and the
preliminary SAR profile shows that the chain tail on the natural product could be subtly
modified to enhance the activity and the aromatic moiety or the terminal olefin on the main
chain can also be modified without any evident loss of activity. The stereo-configuration of
the quaternary chiral center has an important influence on the activity.
Keywords: bakuchiol; natural product analogues; cytotoxic activity
1. Introduction
Natural products from plants are an important source of potential therapeutic agents for human
health. The medicinal plant Psoralea coryliforlia L., a member of the Leguminosae family, has been
used for a long time as a Traditional Chinese Medicine for the treatment of premature ejaculation, knee
pain, pollakiuria, callus, psoriasis, vitiligo and psoriasis [1]. The seed extract has been suggested as a
useful remedy for bone fractures, osteomalacia and osteoporosis [2]. A number of monoterpene

Molecules 2014, 19
2214
phenols occurring in the plant have been isolated and demonstrated to possess interesting biological
activities [3–7], and among them, bakuchiol (15b, Figure 1), one of the major components in the plant
seed, has attracted great attention due to its diverse activities, such as antibacterial, antihelminthic,
antioxidant, and especially antitumor properties [8–23]. In contrast to that, ∆3-2-hydroxybakuchiol
(15a), a congener of bakuchiol, has not attracted much interest among medicinal chemists, probably
due to its scarcity and lability [24,25]. To the best of our knowledge, only Guo and co-workers have
recently investigated its inhibitory effects against monoamine transporters, suggesting that it might be
a potential psychopharmacologic agent for the treatment of psychogenic disorders [26].
Given the fact that the analog bakuchiol shows various biological activities, we have put
∆3-2-hydroxybakuchiol into our natural product-based drug discovery program [27–30]. Recently, a
facile asymmetric synthesis of ∆3-2-hydroxybakuchiol was established and the compound was tested
for antiosteoporosis effects [31,32]. Unexpectedly, this natural product did not show the desired
activity, but it exhibited growth inhibitory activity against osteosarcoma cells (rat UMR106 cell) with
an IC50 value of 69 µM, suggesting that it was worthy of further investigation [33].
Figure 1. The structures of bakuchiol (15b) and ∆3-2-hydroxybakuchiol (15a) and the
proposed modifications.
Herein the synthesis of ∆3-2-hydroxybakuchiol analogues was described and their growth inhibitory
activity against rat UMR106 cells was demonstrated. The preliminary structure-activity relationship
knowledge of this natural product has been obtained by modifying the substituent (G) on the aromatic
ring and the R1 group on the chain, while keeping the main chain unchanged. In addition, we would
also replace the terminal olefin with an ethyl moiety (R2) in order to probe the effect of this moiety on
the activity (Figure 1).
2. Results and Discussion
2.1. Chemistry
Our synthetic approach to the analogues of ∆3-2-hydroxybakuchiol is depicted in Scheme 1. Starting
from (E)-2-methylbut-2-enoyl chloride and (R)-4-isopropyloxazolidin-2-one, the α,β-unsaturated imide 3

Molecules 2014, 19
2215
bearing an Evans’ auxiliary was prepared in excellent yield. Then, the -alkylation of 3 with
tert-butyl iodoacetate afforded the fragment 4 in a moderate yield with an excellent diastereoselectivity
(dr > 20: 1). After selective reduction of the imide group, the key chiral intermediate 5 was obtained in
an acceptable yield. To avoid the formation of the volatile lactone from 5, the free hydroxyl group in 5
was protected with a TBS group to afford compound 6. Upon reduction of the ester group and
subsequent oxidation, compound 8a was prepared in 94% yield (over two steps).
Scheme 1. Synthetic approach to the analogues of ∆3-2-hydroxybakuchiol.
○
○
Reagents and conditions: (a) n-BuLi, THF, 96%; (b) NaHMDS, −78 C, 1.5 h; ICH2CO2But, −50 C, 6 h,
○
68%; (c) LiBH4, THF, 0 C, 3 h, 70%; (d) TBSCl, imidazole, CH2Cl2, rt, 3 h, 84%; (e) DIBALH, CH2Cl2,
○
−78 C, 2 h; (f) IBX, DMSO, rt, 5 h, for 8a: 94%; for 8b: 100%; two steps; (g) Ph3P=CHCO2Et, toluene,
reflux, 2 h, for 9a: 92%; for 9b: 81%; (h) HCl, EtOH, 0 ○C, 7 h, for 10a: 97%; for 10b: 86%; (i) IBX, DMSO,
○
rt, 5 h, for 11a: 95%; for 11b: 97%; (j) CHI3, CrCl2, THF, 0 C, 3 h, for 12a: 86%; for 12b: 80%; (k) ArBr,
n-BuLi/ZnCl2; Pd(OAc)2/PPh3, THF, 60%–98%; (l) RLi, THF, rt, 5 h, up to 34%–100%; for 14b, 14h–j,
additional step required for deprotection of TBDPS group: Bu4NF, THF, quantitative yield; (m) H2, Pd/C
(10%), rt, overnight, 100%.
Compound 8a successfully underwent a Wittig reaction to afford the α,β-unsaturated ester 9a. Next,
the TBS group was removed and oxidized to afford the corresponding aldehyde 11a in 92% yield (over
two steps). Through a Takai-Utimoto reaction with CrCl2 and CHI3, the trans-iodo-olefin 12a was
obtained in up to 86% yield. The iodo-olefin was coupled with different substituted aryl zinc species
via the Negishi reaction to give the desired cross-coupling product 13a,c–f, respectively. After
selective 1,2-addition reactions of the esters 13a, c–g with alkyllithiums, the corresponding products
14a, c–j were obtained in acceptable (up to 73%) yields.

Molecules 2014, 19
2216
In order to assess the effect of the terminal olefin moiety in ∆3-2-hydroxybakuchiol on the
biological activity, compound 14b was prepared. Hydrogenation of 7a provided saturated alcohol 7b in
a quantitative yield which was successfully transformed into 14b by a method similar to that shown
in Scheme 1. As positive control, bakuchiol (15b) and its methyl ether (15c), together with their
corresponding enantiomers 15d and 15e, were also prepared according to our recently reported
method [31].
2.2. Activity against Rat UMR106 Cell
With the various analogues of ∆3-2-hydroxybakuchiol in hand, their cytotoxic activity against rat
UMR106 osteosarcoma cells was tested by the MTT assay after two days of treatment [34] and the
results are shown in Table 1.
Among those compounds, ∆3-2-hydroxybakuchiol (15a) displayed the expected [33] cytotoxic
activity with an IC50 value of 69 µM (Entry 21, Table 1). When the chain tail was modified with an
α,β-unsaturated ester (compound 13a), the activity increased (IC50: 27 µM, Entry 1) compared with
14a (IC50: 66 µM, Entry 7). When the methoxy group was replaced with other substituent (compounds
13c–g), the corresponding activity was significantly reduced (IC50: > 263 µM, Entries 2–6), suggesting
that the substituent on the aromatic ring had an important influence on the activity in the case of
α,β-unsaturated ester analogues.
When the modifications were performed only on the aromatic moiety of ∆3-2-hydroxybakuchiol,
the substituent effect seemed to have somewhat of an effect on the activity (compounds 14a, c, d, f).
For example, the activity was still retained in the case of a para-methoxy (14a; Entry 7), but other
groups such as H and para-methyl led to slightly reduced activities (14c, 14d; Entries 8 and 9).
Notably, a strong electron-withdrawing group gave a slightly increased activity (14f, Entry 11). When
a larger bulky group was used (compounds 14e,g; Entries 10 and 12), the activity was just slightly
decreased. Surprisingly, if the phenolic hydroxyl was moved to the meta-position (14h), its IC50 value
was still up to 123 µM, with about one-fold reduced activity in contrast to ∆3-2-hydroxybakuchiol
(Entry 13). Modification on the R1 group (14i,j) in the tertiary alcohol moiety suggested that this
domain could accommodate a bulky hydrophobic space, and 14j gave the best result (IC50: 17 µM;
Entries 14 and 15). In addition, the terminal double bond could be saturated without influence on
the activity, implied by the almost identical activities of 14b (IC50: 71 µM; Entry 16) and
∆3-2-hydroxybakuchiol.
On the other hand, bakuchiol (15b), with a slight structural difference on the chain tail of
∆3-2-hydroxybakuchiol, showed almost the same potency (IC50: 62 µM, Entry 18). Interestingly,
ent-bakuchiol (15d) had a one-fold enhanced activity (IC50: 33 µM, Entry 20). However, in
comparison with (S- or R)bakuchiol methyl ether showed different influences on the activity, namely,
(S)-bakuchiol methyl ether (15c) maintained the activity (IC50: 60 µM, Entry 17) but (R)-bakuchiol
methyl ether (15e) gave less activity (IC50: 161 µM, Entry 19), indicating that the stereochemistry
played an important role to the activity.

Molecules 2014, 19
2217
Table 1. Cytotoxic activities of ∆3-2-hydroxybakuchiol and its analogues against rat
UMR106 osteosarcoma cell.
Entry
1
Comp.
13a
13c
13d
13e
13f
Ar
4-MeO-C6H4
C6H5
R1
R2
IC50 (µM)
27
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CH=CH2
CH=CH2
CH=CH2
CH=CH2
CH=CH2
CH=CH2
2
330
263
>500
242
511
66
3
4-Me-C6H4
2-C10H7
4
5
4-CF3-C6H4
3,4-OCH2O-C6H4
4-MeO-C6H4
C6H5
6
13g
14a
14c
14d
14e
14f
7
Me2CH(OH) CH=CH2
Me2CH(OH) CH=CH2
Me2CH(OH) CH=CH2
Me2CH(OH) CH=CH2
Me2CH(OH) CH=CH2
Me2CH(OH) CH=CH2
Me2CH(OH) CH=CH2
8
107
87
9
4-Me-C6H4
2-C10H7
10
11
12
13
14
15
16
128
46
4-CF3-C6H4
3,4-OCH2O-C6H4
3-HO-C6H4
4-HO-C6H4
4-HO-C6H4
4-HO-C6H4
14g
14h
14i
115
123
57
Et2CH(OH)
CH=CH2
14j
n-Bu2CH(OH) CH=CH2
17
14b
Me2CH(OH) CH2CH3
71
17
18
19
20

bakuchiol methyl ether (15c)
bakuchiol (15b)
60
62
ent-bakuchiol methyl ether (15e)
ent-bakuchiol (15d)
161
33
(R)
HO
3-2-hydroxybakuchiol (15a)
69
3. Experimental
3.1. General Information
Solvents were distilled from the appropriate drying agents before use. All the reagents were
purchased from Acros (Shanghai, China), Alfa Aesar (Shanghai, China), and National Chemical
Reagents Group Co. Ltd (Shanghai, China). Unless otherwise stated, all the reactions were performed
under argon. Column chromatography: commercial silica gel (Qingdao Haiyang Chemical Group Co.;
300–400 mesh, Qingdao, China). Spots on the TLC plates (GF 254, Yantai Jiangyou Silica R&D Co. Ltd.,
Yantai, China) were detected under UV light or with iodine, KMnO4, and H3PO4·12MoO3·xH2O.

Molecules 2014, 19
2218
1H and 13C-NMR spectra (400 MHz for 1H, and 100 MHz for 13C): Varian Mercury-Plus (Palo Alto, CA,
USA) spectrometer; chemical shifts δ in parts per million, with residual CHCl3 [d (H) 7.26; d (C) 77.0]
as internal standard; J in Hertz. ESI-MS and HR-APCI/ESI-MS: Finnigan Mat-95 mass spectrometer
(Waltham, MA, USA); in m/z. Compounds 3–7a, 8–14a, ∆3-2-hydroxybakuchiol, (S)-bakuchiol and
(R)-bakuchiol as well as their corresponding methyl ethers (15a–e) were prepared by our previously
reported method [32].
3.2. Synthetic Procedures for the New Compounds
(R)-3-(((tert-Butyldimethylsilyl)oxy)methyl)-3-methylpentan-1-ol (7b). A mixture of (S)-3-(((tert-
butyldimethylsilyl)oxy)methyl)-3-methylpent-4-en-1-ol (1.0 g, 4.09 mmol) and Pd/C (100 mg, 10%
w/w) in methanol (20 mL) was purged with H2 gas and was stirred overnight at room temperature
under H2. The reaction mixture was directly passed through a pad of silica gel with ethyl acetate and
the solvent was removed under vacuum. The residue was purified by column chromatography
(petroleum ether/ethyl acetate 10:1) to afford 7b (1.01 g, 100%) as a colorless oil. Rf = 0.26 (petroleum
ether/ethyl acetate 10:1), [α]2D0 +4.8 (c 0.65, CHCl3). 1H-NMR (CDCl3) δ 3.64 (t, J = 5.6 Hz, 2H), 3.41
(brs, 1H), 3.39 (d, J = 10.0 Hz, 1H), 3.34 (d, J = 10.0 Hz, 1H), 1.64–1.48 (m, 2H), 1.39–1.20 (m, 2H),
13
0.91 (s, 9H), 0.85–0.78 (m, 6H), 0.08 (s, 6H). C-NMR (CDCl3) δ 70.6, 58.8, 41.2, 37.4, 29.6, 25.8,
21.7, 18.2, 7.7, −5.6. ESI-MS: 247.1 [M+H], HRMS (ESI): Calcd. for C13H30O2Si [M+H]: 247.2088,
found: 247.2091.
(R)-3-(((tert-Butyldimethylsilyl)oxy)methyl)-3-methylpentanal (8b). IBX (1.71 g, 4.9 mmol) was added
to a solution of 7b (1.01 g, 4.09 mmol) in DMSO (20 mL). The mixture was stirred overnight at room
temperature. Then the mixture was diluted with ethyl acetate (200 mL) and washed successively with
saturated NaHCO3 aq. solution (30 mL × 2), water (30 mL), brine (30 mL), dried over anhydrous
Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column
chromatography (petroleum ether/ethyl acetate 20:1) to afford 8b (1.00 g, 99%) as a colorless oil.
Rf = 0.74 (petroleum ether/ethyl acetate = 10:1), [α]2D0 −2.6 (c 0.50, CHCl3). H-NMR (CDCl3) δ 9.84
1
(t, J = 3.1 Hz, 1H), 3.42 (d, J = 9.7 Hz, 1H), 3.35 (d, J = 9.7 Hz, 1H), 2.32–2.21 (m, 2H), 1.46–1.37
(m, 2H), 0.96 (s, 3H), 0.92–0.83 (m, 12H), 0.03 (s, 6H). 13C-NMR (CDCl3) δ 203.8, 69.6, 51.0, 42.2,
37.8, 29.4, 25.8, 21.3, 7.9, −5.6. ESI-MS: 283.7 [M+K].
(R,E)-Ethyl 5-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylhept-2-enoate (9b). To a solution of
8b (0.978 g, 4.0 mmol) in toluene (10 mL) was added a solution of ethyl-2-(triphenyl-
phosphoranylidene)acetate (1.71 g, 4.9 mmol) in toluene (10 mL). The mixture was stirred for 2 h
under argon at reflux and then cooled to rt. The reaction mixture was concentrated under reduced
pressure, diluted with ether (50 mL) and filtered. The filter cake was washed successively with ether
(10 mL) and petroleum ether (10 mL). The combined filtrate was concentrated under reduced pressure.
The residue was purified by column chromatography (petroleum ether/ethyl acetate 80:1) to afford 9b
(0.953 g, 81%) as a colorless oil. Rf = 0.60 (petroleum ether/ethyl acetate = 20:1), [α]2D0 −11.5 (c 0.60,
1
CHCl3). H-NMR (CDCl3) δ 6.97 (dt, J = 15.7, 7.9 Hz, 1H), 5.81 (d, J = 15.7 Hz, 1H), 4.18 (q,
J = 7.1 Hz, 2H), 3.28 (d, J = 9.7 Hz, 1H), 3.23 (d, J = 9.7 Hz, 1H), 2.14 (d, J = 7.9 Hz, 2H), 1.28 (t,
J = 7.1 Hz, 3H), 0.89 (s, 9H), 0.85–0.76 (m, 6H), 0.02 (s, 6H). 13C-NMR (CDCl3) δ 166.6, 146.8,

Molecules 2014, 19
2219
123.2, 68.6, 60.1, 39.4, 38.8, 29.0, 3.82, 21.1, 18.2, 14.3, 7.8, −5.6. ESI-MS: 315.2 [M+H], HRMS(ESI):
Calcd. for C17H35O3Si [M+H]: 315.2350, found: 315.2356.
(R,E)-Ethyl-5-(hydroxymethyl)-5-methylhept-2-enoate (10b). To a solution of 9b (950 mg, 3.02 mmol)
○
in methanol (10 mL) at 0 C was added concentrated hydrochloric acid (0.75 mL). The mixture was
stirred for 7 h at rt. The reaction was quenched with saturated NaHCO3 (10 mL). The mixture was
concentrated under reduced pressure. The residue was extracted with ethyl acetate (15 mL × 3). The
organic phase was combined, washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, and
the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography
(petroleum ether/ethyl acetate 20:1) to afford 10b (517 mg, 86%) as a colorless oil. Rf = 0.81
(petroleum ether/ethyl acetate = 5:1), [α]2D0 −14.7 (c 0.60, CHCl3). H-NMR (CDCl3) δ 7.10–6.88 (m,
1
1H), 5.86 (ddd, J = 15.5, 3.0, 1.7 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 3.40 (d, J = 10.8 Hz, 1H), 3.36 (d,
13
J = 10.8 Hz, 1H), 2.18 (dd, J = 7.9, 1.3 Hz, 2H), 1.37–1.25 (m, 5H), 0.91–0.81 (m, 6H). C-NMR
(CDCl3) δ 166.4, 146.0, 123.6, 68.9, 60.2, 39.1, 38.6, 28.8, 21.1, 14.33, 7.8. ESI-MS: 201.1 [M+H],
HRMS(ESI): Calcd. for C11H21O3 [M+H]: 201.1485, found: 201.1489.
(R,E)-Ethyl 5-formyl-5-methylhept-2-enoate (11b). Compound 10b (447 mg, 2.23 mmol) and IBX
(938 mg, 3.4 mmol) in a 100 mL flask was dissolved with DMSO (20 mL). The mixture was stirred
overnight at rt. Then the mixture was diluted with ethyl acetate (300 mL), washed successively with
saturated NaHCO3 aq. solution (40 mL × 2), water (40 mL), brine (40 mL), dried over anhydrous
Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column
chromatography (petroleum ether/ethyl acetate 20:1) to afford 11b (430 mg, 97%) as a colorless oil.
Rf = 0.74 (petroleum ether/ethyl acetate = 5:1), [α]2D0 −21.6 (c 0.45, CHCl3) 1H-NMR (CDCl3) δ 7.04–6.89
(m, 1H), 5.86 (ddd, J = 15.5, 3.0, 1.7 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 3.40 (d, J = 10.8 Hz, 1H), 3.36
(d, J = 10.8 Hz, 1H), 2.18 (dd, J = 7.9, 1.3 Hz, 2H), 1.44–1.22 (m, 5H), 0.92–0.79 (m, 6H). 13C-NMR
(CDCl3) δ 205.3, 166.0, 143.6, 124.6, 60.4, 49.3, 36.7, 27.9, 18.6, 14.2, 8.3. ESI-MS: 237.1, [M+K]
HRMS(ESI): Calcd. for C11H19O3 [M+H]: 199.1329, found: 199.1331.
(R,2E,6E)-Ethyl 5-ethyl-7-iodo-5-methylhepta-2,6-dienoate (12b). To a suspension of anhydrous CrCl2
○
(1.85 g, 8.82 mmol) in THF (20 mL) at 0 C was added dropwise a solution of 11b (388 mg,
2.0 mmol) and CHI3 (1.16 g, 2.9 mmol) in THF (10 mL). After 3 h, the mixture was quenched with
10% Na2S2O3 aq. solution (20 mL). The mixture was extracted with ethyl acetate (20 mL × 3).
The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered,
and the filtrate was concentrated under reduced pressure. The residue was purified by column
chromatography (petroleum ether/ethyl acetate 50:1) to afford 12b (504 mg, 80%) as a colorless oil.
Rf = 0.61 (petroleum ether/ethyl acetate = 10:1), [α]2D0 −39.2 (c 0.65, CHCl3) H-NMR (CDCl3) δ
1
6.96–6.75 (m, 1H), 6.44 (d, J = 14.7 Hz, 1H), 5.97 (d, J = 14.7 Hz, 1H), 5.82 (d, J = 15.5 Hz, 1H), 4.19
(q, J = 7.1 Hz, 2H), 2.26–2.13 (m, 2H), 1.43–1.24 (m, 5H), 0.98 (s, 3H), 0.82 (t, J = 7.1 Hz, 3H).
13C-NMR (CDCl3) δ 166.2, 153.2, 144.8, 124.0, 74.3, 60.2, 44.3, 42.6, 32.6, 22.1, 14.2, 8.4. ESI-MS:
323.0 [M+H], HRMS(ESI): Calcd. for C12H20IO2 [M+H]: 323.0502, found: 323.0511.
General procedure for the synthesis of compounds 13b–g, exemplified by (R,2E,6E)-ethyl 7-(4-((tert-
butyldiphenylsilyl)oxy)phenyl)-5-ethyl-5-methylhepta-2,6-dienoate (13b). A dried flask was charged

Molecules 2014, 19
2220
with ZnCl2 (300 mg, 2.2 mmol), and heated by a hot gun under vacuum until the ZnCl2 was melted.
Then the flask was filled with Ar gas and cooled to rt. Anhydrous THF (5 mL) was added into the flask
to dissolve the ZnCl2. Another dried flask was charged with 1-bromo-4-(t-BuPh2SiO)-C6H4Br (823 mg,
○
2.0 mmol) and THF (5 mL) under argon, and then cooled to −78 C. n-BuLi (0.8 mL, 2.0 mmol) was
added dropwise to the bromoarene solution over 30 min, and stirring was continued for 30 min. Then
○
the organolithium solution was added dropwise to the ZnCl2 solution at −78 C over 15 min, and the
resulting solution was stirred at rt for 1 h. Meanwhile, a mixture of [Pd(OAc)2] (22 mg, 0.1 mmol),
PPh3 (26 mg, 0.1 mmol) and THF (2 mL) was stirred at rt for about 30 min until the brown solution
was formed, and this solution was added to the organozinc solution, followed by a solution of the 12b
(322 mg, 1.0 mmol) in THF (2 mL). The mixed solution was stirred overnight at rt. The reaction
solution was quenched with saturated NH4Cl aq. solution (15 mL), and extracted with ethyl acetate
(15 mL × 3). The extract was washed with brine (15 mL), dried over anhydrous Na2SO4, and filtered.
The filtrate was concentrated under reduced pressure. The residue was purified by column
chromatography (petroleum ether/ethyl acetate 80:1) to afford 13b (463 mg, 88%) as a colorless oil.
Rf = 0.43 (petroleum ether/ethyl acetate = 20:1), [α]2D0 −40.4 (c 0.50, CHCl3). H-NMR (CDCl3) δ
1
7.77–7.66 (m, 4H), 7.46–7.31 (m, 6H), 7.10 (d, J = 8.4 Hz, 2H), 6.91 (dt, J = 15.4, 7.6 Hz, 1H), 6.70
(d, J = 8.4 Hz, 2H), 6.16 (d, J = 16.3 Hz, 1H), 5.90 (d, J = 16.3 Hz, 1H), 5.81 (d, J = 15.5 Hz, 1H),
4.16 (q, J = 7.1 Hz, 2H), 2.31–2.18 (m, 2H), 1.49–1.33 (m, 2H), 1.26 (t, J = 7.1 Hz, 3H), 1.09 (s, 9H),
13
1.03 (s, 3H), 0.80 (t, J = 7.4 Hz, 3H). C-NMR (CDCl3) δ 166.4, 154.8, 146.2, 135.7, 135.5, 132.9,
130.6, 129.9, 127.8, 127.2, 126.9, 123.4, 119.6, 60.1, 43.7, 39.6, 33.5, 26.5, 19.4, 14.3, 8.5. ESI-MS:
527.2 [M+H].
(S,2E,6E)-Ethyl 5-methyl-7-phenyl-5-vinylhepta-2,6-dienoate (13c). Yield: 98%, Rf = 0.43 (petroleum
ether/ethyl acetate = 20:1), [α]2D0 −3.1 (c 0.55, CHCl3). H-NMR (CDCl3) δ 7.39–7.17 (m, 5H), 6.93
1
(dt, J = 15.4, 7.6 Hz, 1H), 6.36 (d, J = 16.2 Hz, 1H), 6.20 (d, J = 16.2 Hz, 1H), 5.93–5.82 (m, 2H),
5.11 (d, J = 10.7 Hz, 1H), 5.06 (d, J = 17.5 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 2.41 (d, J = 7.6 Hz, 2H),
13
1.28 (t, J = 7.1 Hz, 3H), 1.23 (s, 3H). C-NMR (CDCl3) δ 166.3, 145.3, 144.4, 137.3, 136.4, 128.5,
128.1, 127.2, 126.2, 123.9, 113.1, 60.2, 43.8, 42.62, 23.7, 14.2. ESI-MS: 271.2 [M+H], 293.1 [M+Na],
HRMS (ESI): Calcd. for C18H22O2Na [M+H]: 293.1512, found: 293.1518.
(S,2E,6E)-Ethyl-5-methyl-7-(p-tolyl)-5-vinylhepta-2,6-dienoate (13d) Yield: 82%, Rf = 0.41 (petroleum
ether/ethyl acetate =20:1), [α]2D0 +3.3 (c 0.55, CHCl3). H-NMR (CDCl3) δ 7.25 (d, J = 7.7 Hz, 2H),
1
7.11 (d, J = 7.7 Hz, 2H), 6.92 (dt, J = 15.4, 7.6 Hz, 1H), 6.32 (d, J = 16.2 Hz, 1H), 6.14 (d, J = 16.2 Hz,
1H), 5.94–5.77 (m, 2H), 5.12–5.01 (m, 2H), 4.17 (q, 7.2 Hz, 2H), 2.40 (d, J = 7.4 Hz, 2H), 2.33 (s,
13
3H), 1.28 (t, J = 7.2 Hz, 3H), 1.21 (s, 3H). C-NMR (CDCl3) δ 166.3, 145.5, 144.6, 137.0, 135.4,
134.5, 129.2, 127.9, 126.1, 123.8, 113.0, 60.2, 43.8, 42.6, 23.7, 21.1, 14.2. ESI-MS: 307.1 [M+Na],
HRMS(ESI): Calcd. for C19H25O2 [M+H]: 285.1849, found: 285.1855.
(S,2E,6E)-ethyl 5-methyl-7-(naphthalen-2-yl)-5-vinylhepta-2,6-dienoate (13e) Yield: 60%, Rf = 0.34
(petroleum ether/ethyl acetate =20:1), [α]2D0 −4.4 (c 0.50, CHCl3). H-NMR (CDCl3) δ 7.84–7.74 (m,
1
3H), 7.71 (s, 1H), 7.59 (d, J = 8.6 Hz, 1H), 7.50–7.37 (m, 2H), 6.96 (dt, J = 15.4, 7.5 Hz, 1H), 6.52 (d,
J = 16.2 Hz, 1H), 6.33 (d, J = 16.2 Hz, 1H), 6.00–5.82 (m, 2H), 5.17–5.05 (m, 2H), 4.18 (q, 7.1 Hz,

Molecules 2014, 19
2221
2H), 2.46 (d, J = 7.5 Hz, 2H), 1.30–1.23 (m, 6H). ESI-MS: 343.3 [M+Na], HRMS (ESI): Calcd. for
C22H25O2 [M+H]: 321.1849, found: 321.1857.
(S,2E,6E)-Ethyl-5-methyl-7-(4-(trifluoromethyl)phenyl)-5-vinylhepta-2,6-dienoate (13f). Yield: 90%,
Rf = 0.41 (petroleum ether/ethyl acetate = 20:1), [α]2D0 +9.8 (c 0.50, CHCl3). H-NMR (CDCl3) δ 7.55
1
(d, J = 8.2 Hz, 2H), 7.45 (d, J = 8.2 Hz, 2H), 6.98–6.84 (m, 1H), 6.39 (d, J = 16.2 Hz, 1H), 6.29 (d,
J = 16.2 Hz, 1H), 5.96–5.82 (m, 2H), 5.20–5.11 (m, 1H), 5.08 (dd, J = 17.4, 0.8 Hz, 1H), 4.18 (q,
J = 7.1 Hz, 2H), 2.43 (dd, J = 7.6, 1.3 Hz, 2H), 1.28 (t, J = 7.1 Hz, 3H), 1.24 (s, 3H). 13C-NMR
(CDCl3) δ 166.2 (C4), 144.9 (C7), 143.9 (C11), 140.8 (C15), 139.1 (C14), 128.9 (C18), 127.0 (C10),
126.3 (C16), 125.5 (C17), 124.1 (C5), 113.6 (13), 60.3 (C2), 43.6 (C8), 42.8 (C9), 23.5 (C12), 14.2
(C1).ESI-MS: 361.2 [M+Na], HRMS(ESI): Calcd. for C19H22F3O2 [M+H]: 339.1566, found: 339.1575.
(S,2E,6E)-Ethyl-7-(benzo[d][1,3]dioxol-5-yl)-5-methyl-5-vinylhepta-2,6-dienoate (13g). Yield: 96%,
Rf = 0.30 (petroleum ether/ethyl acetate = 20:1), [α]2D0 −15.0 (c 0.50, CHCl3). H-NMR (CDCl3) δ
1
6.97–6.86 (m, 2H, C(7)H, C(20)H), 6.81–6.71 (m, 2H, C(16)H, C(17)H), 6.26 (d, J = 16.2 Hz, 1H,
C(14)H), 6.02 (d, J = 16.2 Hz, 1H, C(10)H), 5.94 (s, 2H, C(22)H), 5.92–5.81 (m, 2H, C(5)H, C(11)H),
5.10 (dd, J = 10.7, 0.7 Hz, 1H, C(13)H), 5.05 (d, J = 17.5 Hz, 1H, C(13)H), 4.18 (q, J = 7.1 Hz, 2H,
C(2)H2), 2.42–2.36 (m, 2H, C(8)H), 1.28 (t, J = 7.1 Hz, 3H, C(1)H), 1.20 (s, 3H, C(12)H3). 13C-NMR
(CDCl3) δ 166.3 (C(4)), 147.9 (C(19)), 146.9 (C(18)), 145.4 (C(7)), 144.5 (C(11)), 134.7 (C(14)),
131.8 (C(15)), 127.6 (C(10)), 123.8 (C(5)), 120.7, 113.0 (C(13)), 108.2, 105.5, 101.0 (C(16), C(17),
C(20)), 60.2 (C(2)), 43.8 (C(8)), 42.5 (C(9)), 23.7 (C(12)), 14.2 (C(1)). ESI-MS: 315.2[M+H], 337.2
[M+Na], HRMS(ESI): Calcd. for C19H23O4 [M+H]: 315.1591, found: 315.1602.
General procedure for the synthesis for 14b–g, exemplified by 4-((R,1E,5E)-3-ethyl-7-hydroxy-3,7-
dimethylocta-1,5-dien-1-yl)phenol (14b). To a stirred solution of 13b (267 mg, 0.51 mmol,) in THF
○
(5 mL) at 0 C was added MeLi (1.0 mL, 1.5 mmol). The mixture was stirred overnight at rt. The
reaction was quenched with saturated NH4Cl (10 mL). The mixture was extracted with ethyl acetate
(10 mL × 3). The combined organic phase was washed with brine (10 mL), dried over anhydrous
Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by
column chromatography (petroleum ether/ethyl acetate 5:1) to afford the silyl protected 14b (124 mg,
48%) together with 14b (47 mg, 34%) as a colorless oil. The protected compound could be deprotected
quantitatively into 14b by n-Bu4NF in THF at rt for 3–4 h.
Silyl protected 14b: Rf = 0.45 (petroleum ether/ethyl acetate = 5:1), [α]2D0 −65.5 (c 0.20, CHCl3).
1H-NMR (CDCl3) δ 7.76–7.67 (m, 4H), 7.46–7.31 (m, 6H), 7.09 (d, J = 8.6 Hz, 2H), 6.69 (d, J = 8.6 Hz,
2H), 6.12 (d, J = 16.3 Hz, 1H), 5.90 (d, J = 16.2 Hz, 1H), 5.64–5.50 (m, 2H), 2.12–1.98 (m, 2H),
1.40–1.32 (m, 2H), 1.27 (s, 6H), 1.09 (s, 9H), 0.98 (s, 3H), 0.79 (t, J = 7.4 Hz, 3H). 13C-NMR (CDCl3)
δ 154.6, 140.6, 136.9, 135.5, 132.9, 130.9, 129.8, 127.7, 126.8, 126.5, 123.4, 119.6, 70.7, 43.6, 39.4,
33.3, 29.9, 26.5, 22.9, 19.4, 8.6. ESI-MS: 530.2 [M+NH4].
14b: Rf = 0.09 (petroleum ether/ethyl acetate = 5:1), [α]2D0 −36.3 (c 0.07, CHCl3). H-NMR (CDCl3) δ
1
7.23 (d, J = 8.6 Hz, 2H), 6.77 (d, J = 8.6 Hz, 2H), 6.18 (d, J = 16.3 Hz, 1H), 5.96 (d, J = 16.3 Hz, 1H),
5.68–5.49 (m, 2H), 2.17–2.03 (m, 2H), 1.46–1.34 (m, 2H), 1.30 (s, 6H), 1.02 (s, 3H), 0.82 (t, J = 7.5 Hz,

Molecules 2014, 19
2222
3H). 13C-NMR (CDCl3) δ 154.7, 140.5, 136.8, 130.8, 127.2, 126.4, 123.5, 115.3, 70.9, 43.6, 39.5, 33.3,
29.8, 22.8, 8.6. ESI-MS: 530.2 [M+NH4].
(S,3E,7E)-2,6-Dimethyl-8-phenyl-6-vinylocta-3,7-dien-2-ol (14c) Yield: 73%, Rf = 0.42 (petroleum
ether/ethyl acetate = 5:1), [α]2D0 −9.5 (c 0.55, CHCl3). H-NMR (CDCl3) δ 7.36 (d, J = 8.0 Hz, 2H),
1
7.33–7.25 (m, 2H), 7.20 (t, J = 6.6 Hz, 1H), 6.32 (d, J = 16.2 Hz, 1H), 6.20 (d, J = 16.2 Hz, 1H), 5.89
(dd, J = 17.4, 10.7 Hz, 1H), 5.70–5.55 (m, 2H), 5.09–4.98 (m, 2H), 2.23 (d, J = 6.3 Hz, 2H), 1.38 (s,
13
1H), 1.30 (s, 6H), 1.18 (s, 3H). C-NMR (CDCl3) δ 145.3, 141.2, 137.6, 137.4, 128.5, 127.4, 127.0,
126.1, 122.9, 112.3, 70.7, 43.8, 42. 7, 29.9, 23.4. ESI-MS: 274.2 [M+NH4], HRMS (ESI): Calcd. for
C18H25O [M+H]: 257.1900, found: 257.1899.
(S,3E,7E)-2,6-Dimethyl-8-(p-tolyl)-6-vinylocta-3,7-dien-2-ol (14d) Yield: 98%, Rf = 0.46 (petroleum
ether/ethyl acetate = 5:1), [α]2D0 −9.1 (c 0.55, CHCl3). H-NMR (CDCl3) δ 7.25 (d, J = 7.3 Hz, 2H),
1
7.10 (d, J = 7.3 Hz, 2H), 6.28 (d, J = 16.2 Hz, 1H), 6.14 (d, J = 16.2 Hz, 1H), 5.88 (dd, J = 17.4, 10.7 Hz,
1H), 5.70–5.53 (m, 2H), 5.11–4.94 (m, 2H), 2.32 (s, 3H), 2.22 (d, J = 5.9 Hz, 2H), 1.42 (brs, 1H), 1.29
(s, 6H), 1.17 (s, 3H). 13C-NMR (CDCl3) δ 145.4, 141.1, 136.7, 136.4, 134.9, 129.2, 127.3, 126.0,
123.0, 112.2, 70.7, 43.8, 42.6, 29.8, 23.4, 21.1. ESI-MS: 293.2 [M+Na].
(S,3E,7E)-2,6-Dimethyl-8-(naphthalen-2-yl)-6-vinylocta-3,7-dien-2-ol (14e) Yield: 100%, Rf = 0.41
(petroleum ether/ethyl acetate = 5:1), [α]2D0 −13.7 (c 0.35, CHCl3). H-NMR (CDCl3) δ 7.83–7.74 (m,
1
3H), 7.70 (s, 1H), 7.59 (d, J = 8.6 Hz, 1H), 7.48–7.38 (m, 2H), 6.49 (d, J = 16.2 Hz, 1H), 6.34 (dd,
J = 16.2, 2.0 Hz, 1H), 5.93 (ddd, J = 17.4, 10.7, 2.0 Hz, 1H), 5.72-5.57 (m, 2H), 5.14–5.01 (m, 2H),
13
2.26 (dd, J = 5.9, 1.7 Hz, 2H), 1.41 (s, 1H), 1.30 (s, 6H), 1.23 (s, 3H). C-NMR (CDCl3) δ 145.3,
141.2, 137.9, 135.1, 133.6, 132.7, 128.0, 127.8, 127.6, 126.1, 125.68, 125.5, 123.5, 122.9, 112.4, 70.8,
43.8, 42.8, 29.9, 23.4. ESI-MS: 293.2 [M+Na], HRMS (ESI): Calcd. for C22H26ONa [M+Na]:
329.1876, found: 329.1885.
(S,3E,7E)-2,6-Dimethyl-8-(4-(trifluoromethyl)phenyl)-6-vinylocta-3,7-dien-2-ol (14f) Yield: 96%,
Rf = 0.42 (petroleum ether/ethyl acetate = 5:1), [α]2D0 +2.0 (c 0.75, CHCl3). 1H-NMR (CDCl3) δ 7.54 (d,
J = 8.2 Hz, 2H), 7.44 (d, J = 8.2 Hz, 2H), 6.35 (d, J = 16.3 Hz, 1H), 6.30 (d, J = 16.3 Hz, 1H), 5.89
(dd, J = 17.5, 10.7 Hz, 1H), 5.70–5.53 (m, 2H), 5.09 (dd, J = 10.7, 1.0 Hz, 1H), 5.03 (dd, J = 17.5, 1.0
Hz, 1H), 2.24 (d, J = 6.6 Hz, 2H), 1.37 (brs, 1H), 1.30 (s, 6H), 1.20 (s, 3H). 13C-NMR (CDCl3) δ
144.7, 141.4, 141.1, 140.2, 126.3, 126.2, 125.4, 125.4, 122.5, 112.8, 70.7, 43.7, 42.9, 29.9, 23.2.
ESI-MS: 347.2 [M+Na], HRMS(ESI): Calcd. for C19H24F3O [M+H]: 325.1774, found: 325.1774.
(S,3E,7E)-8-(Benzo[d][1,3]dioxol-5-yl)-2,6-dimethyl-6-vinylocta-3,7-dien-2-ol (14g) Yield: 38%,
Rf = 0.26 (petroleum ether/ethyl acetate = 5:1), [α]2D0 −10.2 (c 0.50, CHCl3). H-NMR (CDCl3) δ 6.91
1
(s, 1H), 6.77 (d, J = 8.0 Hz, 1H), 6.73 (d, J = 8.0 Hz, 1H), 6.22 (d, J = 16.2 Hz, 1H), 6.03 (d, J = 16.2 Hz,
1H), 5.93 (d, J = 1.0 Hz, 2H), 5.87 (dd, J = 17.5, 10.7 Hz, 1H), 5.68–5.52 (m, 2H), 5.05 (d, J = 10.7 Hz,
1H), 5.00 (d, J = 17.5 Hz, 1H), 2.21 (d, J = 6.5 Hz, 2H), 1.42 (brs, 1H), 1.29 (s, 6H), 1.16 (s, 3H).
13C-NMR (CDCl3) δ 147.9, 146.7, 145.3, 141.1, 135.7, 132.2, 127.0, 122. 9, 120.5, 112.3, 108.2,
105.4, 100.9, 70.7, 43.8, 42.6, 29.9, 29.7, 23.4. ESI-MS: 318.4 [M+NH4], HRMS (ESI): Calcd. for
C19H24O3Na [M+Na]: 323.1618, found: 323.1639.

Molecules 2014, 19
2223
3.3. Activity Tests
The MTT assay was used to measure cell viability. All the tested compounds were dissolved in
0.5% DMSO. Before analysis, UMR 106 cells (rat osteosarcoma cell line) were cultured with or
without different concentrations of compounds for 48 h, respectively. At the end of incubation 0.5%
MTT (20 μL) was added to each well, followed by incubation at 37 °C in 5% CO2 atmosphere for 4 h.
The medium was then removed carefully, and DMSO (150 μL) was added to each well. The plates
were shaken gently for 10 min to dissolve the blue formazan crystals. Absorbance was measured at
570 nm using an ELx-800 universal microplate reader (Bio-Tek, Winooski, VT, USA).
4. Conclusions
In summary, a series of the analogues of ∆3-2-hydroxybakuchiol have been synthesized, and some
of them have been found to possess evident cytotoxic activity against rat UMR106 cells. Furthermore,
the SAR study gives a preliminary profile, including: (1) the chain tail on the natural product could be
somewhat modified to enhance the activity; (2) the aromatic moiety or the terminal olefin attached on
the main chain are allowed to be modified without evident loss of activity; (3) the stereoconfiguration
at the quaternary chiral center has an important influence on the activity.
Acknowledgments
We thank National Natural Foundation of China (21242008) and National High-tech R&D
Program of China (2013AA092903) for the financial support. We are grateful to Luyan Zhang for his
helpful discussion.
Conflicts of Interest
The authors declare no conflict of interest.
References
1. Sun, N.J.; Woo, S.H.; Cassady, J.M.; Snapka, R.M. DNA polymerase and topoisomerase II
inhibitors from Psoralea corylifolia. J. Nat. Prod. 1998, 61, 362–366.
2. Miura, H.; Nishida, H.; Linuma, M. Effect of Crude Fractions of Psoralea corylifolia Seed
Extract on Bone Calcification. Planta Med. 1996, 62, 150–153.
3. Yin, S.; Fan, C.-Q.; Yue, J.-M. Cyclobakuchiol C, a new bakuchiol derivative from Psoralea
coryllfolia. J. Asian Nat. Prod. Res. 2007, 9, 29–33.
4. Matsuda, H.; Sugimoto, S.; Morikawa, T.; Matsuhira, K.; Mizuguchi, E.; Nakamura, S.;
Yoshikawa, M. Bioactive constituents from chinese natural medicines. XX. Inhibitors of antigen-
induced degranulation in RBL-2H3 cells from the seeds of Psoralea corylifolia. Chem. Pharm. Bull.
2007, 55, 106–110.
5. Wu, C.-Z.; Cai, X.F.; Dat, N.T.; Hong, S.S.; Han, A.-R.; Seo, E.-K.; Hwang, B.Y.; Nan, J.-X.;
Lee, D.; Lee, J.J. Bisbakuchiols A and B, novel dimeric meroterpenoids from Psoralea corylifolia.
Tetrahedron Lett. 2007, 48, 8861–8864.

Molecules 2014, 19
2224
6. Yin, S.; Fan, C.-Q.; Dong, L.; Yue, J.-M. Psoracorylifols A–E, five novel compounds with
activity against Helicobacter pylori from seeds of Psoralea corylifolia. Tetrahedron 2006, 62,
2569–2575.
7. Backhouse, C.N.; Delporte, C.L.; Negrete, R.E.; Erazo, S.; Zuniga, A.; Pinto, A.; Cassels, B.K.
Active constituents isolated from Psoralea glandulosa L. with antiinflammatory and antipyretic
activities. J. Ethnopharmacol. 2001, 78, 27–31.
8. Majeed, R.; Reddy, M.V.; Chinthakindi, P.K.; Sangwan, P.L.; Hamid, A.; Chashoo, G.;
Saxena, A.K.; Koul, S. Bakuchiol derivatives as novel and potent cytotoxic agents: A report.
Eur. J. Med. Chem. 2012, 49, 55–67.
9. Reddy, M.V.; Thota, N.; Sangwan, P.L.; Malhotra, P.; Ali, F.; Khan, I.A.; Chimni, S.S.; Koul, S.
Novel bisstyryl derivatives of bakuchiol: Targeting oral cavity pathogens. Eur. J. Med. Chem.
2010, 45, 3125–3134.
10. Chen H.; Du, X.; Tang, W.; Zhou, Y.; Zuo, J.; Feng, H.; Li, Y. Synthesis and structure–
immunosuppressive activity relationships of bakuchiol and its derivatives. Bioorg. Med. Chem.
2008, 16, 2403–2411.
11. Chen, Z.; Jin, K.; Gao, L.; Lou, G.; Jin, Y.; Yu, Y.; Lou, Y. Anti-tumor effects of bakuchiol, an
analogue of resveratrol, on human lung adenocarcinoma A549 cell line. Eur. J. Pharmcol. 2010,
643, 170–179.
12. Yan, D.-M.; Chang, Y.-X.; Wang, Y.-F.; Liu, E.-W.; Li, J.; Kang, L.-Y.; Gao, X.-M. In vivo
pharmacokinetics of bakuchiol after oral administration of bakuchiol extraction in rat plasma.
J. Ethnopharmacol. 2010, 128, 697–702.
13. Choi, S.Y.; Lee, S.; Choi, W.-H.; Lee, Y.; Jo, Y.O.; Ha, T.-Y. Isolation and anti-inflammatory
activity of bakuchiol from Ulmus davidiana var. japonica. J. Med. Food 2010, 13, 1019–1023.
14. Lim, S.-H.; Ha, T.-Y.; Kim, S.-R.; Ahn, J.; Park, H.J.; Kim, S. Ethanol extract of
Psoralea corylifolia L. and its main constituent, bakuchiol, reduce bone loss in ovariectomised
Sprague–Dawley rats. Br. J. Nutr. 2009, 101, 1031–1039.
15. Choi, Y.H.; Yon, G.H.; Hong, K.S.; Yoo, D.S.; Choi, C.W.; Park, W.-K.; Kong, J.Y.; Kim, Y.S.;
Ryu, S.Y. In vitro BACE-1 inhibitory phenolic components from the seeds of Psoralea corylifolia.
Planta Med. 2008, 74, 1405–1408.
16. Wu, C.-Z.; Hong, S.S.; Cai, X.F.; Dat, N.T.; Nan, J.-X.; Hwang, B.Y.; Lee, J.J. Lee, D.
Hypoxia-inducible factor-1 and nuclear factor-κB inhibitory meroterpene analogues of bakuchiol,
a constituent of the seeds of Psoralea corylifolia. Bioorg. Med. Chem. Lett. 2008, 18, 2619–2623.
17. Kim, Y.-C.; Oh, H.; Kim, B.S.; Kang, T.-H.; Ko, E.-K.; Han, Y.M.; Kim, B.Y.; Ahn, J.S. In vitro
Protein Tyrosine Phosphatase 1B inhibitory phenols from the seeds of Psoralea corylifolia.
Planta Med. 2005, 71, 87–89.
18. Park, E.-J.; Zhao, Y.-Z.; Kim, Y.-C.; Sohn, D.H. Bakuchiol-induced caspase-3-dependent
apoptosis occurs through c-Jun NH2-terminal kinase-mediated mitochondrial translocation of Bax
in rat liver myofibroblasts. Eur. J. Pharmacol. 2007, 559, 115–123.
19. Adhikari, S.; Joshi, R.; Patro, B.S.; Ghanty, T.K.; Chintalwar, G.J.; Sharma, A.; Chattopadhyay, S.;
Mukherjee, T. Antioxidant activity of bakuchiol:ꢀ Experimental evidences and theoretical
treatments on the possible involvement of the terpenoid chain. Chem. Res. Toxicol. 2003, 16,
1062–1069.

Molecules 2014, 19
2225
20. Haraguchi, H.; Inoue, J.; Tamura, Y.; Mizutani, K. Antioxidative components of Psoralea corylifolia
(Leguminosae). Phytother. Res. 2002, 16, 539–544.
21. Cho, H.; Jun, J.-Y.; Song, E.-K.; Kang, K.-H.; Baek, H.-Y.; Ko, Y.-S.; Kim, Y.-C. Bakuchiol: A
hepatoprotective compound of Psoralea corylifolia on tacrine-induced cytotoxicity in Hep G2
Cells. Planta Med. 2001, 67, 750–751.
22. Haraguchi, H.; Inoue, J.; Tamura, Y.; Mizutani, K. Inhibition of mitochondrial lipid peroxidation
by bakuchiol, a meroterpene from Psoralea corylifolia. Planta Med. 2000, 66, 569–571.
23. Krenisky, J.M.; Luo, J.; Reed, M.J.; Carney, J.R. Isolation and antihyperglycemic activity of
bakuchiol from Otholobium pubescens (Fabaceae), a peruvian medicinal plant used for the
treatment of diabetes. Biol. Pharm. Bull. 1999, 22, 1137–1140.
24. Labbé, C.; Faini, F.; Coll, J.; Connolly, J.D. Bakuchiol derivatives from the leaves of Psoralea
glandulosa. Phytochemistry 1996, 42, 1299–1303.
25. Shah, C.C.; Bhalla, V.K.; Dev, S. Meroterpenoids-V: Psoralea Corylifolia Linn. - 4. 2,3-
Epoxybakuchiol, Delta 1,3-Hydroxybakuchiol, and Delta 3,2-Hydroxybakuchiol. J. Indian Chem.
Soc. 1997, 74, 970–973.
26. Zhao, G.; Zang, S.-Y.; Zheng, X.-W.; Zhang, X.-H.; Guo, L.-H. Bakuchiol analogs inhibit
monoamine transporters and regulate monoaminergic functions. Biochem. Pharmacol. 2008, 75,
1835–1847.
27. Zhang, Q.; Deng, C.; Fang, L.; Xu, W.; Zhao, Q.; Zhang, J.; Wang, Y.; Lei X. Synthesis and
Evaluation of the Analogues of Penicillide against Cholesterol Ester Transfer Protein. Chin. J.
Chem. 2013, 31, 355–370.
28. Deng, C.-L.; Zhang, Q.; Fang, L.-S.; Lei, X.; Lin, G.-Q. A Convergent Approach to
Dibenzodioxocinones: Synthesis of Racemic Penicillide. Helv. Chim. Acta 2012, 95, 626–635.
29. Fang, L.-S.; Zhang, Q.; Deng, C.-L.; Lei, X.; Lin, G.-Q. Regio-selective chlorination of vinca
alkaloids catalyzed by Lewis acid. Sci. China Chem. 2011, 54, 1039–1043.
30. Lei, X.; Yu, X.; Yin, L.; Liu, Z.; Tang, P.C. Synthesis and biological evaluation of C-12'
substituted vinflunine derivatives. Bioorg. Med. Chem. Lett. 2008, 18, 4602–4605.
31. Shi, L.; Zhang, J.; Lei, X.; Lin, G. Synthesis of racemic Δ3-2-Hydroxybakuchiol and its
analogues. Helv. Chim. Acta 2010, 93, 555–564.
32. Xu, Q.-Q.; Zhao, Q.; Shang, G.-S.; Yang, X.-C.; Lei, X. A facile asymmetric synthesis of Δ3-2-
Hydroxybakuchiol, Bakuchiol and ent-Bakuchiol. Tetrahedron 2013, 69, 10739–10746.
33. Cha, M.-R.; Choi, C.W.; Lee, J.Y.; Kim, Y.S.; Yon, G.H.; Choi, S.-U.; Ryn, S.Y. Anti-proliferative
effect of synthesized bakuchiol analogues on cultured human tumor cell lines. Bull. Korean
Chem. Soc. 2012, 33, 2378–2380.
34. Zheng, C.; Hua, C.; Ma, X.; Peng, C.; Zhang, H.; Qin, L. Cytotoxic phenylpropanoid glycosides
from Fagopyrum tataricum (L.) Gaertn. Food Chem. 2012, 132, 433–438.
Sample Availability: Samples of the compounds are available from the authors.
© 2014 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article
distributed under the terms and conditions of the Creative Commons Attribution license
(http://creativecommons.org/licenses/by/3.0/).