Semi-synthesis and anti-proliferative activity evaluation of novel analogues of Honokiol

Article abstract of DOI:10.1016/j.bmcl.2009.06.071

A series of honokiol analogues were synthesized by modifying the 5- and/or 3′-position(s) of honokiol to assess their anti-tumor effects. Some compounds exerted more potent anti-proliferative activities than those of honokiol on K562 leukemia cells, A549

Full text of DOI:10.1016/j.bmcl.2009.06.071

Bioorganic & Medicinal Chemistry Letters 19 (2009) 4702–4705
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Semi-synthesis and anti-proliferative activity evaluation of novel analogues of
Honokiol
Youfu Luo a,b, , Yongbin Xu a, , Lijuan Chen a, , , Jia Hu a, Cheng Peng c, DaChun Xie a, Jianyou Shi a,
*
Wencai Huang b, Guobin Xu a, Ming Peng a, Jing Han a, Rui Li a, Shengyong Yang a, Yuquan Wei a
a State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, PR China
b Institute for Chemical Engineering, Sichuan University, Chengdu, Sichuan 610065, PR China
c Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610075, PR China
a r t i c l e i n f o
a b s t r a c t
A series of honokiol analogues were synthesized by modifying the 5- and/or 30-position(s) of honokiol to
assess their anti-tumor effects. Some compounds exerted more potent anti-proliferative activities than
those of honokiol on K562 leukemia cells, A549 alveolar basal epithelial cells, SPC-A1 adenocarcinoma
cells and A2780 human ovarian carcinoma cells in vitro. Compounds 2b, 3a, and 3c displayed most potent
anti-proliferative activities against these tested cell strains and their anti-drug resistance effects were
evaluated in vitro on cisplatin-resistant A2780 human ovarian carcinoma cells. The structure–activity
relationship was also proposed.
Article history:
Received 11 February 2009
Revised 2 June 2009
Accepted 18 June 2009
Available online 21 June 2009
Keywords:
Honokiol
Analogue
Ó 2009 Published by Elsevier Ltd.
Anti-proliferative activity
Anti-drug resistance effect
Semi-synthesis
Honokiol, a significant bioactive component extracted from the
root, stem bark and the seeds cones of Magnolia officinalis, demon-
strates various biological activities such as anti-oxidative,1 anti-
arrhythmic,2 anti-inflammatory,3 anti-thrombocytic,4 anti-angio-
genesis,5 anti-tumor,6 anxiolytic effects,7 and anti-HIV activity8. Re-
cent studies in our laboratory also indicate that honokiol induces
apoptosis in tumor cells, inhibits angiogenesis and has synergistic
anti-tumor activities combined with chemotherapy agents and
radiotherapy in vitro and in vivo.9 These unusual combined biolog-
ical properties encourage further structure modification to increase
the potencies and understand the underlying mechanism. However,
until now, only few analogues have been reported in the litera-
tures.10–13 Kong et al.10 and Esumi et al.11 reported that honokiol’s
biological effects are attributed to the bisphenol structure bearing
allyl moieties. Accordingly, to further clarify a structure–activity
relationship, make clear the action mechanism and improve the
anti-proliferative potencies of these compounds, we now describe
the semi-synthesis of a novel series of honokiol analogues with dif-
ferent groups at the 5- and/or 30-positions and in vitro evaluation as
potential inhibitors to various tumor cell strains.
derivatives (2a–c) of honokiol in our previous Letter.14 Since the
formyl group usually has high reactivity toward many chemical re-
agents, the introduction of formyl groups (a formyl group) to the 5-
and/or 30-position(s) of honokiol provided us convenient ap-
proaches (see Scheme 1) to modify honokiol through such various
kinds of chemical reactions as aldol condensation, Knovenagel con-
densation, Wittig reaction, and nucleophilic addition/elimination.
The oxime compounds15 3a–c were prepared in parallel by
respectively refluxing 2a–c with hydroxylamine hydrochloride in
the presence of triethylamine as catalyst in methanol for 3 h.
The aldol condensation of the formylated honokiols 2a–b with
1.2 equiv ethyl cyanoacetate proceeded gradually in refluxing etha-
nol for 48 h16 with 4 Å molecular sieves powder as catalyst to afford
compounds 4a–b in 85–88% yields. Of note, some salicylaldehydes
were reported to undergo tandem Knoevenagel/Michael processes
with 2.0 equiv ethyl cyanoacetate to produce compounds bearing
a 4H-chromene moiety in the presence of 4Å molecular sieves as cat-
alyst.17 However, the above formylated derivatives of honokiol bear-
ing a salicylaldehyde moiety did not trigger this reaction cascade,
and terminated at Knoevenagel condensation step. The inertia to
this reaction condition of the formylated honokiols could be inter-
preted as the steric-hindrance effects caused by the bulky biaryl
structure.
We have reported approaches for the synthesis, HSCCC isolation
and anti-proliferative effects evaluation of three C-formylated
Compounds 5a–c were synthesized in parallel by, respectively,
heating 2a–c with 2,4-thiazolidinedione in acetic acid in the pres-
ence of b-alanine as catalyst at 100 °C for 12 h.18 The six Schiff base
* Corresponding author. Tel.: +86 28 85164063; fax: +86 28 85164060.
E-mail address: lijuan17@hotmail.com (L. Chen).
Youfu Luo, Yongbin Xu and Lijuan Chen equally contributed.
0960-894X/$ - see front matter Ó 2009 Published by Elsevier Ltd.
doi:10.1016/j.bmcl.2009.06.071

Y. Luo et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4702–4705
4703
Scheme 1. Synthesis of compounds 3a–c, 4a–b, 5a–c, 6a–f. Reagents and conditions: (i) hydroxylamine hydrochloride, triethylamine, methanol, reflux, 3 h; (ii) ethyl
cyanoacetate, 4 Å molecular sieves powder, anhydrous ethanol, reflux, 48 h; (iii) 2,4-thiazolidinedione, acetic acid, b-alanine, 100 °C,12 h; (iv) ethanol, reflux, 2 h.
derivatives 6a–f were prepared similarly by refluxing 2a with the
corresponding amine in ethanol for 2 h.19
Intramolecularly cyclodehydration of the oxime 3a afforded
compound 7 by stirring with thionyl chloride and pyridine at
0 °C for 2 h20 (see Scheme 2).
38.8, 38.4 and 41.8 l
M, respectively. In 30-formylhonokiol (2a),
20-hydroxy group can form intramolecular hydrogen bond with
30-formyl group and the hydrogen bond would decrease its ability
to interact with biological target molecules.
The above results suggest that 20-hydroxy group is pharmaco-
phoric moiety in the suppression of tumor cells growth.
All of the compounds described except 2a–c were purified by
flash chromatography and their purities were above 98.5% by
HPLC. The structures of all honokiol analogues were identified by
As to 5-formylhonokiol (2b), its inhibitory activities on some tu-
mor cell strains are increased by about twofold although intramo-
lecular hydrogen bond could be formed between 4-hydroxy group
and 5-formyl group. From this finding it can be assumed that a pro-
ton donor at 4-position is unfavorable for the biological activities.
Derivatives with depletion of hydrogen atom in 4-hydroxy group
are necessary to be synthesized to evaluate the anti-proliferative
activities in vitro. The synthesis of these analogues is under pro-
gress in our group.
13
ESI-HRMS, 1H NMR and C NMR. The two isomers, 30-formylhon-
okiol and 5-formylhonokiol, were further characterized unambigu-
ously by heteronuclear multiple-bond correlation (HMBC) spectra
(see Supplementary data).
The anti-proliferative activity assessment was performed by
standard procedure which was described detailed in our previous
Letter.14 The IC50 values of honokiol and its analogues were listed
in Table 1.
It could be seen in Table 1 that the introduction of little hin-
drance groups such as formyl group or its oxime to the 5- and/or
30-position(s) of honokiol (compounds 2a–c, 3a–c, 6e) exhibited
comparable or slightly more potent anti-proliferative activities
than that of honokiol. Adversely, the potencies of compound 7 de-
creased almost threefold compared with compound 3a after intra-
molecular cyclization between the hydroxy group at 20-position
and the oxime at 30-position. The intramolecular cyclodehydration
caused the loss of hydrogen atom at 2-position, likely prohibiting
the formation of intermolecular hydrogen or ionic bond between
20-hydroxy group and possible biomolecular targets.
Introduction of a bulky subsituent to the 5- and/or 30-posi-
tion(s) of honokiol (compounds 4a–b, 5a–c) led to decreased ef-
fects conspicuously. Thus 2,4-thiazolidinedione, widely thought
to be a pharmacophore in some effective inhibitors of phosphati-
dylinositol 3-kinase (PI3K),21 a signaling transduction molecule in-
volved in many tumors, was subject to reacted with the formylated
honokiols 2a–c through Knoevenagel condensation to produce
compounds 5a–c, whose IC50 values for all tested tumor cells in-
creased significantly. As the assay used herein is cell-based, no
statement can be made on the mechanism underlying the observed
low inhibitory effects against the tested tumor cell strains so far.
Therefore in order to be able to evaluate the potential of these
compounds as PI3K inhibitors, it will be necessary perform a
cell-free assay on direct PI3K inhibition.
The anti-proliferative effects of the introduction of substituted
phenyl groups (compounds 6b–d) or aliphatic substituents (com-
pounds 6a, 6f) to the 5- and/or 30-position(s) of honokiol by imine
bond formation starting from the formylated honokiols 2a–c were
also evaluated. Analogues with substituted phenyl group retained
partial or full anti-proliferative activities except compound 6d,
while aliphatic ones conspicuously decreased the effects in vitro,
especially for compound 6f, whose IC50 values for the three tested
This deduction meets, to some extent, the slightly decreased
anti-proliferative effects of 30-formylhonokiol (2a) in comparison
to honkiol, whose IC50 values for K562, SPC-A1, and A549 were
tumor cell strains were all above 40
displayed no anti-proliferative effects at our maximum tested con-
centration (40 g/mL), sharply contrast with other phenyl substi-
lg/mL. Of note, compound 6d
Scheme 2. Synthesis of compound 7. Reagents and conditions: (i) thionyl chloride,
pyridine, diethyl ether, reflux, 2 h.
l

4704
Y. Luo et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4702–4705
Table 1
IC50 values of Honokiol and its analogues against various tumor cells
OH
R2
R1
MW
OH
Entry
R1
R2
IC50 (lM)
K562
SPC-A1
A549
A2780
A2780/cis
1
–H
–CHO
–CH@N–OH
–CH@C(CN)COOEt
–H
–H
–H
–H
272
294
309
389
21.1
38.8
20.7
95.1
36.1
38.4
45.0
92.5
35.0
41.8
40.4
87.4
30.5
n.t.a
33.0
n.t.
41.2
n.t.
37.2
n.t.
2a
3a
4a
O
H
C
S
5a
–H
393
91.6
>101.8
91.6
n.t.
n.t.
NH
O
7
–CH@N–O–
–H
–H
–H
–H
–H
–H
–H
–CHO
291
375
384
369
384
336
377
294
309
389
78.4
90.7
29.2
32.2
>104.2
42.6
>106.1
11.9
24.9
47.6
77.3
88.0
40.1
40.7
>104.2
50.3
>106.1
25.5
53.1
62.0
65.6
93.3
38.8
39.8
>104.2
41.1
>106.1
41.8
39.5
n.t.
n.t.
n.t.
n.t.
n.t.
n.t.
n.t.
16.7
n.t.
n.t.
n.t.
n.t.
n.t.
n.t.
n.t.
n.t.
n.t.
22.4
n.t.
n.t.
6a
6b
6c
6d
6e
6f
2b
3b
4b
–CH@N–cyclohexyl
–CH@N–C6H5NH2
–CH@N–C6H5
–CH@N–N–C6H5
–CH@N–CH2CH2NH2
–CH@N–Hexyl(n)
–H
–H
–H
–CH@N–OH
–CH@C(CN)COOEt
57.6
O
H
C
S
5b
–H
393
81.4
>101.8
>101.8
n.t.
n.t.
NH
O
2c
3c
–CHO
–CH@N–OH
–CHO
–CH@N–OH
322
352
36.0
21.5
45.3
43.8
55.0
32.4
n.t.
20.2
n.t.
29.3
O
O
H
C
S
H
C
S
5c
520
>76.9
>76.9
>76.9
n.t.
n.t.
NH
NH
O
O
a
n.t.: not tested. Values are geometric means of at least two experiments with six data points in each experiment.
tuted derivatives. More studies should be conducted to investigate
whether the introduced phenyl moiety play a part in the suppres-
sion of these tumor cell strains.
oxime, especially at the 5-position would be envisaged in order to
implement a more successful modification of honokiol in order to
generate more potent analogues.
Additionally, honokiol had been reported to overcome conven-
tional drug resistance in human multiple myeloma by induction of
caspase-dependent and -independent apoptosis.22 Herein we
chose three compounds (2b, 3a, and 3c) with most potent inhibi-
tory effects on the tested cell strains to evaluate their activities
on cisplatin-sensitive and -resistant A2780 human ovarian carci-
noma cells in order to investigate their anti-drug resistance effects
against cisplatin-resistant tumor cells. Two of the tested com-
pounds (2b and 3c) displayed more potent inhibitory activities
than those of honokiol on A2780/cis cells as well as on A2780. This
observation suggests that honokiol and some semi-synthetic ana-
logues can overcome cisplatin-resistant human ovarian carcinoma
cells.
Acknowledgment
We are grateful to the National Natural Science Foundation of
China for financial support of this research (30772776).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2009.06.071.
References and notes
In conclusion, 18 analogues23 have been synthesized by intro-
duction of diverse groups to the 5- or 30-position(s) of honokiol
and the anti-proliferative activities have been evaluated in vitro.
The structure–activity data acquired show that the hydroxy
groups, especially 20-hydroxy play a crucial role on anti-prolifera-
tive activities, and imply that the introduction of a formyl group
to the 5-position of honokiol enhances the potencies. The discovery
of compounds 2b, 3a, and 3c, especially 2b, provides a new insight
on the synthesis and anti-proliferative evaluation of new honokiol
analogues. As a result of the above findings, the formyl group or its
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J = 4.0 Hz, 2H), 3.36 (d, J = 4.0 Hz, 2H), 3.24 (s, 1H), 1.36–1.82 (m, 10H); 13C
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Xie, D. C.; Fu, A. F.; Shi, J. Y.; Yang, S. Y.; Wei, Y. Q. J. Chromatogr., A 2008, 1178,
160.
15. Typical procedure for the synthesis of the oxime derivatives 3a–c: Compound 3a
was prepared as follows. The solution of 30-formylhonokiol (2a) (0.1 mmol),
methanol (2 mL), and hydroxylammonium chloride (0.5 mmol) was bufferd to
a pH of 8 with triethylamine and then heated under reflux for 3 h. The mixture
was poured into distilled water (10 mL), filtered, washed with distilled water
(3 ꢀ 5 mL), and dried in vacuo at 50 °C for 24 h. The product was yellowish
white solid with a yield of 90% in purity of 99%.
NMR (100 MHz, CDCl3), d (ppm), 162.43, 157.39, 153.44, 137.69, 136.60,
133.26, 131.32, 130.58, 129.77, 129.56, 129.41, 128.89, 124.87, 118.68, 116.47,
115.71, 115.58, 39.26, 35.42, 34.28, 34.28, 30.95, 25.49, 24.32; MS: m/z
375.2198 (M+).
Compound 6b: 1H NMR (400 MHz, CDCl3), d (ppm), 8.61 (s, 1H), 6.58–7.42 (m,
9H), 5.95–6.09 (m, 2H), 5.11–5.22 (m, 4H), 3.47 (d, J = 4.0 Hz, 2H), 3.38 (d,
J = 4.0 Hz, 2H); 13C NMR (100 MHz, CDCl3), d (ppm), 158.75, 156.59, 153.48,
145.81, 139.09, 137.59, 136.61, 133.59, 131.36, 130.42, 130.37, 130.09, 129.56,
128.86, 125.09, 122.34, 122.27, 119.44, 116.45, 115.84, 115.68, 115.68, 115.58,
39.28, 35.31; MS: m/z 384.1838 (M+).
Compound 6c: 1H NMR (400 MHz, CDCl3), d (ppm), 8.66 (s, 1H), 6.88–7.44 (m,
10H), 5.96–6.10 (m, 2H), 5.09–5.24 (m, 4H), 3.48 (d, J = 4.0 Hz, 2H), 3.40 (d,
J = 4.0 Hz, 2H); 13C NMR (100 MHz, CDCl3), d (ppm),162.71, 156.81, 153.55,
148.24, 137.43, 136.50, 134.43, 131.39, 130.90, 130.32, 130.28, 129.73, 129.42,
129.33, 128.91, 126.91, 124.98, 121.15, 121.15, 119.12, 116.57, 115.98, 115.63,
39.22, 35.37; MS: m/z 369.1729 (M+).
Compound 6d: 1H NMR (400 MHz, CDCl3), d (ppm), 7.83 (s, 1H), 7.43–6.87
(m,10H), 6.07–5.94 (m, 2H), 5.24–5.06 (m, 4H), 3.48 (d, J = 6.4 Hz, 2H), 3.35 (d,
J = 6.4 Hz, 2H); 13C NMR (100 MHz, CDCl3), d (ppm), 153.50, 152.41, 143.31,
141.36, 137.58, 136.49, 131.45, 131.42, 130.75, 130.65, 129.48, 129.48, 129.20,
128.98, 128.19, 124.94, 120.81, 118.52, 116.62, 115.80, 115.64, 112.63, 112.63,
39.27, 35.44; MS: m/z 385 (M+).
16. Typical procedure for the synthesis of compounds 4a–b: 30-Formylhonokiol (2a)
(0.1 mmol) was mixed with ethanol (2 mL) and ethyl cyanoacetate (0.2 mmol)
in a reaction tube of 10 mL. 4 Å molecular sieves power (20 mg) was added and
stirred under reflux for 48 h, then filtered and evaporated. The resulting
colorless oil was columned using an eluent of 25% ethyl acetate in petroleum
ether (v/v). The product was yellow solid with a yield of 85% in purity of 99%).
17. Yu, N.; Aramini, J. M.; Germann, M. W.; Huang, Z. Tetrahedron Lett. 2000, 41,
6993.
Compound 6e: 1H NMR (400 MHz, CDCl3), d (ppm), 8.33 (s, 1H), 7.36 (d,
J = 4.0 Hz, 1H), 7.35 (d, J = 4.0 Hz, 1H), 7.16 (d, J = 2.0 Hz, 1H), 6.97 (d, J = 2.0 Hz,
1H), 6.84 (q, J = 2.8, 8.0 Hz, 1H), 5.88–6.08 (m, 2H), 5.02–5.22 (m, 2H), 3.45 (d,
J = 6.4 Hz, 2H), 3.32 (d, J = 6.4 Hz, 2H), 0.88 (s, 1H); 13C NMR (100 MHz, CDCl3),
18. Typical procedure for the synthesis of compounds 5a–c: 30-Formylhonokiol (2a)
(0.1 mmol) was dissolved in 2 mL acetic acid. 2,4-Thiazolidinedione (0.2 mmol)
and b-alanine (0.2 mmol) were added and left the mixture to stir at 100 °C for
12 h. The reaction mixture was poured into distilled water (5 mL), filtered,
washed with distilled water (10 ꢀ 5 mL), and dried in vacuo at 50 °C for 24 h.
The product was yellow solid with a yield of 92% in purity of 99%.
19. Typical procedure for the synthesis of the Schiff base derivatives 6a–f: 30-
Formylhonokiol (2a) (0.1 mmol) was dissolved in ethanol (2 mL) and the
corresponding amine (0.2 mmol) was added and left to stir under reflux for 2 h.
The reaction mixture was evaporated to afford brown oily residue. This residue
was columned to get clear yellow oil with a yield of 86% in purity of 98.5%.
20. Kalkote, U. R.; Goswami, D. D. Aust. J. Chem., 1977, 30, 1847–1850: Synthesis of
the compound 7. A mixture of compound 3a (30.9 mg, 0.1 mmol), diethyl ether
d
(ppm), 166.81, 156.70, 153.51, 137.46, 136.60, 133.64, 131.30, 130.27,
130.20, 129.88, 129.43, 128.81, 125.10, 118.51, 116.40, 115.85, 115.54, 59.59,
35.28, 30.93; MS: m/z 336.1838 (M+).
Compound 6f: 1H NMR (400 MHz, CDCl3), d (ppm), 9.90 (s, 1H), 8.33 (s, 1H) ,
7.41–7.31 (m, 2H) , 7.18 (d, J = 2.4 Hz, 1H), 7.01 (d, J = 2.4 Hz, 1H), 6.88–6.84
(m, 1H), 6.09–5.94 (m, 2H), 5.23–5.05 (m, 4H), 3.59–3.31 (m, 6H), 1.66 (s, 2H),
1.30–1.23 (m, 11H), 0.87 (t, J = 6.8, 13.6 Hz, 3H); 13C NMR (100 MHz, CDCl3), d
(ppm), 164.65, 157.45, 153.43, 137.64, 136.60, 133.36, 131.32, 130.53, 129.76,
129.58, 129.45, 128.87, 124.90, 118.59, 116.45, 115.75, 115.58, 59.21, 39.26,
35.37, 31.83, 30.82, 29.70, 29.31, 29.19, 27.15, 18.83; MS: m/z 378 (M+).
Compound 7: 1H NMR (400 MHz, CDCl3), d (ppm), 8.71 (s, 1H), 7.72 (q, J = 2.4,
8.4 Hz, 1H), 7.68 (d, J = 2.4 Hz, 1H), 7.52 (s, 1H), 7.43 (s, 1H), 7.03 (d, J = 8.4 Hz,
1H), 5.99–6.10 (m, 2H), 5.12–5.23 (m, 4H), 3.53 (q, J = 6.0, 12.6 Hz, 4H); 13C
(2 mL) and pyridine (807
lL, 10 mmol) was stirred under the atmosphere of N2
at 0 °C for 15 min. Thionyl chloride (71
l
L, 1 mmol) was added in one portion
NMR (100 MHz, CDCl3), d (ppm), 159.00, 154.58, 146.32, 137.12, 136.67,
136.25, 130.37, 129.38, 128.01, 127.72, 125.92, 123.98, 122.44, 119.21, 116.69,
116.44, 116.30, 39.81, 35.24; MS: m/z 291.1259 (M+).
and stirred for 2 h. Then the reaction mixture was treated with crushed ice
(10 g) and white viscous solid precipitated. The white solid was collected,
washed with distilled water (10 ꢀ 5 mL) and taken by ethanol. The obtained
solution was dried by MgSO4, filtered. The filtrate was evaporated and the
residue was columned to get 15.2 mg of white powder with a yield of 52% in
purity of 99%.
Compound 3b: 1H NMR (400 MHz, DMSO-d6), d (ppm), 8.43 (s, 1H), 7.43 (d,
J = 2.4 Hz, 1H), 7.33 (d, J = 2.0 Hz, 1H), 7.03 (d, J = 2.4 Hz, 1H), 6.96 (q, J = 2.0,
8.4 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 5.92–6.04 (m, 2H), 5.02–5.13 (m, 4H), 3.41
(d, J = 6.8 Hz, 2H), 3.35 (d, J = 6.4 Hz, 2H); 13C NMR (100 MHz, DMSO-d6), d
(ppm),153.31, 152.63, 151.67, 138.69, 137.00, 132.12, 130.87, 130.48, 130.28,
129.27, 128.45, 127.30, 126.62, 116.99, 116.28, 115.78, 33.88; MS: m/z
309.1365 (M+).
21. Montserrat, C.; Thomas, R.; Hong, J.; Vittoria, A.; Felix, R.; Jeffrey, S.; Chiara, F.;
Christian, C.; Corine, G.; Bernard, F. O.; Thierry, M.; Denise, G.; Dominique, P.;
Didier, L.; Pierre-Alain, V.; Emilio, H.; Matthias, P. W.; Rocco, C.; Matthias, K. S.;
Chistian, R. Nat. Med. 2005, 11, 936.
22. Ishitsuka, K.; Hideshima, T.; Hamasaki, M.; Raje, N.; Kumar, S.; Hideshima, H.;
Shiraishi, N.; Yasui, H.; Roccaro, A. M.; ichardson, P.; Podar, K.; Le Gouill, S.;
Chauhan, D.; Tamura, K.; Arbiser, J. L.; Anderson, K. C. Blood 2005, 106, 1794.
23. Spectral data for the honokiol anologues:
Compound 4b: 1H NMR (400 MHz, CDCl3), d (ppm), 8.55 (s, 1H), 7.65 (d,
J = 2.0 Hz, 2H), 7.08 (d, J = 8.0 Hz, 2H), 6.92 (d, J = 8.0 Hz, 1H), 5.92–6.03 (m,
2H), 5.06–5.18 (m, 4H), 4.40 (q, J = 7.2, 14.4 Hz, 2H), 3.63 (d, J = 6.8 Hz, 2H),
3.36 (d, J = 6.8 Hz, 2H), 1.26–1.41 (m, 3H); 13C NMR (100 MHz, CDCl3), d (ppm),
163.13, 156.90, 152.10, 151.07, 149.17, 137.53, 136.06, 134.76, 134.73, 132.67,
130.43, 129.62, 128.65, 128.10, 126.18, 117.98, 117.85, 117.40, 116.47, 115.83,
62.05, 39.32, 33.20, 14.21; MS: m/z 389.1627 (M+).
Compound 3a: 1H NMR (400 MHz, DMSO-d6), d (ppm), 11.64 (s, 1H), 10.41 (s,
1H), 9.52 (s, 1H), 8.39 (s, 1H), 7.24 (q, J = 2.0, 8.0 Hz, 1H), 7.22 (d, J = 2.0 Hz, 1H),
7.14 (d, J = 2.0 Hz, 1H) , 7.06 (d, J = 2.0 Hz, 1H), 6.86 (d, J = 8.0 Hz, 1H), 5.91–
6.04 (m, 2H), 5.00–5.11 (m, 4H), 3.33 (t, J = 6.4, 11.2 Hz, 4H); 13C NMR
(100 MHz, DMSO-d6), d (ppm), 154.45, 152.33, 152.13, 151.68, 138.28, 137.56,
131.80, 131.17, 131.00, 129.22, 129.00, 128.74, 128.36, 125.90, 117.94, 116.17,
115.84, 114.92, 34.30; MS: m/z 309.1365 (M+).
Compound 5b: 1H NMR (400 MHz, DMSO-d6), d (ppm), 9.52 (d, J = 4.0 Hz, 1H),
8.14 (s, 1H), 7.55 (d, J = 2.0 Hz, 1H), 7.37 (d, J = 2.0 Hz, 1H), 7.05 (d, J = 2.0 Hz,
1H), 6.96 (q, J = 2.0, 8.0 Hz, 1H), 6.86 (d, J = 2.0 Hz, 1H) , 5.90–6.03 (m, 2H),
5.00–5.11 (m, 4H), 3.30 (d, J = 6.8 Hz, 4H); 13C NMR (100 MHz, DMSO-d6), d
(ppm), 168.70, 167.74, 153.55, 152.76, 138.68, 136.95, 131.00, 130.96, 130.56,
130.16, 128.71, 128.67, 128.46, 127.28, 126.75, 123.05, 121.58, 116.48, 116.41,
116.17,34.32, 22.52; MS: m/z 393.1035 (M+).
Compound 4a: 1H NMR (400 MHz, CDCl3), d (ppm), 8.55 (s, 1H) , 7.49 (d,
J = 2.0 Hz, 1H), 7.35 (m, 1H), 7.33 (d, J = 2.0 Hz, 1H), 7.31 (d, J = 2.0 Hz, 1H), 6.90
(d, J = 8.4 Hz, 1H), 5.93–6.11 (m, 2H), 5.12–5.21 (m, 4H), 4.41 (q, J = 7.2,
14.4 Hz, 2H), 3.47 (t, J = 8.0, 16.0 Hz, 4H), 1.41 (t, J = 7.2, 14.4 Hz, 3H); 13C NMR
(100 MHz, CDCl3), d (ppm), 163.22, 157.18, 154.54, 150.49, 149.27, 136.60,
136.37, 136.20, 135.94, 131.16, 130.21, 126.74, 127.47, 127.06, 125.95, 118.26,
117.69, 116.99, 116.37, 115.77, 61.95, 39.21, 34.76, 14.19; MS: m/z 389.1627
(M+).
Compound 3c: 1H NMR (400 MHz, DMSO-d6), d (ppm), 8.44 (s, 1H), 8.40 (s, 1H),
7.46 (d, J = 2.0 Hz, 1H), 7.35 (d, J = 2.0 Hz,1H), 7.18 (d, J = 2.0 Hz, 1H), 7.12 (d,
J = 2.0 Hz, 1H), 5.92–6.06 (m, 2H), 5.05–5.13 (m, 4H), 3.43 (d, J = 6.8 Hz, 2H),
3.34 (d, J = 6.8 Hz, 2H); 13C NMR (100 MHz, DMSO-d6), d (ppm), 153.64, 152.06,
151.55, 151.55, 138.15, 136.88, 132.11, 131.75, 131.34, 129.43, 129.39, 129.15,
128.28, 126.82, 117.97, 117.10, 116.34, 116.23, 33.85, 33.81; MS: m/z 352.1423
(M+).
Compound 5a: 1H NMR (400 MHz, DMSO-d6), d (ppm), 8.07 (s, 1H), 7.14 (s, 1H),
7.13 (s, 1H), 7.12 (s, 1H), 6.86 (d, J = 2.0 Hz, 1H), 6.85 (d, J = 2.0 Hz, 1H), 5.90–
6.00 (m, 2H), 5.00–5.13 (m, 4H), 3.32 (t, J = 7.2, 7.6 Hz, 4H); 13C NMR (100 MHz,
DMSO-d6), d (ppm), 168.62, 167.66, 154.73, 152.03, 137.93, 137.38, 133.60,
132.44, 131.75, 130.99, 128.74, 128.65, 128.39, 126.52, 126.32, 123.17, 122.98,
116.54, 116.01, 115.22, 34.29, 21.39; MS: m/z 393.1035 (M+).
Compound 5c: 1H NMR (400 MHz, DMSO-d6), d (ppm), 8.13 (s, 1H), 8.10 (s, 1H),
7.42 (d, J = 2.0 Hz, 1H), 7.32 (d, J = 2.0 Hz, 1H), 7.18 (d, J = 2.0 Hz, 1H), 7.15 (d,
J = 2.0 Hz, 1H), 5.93–6.05 (m, 2H), 5.04–5.23 (m, 2H), 3.46 (d, J = 6.4 Hz, 2H),
3.38 (d, J = 8.0 Hz, 2H); 13C NMR (100 MHz, DMSO-d6), d (ppm), 168.65, 168.58,
167.68, 167.61, 154.09, 152.04, 137.84, 136.67 (2), 133.77, 133.25, 132.71,
130.63, 129.95, 128.79, 128.59, 128.50, 127.39, 127.16, 123.58, 123.32, 121.86,
116.66, 116.63, 34.29, 21.39; MS: m/z 520.0763 (M+).
Compound 6a: 1H NMR (400 MHz, CDCl3), d (ppm), 8.37 (s, 1H), 7.40 (q, J = 1.6,
5.6 Hz, 1H) 7.36 (d, J = 1.6 Hz, 1H), 7.17 (d, J = 1.6 Hz, 1H), 7.01 (d, J = 1.6 Hz,