Tailoring 3,3'-dihydroxyisorenieratene to hydroxystilbene: Finding a resveratrol analogue with increased antiproliferation activity and cell selectivity

Article abstract of DOI:10.1002/chem.201403024

Four novel compounds were designed by "tailoring" 3,3'-dihydroxyisorenieratene (a natural carotenoid) based on an isoprene unit retention truncation strategy. Among them, the smallest molecule 1 (2,3,6,2',3',6'-hexamethyl-4,4'-dihydroxy-trans-stilbene) was concisely synthesized in a one-pot Stille-Heck tandem sequence, and surfaced as a promising lead molecule in terms of its selective antiproliferative activity mediated by blocking the NCI-H460 cell cycle in G1 phase. Additionally, theoretical calculations and cell uptake experiments indicate that the unique polymethylation pattern of compound 1 significantly induces a conformational change shift out of planarity and increases its cell uptake and metabolic stability. The observation should be helpful to rationally design resveratrol-inspired antiproliferative agents. Four novel compounds were designed by "tailoring" 3,3'-dihydroxyisorenieratene (a natural carotenoid) based on an isoprene unit retention truncation strategy. Among them, the smallest molecule 1 was concisely synthesized by a one-pot Stille-Heck tandem sequence, and surfaced as a promising lead molecule in terms of its selective antiproliferative activity (see figure).

Full text of DOI:10.1002/chem.201403024

DOI: 10.1002/chem.201403024
Communication
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Natural Products
Tailoring 3,3’-Dihydroxyisorenieratene to Hydroxystilbene:
Finding a Resveratrol Analogue with Increased Antiproliferation
Activity and Cell Selectivity
Yan-Fei Kang,[a] Wen-Jing Yan,[a] Ting-Wen Zhou,[b] Fang Dai,[a] Xiu-Zhuang Li,[a] Xia-
Zhen Bao,[a] Yu-Ting Du,[a] Cui-Hong Yuan,[a] Hai-Bo Wang,[a] Xiao-Rong Ren,[a] Qiang Liu,[a]
Xiao-Ling Jin,[a] Bo Zhou,*[a] and Jie Zhang*[b]
Abstract: Four novel compounds were designed by “tai-
loring” 3,3’-dihydroxyisorenieratene (a natural carotenoid)
based on an isoprene unit retention truncation strategy.
Among them, the smallest molecule 1 (2,3,6,2’,3’,6’-hex-
amethyl-4,4’-dihydroxy-trans-stilbene) was concisely syn-
thesized in a one-pot Stille–Heck tandem sequence, and
surfaced as a promising lead molecule in terms of its se-
lective antiproliferative activity mediated by blocking the
NCI-H460 cell cycle in G1 phase. Additionally, theoretical
calculations and cell uptake experiments indicate that the
unique polymethylation pattern of compound 1 signifi-
cantly induces a conformational change shift out of pla-
narity and increases its cell uptake and metabolic stability.
The observation should be helpful to rationally design re-
sveratrol-inspired antiproliferative agents.
Scheme 1. Molecular structures of resveratrol (RES), 4,4’-dihydroxy-trans-
stilbene (4,4’-DHS), 3,3’-dihydroxyisorenieratene (DHIR) and its “tailored”
molecules 1–4 based on an isoprene unit retention truncation strategy. The
dotted lines were used to show the isoprene units of DHIR.
Natural products provide extraordinarily diverse chemical scaf-
folds and are often used as starting points for drug discover-
y.[1]Resveratrol (3,5,4’-trihydroxy-trans-stilbene, RES, Scheme 1)
is a polyphenol derived from grapes, mulberries, peanuts and
other plant sources.[2] During the past two decades, this dietary
molecule has attracted much interest due to its fascinating
wide spectrum of biological functions, especially its cancer
chemoprevention activity.[2] Extensive effort was devoted to its
structure modifications to improve its some flaws such as
short half-life and low bioavailability[3] and to enhance its anti-
cancer activity.[4] These structure modifications focused mainly
on the olefinic bridge and the benzene ring parts, or a combi-
nation of both parts.[5] Among these modifications, however,
directly introducing one or more methyl groups on the ben-
zene rings of the stilbene skeleton is relatively scarce. To the
best of our knowledge, only Fukuhara and co-workers investi-
gated antioxidant activity and genotoxicity of the RES analogs
with methyl groups ortho to the 4’-hydroxy group, and found
that the modification mode increased antioxidant activity cou-
pled with reduced genotoxicity.[6] Although the methyl is
a chemically inert group, it has been widely used in molecular
modification strategies by medicinal chemist for optimizing
drug leads since its stereoelectronic effect on biomacromole-
cules could produce diverse biological effects, such as selectivi-
ty among bioreceptors, increased potency, and protection
against enzyme metabolism as summarized in the two excel-
lent reviews.[7]
[a] Y.-F. Kang,+ W.-J. Yan,+ Dr. F. Dai, Dr. X.-Z. Li, X.-Z. Bao, Y.-T. Du, C.-H. Yuan,
H.-B. Wang, X.-R. Ren, Dr. Q. Liu, Dr. X.-L. Jin, Prof. Dr. B. Zhou
State Key Laboratory of Applied Organic Chemistry
Lanzhou University
222 Tianshui Street S., Lanzhou 730000 (China)
Fax: (+86)931-8915557
E-mail: bozhou@lzu.edu.cn
[b] T.-W. Zhou,+ Prof. Dr. J. Zhang
Fujian Provincial Key Laboratory of Neurodegenerative Disease
and Aging Research, Institute of Neuroscience
College of Medicine, Xiamen University
Xiamen, Fujian 361102 (China)
Recently, 3,3’-dihydroxyisorenieratene (DHIR) (Scheme 1),
a natural and polymethylated carotenoid of microbial origin,
was well-documented to be an excellent antioxidant and pho-
toprotecting agent in model and cell systems.[8] This unique
carotenoid (tetraterpene) structurally characterizes a polyenic
backbone of nine conjugated double bonds substituted with
E-mail: jiezhang@xmu.edu.cn
[+] These authors contributed equally to this work.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201403024.
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phenolic end groups. Unfortunately, this molecule has two vio-
lations (MWT >500 and logp @5) of Lipinski’s rule of five that
determines if a substance is drug-like.[9] Although this rule is
general and some pharmacological compounds do not fulfill
all aspects, adhering to the concept of “the simple is the best”,
we attempted to tailor its conjugated link and to improve the
flaws, by in turn reducing an isoprene unit, dubbed as an iso-
prene unit retention truncation strategy. The truncation gener-
ated four novel compounds, 1–4 (Scheme 1). We noted that
this smallest diterpene (1) is structurally similar to 4,4’-dihy-
droxy-trans-stilbene (4,4’-DHS, Scheme 1), a more active antiox-
idant and cytotoxic agent than RES.[5g,10c,d,11] The only differ-
ence between them is that the former bears six additional
methyl groups on the two phenyl rings where four methyl
groups are ortho to the double bonds. We believe that the un-
usual polymethylation pattern not only maintains the terpene
structure of compound 1, but also would help improve its bio-
logical functions. Therefore, as part of our continuing search
for RES-inspired antioxidants and cancer chemoprevention
agents,[5g,10] we decided to synthesize compounds 1–4 for find-
ing selective antiproliferative agents.
reaction and
a
tandem Heck–Decarboxylation–Heck ap-
proach[12] developed by Sinha and co-workers, probably due to
increasing steric hindrance created by the six methyl groups,
ultimately it was successfully achieved in seven steps from 5
using the Wittig reaction. In view of 1 being the most active in
the subsequent cell system-based activity assays (see below),
we thus explored a concise synthesis as shown in Scheme 3, in
Scheme 3. A concise synthesis of compound 1 by a one-pot Stille–Heck
tandem sequence.
which 1 was constructed from 4-bromo-2,3,5-trimethylphenol
in 65% yield following a one-pot Stille–Heck tandem sequence
through the use of tributylvinyltin, bis(tri-tert-butylphosphine)-
palladium(0) and cesium fluoride as substrate, catalyst and
base, respectively. The strategy offers several advantages such
as significantly shortening the reaction steps, being protecting-
group-free and overcoming the unfavorable steric hindrance.
Although the Stille–Heck tandem reaction as the key step was
also successfully applied in the synthesis of steroids and ste-
roid analogs,[13a] (Æ)-frondosin B[13b] and so on, this strategy
was first employed to synthesize a polymethylated hydroxystil-
bene in the current work.
The synthesis of the four compounds was accomplished
using classical methods according to a divergent strategy al-
lowing the use of common intermediates (Scheme 2, for de-
tails and characterization see the Supporting Information). Spe-
cifically, the asymmetric 2 and 4 were synthesized in nine and
eleven steps from commercial 2,3,5-trimethylphenol 5 by
Wittig–Horner reaction as the key step, respectively, whereas
the symmetric 3 was prepared in eight steps from the same
raw material via McMurry coupling. After the failure in con-
structing the symmetric 1 by McMurry coupling, Wittig–Horner
Because inflammation is implicated in the etiology and
pathogenesis of cancer[14] and RES could modulate a variety of
molecular processes in the development of inflammation,[15]
we initially examined anti-inflam-
matory activity of compounds
1–4, RES and its active analog,
4,4’-DHS by assaying the inhibi-
tion of nitric oxide (NO) produc-
tion induced by lipopolysacchar-
ide in macrophages (RAW 264.7).
Among them, 1 and 4,4’-DHS
bearing para-dihydroxy groups
were the most potent ones
(IC50 =3.1 and 2.3 mm, respective-
ly), and displayed about 15- and
20-fold increase in potency rela-
tive to RES (Table 1). Comparison
of the IC50 values of compounds
1–4 clearly appears that the NO-
inhibitory ability decreases as
the core polyene chain is length-
ened. The overall activity order is
at least in part due to their dif-
Scheme 2. Synthesis of compounds 1–4. Reagents and conditions: a) MeI, NaH, THF, 258C, 12 h, 91%. b) DMF,
POCl3, 1108C, 6 h, 60%. c) NaBH4, EtOH, 808C, 3 h, 95%. d) PBr3, CH2Cl2, 08C, 1 h, 91%. e) PPh3, Et2O, 258C, 2 d,
85%. f) 7, NaH, DMSO, 258C, 1 h, 10%. g) BBr3, CH2Cl2, 08C, 12 h, 66%. h) Acetone, 10% NaOH, H2O, 258C, 7 h,
76%. i) 2-(Diethoxyphosphoryl)acetate, NaH, THF, 658C, 85%. j) LiAlH4, AlCl3, THF, 258C, 24 h, 84%. k) PBr3, CH2Cl2,
À108C, 2 h, 95%. l) P(OEt)3, 1208C, 3 h, 80%. m) 7, nBuLi, DMPU, THF, 08C, 1 h, 75%. n) MeI, Mg, Et2O, 1808C, 4 h,
45%. o) MnO2, Na2CO3, CH2Cl2, 258C, 48 h, 68%. p) Zn, TiCl4, THF, 658C, 3 h, 81%. q) MeI, Mg, Et2O, 1808C, 4 h,
40%. r) 26, nBuLi, DMPU, THF, 08C, 1 h, 72%. s) DIBAL-H, CH2Cl2, À308C, 36 h, 60%. t) MnO2, Na2CO3, CH2Cl2, 258C,
48 h, 61%. u) 16, nBuLi, DMPU, THF, 08C, 1 h, 70%. v) MeI, Mg, Et2O, 1808C, 4 h, 30%.
ference in solubility and uptake
into the membranes which
strongly depends on their lipo-
philicity characterized by the oc-
tanol-water partition coefficient,
P. On the basis of the calculated
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and 4,4’-DHS exhibited a planar geometry, in the case of 1,
a 1,3-allylic strain between one of the ortho-methyl groups and
an olefin hydrogen induced a significant conformational shift
out of planarity as indicated by a dihedral angle of 458 or 768
between the aromatic ring and double bond, as well as be-
tween the two aromatic rings, respectively. The change in the
conformation would facilitate binding of compound 1 with
possible target proteins, thereby increasing its activity and cell
selectivity. Furthermore, we compared their cellular uptake and
metabolic stability in NCI-H460 cells by HPLC analysis of meth-
anol extracted cell lysates. As shown in the inset of Figure 2,
Table 1. Antiinflammatory and antiproliferative activities of the
compounds investigated.
Comps. IC50
[mm][a, b] for inhibition ClogP[c]
of NO release
IC50 [mm][a,d]
NCI-H460 MRC-5
1
2
3
4
3.10Æ0.1
15.6Æ1.2
43.9Æ1.4
82.9Æ4.7
2.30Æ0.2
46.1Æ0.6e
6.294
7.501
9.108
10.715
3.5
3.70Æ0.22 47.4Æ4.1
26.4Æ1.1
11.3Æ0.1
81.5Æ2.4
12.8Æ1.5
29.7Æ0.8
18.8Æ1.6
>100
4,4’-DHS
RES
15.5Æ1.1
50.5Æ3.2
2.833[f] 71.0Æ3.7
[a] Data are expressed as the mean ÆSD for three determinations. [b] IC50
value is the concentration of compound tested to inhibit 50% of NO re-
lease induced by LPS (1 mgmLÀ1) in RAW 264.7 cells. [c] Calculated by Bio-
Loom software.[16] [d] IC50 value is the concentration of a compound
tested to cause 50% inhibition of cell viability after 72 h of treatment.
[e] Cited from Ref. [21]. [f] Cited from Ref. [5g].
logP (ClogP) values[16] (Table 1), we can conclude that excessive
increase of lipophilicity leads to improper localization of com-
pounds in the membranes, thereby decreasing their NO-inhibi-
tory ability, but on the contrary, moderate increase of lipophi-
licity will strength the ability.
We next investigated their antiproliferative activity in human
non-small cell lung cancer cells (NCI-H460) and normal human
embryonic lung fibroblasts (MRC-5) by a classic MTT assay.[17]
Interestingly, in NCI-H460 cells, 1 ranked top among the test
compounds with an IC50 value of 3.7 mm, and was about
twenty and three times more potent than RES and 4,4’-DHS, re-
spectively (Table 1). Most notably, 1 manifested strong prefer-
ence for inhibiting cell proliferation between lung cancer cells
(NCI-H460) and normal lung cells (MRC-5) with the IC50 values
being 3.7 and 47.4 mm, respectively, whereas the preference
disappeared in the case of RES and even 4,4’-DHS. The in-
creased activity and better cell selectivity of 1 compared to
4,4’-DHS, clearly suggest the contribution of the unusual poly-
methylation pattern, which probably assists in binding of the
former with possible target proteins or in increasing its cellular
uptake, metabolic stability and other pharmacological proper-
ties. To clarify these points, we calculated the geometries of
compound 1, RES and 4,4’-DHS in the lowest energy conforma-
tion by the Gaussian 09 program (Figure 1).[18] Although RES
Figure 2. Cellular uptake of compound 1, RES and 4,4’-DHS (30 mm) deter-
mined by HPLC analysis of methanol extracted cell lysates.
RES and 4,4’-DHS exhibited quick uptake but they were also
rapidly metabolized after 1 and 2 h of incubation, respectively.
In comparison, compound 1 displayed much faster and more
efficient cell uptake, and better metabolic stability during 6 h
(Figure 2). These results provide evidence that the polymethy-
lation pattern significantly contributes to the increased cell
uptake and metabolic stability of compound 1, and can ex-
plain, at least in part, why it displays better performances.
To gain insights in the antiproliferative activity mechanism
of 1 in NCI-H460 cells, its effects on cell apoptosis and cell
cycle distribution were analyzed by flow cytometry. Interesting-
ly, no obvious cell apoptosis occurred (Figure S1 in the Sup-
porting Information) but a clear dose-dependent block of cells
in G1 phase appeared (Figure 3) after treating cells with 1 for
24 h, suggesting that its antiproliferative activity is mainly
mediated by cell cycle arrest instead of apoptosis. In contrast,
10 mm RES neither induced obvious cell apoptosis nor arrested
cell cycle. Noticeably, 10 mm 4,4’-DHS increased accumulation
of cells in S phase (Figure 3), highlight a different arrest mecha-
nism from that of 1. Previously, depending on the cell types
used, RES was shown to arrest cell cycle in G1, S or G2/M
phase.[2d] Additionally, 4,4’-DHS was demonstrated to induce an
accumulation of human lung fibroblasts[11a] and hepatoma
HepG2 cells[5g] predominantly in G1 phase.
To further elucidate the 1-mediated cell cycle arrest, we
used the fluorescent, ubiquitination-based cell cycle indicator
(FUCCI)[19] technology to visualize cell cycle progression in
Figure 1. Geometries of compound 1, RES and 4,4’-DHS in the lowest energy
conformation.
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In summary, this work pro-
vides an example of successful
design of a concise lead mole-
cule inspired from a complex
natural product, DHIR. Specifical-
ly, the four compounds were de-
signed by “tailoring” DHIR based
on an isoprene unit retention
truncation
strategy.
Among
them, 1, the smallest molecule
with a stilbene skeleton, was
concisely synthesized by a one-
pot Stille–Heck tandem se-
quence, and turned out to be
a promising lead molecule in
terms of its selective antiprolifer-
ative activity on NCI-H460 cells.
Mechanistic study reveals that
the activity is not mediated by
inducing apoptosis, but by
Figure 3. Flow cytometric analysis for cell cycle progression of NCI-H460 cells after 24 h of treatment with com-
pound 1 at the indicated concentrations or DMSO (control). Percentage of cells within G0/G1, S and G2M phases
is indicated in every diagram. Each experiment was performed in triplicate.
living NCI-H460 cells. Briefly, the FUCCI cell cycle system con-
tains two cell cycle monitor vectors: pFUCCI-S/G2/M Green
and pFUCCI-G1 Red. pFUCCI-S/G2/M Green accumulates
during S/G2/M phases but is degraded during G1 phase; On
the contrary, pFUCCI-G1 Red accumulates in G1 phase but is
degraded in S/G2/M phases (Figure S2A).[19] With vehicle ad-
ministration, the NCI-H460 cells proliferated normally (left
panel of Figure S2B), and the “red cells” in G1 phase, entered
into S phase accompanying with the degradation of pFUCCI-
G1 Red in 13 h. However, after treatment with 10 mm 1, the
“red cells” (G1 phase) never turned green in 13 h (right panel
of Figure S2B), suggesting that administration of 1 significantly
suppresses the cells in G1 phase, which is completely consis-
tent with our flow cytometry data.
blocking cell cycle in G1 phase via down-regulation of Cdk2,
Cdk4, cyclin A and cyclin E. Additionally, theoretical calcula-
tions and cell uptake experiments indicate that the unique pol-
ymethylation pattern of compound 1 significantly induces
a conformational change shift out of planarity and increases its
cell uptake and metabolic stability. The observation should be
helpful to rationally design RES-inspired antiproliferative
agents.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (Grant Nos 21172101 and 81271421), the
111 Project.
The cell progression is strictly controlled by cyclins, cyclin-
dependent kinases (Cdks) and Cdk inhibitors.[20] To better un-
derstand how the cell cycle arrest is mediated by 1, we finally
performed the protein expression level analysis of cyclins and
Cdks in NCI-H460 cells by Western blot (Figure 4). Treatment of
1 dramatically decreased the expression levels of Cdk2, Cdk4,
cyclin A and cyclin E in whole cell and cytolasmic lysates, and
did not affect the levels of other Cdks or cyclins. These data
are consistent with the finding that compound 1 administration
arrests cell cycle in G1/S transition, since it is the activation of
Cdk4 and Cdk2 to proceed with the G1/S transition.[20]
Keywords: antiproliferation · cell cycle · isoprene units ·
methylation reactions · resveratrol
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Received: April 10, 2014
Published online on && &&, 0000
Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Communication
COMMUNICATION
Four novel compounds were designed
by “tailoring” 3,3’-dihydroxyisoreniera-
tene (a natural carotenoid) based on an
isoprene unit retention truncation strat-
egy. Among them, the smallest mole-
cule 1 was concisely synthesized by
a one-pot Stille–Heck tandem sequence,
and surfaced as a promising lead mole-
cule in terms of its selective antiprolifer-
ative activity (see figure).
&
Natural Products
Y.-F. Kang, W.-J. Yan, T.-W. Zhou, F. Dai,
X.-Z. Li, X.-Z. Bao, Y.-T. Du, C.-H. Yuan,
H.-B. Wang, X.-R. Ren, Q. Liu, X.-L. Jin,
B. Zhou,* J. Zhang*
&& – &&
Tailoring 3,3’-Dihydroxyisorenieratene
to Hydroxystilbene: Finding
a Resveratrol Analogue with Increased
Antiproliferation Activity and Cell
Selectivity
&
&
Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!