Absolute configurations of integracins A, B, and 15'-dehydroxy-integracin B

Article abstract of DOI:10.1002/chir.22012

Integracins A (1) and B (2), potent HIV-1 integrase inhibitors, and 15'-dehydroxy-integracin B (3) were isolated for the first time from Chinese mangrove plant Sonneratia hainanensis. Their absolute configurations were determined by the Mosher's method and specific rotation analysis of alcohols (6 and 7) obtained from integracin A in two steps and by chemical correlation. Integracin A (1) also exhibited significant cytotoxicity against the tumor cell lines HepG2 and NCI-H460 with both 100% inhibitions at 25 μg/ml. Copyright

Full text of DOI:10.1002/chir.22012

CHIRALITY (2012)
Absolute Configurations of Integracins A, B, and 15-Dehydroxy-
Integracin B
1
HAI-LI LIU,1 XIAO-YIN HUANG,1 JIA LI,1 GUO-RONG XIN,2 AND YUE-WEI GUO
*
1State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, People’s Republic of
China
2Institute of Biological Science, Sun Yat-Sen University, Guangzhou 510275, People’s Republic of China
ABSTRACT
Integracins A (1) and B (2), potent HIV-1 integrase inhibitors, and 15-dehydroxy-
integracin B (3) were isolated for the first time from Chinese mangrove plant Sonneratia hainanensis.
Their absolute configurations were determined by the Mosher’s method and specific rotation analysis
of alcohols (6 and 7) obtained from integracin A in two steps and by chemical correlation. Integracin
A (1) also exhibited significant cytotoxicity against the tumor cell lines HepG2 and NCI-H460 with
both 100% inhibitions at 25 mg/ml. Chirality 00:000 –000,2012. © 2012 Wiley Periodicals, Inc.
KEY WORDS: Sonneratia hainanensis; Sonneratiaceae; alkylresorcinol dimers
INTRODUCTION
MATERIALS AND METHODS
General and Instrumentation
Alkylresorcinols (ARs) are amphiphilic 1,3-dihydroxy-5-
alkylbenzene homologues with odd-numbered alkyl side chains
that occur in many different living organisms such as higher and
lower plants, algae, fungi, bacteria, and animals, and are impor-
tant in many aspects of cellular biochemistry and physiology.1,2
Although dimeric ARs are quite rarely found in nature, they
represent a prominent class of biologically active metabolites.2–6
Up to now, only six dimeric ARs, namely integracins A–D,3,4
15-dehydroxy-integracin B,5 and spinosulfate A,6,7 have been
discovered either from fungi or plants. All these intriguing
metabolites possess a common undecylresorcinol dimer
skeleton characterized by the presence of 5-undecylresorcinolic
acid residue esterified at C-14 of 5-undecylresorcinol. In most
cases, the C-15 in 5-undecylresorcinolic acid residue is oxygen-
ated, as exemplified by integracins A (1)3 and B (2).3 In
addition, sulfated undecylresoricinol dimers, such as integracin
D,3 were also found in nature. Because of the promising
bioactivities3,5–7 exhibited by dimeric ARs, these compounds
have attracted more attentions of both chemists and pharmacol-
ogists in the recent years.
Specific rotations were determined on a Perkin-Elmer 341 polarimeter
(Waltham, MA, USA). NMR spectra were measured on a Bruker DRX-
300 spectrometer (Karlsruhe, Germany). Chemical shifts were recorded
in mg/g (d) in CDCl3 with tetramethylsilane as an internal reference.
ESIMS (70 eV) were carried out using a Q-TOF Micro LC-MS/MS mass
spectrometer. Silica gel (200ꢀ300 mesh, Qingdao Haiyang Chemical Co.
Ltd., Qingdao, China) and Sephadex LH-20 (Amersham Biosciences,
Piscataway, NJ, USA) were also used for column chromatography (CC).
TLC plates were precoated with silica gel GF254 (Merck (Darmstadt,
Germany), 0.25 mm)(ordinary phase), and detection was achieved by
spraying with 10% H2SO4 in ethanol followed by heating.
Plant Material
A specimen of S. hainanensis was collected at Mangrove National Nature
Reserve, Hainan Province, People’s Republic of China, in September 2006,
and identified by Associate Prof. G-R. Xin of Institute of Biological Science,
Sun Yat-Sen University. A voucher specimen (no. 06P-33) is available for
inspection at the Herbarium of Shanghai Institute of Materia Medica, CAS.
Extraction and Isolation
In the course of our ongoing research program on bioactive
substances from mangroves along the Chinese coasts,8–11 we
have recently examined the stems and the leaves of the
mangrove plant Sonneratia hainanensis, resulting in the
isolation of a new diphenacyl-piperidine alkaloid, sonneratine
A,12 together with three known dimeric alkyl aromatics, namely
integracins A (1),3 B (2)3, and 15-dehydroxy-integracin B (3)5
(Fig. 1). Although compounds 1–3 were already isolated and
characterized several years ago from fungi Cytonaema sp.3
and Cytonaema sp.,5 respectively, their absolute configurations
have not been resolved yet. Integracins A (1) and B (2) were
reported possessing potent recombinant HIV-1 integrase
inhibitory activities (IC50 = 3.2, 6.1 mM, respectively), whereas
compound 3 was reported as a potent inhibitor of macrophage
colony stimulating factor (cFMS) receptor tyrosine kinase
(IC50 = 0.4 mM), which stimulated our interest to determine
their absolute configurations to explore their structure and
activity relationship as well as the mechanism of their pharma-
cological function. This article describes the determination of
the absolute configuration of dimeric ARs 1–3.
The air-dried powder of the leaves and stems (2.6 kg) of S. hainanensis
were exhaustively extracted with MeOH (3 ꢁ 5 l, each 7 d) at room
temperature. Evaporation of the solvent under reduced pressure provided
the MeOH extract (225 g) that was dissolved in H2O (1:1) and extracted, in
Additional Supporting Information may be found in the online version of this
article.
Contract grant sponsor: Natural Marine “863” Project; Contract grant number:
2011AA09070102.
Contract grant sponsor: Natural Science Foundation of China; Contract grant
numbers: 40976048.30730108.21021063.
Contract grant sponsor: STCSM International Cooperation Project between
SIMM/China and ICB/Italy; Contract grant number: 10540702900.
Contract grant sponsor: the NSFC-TRF International Cooperation Project;
Contract grant number: 20911140471.
Contract grant sponsor: Foundation of SIMM/SKLDR; Contract grant numb-
ers: SIMM1105KF-04.SIMM1106KF-11.
*Correspondence to: Y-W. Guo, State Key Laboratory of Drug Research,
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zu
Chong Zhi Rd. 555, Zhangjiang Hi-Tech Park, Shanghai 201203, People’s
Republic of China. E-mail: ywguo@mail.shcnc.ac.cn
Received for publication 8 July 2011; Accepted 18 December 2011
DOI: 10.1002/chir.22012
Published online in Wiley Online Library
(wileyonlinelibrary.com).
© 2012 Wiley Periodicals, Inc.

LIU ET AL.
reaction mixture was quenched with H2O and extracted with CHCl3.
7
17
14
1
5
HO
The CHCl3 extract was then purified by silica gel CC to afford alcohols 6
(4.0 mg) and 7 (4.4 mg).
O
O
7'
3
8'
Alcohol 6. Colorless oil; Yield 89%; ½aꢃ 20 = ꢀ2.0 (CHCl3, c 0.20); ESIMS:
1'
18'
15'
6'
OH
HO 2'
D
m/z = 639.4 ([2M+ Na]+); 1H NMR (CDCl3, 300 MHz): d = 0.93 (3H, t,
J = 6.6 Hz, Me-17), 1.32ꢀ1.44 (12H, m), 1.54ꢀ1.60 (4H, m, H2-13, H2-15),
2.54 (2H, t, J=7.5Hz, H2-7), 3.59 (1H, m, H-14), 3.78 (6H, s, OMe-1, OMe-3),
6.30 (1H, d, J=2.1Hz, H-2), 6.34 (2H, d, J=2.1Hz, H-4, H-6).
R
4'
OH
1 R = OAc
2 R = OH
3 R = H
Alcohol 7. Colorless oil; Yield 89%; ½aꢃ 20 = +2.0 (CHCl3, c 0.20); ESIMS:
D
7'
m/z = 361.2 ([M + Na]+); 1H NMR (CDCl3, 300MHz): d =0.92 (3H, t, J=6.6Hz,
Me-18), 1.25ꢀ1.42 (12H, m), 1.54ꢀ1.59 (2H, m, H2-16), 1.72 (2H, m, H2-14),
2.64 (2H, t, J=7.8Hz, H2-8), 3.59 (1H, m, H-15), 3.80 (3H, s, OMe-4), 3.83
(3H, s, OMe-2), 4.66 (2H, s, H2-7), 6.33 (2H, s, H-3, H-5).
CH2OH
8'
6'
15'
MeO
HO
2'
S
OH
4'
OMe
4
8
2-Methoxy-2-phenyl-2-(trifluoromethyl)acetic acid (MTPA)
esters of 6
14
1
5
The (S)-MTPA ester was obtained by treating 6 (2.0 mg) with (R)-MTPA
chloride in dry pyridine for approximately 16h under stirring at room
temperature. The reaction mixture was purified by silica gel CC to afford
pure (S)-MTPA ester (6S, 3.2 mg). The same procedure was adopted for
the preparation of the (R)-MTPA ester (6R, 3.0 mg) using (S)-MTPA
chloride.
(S)-MTPA ester (6S). Colorless oil; Yield 89%; ESIMS: m/z = 547.3
([M + Na]+); 1H NMR (CDCl3, 300 MHz): d = 0.92 (3H, t, J = 7.2 Hz,
Me-17), 1.15 (2H, m, H2-12), 1.22 (2H, m, H2-9), 1.25 (4H, m, H2-10,
H2-11), 1.32 (2H, m, H2-16), 1.54 (2H, m, H2-13), 1.56 (3H, m, H2-8,
Ha-15), 1.65 (1H, m, Hb-15), 2.53 (2H, t, J = 7.5 Hz, H2-7), 3.78 (6H, s,
OMe-1, OMe-3), 5.10 (1H, m, H-14), 6.30 (1H, t, J = 2.1 Hz, H-2), 6.34
(2H, d, J = 2.1 Hz, H-4, H-6).
(R)-MTPA ester (6R). Colorless oil; Yield 88%; ESIMS: m/z = 547.3
([M + Na]+); 1H NMR (CDCl3, 300 MHz): d = 0.85 (3H, t, J = 7.2 Hz,
Me-17), 1.20 (2H, m, H2-16), 1.29 (8H, m, H2-9ꢀH2-12), 1.52 (1H, m,
Ha-15), 1.55 (1H, m, Hb-15) 1.58 (3H, m, H2-8, Ha-13), 1.63 (1H, m,
Hb-13), 2.53 (2H, t, J = 7.5 Hz, H2-7), 3.78 (6H, s, OMe-1, OMe-3), 5.10
(H, m, H-14), 6.30 (1H, t, J = 2.1 Hz, H-2), 6.34 (2H, d, J = 2.1 Hz, H-4, H-6).
OH
3
OH
MeO
O
7'
1'
15'
HO 2'
6'
OH
4'
9
OH
OH
7
S
1
3
9
10
Fig. 1. Structures of compounds 1–4 and 8–10.
5
Preparation of 2 from 1
A solution of 1 (3 mg) in acetone (3 ml) was treated with excess K2CO3,
stirred for 16 h at room temperature, filtered, and evaporated. The
residue was purified by silica gel CC to afford 2 (2.5 mg, 89%).
this order, with EtOAc and n-BuOH. The EtOAc extract was evaporated in
vacuo to give a residue (31 g), which was subjected to silica gel CC eluted
successively with petroleum ether/EtOAc (90:10, 70:30, 50:50) followed
by CHCl3/MeOH (90:10, 70:30) to give eight fractions. Fraction 6,
showing interesting red TLC spots after spraying with H2SO4, was
subjected to Sephadex LH-20 (Amersham, Biosciences, Piscataway, NJ,
USA) CC (MeOH) and silica gel (Qingdao Haiyang Chemical Co. Ltd.,
Qingdao, China) CC (eluted with CHCl3/MeOH [95:5, 90:10, 85:15,
80:20]) and then purified by Sephadex LH-20 CC (PE/CHCl3/MeOH = 2:1:1),
yielding pure compounds 1 (15.0 mg), 2 (2.3 mg), and 3 (0.5 mg).
Antitumor Bioassay
The in vitro cytotoxic activities against HepG2, NCI-H460, and
SW-1990 cell lines were investigated by using methyl-thiazol-tetrozolium
assay. Cell suspensions were seeded in 96-well plates and incubated for
8–24 h at 37 ꢂC in a 5% CO2 incubator. 10ml of the test compound solutions
(in DMSO) at various concentrations were added to each well, and the
culture was incubated for 48–96 h at 37 ꢂC in a 5% CO2 incubator. After
the treatment, 20ml of the methyl-thiazol-tetrozolium solution (5mg/ml)
was added to each well, and cells were incubated at 37ꢂ C in 5% CO2. After
incubation for 4 h, the medium was removed and 150ml of DMSO was
added. The absorbance (OD value) was measured at 550nm. Inhibition
rate= (ODcontrolꢀODcompound)/ODcontrol ꢁ 100%. Evaluation criteria were
followed by inhibition rate at reasonable concentrate: 0%–20% (invalid);
20%–50% (weak); 50%–75% (moderate); 75%–100% (potent).
Preparation of 1,3,2,4 -Tetra-O-methylintegracin A (5)
A solution of integracin A (1, 10 mg) in acetone (3 ml) was treated with
CH3I (2 ml) and excess K2CO3, stirred for 6 h at room temperature,
filtered, and evaporated. The residue was purified by silica gel CC to
afford 5 (10 mg).
1,3,2,4-Tetra-O-methylintegracin A (5). Colorless oil; Yield 92%; ESIMS:
m/z = 707 ([M + Na]+); Hydrogen-1 (1H) NMR (CDCl3, 300 MHz): d = 0.90
(3H, t, J= 7.2 Hz, Me-17), 0.94 (3H, t, J = 7.5Hz, Me-18), 1.26ꢀ1.35 (20H, m),
1.45ꢀ1.52 (8H, m), 1.56ꢀ1.63 (4H, m, H2-13, H2-15), 2.02 (3H, s, Me-200),
2.53 (4H, m, H2-7, H2-8), 3.76 (3H, s, OMe-4), 3.78 (6H, s, OMe-1, OMe-3),
3.80 (3H, s, OMe-2), 4.86 (H, m, H-15), 5.12 (H, m, H-14), 6.29 (H, d,
J= 2.1 Hz, H-3), 6.30 (H, br s, H-2), 6.32 (H, d, J= 2.1 Hz, H-5), 6.34 (2H, d,
J= 2.1 Hz, H-4, H-6).
RESULTS AND DISCUSSION
The powdered stems and leaves of S. hainanensis (2.6kg)
were extracted exhaustively with MeOH. The MeOH extract
was partitioned consecutively between EtOAc and H2O, n-
BuOH and H2O, respectively. The EtOAc-soluble portion was
subjected to CC over silica gel and Sephadex LH-20 to afford
integracins A (1, 15.0 mg), B (2, 2.3 mg), and 15-dehydroxy-
integracin B (3, 0.5 mg), respectively.
Ester Reduction of 1,3,2,4 -Tetra-O-methylintegracin A (5)
A solution of 5 (10 mg) in dry CH2Cl2 (5 ml) was treated with 0.3 ml
[(CH3)2CHCH2]2AlH (1 M in hexane), stirred for 3.5 h at ꢀ78 ꢂC. The
Chirality DOI 10.1002/chir

ABSOLUTE STEREOCHEMISTRY OF INTEGRACINS A, B, AND 15-DEHYDROXY-INTEGRACIN B
-12
-27
+12
+30
The most abundant compound 1, which amounted to more
-21
-12
-42
+21
than 80% of the total yield of undecylresorcinol dimer fraction,
MeO
R
14
was readily identified as integracin A by comparison of its
+36
-12
-6
27
OMTPA
[a]D value, optical rotation sign ( ½aꢃ
= ꢀ9.7 (MeOH, c
D
0.38)), and NMR data with those previously reported in the
OMe
literature.3 Together with integracin A, two closely related
Fig. 2. Dd values (dS –dR) (Hz) for the protons near C-14 of (S)- and (R)-
MTPA esters of 6.
22
analogs, integracin B (2) (½aꢃ
= ꢀ10.0 (MeOH, c 0.10))3
D
and 15-dehydroxy-integracin B (3),5 were also isolated and
characterized.
Analysis of the structures of 1–3 revealed that there is
a common chiral center at C-14. Moreover, an additional
chiralilty center at C-15 is identified in both 1 and 2.
To determine the absolute configuration of 1 by utilizing
Mosher’s NMR method,13,14 the cleavage of the benzoate
and acetate ester bonds was necessary. Following the
reported hydrolysis conditions,3,4 integracin A was treated
with 4N NaOH and 1N HCl, respectively, but strangely
enough, we failed to obtain the expected monomeric alcohols.
Fortunately, the desired two alcohols (6 and 7) were
obtained by treating 1 first with CH3I and K2CO3 in acetone,
then reducing the methylated product with diisobutylalumi-
nium hydride at ꢀ78 ꢂC (Scheme 1). The alcohols 6 and 7
were fully characterized by detailed analysis of their two-
dimensional NMR spectra [1H-1H correlated spectroscopy
(COSY), heteronuclear single-quantum coherence (HSQC),
and heteronuclear multiple-bond correlation (HMBC)]. Having
these compounds in hands, we could study their absolute
configuration.
positive d values were observed for the protons H2-15, H2-16,
and Me-17. According to the Mosher’s rule,13,14 this
allowed establishing the absolute configuration at C-14 in
6 as (R).
It is obvious, bearing in mind the dimeric nature of integracin
A, that 15-OH in 7 should possess the same absolute configura-
tion as that of 6. This assumption was supported by comparison
20
of its optical rotation sign and value ½aꢃ
= + 2.0 (CHCl3,
D
20
c 0.20) with those of model compound 4 (½aꢃ
= ꢀ5.6 (CHCl3,
D
c 2.85)),15 which was previously reported as the reduced
primary hydroxyl derivative of lasiodiplodin with (S) configura-
tion at C-15. On the basis of earlier evidences, we proposed
(14R, 15R) configuration for integracin A (1).
Integracin B (2) is simply a deacetyl derivative of integracin
A (1). The absolute configuration of 2 should be the same as
that of 1 based on the biogenetic consideration. To confirm
this, chemical correlation between 1 and 2 was conducted.
Stirring 1 in excess K2CO3 for 16 h at room temperature
afforded the expected deacetyl product that has the same
spectroscopic data in all respect ([a]D value, 1H and 13C
NMR data) as 2, and thus the absolute configuration of 2
was assigned as depicted.
Treatment of
6 with (R)-(-) and (S)-(+)-a-methoxy-a-
(trifluromethyl)phenylacetyl choloride (MTPA-Cl) in dry
pyridine at room temperature yielded the corresponding
diastereomeric (6S ) and (6R )-MTPA esters, respectively.
Assignment of the 1H NMR signals of the esters was achieved
1
by carefully analyzing their H-1H COSY, HSQC, and HMBC
Compound 3 is a 15-dehydroxy derivative of 2. The low
amount (0.5 mg) of 3 did not allow determining its absolute
configuration by chemical methods. Given that the 15-
dehydroxy-integracin B (3) and integracins A (1) and B (2)
spectra. The chemical shift differences (Dd = d(S)-MTPA-ester
ꢀ
d(R) -MTPA-ester) of the protons surrounding the C-14 chirality
center were disclosed in Figure 2. Consistent negative d
values were recorded for protons H2-8ꢀH2-13, whereas
MeO
HO
14
14
5
5
(a)
(b)
O
O
O
O
reduction
methylation
OMe
MeO
OH
HO
15'
15'
5
5
O
O
OH
O
OMe
5
O
1
CH2OH
OMe
MeO
14
+
MeO
15'
OR
OH
OMe
7
6
R = H
6S R = (S)-MTPA
6R R = (R)-MTPA
(a) CH3I/acetone, K2CO3;
(b) [(CH3)2CHCH2]2AlH/N2, CH2Cl2, -78°C, 3.5 h
Scheme 1. Chemical degradation of compound 1.
Chirality DOI 10.1002/chir

LIU ET AL.
have a common polyketide pathway, we anticipated that the
LITERATURE CITED
absolute configuration of C-14 in 3 should be the same as
those of 1 and 2.
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phenolic amphiphiles and their biological activity. Chem Rev 1999;99:1–25.
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to test their other pharmacological activities, such as cytotoxic
and enzyme inhibitory activities, etc. The bioassay results
showed that integracin A (1) could significantly inhibit the
growth of the tumor cell lines HepG2 and NCI-H460 with
100% inhibitions at 25 mg/ml.
2. Ross AB, Kamal-Eldin A, Åman P. Dietary alkylresorcinols: absorption,
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Lingham RB, Felock P, Hazuda DJ. Discovery, structure and HIV-1
integrase inhibitory activities of integracins, novel dimeric alkyl aromatics
from Cytonaema sp. Tetrahedron Lett 2002;43:1617–1620.
The real origin of undecylresorcinol dimers 1–3 is a mat-
ter worthy discussing. As mentioned previously, dimeric
ARs were mainly isolated from fungi. However, they were
also isolated from plants. Just very recently, a new undecyl-
resorcinol dimer, integracin D, the sulfonated derivative of
integracin A, along with integracin A has been isolated from
Chinese mangrove plant Laguncularia racemosa,4 but
surprisingly, the absolute configurations of integracin D
were reported (14S, 15S), opposite to those of integracins
A (1) and B (2) isolated from the title plant in our study.
Because the assigned absolute configuration for integracin
D4 was based on the comparison of specific rotation values
of hydrolyzed derivatives (8 and 9) of integracin D with that
of model compound 10,16 the quite different structures
(Fig. 1) led the assignment of the absolute configuration
by simply because comparison of [a]D values of 8 and 9
with that of 10 was far from conclusive and invalid. A more
rigorous approach will be necessary to unambiguously deter-
mine the correct absolute stereochemistry of integracin D
and also integracin A isolated from L. racemosa. Compounds
1–3 repeatedly isolated from different natural sources
strongly suggest that they might be produced by microor-
ganism, such as endophytic fungi or epiphytic bacteria.
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the endophytic or associated microorganisms from the title
plant so as to clarify the real origin of these interesting
bioactive molecules as well as to understand their real
biological and ecological roles.
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CONCLUSION
In summary, the absolute configuration of integracins
A (1), B (2), and 15-dehydroxy-integracin B (3), three
undecylresorcinol dimers isolated from Chinese mangrove
plant S. hainanensis, was determined by a combination of
advanced Mosher’s method and optical rotation analysis on
opportune ester reduction alcohols (6 and 7) and by
chemical correlation.
Chirality DOI 10.1002/chir