Total synthesis and antihypertensive activity of (±)7,8-dihydroxy-3-methyl-isochromanone-4

Article abstract of DOI:10.1016/j.bmcl.2008.12.102

This letter describes the total synthesis, preliminary biological evaluation and mechanism studies of a novel and structurally unique isochromanone, (±)7,8-dihydroxy-3-methyl-isochromanone-4 (1), a nature product contained in banana (Musa sapientum L.) pe

Full text of DOI:10.1016/j.bmcl.2008.12.102

Bioorganic & Medicinal Chemistry Letters 19 (2009) 1822–1824
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Total synthesis and antihypertensive activity of ( )7,8-
dihydroxy-3-methyl-isochromanone-4
a
a
b
b,
*
Jie Liu a, Hao Ren a, Jinyi Xu a, , Renren Bai , Qi Yan , Wenlong Huang , Xiaoming Wu
,
*
Jihua Fu c, Qiujuan Wang c, Qian Wu c, Rong Fu c
a Department of Medicinal Chemistry, China Pharmaceutical University, Tongjia Xiang 24, Nanjing, Jiangsu 210009, China
b Center of Drug Discovery, China Pharmaceutical University, Nanjing 210038, China
c Department of Physiology, China Pharmaceutical University, Nanjing 210009, China
a r t i c l e i n f o
a b s t r a c t
Article history:
This letter describes the total synthesis, preliminary biological evaluation and mechanism studies of a
novel and structurally unique isochromanone, ( )7,8-dihydroxy-3-methyl-isochromanone-4 (1), a nature
product contained in banana (Musa sapientum L.) peel. The bioassay showed that compound 1 displays
potent antihypertensive activity in renal hypertensive rats and further mechanism studies revealed that
it is an ACE inhibitor.
Received 24 September 2008
Revised 4 December 2008
Accepted 26 December 2008
Available online 31 December 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
( )7,8-Dihydroxy-3-methyl-
isochromanone-4
Total synthesis
Antihypertensive activity
ACE inhibitors
Hypertension is a leading cause of the human angiocardiopathy
death, approximately 1 billion individuals worldwide are esti-
mated to have blood pressure (BP) levels that warrant treatment,
and the prevalence of chronic heart disease and end-stage renal
disease has increased in recent years. Therapeutic intervention is
the most common method used to control hypertension and re-
duce hypertension-related organ damage. During the last few
decades, great progress has been made in finding new antihyper-
tensive drugs and currently there are three main categories of anti-
hypertensive drugs available: (1) diuretics, adrenergic receptor
blockers; (2) calcium channel blockers and (3) inhibitors targeting
the renin–angiotensin system (RAS), namely angiotensin-convert-
ing enzyme (ACE) inhibitors and angiotensin type 1 (AT1) receptor
antagonists. Despite the development of antihypertensive drugs,
effective BP control remains a major medical challenge and there
has been a consistent demand for novel and more effective thera-
pies. Antihypertensive product from plants is an important re-
source to find new lead for further structure modification.1
a novel and structurally unique isochromanone, ( )7,8-dihydroxy-
3-methyl-isochromanone-4 (1), isolated from banana (Musa sap-
ientum L.) peel extract.3 The structure of compound 1 has been
identified by extensive spectra. A preliminary bioassay proved that
compound 1 displays potent antihypertensive activity in a renal
hypertensive rats (RHRs). However, the low abundance of this
compound impeded the further biological tests both in vitro and
in vivo. As our long-term interest, we initialized the project to-
wards the study of total synthesis of compound 1 and its deriva-
tives. In this letter, we wish to report the total syntheses of
compound 1 as well as its biological evaluations.
O
5
11
4
9
6
7
3
O
2
10
HO
1
8
The peel of banana has a great resource in China, which
has been widely used as a folk medicine for antihypertension,
antiulceration, antibacterial and so on.2 Recently, we first reported
OH
1
In our recent study, a more efficient synthesis of compound 1
was found. The synthetic route is shown in Scheme 1. Metal-
halogen exchange provided favourable conditions leading o-brom-
ophenylalkanoic acid to self-condensation.4 Treatment of o-brom-
* Corresponding authors. Tel.: +86 25 83271445, +86 25 83242366; fax: +86 25
83302827.
E-mail addresses: jinyixu@china.com (J. Xu), xmwu@cpu.edu.cn (X. Wu).
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.12.102

J. Liu et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1822–1824
1823
Br
Br
b, c
a
OH
OH
O
COOH
H3CO
H3CO
O
H3CO
OCH3
OCH3
OCH3
2
3
4
O
e
d
O
O
H3CO
HO
OCH3
OH
1
5
Scheme 1. Reagents and conditions: (a) NBS, THF, rt, 93%; (b) CH3BrCHCOOC2H5, anhydrous DMF, NaH, rt, 82%; (c) MeOH, 10% NaOH, rt, then 10% HCl, 92%; (d) n-BuLi,
anhydrous THF, ꢀ78 °C to room temperature, 60%; (e) AlCl3, CHCl3, reflux, 50%.
ophenylalkanoic acid with n-BuLi in THF at temperatures ranging
Control
from ꢀ110 to 0 °C afforded the expected benzocycloalkenone in
good yield.5 As shown in Scheme 1, compound 3 was achieved
Captopril
through a regioselective bromination with NBS in quite high yield.
Subsequent alkylation of 3 with ethyl 2-bromopropionate in pres-
ence of NaH, followed by saponification of the ethyl ester gave
compound 4.6 Intermediate 4 was treated with n-BuLi in THF at
ꢀ78 °C, and then the temperature was allowed to rise to room tem-
perature to give compound 5, in 60% yield. After deprotection of
phenolic methyl ether 5 by AlCl3 in CHCl3, target compound
( )7,8-dihydroxy-3-methyl-isochromanone-4 (1) was obtained.
The spectral data of synthetic compound 1 was identical with
those of natural sample 1.7
The compound 1 showed potent antihypertensive activity on
the two-kidney–one-clip renal hypertensive rats8,9 and the anti-
hypertensive activity of synthetic compound 1 was identical
with that of natural sample 1. In acute antihypertensive tests,
captopril was used as a positive control, the maximum antihy-
pertensive effect on systolic arterial pressure (SAP) and diastolic
arterial pressure (DAP) of compound 1 at the dose of 100.0 mg/
kg/day was approximately equivalent to that of captopril at the
dose of 25.0 mg/kg/day. The therapeutic effects of compound 1
occurred evidently 2 h after treatment and lasted for 6–8 h (Figs.
1 and 2).
Compound 1
Time(h)
Figure 2. The acute antihypertensive activity of compound
1 in RHRs (DAP,
diastolic arterial pressure). Data are presented as mean SEM, n = 8. Significance
indicated by: *P < 0.05; **P < 0.01, versus control.
In therapeutic antihypertensive tests, the maximum antihyper-
tensive effect on SAP and DAP of compound 1 (100.0 mg/kg/day)
and captopril (25.0 mg/kg/day) were also approximately equiva-
lent. RHRs were given compound 1 and captopril by gastic perfu-
sion for 12 days. Both SAP and DAP in compound 1-treated group
were decreased significantly on the second day after treatment,
and then were maintained at constant level. Stopped administra-
Control
Captopril
Compound 1
Control
Captopril
Compound 1
stop administration
Time(h)
Time(d)
Figure 1. The acute antihypertensive activity of compound 1 in RHRs (SAP, systolic
arterial pressure). Data are presented as mean SEM, n = 8. Significance indicated
by: *P < 0.05; **P < 0.01, versus control.
Figure 3. The therapeutic antihypertensive activity of compound 1 in RHRs (SAP,
systolic arterial pressure). Data are presented as mean SEM, n = 8. Significance
indicated by: *P < 0.05; **P < 0.01, versus control.

1824
J. Liu et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1822–1824
compared with the negative control, the inhibition of ACE by com-
Control
pound 1 increases markedly with the increased concentration of
compound 1 from 10ꢀ12 to 10ꢀ8 mol/L, which is approximately
equivalent to that of captopril. Conversely, the inhibition of ACE
by compound 1 decreases with the increased concentration of
compound 1 from 10ꢀ8 to 10ꢀ5 mol/L, but the inhibitory activity
against ACE by captopril has no change under the same concentra-
tion. While compared with the negative control, the compound 1-
induced inhibition of ACE increases with the increased concentra-
tion between 10ꢀ5 and 10ꢀ4 mol/L. This result is interesting and
further studies on the mechanism of compound 1 are currently
in progress and will be reported in due course.
Captopril
Compound 1
In summary, the present contribution describes the total syn-
theses of ( )7,8-dihydroxy-3-methyl-isochromanone-4. The cur-
rent method presents a very promising synthetic process for
stop administration
Time(d)
Figure 4. The therapeutic antihypertensive activity of compound 1 in RHRs (DAP,
diastolic arterial pressure). Data are presented as mean SEM, n = 8. Significance
indicated by: *P < 0.05; **P < 0.01, versus control.
compound
1 and its derivatives. The preliminary bioassay
showed that compound 1 displays potent antihypertensive activ-
ity in renal hypertensive rats. The mechanism studies found that
compound 1 has moderate ACE inhibitory activity and beneficial
effects in reducing blood pressure, which indicates that ACE is its
potential target, or at least one of its acting targets. In view of
these properties, ( )7,8-dihydroxy-3-methyl-isochromanone-4 is
likely to have an interesting therapeutic potential for the devel-
opment of more efficient antihypertensive natural drugs, in order
to improve the pharmacological treatment of hypertension.
Table 1
ACE inhibitory activity of compound 1 in vitro
Level
(mol/L)
Restrain rate of
captopril (%)
Restrain rate of
compound 1 (%)
Restrain rate of
DMSO
*
*
*
*
*
*
*
*
10ꢀ4
10ꢀ5
10ꢀ6
10ꢀ7
10ꢀ8
10ꢀ10
10ꢀ11
10ꢀ12
94 0.2
94 0.3
95 0.1
77 12
61 16
61 12
97 0.2
74 11
*
*
96
5
87
9
Acknowledgment
*
*
*
*
*
*
48 0.1
47 0.6
42 0.6
44 13
41 24
34 15
This study was supported by grant from National Natural Sci-
ence Fund (No. 30873144) for financial assistance.
18 34
(x ꢃ s, n = 6), *P < 0.05 versus control.
ꢀ
References and notes
1. Li, Y. C. Curr. Opin. Investig. Drugs 2007, 8, 750.
2. Cidian, Z. D. Grand Dictionary of Chinese Traditional Medicine; Shanghai Science
and Technology Press: Shanghai, 2005. pp 178.
120
3. (a) Wu, X. M.; Huang, W. L.; Qian, H.; Rao, G. L.; Fu, J. H.; Liu, C. L. Chinese
Patent: CN 1857530.A, 2006.; (b) Wu, X. M.; Huang, W. L.; Liu, J.; Xu, J. Y.; Qian,
H.; Rao, G. L.; Fu, J. H.; Ye, W. C. Chinese Patent Application: CN 10020464.9,
2007.
Captopril
100
Compound 1
80
4. Parham, W. E.; Sayed, Y. A. J. Org. Chem. 1974, 39, 2051.
5. Sudani, M.; Yoshio, T.; Eiichi, Y.; Tadashi, K. Tetrahedron Lett. 1981, 22,
4253.
60
40
20
0
6. Qandil, A. M.; Ghosh, D.; Nichols, D. E. J. Org. Chem. 1999, 64, 1407.
7. Analytical data for synthetic compound 1: Mp 174–176 °C (dec.). 1H NMR (CDCl3,
300 MHz): d (ppm) 7.44 (d, 1H, J = 8.5 Hz, Ar–H); 6.92 (d, 1H, J = 8.5 Hz, Ar–H),
5.05 (d, 1H, J = 15.5 Hz, –CH2–), 4.75 (d, 1H, J = 15.5 Hz, –CH2–), 4.18 (q, 1H,
J = 6.5 Hz, –CH–), 1.38 (d, 3H, J = 6.5 Hz, –CH3). IR (KBr, cmꢀ1): 3432, 3428,
2987, 1664, 1613, 1558, 1480, 1450, 1394, 1363, 1306, 1256, 1216, 1120, 1074,
951, 908, 825, 788. ESI-MS: 193 [MꢀH]ꢀ. Anal. Calcd for C10H10O4ꢁ1/2H2O: C,
59.11; H, 5.42; O, 35.47. Found: C, 58.75; H, 5.72; O, 35.53. Analytical data for
-14
-12
-10
-8
-6
Log C
-4
-2
0
natural sample 1: m.p. 174–176 °C (dec.), ½a D20
ꢂ
ꢀ7.75 (c 0.34, acetone). 1H NMR
(CD3COCD3, 300 MHz): d (ppm) 7.43 (d, 1H, J = 8.5 Hz, Ar–H); 6.91 (d, 1H,
J = 8.5 Hz, Ar–H), 5.03 (d, 1H, J = 15.5 Hz, –CH2–), 4.75 (d, 1H, J = 15.5 Hz, –CH2–),
4.22 (q, 1H, J = 6.1 Hz, –CH–), 1.38 (d, 3H, J = 6.1 Hz, –CH3). 13C NMR
(CD3COCD3): d (ppm) 195.17 (C-4), 170.02 (C-7), 150.58 (C-8), 140.50 (C-10),
130.79 (C-5), 123.34 (C-6), 115.01 (C-9), 78.01 (C-3), 63.30 (C-1), 15.95 (C-11).
ESI-MS: 193 [MꢀH]ꢀ. IR (KBr, cmꢀ1): 3432, 3428, 2987, 2844, 1664, 1613,
1480, 1394, 1306, 1220.
Figure 5. ACE inhibitory activity test of compound 1.
tion for three days, the blood pressure went up but still in the low-
er level comparing with the placebo (Figs. 3 and 4).
The preliminary test showed that compound 1 has moderate
ACE inhibitory activity in vitro (Table 1 and Fig. 5). In the test,
ACE was obtained from pig lung extract.10 The results showed that,
8. Ko, F. N.; Yu, S. M.; Su, M. J.; Wu, Y. C.; Teng, C. M. Br. J. Pharmacol. 1993, 10, 882.
9. Orallo, F.; Alzueta, A. F.; Toimil, M. C.; Calleja, J. M. Br. J. Pharmacol. 1995, 114,
1419.
10. Cushman, D. W.; Cheung, S. H. Biochem. Plarmacol. 1971, 20, 1637.