Synthesis and anti-human immunodeficiency virus activity of the skeleton isomers of 3′,,4′-di-(O)-(-)-camphanoyl-(+)-khellactone

Article abstract of DOI:10.1248/cpb.59.1075

Optically active structural isomers (1b - f and dst-1b - f) of 3′,4′-di-(O)-(-)-camphanoyl-(+)-khellactone (DCK) were synthesized and their anti-human immunodeficiency virus (HIV) activity was investigated. The value of the sensitivity index (SI) of 1b was greater than that of DCK.

Full text of DOI:10.1248/cpb.59.1075

August 2011
Communication to the Editor
Chem. Pharm. Bull. 59(8) 1075—1076 (2011)
1075
Synthesis and Anti-human
Immunodeficiency Virus Activity of
ꢀ ꢀ
the Skeleton Isomers of 3 ,4 -Di-(O)-
ꢁ
ꢂ
( )-camphanoyl-( )-khellactone
Hiromi NISHIOKA,a Koji UESUGI,a Norihiro UEDA,a
Yuka KONDO,a Megumi TSUJI,a Hitoshi ABE,b
Takashi HARAYAMA,a Takayuki HAMASAKI,c
c
,a
*
Masanori BABA, and Yasuo TAKEUCHI
a Division of Pharmaceutical Sciences, Graduate School of
Medicine, Dentistry and Pharmaceutical Sciences, Okayama
University; 1–1–1 Tsushima-Naka, Kita-ku, Okayama 700–8530,
b
Japan: Faculty of Engineering, Toyama University; 3190 Gofuku,
Toyama 930–8555, Japan: and c Division of Antiviral Chemotherapy
Center for Chronic Viral Diseases Graduate School of Medical and
Dental Sciences, Kagoshima University; 8–35–1 Sakuragaoka,
Kagoshima 890–8544, Japan.
Fig. 1. Structure of DCK and Its Skeleton Isomers
Received April 19, 2011; accepted May 18, 2011; published online
May 20, 2011
Optically active structural isomers (1b—f and dst-1b—f) of
3ꢀ,4ꢀ-di-(O)-(ꢁ)-camphanoyl-(ꢂ)-khellactone (DCK) were syn-
thesized and their anti-human immunodeficiency virus (HIV)
activity was investigated. The value of the sensitivity index (SI)
of 1b was greater than that of DCK.
Key words anti-human immunodeficiency virus; coumarin; asymmetric
dihydroxylation; new Mosher’s method; 3ꢀ,4ꢀ-di-(O)-(ꢁ)-camphanoyl-(ꢂ)-
khellactone
3ꢀ,4ꢀ-Di-(O)-(ꢁ)-camphanoyl-(ꢂ)-khellactone (DCK) is
well known as an anti-human immunodeficiency virus (HIV)
compound with remarkably high activity. Lee and his co-
workers reported the structure–activity relationship (SAR) of
the analogue of DCK (1a); in particular, they discussed the
optimization of substituents on the angular benzo[2,1-b:4,3-
bꢀ]dipyran skeleton.1—6) We believe that one of the most im-
portant studies on the SAR of DCK must involve the
arrangement of an angular benzodipyran skeleton. In this
paper, we describe the synthesis and anti-HIV activity of the
optically active structural isomers (1b—f and dst-1b—f) of
DCK (Fig. 1).
Our desired compounds (1b—d and dst-1b—d) can be ob-
tained from hydroxycoumarin by the method used to synthe-
size DCK. 6-, 5-, or 8-hydroxycoumarin (2b—d) and ben-
zodipyran derivatives (3b—d) were successfully prepared by
mainly using our reported method.7) The Sharpless asym-
metric dihydroxylation of 3b—d with dihydroquinine-2,5-
diphenyl-4,6-pyrimidinediyl diether ((DHQ)2PYR) afforded
the optically active diols (4b—d), which exhibited an R,R
configuration. On the other hand, dihydroxylation of 3b—d
with dihydroquinidine-2,5-diphenyl-4,6-pyrimidinediyl di-
ether ((DHQD)2PYR) yielded S,S diols (ent-4b—d). Cam-
Chart 1
Table 1. Dihydroxylation of 3b—f with (DHQ)2PYR or (DHQD)2PYR
Ligand via Chart 1
Starting
material (3)
Product
Ligand
Yield %a)
ee %b)
(4)
3b
3b
3c
3c
3d
3d
3e
3e
3f
(DHQ)2PYR
(DHQD)2PYR
(DHQ)2PYR
(DHQD)2PYR
(DHQ)2PYR
(DHQD)2PYR
(DHQ)2PYR
(DHQD)2PYR
(DHQ)2PYR
(DHQD)2PYR
4b
ent-4b
4c
ent-4c
4d
ent-4d
4e
ent-4e
4f
23
43
58
66
24
54
28
61
72
41
57
75
57
68
67
68
53
58
90
76
3f
ent-4f
a) After recrystallization. b) Determined by chiral HPLC analysis.
phanoylation of 4b—d afforded the final products (1b8)—d). the modified Mosher’s method (Fig. 2).9) The reaction of
Other isomers (1e, f and dst-1e, f) were prepared in the simi- 4b—f and ent-4b—f with (R)-a-methoxy-a-trifluoromethyl-
lar manner (Chart 1). In the case of asymmetric dihydroxyla- aphenylacetic acid ((R)-MTPA) afforded monoester (5b—f
tion, even though the values of yield and enantiomeric excess and dst-5b—f), where the hydroxy group of the benzylic po-
(ee) were never high, we could still obtain 4b—f and those sition was selectively esterified. The difference (Dd) between
1
enantiomer (ent-4b—f) (Table 1).
the chemical shift (ppm) of each peak in the H-NMR of
The absolute structure of 4b—f was determined by using 5b—f and dst-5b—f is shown in Fig. 2.
∗ To whom correspondence should be addressed. e-mail: take@pharm.okayama-u.ac.jp
© 2011 Pharmaceutical Society of Japan

1076
Vol. 59, No. 8
of the test compounds. After the cells were incubated for 4 d
at 37 °C, the number of viable cells was monitored by the 3-
(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
(MTT) method. The cytotoxicity of the compounds was si-
multaneously evaluated with their antiviral activity, on the
basis of the viability of mock-infected cells. All experiments
were repeated twice.
Among 1b—f and those diastereomers (dst-1b—f), we
could not find any derivative whose anti-HIV activity was
more potent than that of DCK. However, the selective index
(SI) of 1b, whose anti-HIV activity (EC50ꢄ0.23 mM) was al-
most the same as that of DCK, was greater than that of DCK
(Table 2). We expect the DCK analogues to also exhibit anti-
HIV activity.
Acknowledgment We are grateful to the SC-NMR Laboratory of
Okayama University for the use of the facilities.
Fig. 2. Analysis Using New Mosher’s Method for the Absolute Structure
of 5
References and Notes
1) Huang L., Kashiwada Y., Cosentino L. M., Fan S., Lee K.-H., Bioorg.
Med. Chem. Lett., 4, 593—598 (1994).
Table 2. Anti-HIV Activity of 1
2) Huang L., Kashiwada Y., Cosentino L. M., Fan S., Chen C. H.,
McPhail A. T., Fujioka T., Mihashi K., Lee K.-H., J. Med. Chem., 37,
3947—3955 (1994).
3) Xie L., Crimmins M. T., Lee K.-H., Tetrahedron Lett., 36, 4529—4532
(1995).
4) Xie L., Takeuchi Y., Cosentino L. M., McPhail A. T., Lee K.-H., J.
Med. Chem., 44, 664—671 (2001).
5) Xie L., Takeuchi Y., Cosentino L. M., Lee K.-H., J. Med. Chem., 42,
2662—2672 (1999).
6) Tang J., Qian K., Zhang B.-N., Chen Y., Xia P., Yu D., Xia Y., Yang Z.-
Y., Chen C.-H., Morris-Natschke S. L., Lee K.-H., Bioorg. Med.
Chem., 18, 4363—4373 (2010).
7) Nishita Y., Uesugi K., Satoh Y., Harayama T., Yakugaku Zasshi, 118,
599—608 (1998).
Conpound (1)
EC50 (mM)a)
CC50 (mM)b)
SI (CC50/EC50)c)
1a (DCK)
1b
dst-1b
1c
dst-1c
1d
dst-1d
1e
0.17
0.23
ꢆ100
4.3
ꢆ100
ꢆ100
ꢆ100
ꢆ100
ꢆ100
ꢆ100
1.79
ꢆ4.0
52
ꢆ23
226
—
ꢆ23
—
—
—
—
—
ꢆ100
ꢆ100
ꢆ100
ꢆ100
ꢆ100
ꢆ100
ꢆ100
ꢆ100
30.3
dst-1e
1f
—
16
ꢆ263
dst-1f
AZTd)
0.076
ꢆ20
8) 1b: Colorless needles. mp 210—212 °C [deꢄ90.5%] (AcOEt–hexane).
IR (KBr) cmꢁ1: 1790, 1730. 1H-NMR (300 MHz, CDCl3) d: 0.88 (3H,
s, 3ꢅ-CH3), 0.98 (3H, s, 3ꢀ-CH3), 1.10, 1.11 (each 3H, each s, 7ꢅ-CH3),
1.13 (6H, s, 7ꢀ-CH3), 1.45, 1.48 (each 3H, each s, 8-CH3), 1.67—2.54
(8H, m, CH2), 5.40 (1H, d, Jꢄ4.5 Hz, 9-H), 6.46 (1H, d, Jꢄ9.9 Hz, 2-
H), 6.67 (1H, d, Jꢄ4.5 Hz, 10-H), 7.11 (1H, d, Jꢄ9.3 Hz, 6-H), 7.34
(1H, d, Jꢄ9.3 Hz, 5-H), 7.50 (1H, d, Jꢄ9.9 Hz, 1-H). FAB-MS (posi-
tive ion mode) m/z: 623. Anal. Calcd for C34H38O11: C, 65.58, H, 6.15.
Found: C, 65.50, H, 6.18. [a]D23.1 ꢁ60.36 (cꢄ0.76, CHCl3). Diastere-
omer excess was determined by chiral HPLC analysis.
9) Ohtani I., Kusumi T., Kashman Y., Kakisawa H., J. Org. Chem., 56,
1296—1298 (1991).
a) EC50: 50% effective concentration based on the inhibition of HIV-1-induced cell
death in virus-infected MT-4 cells. b) CC50: 50% cytotoxic concentration based on
the reduction of viability in mock-infected MT-4 cells. c) Selectivity index: ratio
CC50/EC50
.
d) AZT (zidovudine) was used as positive control.
The activity of compound (1) against HIV-1 replication
was based on the inhibition of virus-induced cytopathogenic-
ity in MT-4 cells. Briefly, the cells (1ꢃ105 cells/ml) were in-
fected with HIV-1 at a multiplicity of infection (MOI) of 0.1
and were cultured in the presence of various concentrations