Anti-HIV agents. Part 55: 3′R,4′R-Di-O-(-)-camphanoyl-2′,2′- dimethyldihydropyrano[2,3-f]chromone (DCP), a novel anti-HIV agent

Article abstract of DOI:10.1016/S0960-894X(03)00201-4

3′R,4′R-Di-O-(-)-camphanoyl-2′,2′- dimethyldihydropyrano[2,3-f]chromone (DCP) (2) was designed and synthesized on the basis of a structure-activity relationship study of 3′R,4′R-di-O-(-)-camphanoyl-(+)-cis-khellactone DCK (1) and its analogues. DCP (2), a pyranochromone, and DCK (1), a pyranocoumarin, have different skeletons. Compound 2 showed potent in vitro inhibition of HIV-1 replication in H9 lymphocyte cells with an EC₅₀ of 6.78×10^-4 μM and TI of 14,500. These values are comparable with those for DCK (1) and better than those of AZT in the same assay.

Full text of DOI:10.1016/S0960-894X(03)00201-4

Bioorganic & Medicinal Chemistry Letters 13 (2003) 1575–1576
Anti-HIV Agents. Part 55:y 30R,40R-Di-(O)-(ꢀ)-camphanoyl-20,20-
dimethyldihydropyrano[2,3-f]chromone (DCP),
a Novel Anti-HIV Agent
Donglei Yu,a Arnold Brossi,a Nicole Kilgore,b Carl Wild,b
Graham Allawayb and Kuo-Hsiung Leea,*
aNatural Products Laboratory, School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA
bPanacos Pharmaceuticals, Inc., 217 Perry Parkway, Gaithersburg, MD 20877, USA
Received 4 December 2002; accepted 31 January 2003
Abstract—30R,40R-Di-O-(ꢀ)-camphanoyl-20,20-dimethyldihydropyrano[2,3-f]chromone (DCP) (2) was designed and synthesized on
the basis of a structure–activity relationship study of 30R,40R-di-O-(ꢀ)-camphanoyl-(+)-cis-khellactone DCK (1) and its analogues.
DCP (2), a pyranochromone, and DCK (1), a pyranocoumarin, have different skeletons. Compound 2 showed potent in vitro
inhibition of HIV-1 replication in H9 lymphocyte cells with an EC50 of 6.78ꢁ10ꢀ4 mM and TI of 14,500. These values are com-
parable with those for DCK (1) and better than those of AZT in the same assay.
# 2003 Elsevier Science Ltd. All rights reserved.
Our previous papers reported the discovery of 30,40-di-
O-(S)-camphanoyl-(+)-cis-khellactone (DCK, 1) as a
potent anti-HIV agent. It has a remarkable EC50 value
of 2.56ꢁ10ꢀ4 mM and a therapeutic index (TI) of
1.37ꢁ105 in HIV-1 infected H9 lymphocytes, and was
more potent than AZT in the same assay.1,2 Although
their molecular target has not been identified, at least 20
DCK analogues have shown promising inhibitory
activity against HIV-1 replication in H9 lymphocytes.3
However, to conduct a QSARstudy of DCK-type
compounds, structural variety is needed. Thus, we
replaced the coumarin nucleus in DCK with a chro-
mone system in 30R,40R-di-O-(ꢀ)-camphanoyl-20,20-
dimethyldihydropyrano[2,3-f]chromone (DCP) (2). This
article reports the synthesis of 2 and its bioassay data in
H9 lymphocytes (Fig. 1).
Figure 1. Structures of DCK (1) and DCP (2).
group; therefore, we changed the coumarin skeleton to a
planar aromatic chromone. Coumarin and chromone
are both benzopyranones, but they differ in the posi-
tions of the carbonyl group and double bond in their
pyranone (A) ring.
Our previous SARstudy of DCK analogues showed
that the aromaticity and planarity of the coumarin
nucleus and the absolute configurations of the 30 and 40
position in the pyrano ring are key factors for the anti-
HIV activity.2ꢀ5 In this paper, we wanted to determine
the importance of the position of the A ring carbonyl
The synthesis of DCP (2) was accomplished by a 5-step
sequence, as illustrated in Scheme 1. 7-Hydroxy-
chromone (4) was prepared in a 65% yield by treating
20,40-dihydroxyacetophone (3) with triethyl ortho-
formate and 70% perchloric acid, followed by aqueous
hydrolysis of the intermediate perchlorate salt.6 Com-
pound 4 was then converted in two steps to 20,20-dimethyl-
dihydropyrano[2,3-f]chromone (6) in a 30% yield.4 The
*Corresponding author. Tel.: +1-919-962-0066; fax: +1-919-966-
3893; e-mail: khlee@unc.edu
yFor part 54, see: J. Wu, S. L. Morris-Natschke and K. H. Lee, J.
Chin. Chem. Soc., Submitted for publication.
0960-894X/03/$ - see front matter # 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0960-894X(03)00201-4

1576
D. Yu et al. / Bioorg. Med. Chem. Lett. 13 (2003) 1575–1576
Scheme 1. Synthesis of DCP (2): (i) 70% perchloric acid, triethyl orthoformate, 40 min; (ii) H2O, reflux, 5 min; (iii) K2CO3, KI, 3-chloro-3-methyl-1-
butyne, DMF, 80 ꢂC, 18–24 h; (iv) Diethylaniline, reflux, 4 h; (v) K3Fe(CN)6, K2Os2O2(OH)4, K2CO3, (DHQ)2PYRin t-butanol/H2O 1:1, 0 ꢂC, 24 h;
(vi) camphanoyl chloride, pyridine/CH2Cl2, rt, 1–2 days.
Acknowledgements
Table 1. Anti-HIV activities of DCP (2) in acutely infected H9 lym-
phocytes
This investigation was supported by Grant AI-33066
from the National Institute of Allergies and Infectious
Diseases awarded to K. H. Lee.
Compd
IC50, mMa
EC50, mMb
T.I.c
DCK (1)
DCP (2)
AZT
35
9.83
500
2.56ꢁ10ꢀ4
6.78ꢁ10ꢀ4
0.045
136,719
14,500
11,200
References andNotes
aConcentration that inhibits uninfected H9 cell growth by 50%.
bConcentration that inhibits viral replication by 50%.
cIn vitro therapeutic index (TI=IC50/EC50).
1. Huang, L.; Kashiwada, Y.; Cosentino, L. M.; Fan, S.; Lee,
K. H. Bioorg. Med. Chem. Lett. 1994, 4, 593.
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K. H. Med. Res. Rev. 2003, 23, 322.
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5. Xie, L.; Takeuchi, Y.; Cosentino, L. M.; McPhail, A. T.;
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Chemical Reviews 1994, 94, 2483.
dihydroxy pyranochromone (7) was prepared in a 40%
yield, as in the asymmetric synthesis of DCK, by
Sharpless asymmetric dihydroxylation (AD) of 6 with
K3Fe(CN)6 as oxidant in conjunction with catalytic
amounts of K2OsO2(OH)4 and (DHQ)2-PYRas a chiral
catalyst.7ꢀ9 Compound 7 was then reacted with (ꢀ)-(S)-
camphanoyl chloride at room temperature for 48 h,
monitored by TLC, to produce DCP (2) in a 71%
yield.10 The % ee of the AD reaction was more than
90%.
DCP (2) was tested against HIV-1 replication in acutely
infected H9 lymphocytes. The anti-HIV data, along
with those of AZT and DCK included in the same assay
for comparison, are shown in Table 1. DCP (2) showed
potent activity with a remarkable EC50 of 6.78ꢁ10ꢀ4
mM and TI of 14,500. These values are comparable with
those of DCK and better than those of AZT in the same
assay.11
8. Xie, L.; Crimmins, M. T.; Lee, K. H. Tetrahedron Lett.
1995, 36, 4529.
9. Mehltretter, G. M.; Dobler, C.; Sundermeier, U.; Beller, M.
Tetrahedron Lett. 2000, 41, 8083.
10. 30R,40R-di-(O)-(ꢀ)-camphanoyl-20,20 -dimethyldihydro-
pyrano[2,3-f]chromone (2): mp 90–92 ꢂC; [a]D ꢀ95.3ꢂ
(c 0.17, CHCl3); ESI–MS: 645 (M+Na)+; 1H NMR
(300 MHz, CDCl3) d 8.15 (1H, d, J=9.0, Hz, H-5), 7.69 (1H,
d, J=6.3, H-2), 6.94 (1H, d, J=9.0, H-6), 6.72 (1H, d, J=4.8,
H-40), 6.32 (1H, d, J=6.3, H-3), 5.37 (1H, d, J=4.8, H-30),
2.46, 2.20, 1.90, 1.74 (each 2H, m, camphanoyl CH2), 1.52,
This modification study indicated that the coumarin
nucleus can be replaced by a similar skeleton without
loss of activity; therefore, the carbonyl group can be in
position 4 of the nucleus. Additional modification and
SARstudies are in progress with an aim to continually
improve pharmacological properties.
1.47 (each 3H, s, 20-CH3), 1.11, 1.10, 1.08, 1.02, 0.99, 0.89
1
.
(each 3H, s, camphanoyl CH3). Anal. (C34H38O11 1 2H2O), C,
H.
11. HIV growth inhibition assay in H9 lymphocytes was per-
formed by Panacos, Inc. and has been described previously.5