C O MMU N I C A T I O N S
Table 1. Antifungal Activity of 1 and 2 (MICa/MFCb, µg/mL)
Coruscanone A shows similarity to some extent to 1,4-benzoquinone
compounds whose biological action is often linked to electron-
transfer rates and redox potentials.10 It is likely, however, that
coruscanone A functions through a unique antifungal mechanism.
Taking into account its antifungal potency, certain selectivity,
acceptable cytotoxicity (comparable to amphotericin B, refer to
Supporting Information), and its ready access by synthesis, corus-
canone A may serve as a template for a new class of antifungal
agents for the treatment of life-threatening disseminated candidi-
asis.11 Investigation of its mechanism of action using a genomic
profiling approach12 and preparation of a series of derivatives for
structure-activity relationship studies are underway in our labora-
tory.
C. albicans
Cr. neoformans
ATCC 90028
ATCC 90113
1
2
0.78/1.56
50/NAc
6.25/6.25
NA/NA
amphotericin B
2.50/5.00
2.50/2.50
a Minimum inhibitory concentration. b Minimum fungicidal concentra-
tion. c Not active.
Table 2. Antifungal Activity of 1 against Azole-Susceptible and
-Resistant C. albicans Strains [IC50/IC80/IC95 (µg/mL)]a
C. albicans
1
fluconazole
isolate 15a
isolate 25a
isolate 55a
isolate 85a
isolate 15b,c
isolate 175b,c
0.60/1.00/1.50
0.90/1.00/1.50
0.40/0.60/0.70
0.90/1.00/1.50
0.45/0.60/0.75
0.30/0.90/1.50
1.00/1.50/2.00
1.00/5.00/10.00
7.50/10.00/10.00
15.00/20.00/25.00
0.10/0.20/100.00
40.00/95.00/NAb
Acknowledgment. We thank Dr. Ted White and Dr. Spencer
Redding for kindly providing the fluconazole-resistant C. albicans
strains, Dr. Charles D. Hufford for critically reviewing the
manuscript, Dr. D. Chuck Dunbar and Mr. Frank M. Wiggers for
obtaining some spectroscopic data, and Dr. Ameeta Agarwal, Ms.
Sharon Sanders, and Ms. Belynda Smiley for technical assistance.
This work was supported by the NIH, NIAID, Division of AIDS,
Grant No. AI 27094, and the USDA Agricultural Research Service
Specific Cooperative Agreement No. 58-6408-2-0009.
a Patient isolates: isolate 1, azole-susceptible strain; isolates 2, 5, 8, and
17, azole-resistant strains with increasing azole resistance. Growth inhibition
concentrations represented by IC50, IC80, and IC95 reflect a dose-effect
curve. b Not active at highest test concentration of 100 µg/mL.
in a regio- and stereoselective manner 4-ylidenebutenolide 5.
Treatment of 5 with NaOMe in MeOH resulted in rearrangement
to cylopentendione 2, which was further methylated with Me2SO4/
K2CO3 in acetone to furnish 1.
1
Supporting Information Available: Experimental details and H
NMR spectra of key compounds. This material is available free of
Coruscanones A and B (1, 2) were evaluated using our published
bioassay protocols4 for in vitro antifungal activity. Compound 1
showed potent activity against Candida albicans and Cryptococcus
neoformans, two major opportunistic pathogens associated with
AIDS patients (Table 1). Of particular significance is its strong
activity against fluconazole-resistant C. albicans strains isolated
from patients during fluconazole therapy.5 In the isolates showing
up to a 400-fold less susceptibility to fluconazole, 1 retained
equivalent activity relative to the susceptible strains (Table 2). It
is important to note that O-methylation of the enolic hydroxyl group
plays a key role in the antifungal activity of coruscanone A when
compared to coruscanone B.
Natural cyclopentenediones with structures similar to that of
coruscanone A comprise only a few compounds with limited
distributions.6 Recently, a synthetic analogue of this unique class,
2-(1-methoxy-3-phenyl-2-propenylidene)cyclopent-4-ene-1,3-
dione (6), was identified as a potent inhibitor of human chymase,
a potential drug target associated with cardiovascular diseases and
chronic inflammation following fibrosis.7 The synthesis of 6 was
inspired by the natural product methyllinderone (7),6a a moderate
inhibitor of the enzyme identified from the screening of a compound
library.7 More recently, methyllucidone (8a, 8b) isolated from
Lindera erythrocarpa was reported to have moderate antifungal
activity against wheat leaf rust caused by Puccinia recondite.8
Although the cyclopent-4-ene- and cyclopentane-1,3-dione structural
moieties are present in a number of synthetic compounds with
therapeutic applications or potential,9 the 2-methoxymethylenecy-
clopent-4-ene-1,3-dione moiety that is responsible for the activity
of coruscanone A is an unexplored functional group for antifungal
activity against C. albicans and Cr. neoformans.
References
(1) (a) Forse´n, S.; Mere´nyi, F.; Nilsson, M. Acta Chem. Scand. 1964, 18,
1208. (b) Ng, S.; Lee, H.-H.; Bennett, G. J. Magn. Reson. Chem. 1990,
28, 337.
(2) Ferreira, D.; Roux, D. G. J. Chem, Soc. Perkin Trans. I 1977, 134.
(3) Clemo, N. G.; Gedge, D. R.; Pattenden, G. J. Chem. Soc., Perkin Trans.
1 1981, 1448.
(4) (a) Li, X.-C.; ElSohly, H. N.; Nimrod, A. C.; Clark, A. M. J. Nat. Prod.
1999, 62, 767. (b) Li, X.-C.; Jacob, M. A.; ElSohly, H. N.; Nagle, D. G.;
Smillie, T. J.; Walker, L. A. Clark, A. M. J. Nat. Prod. 2003, 69, 1132.
(5) (a) Marr, K. A., Lyons, C. N.; Rustad, T.; Bowden, R. A.; White, T. C.
Antimicrob. Agents Chemother. 1998, 42, 2584. (b) White T. C. Antimi-
crob. Agents Chemother. 1997, 41, 1482. (c) Pfaller, M. A.; Rhine-
Chalberg, J.; Redding, S. W.; Smith, J.; Farinacci, G.; Fothergill, A. W.;
Rinaldi, M. G. J. Clin. Microbiol. 1994, 32, 59.
(6) (a) Kiang, H. H.; Sim, K. Y. J. Chem. Soc. 1962, 4338. (b) Lee, H. H.
Tetrahedron Lett. 1968, 4243. (c) Liu, S. Y.; Ogihara, Y. Yakugaku Zasshi
1975, 95, 114. (d) Leong, Y.-W.; Harrison, L. J.; Bennett, G. J.; Kadir,
A. A.; Connolly, J. D. Phytochemistry 1998, 47, 891.
(7) Aoyama, Y.; Konoike, T.; Kanda, A.; Naya, N.; Nakajima, M. Bioorg.
Med. Chem. Lett. 2001, 11, 1695.
(8) Choi, Y. H.; Kwon, S. Y.; Kim, J. H.; Beak, N. I.; Choi, G. J.; Cho, K.
Y.; Lee, B. M. Han’guk Nonghua Hakhoechi 2003, 46, 151.
(9) (a) Grohe, K.; Frohberger, P. E.; Scheinpflug, H. DE 2248819, 1974. (b)
Inayama, S.; Mamoto, K.; Shibata, T.; Hirose, T. J. Med. Chem. 1976,
19, 433. (c) Kawada, H.; Hayashi, S.; Kasugai, A.; Shigematsu, T. JP
52079022, 1977. (d) Simonov, V. V.; Anishchenko, A. F.; Popova, E.
N.; Dunaeva, T. P.; Gazizov, R. T.; Simonov, V. D. DE 2804271, 1978.
(e) Iwataki, I.; Shibuya, M.; Nakada, A.; Mizuno, M. JP 53101336, 1978.
(f) Kobayashi, E.; Koyama, N.; Kato, I. PCT Int. Appl., WO 9904777,
1999. (g) Shestak, P.; Novikov, V. L.; Stekhova, S. I.; Gorshkova, I. A.
Pharm. Chem. J. 1999, 33, 18. (h) Hori, H.; Nagasawa, H.; Ishibashi,
M.; Uto, Y.; Hirata, A.; Saijo, K.; Ohkura, K.; Kirk, K. L.; Uehara, Y.
Bioorg. Med. Chem. 2002, 10, 3257.
(10) (a) Voet, D.; Voet, J. B.; Pratt, C. W. Fundamentals of Biochemistry;
Wiley: New York. 1999. (b) Adams, R. D.; Miao, S. J. Am. Chem. Soc.
2004, 126, 5056.
(11) (a) Odds, F. C. Int. J. Stand. AIDS 1992, 3, 157. (b) Coleman, D. C.;
Bennett, D. E.; Sullivan, D. J.; Gallagher, P. J.; Henman, M. C.; Shanley,
D. B.; Russell, R. J. Crit. ReV. Microbiol. 1993, 19, 61.
(12) Agarwal, A. K.; Rogers, P. D.; Baerson, S. R.; Jacob, M. R.; Barker, K.;
Cleary, J. D.; Walker, L. A.; Nagle, D. G., Clark, A. M. J. Biol. Chem.
2003, 278, 34998.
It is extremely rare to find a natural product like coruscanone A
that exhibits such a high antifungal potency against C. albicans.
JA048081C
9
J. AM. CHEM. SOC. VOL. 126, NO. 22, 2004 6873