Journal of Medicinal Chemistry
Brief Article
H), 3.70 (s, 2 H), 2.66−2.57 (m, 1 H), 2.51−2.39 (m, 2 H), 2.19 (s, 3
H), 2.07−1.90 (m, 2 H), 1.73−1.47 (m, 4 H), 1.29−1.08 (m, 1 H),
0.90 and 0.89 (2 d, J = 6.4 Hz, 3 H, CH3 of two diastereomers). 13C
NMR δ 163.7, 163.6, 163.0, 161.8, 156.5, 133.0, 129.9, 129.7, 115.9,
109.1, 100.1, 97.5, 79.7, 79.65, 53.5, 52.8, 52.7, 39.2, 38.8, 38.7, 37.2,
37.1, 36.8, 32.4, 32.3, 31.0, 28.4, 20.2, 14.7, 14.6. MS (electrospray
discovery of carbazole analogs as small molecule inhibitors of Aβ
oligomer-induced cytotoxicity. Brain Res. 2007, 1130, 223−234.
(5) Jin, L.-W.; Shie, F. S; Maezawa, I.; Vincent, I.; Bird, T.
Intracellular accumulation of amyloidogenic fragments of amyloid-beta
precursor protein in neurons with Niemann−Pick type C defects is
associated with endosomal abnormalities. Am. J. Pathol. 2004, 164,
975−985.
(6) Hong, H. S.; Rana, S.; Barrigan, L.; Shi, A.; Zhang, Y.; Zhou, F.;
Jin, L.-W.; Hua, D. H. Inhibition of Alzheimer’s amyloid toxicity with a
tricyclic pyrone molecule in vitro and in vivo. J. Neurochem. 2009, 108,
1097−1108.
(7) Wolozin, B. Cholesterol and the biology of Alzheimer’s disease.
Neuron 2004, 41, 7−10.
(8) Patel, N. V.; Forman, B. M. Linking lipids, Alzheimer’s and
LXRs? Nucl. Recept. Signaling 2004, 2, e001.
(9) Fukumoto, H.; Deng, A.; Irizarry, M. C.; Fitzgerald, M. L.;
Rebeck, G. W. Induction of the cholesterol transporter ABCA1 in
central nervous system cells by liver X receptor agonists increases
secreted Abeta levels. J. Biol. Chem. 2002, 277, 48508−48513.
(10) Kim, W. S.; Chan, S. L.; Hill, A. F.; Guillemin, G. J.; Garner, B.
Impact of 27-hydroxycholesterol on amyloid-beta peptide production
and ATP-binding cassette transporter expression in primary human
neurons. J. Alzheimer’s Dis. 2009, 16, 121−131.
+
ionization) m/z 382.4 (M + H+), 276.5. HRMS calcd for C23H28NO4
(M + H+), 382.2018; found, 382.2013.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and spectroscopic data for com-
pounds 2−6, detailed protocols for MC65 cells assay, inhibition
of ACAT, and upregulation of ABCA1. This material is
AUTHOR INFORMATION
Corresponding Author
*Phone: (785)532-6699. Fax: (785)532-6666. E-mail: duy@
■
Author Contributions
(11) Mahley, R. W.; Weisgraber, K. H.; Huang, Y. Apolipoprotein E4:
a causative factor and therapeutic target in neuropathology, including
Alzheimer’s disease. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 5644−
5651.
(12) Puglielli, L.; Tanzi, R. E.; Kovacs, D. M. Alzheimer’s disease: the
cholesterol connection. Nature Neurosci. 2003, 6, 345−351.
(13) Huttunen, H. J.; Kovacs, D. M. ACAT as a drug target for
Alzheimer’s disease. Neurodegener. Dis. 2008, 5, 212−214.
(14) Hutter-Paier, B.; Huttunen, H. J.; Puglielli, L.; Eckman, C. B.;
Kim, D. Y.; Hofmeister, A.; Moir, R. D.; Domnitz, S. B.; Frosch, M. P.;
Windisch, M.; Kovacs, D. M. The ACAT inhibitor CP-113,818
markedly reduces amyloid pathology in a mouse model of Alzheimer’s
disease. Neuron 2004, 44, 227−238.
(15) Schmitz, G.; Robenek, H.; Beuck, M.; Krause, R.; Schurek, A.;
Niemann, R. Ca+2 antagonists and ACAT inhibitors promote
cholesterol efflux from macrophages by different mechanisms. I.
Characterization of cellular lipid metabolism. Arterioscler. Thromb.
Vasc. Biol. 1988, 8, 46−56.
(16) Hua, D. H.; Huang, X.; Tamura, M.; Chen, Y.; Woltkamp, M.;
Jin, L.-W.; Perchellet, E. M.; Perchellet, J. P.; Chiang, P. K.;
Namatame, I.; Tomoda, H. Syntheses and Bioactivities of Tricyclic
Pyrones. Tetrahedron 2003, 59, 4795−4803.
(17) Pokhrel, L.; Kim, Y.; Nguyen, T. D. T.; Prior, A. M.; Lu, J.;
Chang, K.-O.; Hua, D. H. Synthesis and anti-norovirus activity of
pyranobenzopyrone compounds. Bioorg. Med. Chem. Lett. 2012, 22,
3480−3484.
(18) Nicolaou, K. C.; Montagnon, T.; Baran, P. S.; Zhong, Y.-L.
Iodine(V) reagents in organic synthesis. Part 4. o-Iodoxybenzoic acid
as a chemospecific tool for single electron transfer-based oxidation
processes. J. Am. Chem. Soc. 2002, 124, 2245−2258.
(19) Kemp, S. J.; Storey, L. J.; Storey, J. M. D.; Richard, J.;
Harrington, C. R.; Wischik, C. M.; Clunas, S.; Heinrich, T. K.
Preparation of benzothiazole, imidazothiazole, imidazopyrimidine and
imidazopyridine compounds as ligands for aggregated tau molecules
useful in diagnosis, prognosis and treatment of diseases. PCT Int.
Appl. WO 2010034982 A1 20100401, 2010.
Professors Hua, Jin, and Chang directed and designed the
chemistry and biological chemistry. L. Pokhrel and T.D.T.
Nguyen carried out the chemical synthesis, Dr. Maezawa
conducted the MC65 cell assays, and Dr. Chang performed the
inhibition of ACAT and expression of ABCA1 transporter gene.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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We thank Mahendra Thapa for technical assistance with the
synthesis of compounds 6a and 6b. This work was generously
supported by the NIH grant R01 AG025500 to D.H.H. and
L.W.J. and U01 AI081891 and K-INBRE 5P20RR016475−11
to K.O.C. and D.H.H.
ABBREVIATIONS USED
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AβO, amyloid beta oligomers; ACAT, acyl-CoA:cholesterol
acyltransferase; ABCA1, ATP-binding cassette subfamily A
member 1; AD, Alzheimer’s disease; APP, amyloid precursor
protein; APOE, apolipoprotein E; CE, cholesteryl ester; DMF,
N,N-dimethylformamide; DMSO, dimethyl sulfoxide; EDC, 3-
(3-dimethylaminopropyl)-1-ethylcarbodiimide hydrochloride;
IBX, 2-iodoxybenzoic acid; IC50, inhibition concentration at
50%; LXR, liver X receptor; MTT, 3-(4,5-dimethylthiazol-2-yl)-
2,5-diphenyltetrazolium bromide; NBD, 25-[N-[(7-nitro-2-1,3-
benzoxadiazol-4-yl)methyl]amino]-27-norcholesterol; NHS, N-
hydroxysuccinimide; TC, tetracycline; TP, tricyclic pyrone
REFERENCES
■
(1) Reitz, C. Alzheimer’s disease and the amyloid cascade hypothesis:
a critical review. Int. J. Alzheimer’s Dis. 2012, article ID 369808, 11 pp.
(2) Jin, J.-W.; Hua, D. H.; Shie, F.-S.; Maezawa, I.; Sopher, B.;
Martin, G. M. Novel tricyclic pyrone compounds prevent intracellular
APP C99-induced cell death. J. Mol. Neurosci. 2002, 19, 57−61.
(3) Maezawa, I.; Hong, H.-S.; Wu, H.-C.; Battina, S. K.; Rana, S.;
Iwamoto, T.; Radke, G. A.; Pettersson, E.; Martin, G. M.; Hua, D. H.;
Jin, L. W. A novel tricyclic pyrone compound ameliorates cell death
associated with intracellular amyloid-beta oligomeric complexes. J.
Neurochem. 2006, 98, 57−67.
(20) Mak, C. C.; Bampos, N.; Darling, S. L.; Montalti, M.; Prodi, L.;
Sanders, J. K. M. A strategy for the assembly of multiple porphyrin
arrays based on the coordination chemistry of Ru-centered porphyrin
pentamers. J. Org. Chem. 2001, 66, 4476−4486.
(21) Meyer, E.; Joussef, A. C.; Gallardo, H.; de Souza, L. de B. P.
Synthesis of new 4,5-dihydro-3(2H)-pyridazinone derivatives. Synth.
Commun. 2004, 34, 783−793.
(22) Silva, P. L.; Pires, P. A. R.; Trassi, M. A. S.; El Seoud, O. A.
Solvation in pure liquids: what can be learned from the use of pairs of
indicators? J. Phys. Chem. B 2008, 112, 14976−14984.
(4) Hong, H.-S.; Maezawa, I.; Yao, N.; Diaz-Avalos, R.; Rana, S.; Hua,
D. H.; Cheng, R. H.; Lam, K. S.; Jin, L.-W. Combining the rapid MTT
formazan exocytosis assay and the MC65 protection assay led to the
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dx.doi.org/10.1021/jm3012189 | J. Med. Chem. 2012, 55, 8969−8973