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1,2,3,4-Tetrahydro-6,7-dimethoxy-2-((6-methoxy-2H-chromen-3-
yl)methyl)isoquinoline (11): Purification by column chromatogra-
phy (CHCl3/EtOAc, 9:1) gave a yellow solid (34%); mp: 2388C
Further experiments are in progress to confirm 13 as a P-gp
stimulator able to cause b-amyloid efflux.
The apparent discrepancy between the modulating activity
shown by compound 13 in the calcein-AM assay and the stim-
ulator profile displayed in our everted gut sac assay can be ex-
plained by considering that the ex vivo model is a more com-
plex system where other pumps are involved in the final
effect, whereas in the in vitro assay only P-gp interactions are
measured. Therefore, the in vitro method is useful to deter-
mine the potency of the tested compounds, while the ex vivo
model is more predictive of the final physiological effect.
The present study provides evidenced that b-benzopyrane
derivative 13 is a potent P-gp ligand with increased selectivity
for P-gp over the MRP1 pump when compared with the lead
compound MC18. However, initial results indicate that 13 is a
P-gp inducing agent, whereas MC18 is a potent P-gp inhibitor.
This is an important finding because a potential application of
P-gp stimulators is the treatment of AD, since in vitro studies
have shown that b-amyloid is a P-gp substrate, and conse-
quently that P-gp is involved in the clearance of b-amyloid
from both healthy (aging) and AD cells. Therefore, restoration
of P-gp activity by stimulators in situations where P-gp activity
or expression is decreased, such as Parkinson’s and Alzheimer’s
diseases, could be a new perspective in the therapy of these
disorders.
1
(dec); H NMR (300 MHz, CDCl3): d=6.80–6.50 (m, 5H), 6.38 (s, 1H),
4.79 (s, 2H), 3.95–3.87 (m, 9H), 3.59 (s, 2H), 3.22 (s, 2H), 2.92–
2.71 ppm (m, 4H); GC–MS: m/z (%): 367 [M+] (1.3), 174 (100); Anal.
calcd for C22H25O4N·HCl·0.5H2O: C 63.99, H 6.59, N 3.47; found: C
63.38, H 6.30, N 3.33.
(3,4-Dihydro-6,7-dimethoxyisoquinolin-2(1H)-yl)(3,4-dihydro-6-
methoxy-2H-chromen-3-yl)methanone (12): Purification by
column chromatography (CHCl3/EtOAc, 19:1) gave a white waxy
1
solid (38%); H NMR (300 MHz, CDCl3): d=6.81–6.58 (m, 5H), 4.7 (s,
2H), 4.41–4.33 (m, 1H, OCH), 4.21–4.18 (m, 1H), 3.91–3.72 (m,
11H), 3.31–3.29 (m, 2H), 2.90–2.78 ppm (m, 3H); GC–MS: m/z (%):
383 [M+] (100), 192 (53.3).
1,2,3,4-Tetrahydro-2-((3,4-dihydro-6-methoxy-2H-chromen-3-yl)-
methyl)-6,7-dimethoxyisoquinoline (13): Purification by column
chromatography (CHCl3) gave a white solid (84%); mp: 222–
1
2248C; H NMR (300 MHz, CDCl3): d=6.90–6.58 (m, 5H), 3.92–3.88
(m, 1H) 4.32–4.22 (m, 1H), 3.84–3.72 (m, 9H), 3.61 (s, 2H), 2.34–
3.05 ppm (m, 9H); GC–MS: m/z (%): 369 [M+] (12.7), 206 (100);
Anal. calcd for C22H27O4N·HCl: C 65.10, H 6.95, N 3.45; found: C
65.00, H 6.96, N 3.49.
Acknowledgements
This study was supported by research Grant PRIN 20097FJHPZ_
001 from MIUR (Italy) for the scientific program in CHIM/08 field.
Experimental Section
Keywords: alzheimer’s disease · benzopyranes · everted gut
Compound 3 was prepared as reported in Ref. [18], and com-
pounds 7–9 were synthesized as reported in Ref. [19]. All charac-
terization data were in accordance with those previously report-
ed.[18,19] 1H NMR spectra were recorded in CDCl3 at 300 MHz on a
Varian Mercury-VX Spectrometer. All chemical shift values (d) are
reported in ppm. MS data were collected on an HP6890-5973 MSD
GC–MS instrument
sac assay · multidrug resistance-associated proteins
glycoprotein stimulators
· P-
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6.0 Hz, 2H), 3.88 (s, 3H), 3.60 (t, J=7.0 Hz, 2H), 2.70–2.67 ppm (m,
4H).
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1,2,3,4-Tetrahydro-2-((E)-3-(2,3-dihydro-8-methoxychromen-4-yli-
dene)propyl)-6,7-dimethoxyisoquinoline (5): Purification by
column chromatography (CH2Cl2/MeOH, 19:1) gave a yellow solid
(21%); mp: 223–2248C; 1H NMR (300 MHz, CDCl3): d=6.85–6.50
(m, 5H), 6.05 (t, J=7.0 Hz, 1H), 4.30 (t, J=5.0 Hz, 2H), 3.90–3.62
(m, 11H), 2.90–2.72 (m, 4H), 2.72–2.60 (m, 4H), 2.55–2.45 ppm (m,
2H); GC–MS: m/z (%): 395 [M+] (6.8), 206 (100); Anal. calcd for
C24H29NO4·HCl·H2O: C 64.06, H 7.17, N 3.11; found: C 64.69, H 6.83,
N 3.31.
(3,4-Dihydro-6,7-dimethoxyisoquinolin-2(1H)-yl)(6-methoxy-2H-
chromen-3-yl)methanone (10): Purification by column chromatog-
raphy (petroleum ether/EtOAc, 1:1) gave a yellow waxy solid
(32%); 1H NMR (300 MHz, CDCl3): d=6.82–6.62 (m, 5H), 6.60 (s,
1H), 4.86 (s, 2H), 3.98–4.10 (m, 2H), 4.75 (s, 2H), 3.96 (s, 3H), 3.90
(s, 3H), 3.88 (s, 3H), 2.91–2.80 ppm (m, 2H); GC–MS: m/z (%):
381[M+] (78.6), 192 (100).
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ChemMedChem 2012, 7, 391 – 395