Synthesis of dimeric quinazolin-2-one, 1,4-benzodiazepin-2-one, and isoalloxazine compounds as inhibitors of amyloid peptides association

Article abstract of DOI:10.1002/ardp.200800196

The synthesis of dimeric compounds derived from quinazolin-2-one and 1,4-benzodiazepin-2-one possessing a piperazine or homopiperazine spacer was investigated. In addition, a piperazine spacered bis-isoalloxazine and a bis-riboflavin compound were prepared and their ability to interrupt the association of prion proteins and Alzheimer-specific Aβ peptides was investigated using a fast screening system based on flow cytometry. The bis-isoalloxazine 14 was identified as a new lead structure.

Full text of DOI:10.1002/ardp.200800196

Arch. Pharm. Chem. Life Sci. 2009, 342, 445–452
A. Barthel et al.
445
Full Paper
Synthesis of Dimeric Quinazolin-2-one, 1,4-Benzodiazepin-2-
one, and Isoalloxazine Compounds as Inhibitors of Amyloid
Peptides Association
Alexander Barthel1, Lothar Trieschmann2, Dieter Strꢀhl1, Ralph Kluge1, Gerald Bꢀhm3,
and Renꢁ Csuk1
1 Martin-Luther-Universitꢀt Halle-Wittenberg, Organische Chemie, Halle (Saale), Germany
2
Scil Proteins Production GmbH, Halle (Saale), Germany
3 IGZ BioMed/ZmK Wꢁrzburg, Wꢁrzburg, Germany
The synthesis of dimeric compounds derived from quinazolin-2-one and 1,4-benzodiazepin-2-one
possessing a piperazine or homopiperazine spacer was investigated. In addition, a piperazine
spacered bis-isoalloxazine and a bis-riboflavin compound were prepared and their ability to
interrupt the association of prion proteins and Alzheimer-specific Ab peptides was investigated
using a fast screening system based on flow cytometry. The bis-isoalloxazine 14 was identified as
a new lead structure.
Keywords: Anti-Alzheimer / Antiprion / 1,4-Benzodiazepin-2-one / Isoalloxazine / Quinazolin-2-one /
Received: October 30, 2008; accepted: March 16, 2009
DOI 10.1002/ardp.200800196
Introduction
The aggregation of b-sheet-enriched proteins in the cen-
tral nervous system is a common process in a variety of
neurodegenerative diseases, finally leading to a loss of
neuronal tissue. Consequently, memory and cognitive
skills decrease in the course of these diseases. Well
known examples are the Alzheimer disease (AD), which
affects more than 24 million people worldwide, and
prion-based diseases like Creutzfeld–Jakob disease (CJD),
Kuru, or the Gerstmann–Strꢀussler–Scheinker syn-
drome in humans, and BSE in cattle. In persons suffering
from Alzheimer, Ab-peptides consisting of 39-42 amino
Scheme 1. Inhibitors of peptide - protein association.
acids are deposited. They are released from the cellular
APP protein by action of b- and c-secretase. In contrast to
AD, in prion-based diseases the generation of the b-sheet-
enriched proteins is not provoked by enzymes. The cellu-
lar prion protein PrPc is refolded into the pathogenic
form PrPSc spontaneously or this process is catalyzed by
already misfolded species. Additional factors for prion
propagation have been discussed.
During the last decade, different compounds have
been investigated as potential therapeutics acting as
inhibitors of these association processes. Prominent
examples are curcumin I for Alzheimer-specific Ab-pepti-
des and congo red II [1] or the dimeric acridine com-
pounds III [2] for prion proteins (Scheme 1). The binding
of the acridine-derived compounds involves – among
Correspondence: Prof. Dr. Renꢂ Csuk, Bereich Organische Chemie,
Martin-Luther-Universitꢀt Halle-Wittenberg, Kurt-Mothes-Strasse 2, D-
06120 Halle (Saale), Germany.
E-mail: rene.csuk@chemie.uni-halle.de
Fax: +49 345 552-7030
Abbreviation: flow cytometry assay (FACS)
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Arch. Pharm. Chem. Life Sci. 2009, 342, 445–452
Results and discussion
Quite recently, we became interested in the synthesis of
dimeric heterocyclic compounds possessing piperazine
or homopiperazine spacer units. Hereby, we focused on
quinazolin-2-one and the 7-membered ring analogue 1,4-
benzodiazepin-2-one as interacting segments. In addi-
tion, the synthesis of a piperazine spacered isoalloxazine
14 and a related riboflavin-derived compound 17 was
investigated. The screening for their anti-prion and anti-
Alzheimer activity was performed using flow cytometry
(FACS analysis).
Quinazolin-2-one (Scheme 2, 1) can be prepared in a
one-pot synthesis starting from commercially available 2-
amino-5-chlorobenzophenone by its reaction with chlor-
osulfonyl isocyanate [4]. Its 7-membered ring analogue,
1,4-benzodiazepin-2-one (Scheme 2, 2), is also accessible
from this starting material via a three-step synthesis [5].
Reagent and conditions: (i) 1.) ClSO2NCO, DCM, 5 h; 2.) H2O, 5 h; (ii) 1.) chloroace-
tyl chloride TEA, DMAP, 1 h; 2.) KI, CH3CN, 24 h; 3.) (NH4)2CO3, CH3CN, reflux, 10 h.
Scheme 2. Synthesis of quinazolin-2-one 1 and 1,4-benzodiaze-
pin-2-one 2.
other things – the amino acid residues gln227, tyr225,
and tyr226 of the PrP at the C-terminal helix [3], suggest-
ing that p-p interactions are important for the inhibition Thus, 2-amino-5-chlorobenzophenone was allowed to
react with chloroacetyl chloride followed by an exchange
of the chloro-substituent by iodine and a ring-closure
reaction using ammonium carbonate.
Both heterocyclic compounds can be transformed into
the desired bis-derivatives (Scheme 3) by a similar
of the protein association. As already shown, the potency
of the bis-acridines [2] depends on the structure of the
interacting heterocycle as well as on the spacer. However,
best results were observed for the rigid 1,4-bis-(3-amino-
propyl)piperazine spacer.
Reagent and conditions: (i) NaH, DMF, 15 min, 1,3-diiodopropane, 30 min; (ii) piperazine or homopiperazine, NaHCO3, DMF, 408C, 24 h.
Scheme 3. Synthesis route to target compounds 16–18.
Reagent and conditions: (i) Succinic anhydride, TEA, DMAP, DCM, 5 h; (ii) LiAlH4, THF, reflux, 24 h; (iii) 1.) aniline, NaNO2, AcOH, aq. HCl, 58C, 30 min; 2.)
10, aq. NaOH, 108C, 2 h; (iv) barbituric acid, 1,4-dioxane, AcOH, reflux, 5 h; (v) I2, PPh3, imidazole, DCM, 1 h; (vi) piperazine, NaHCO3, DMF, 408C, 24 h.
Scheme 4. Synthesis route to bis-isoalloxazine 14.
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Arch. Pharm. Chem. Life Sci. 2009, 342, 445–452
Inhibitors of Amyloid Peptides Association
447
Reagent and conditions: (i) Ac2O, AcOH, HClO4, 408C, 30 min; (ii) 1,3-diiodopropane, Cs2CO3, DMF, 1 h; (iii) piperazine, NaHCO3, DMF, 408C, 24 h.
Scheme 5. Synthesis of the bis-riboflavin 17.
sequence. The alkylation of the lactame was performed
The bis-riboflavin 17 was obtained in a three-step syn-
using an excess of 1,3-diiodopropane and sodium hydride thesis starting from riboflavin. To increase the solubility
[6], thus affording compounds 3 and 4 in 70% and 62% in organic solvents and to prevent side reaction from the
yield, respectively. For the diazepam derivative possess- D-ribityl side chain, the hydroxy groups were acetylated
ing a 3-iodopropyl chain in equatorial position, two with acetic anhydride in the presence of catalytical
different NMR signals are observed for the ring methyl- amounts of HClO4 [9]. Alkylation with 1,3-diiodopropane
ene group; in addition, the protons of the 3-iodopropyl using Cs2CO3 [10] as a base afforded compound 16; subse-
chain are magnetically unequal. These observations quent reaction with piperazine yielded the desired bis-
probably arise from restricted rotation. Finally, the alky- riboflavin 17. The synthesis of the analogous homopiper-
lation of the piperazine or homopiperazine-moiety was azine compounds, however, failed under these condi-
achieved using NaHCO3 as a base in DMF, affording com- tions.
pounds 5–8. The use of other bases invariantly gave sig-
nificant lower yields due to an increase in elimination
reactions.
Conclusion
Different synthetic approaches have been reported for
the synthesis of isoalloxazines. Following TISHLER'S
Our compounds were investigated for their anti-Alz-
approach [7], our own synthesis started from readily heimer and anti-prion activity using a flow cytometry
available 3,4-dimethylaniline. Acylation using succinic assay (FACS). Using suitable fluorescence-labeled peptides
anhydride followed by reduction with LiAlH4 [8] afforded and proteins, the association of peptides and proteins is
the corresponding amino alcohol 10; its treatment with measured as an appearance of particles with appropriate
phenyl diazonium salt furnished the azo compound 11. side and forward scattering and fluorescence intensities.
By this sequence, the desired 4-(4,5-dimethyl-2-phenyldia- The association can be quantified and the inhibitory
zenium-phenylamino)-1-butanol (11) was obtained in effect of compounds is calculated with reference to stand-
56% yield.
ard association conditions. The ability of our compounds
Finally, 11 was allowed to reacted with barbituric acid to interrupt the addition of fluorescence-marked mono-
to yield the isoalloxazine derivative 12. The hydroxy meric Ab or prion proteins to preformed fibrils was
group was transformed into the corresponding iodinated examined at concentrations of 0.1, 1.0, and 4.0 lM. As a
compound 13 using triphenylphosphane, iodine, and standard, we used the dimeric 6-chlor-2-methoxyacridine
imidazole. In the concluding step, the piperazine moiety derivative III. The quinazolin-2-one and 1,4-dibenzothia-
was alkylated to afford the bis-isoalloxazine 14.
zepin-2-one compounds revealed only a weak inhibitory
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Arch. Pharm. Chem. Life Sci. 2009, 342, 445–452
Table 1. Results of FACS analysis for Ab and PrP.
6-Chloro-4-phenylquinazolin-2(1H)-one 1
To
a solution of 2-amino-5-chlorobenzophenone (10.0 g,
Com-
pound
% of control Ab peptides
(lM)
% of control PrPsc
43.0 mmol) in CH2Cl2 (50 mL) chlorosulfonyl isocyanate (7.3 g,
52.0 mmol) was added dropwise at 08C and stirred for an addi-
tional 5 h at 258C. To the resulting solution H2O (10 mL) was
added and stirring was continued for 5 h. The precipitate was fil-
tered off, washed with H2O (10 mL) and dried in vacuo. Com-
pound 1 (9.4 g, 85%) was obtained as a yellow solid. M.p.: 316–
3178C (lit.: 321–3238C [11], 3188C [12], 316–3188C [13], 3128C
[14]); IR (KBr) m: 2821m, 1780w, 1650s, 1615s, 1591s, 1539m,
1476s, 1458s, 1403m, 1363m, 1338m, 1308m, 1257m, 1177m,
1156w, 1088w, 1073w, 1000m cm-1; 1H-NMR (400 MHz, DMSO-d6)
(lM)
0.1
1.0
4.0
0,1
1.0
4.0
I
5
6
7
8
48
65
66
85
76
45
63
2
61
24
81
78
3
6
77
5
80
75
2
86
85
73
77
71
71
73
46
79
56
73
71
54
66
28
82
72
79
70
36
32
14
17
3
4
d 12.10 (br s, 1H, NH), 7.76 (dd, JH,H = 9.1 Hz, JH,H = 2.5 Hz, 1H,
CH(7)), 7.68–7.65 (m, 2H, CH(29)), 7.62–7.58 (m, 3H, Harom.), 7.52
(d, 4JJH,H = 2.5 Hz, 1H, CH(5)), 7.37 (d, 3JH,H = 9.1 Hz, 1H, CH(8)); 13C-
NMR (100 MHz, DMSO-d6) d: 174.3 (s, C=N), 155.0 (s, C=O), 142.7 (s,
C(8a)), 136.5 (s, C(1')), 135.3 (d, CH(7)), 131.0 (d, CH(49)), 129.4 (d,
CH(29)), 129.0 (d, CH(39)), 127.4 (d, CH(5)), 126.3 (s, C(6)), 118.3 (d,
CH(8)), 115.5 (s, C(5a)); UV-vis (methanol) kmax (loge): 249 nm
(4.48); MS (ESI, MeOH) m/z: 257.1 [M(35Cl) + H]+ (60%), 259.1
[M(37Cl) + H]+ (19%), 279.2 [M(35Cl) + Na]+ (30%), 281.2 [M(37Cl) + Na]+
(10%), 535.1 [M(M(35Cl) + Na)]+ (100%), 537.1 [M(M(37Cl) + Na)]+
(32%).
68
18
effect onto the prion - protein association. For Alzheimer-
specific Ab peptides the homopiperazine-spacered quina-
zolin-2-one derivative 6 showed promising results,
whereas the analogous piperazine compound 5 revealed
only a low potency. This emphasizes the important role
of the spacer. Unfortunately, the 1,4-benzodiazepin-2-one
compounds exhibited only a negligible inhibitory effect
on Ab peptides, suggesting that the planarity of the het-
erocycle is essential. The bis-isoalloxazine compound 14,
however, showed comparable results to the lead struc-
ture I for PrP proteins as well as for Ab peptides. Also the
bis-riboflavine revealed a considerable inhibitory effect
for PrP and at 4 lM also for the Alzheimer-specific Ab pep-
tides.
In summary, the dimeric quinazolin-2-one and 1,4-ben-
zodiazepin-2-one compounds revealed only low activities
as compared to the isoalloxazine and riboflavin-derived
compounds. The latter compounds are comparable to
the potent bis-acridine I, thus rendering them as interest-
ing new lead structures.
7-Chloro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-
one 2
To
a solution of 2-amino-5-chlorobenzophenone (11.35 g,
49.00 mmol), TEA (10 mL) and DMAP (30 mg) in CH2Cl2 (100 mL)
chloroacetyl chloride (5.9 g, 52.00 mmol) was added dropwise at
08C and stirring at 258C was continued for 1 h. The precipitate
was filtered off and washed with CH2Cl2 (100 mL). The filtrate
was washed with aq. Na2CO3 solution (150 mL) and H2O (100 mL),
dried over Na2SO4, and evaporated to dryness. After recrystalliza-
tion from EtOH the intermediary chloro-acetyl compound
(13.7 g, 91%) was obtained as light yellow solid. This intermedi-
ate and KI (18.6 g, 0.1 mol) were dissolved in CH3CN (200 mL)
and stirred at room temperature over night. The solvent was
removed in vacuo and the residue treated with CH2Cl2 (100 mL)
and H2O (100 mL). The phases were separated, the organic layer
was washed with H2O (100 mL), dried over Na2SO4, and concen-
trated in vacuo. A solution of this iodoacetyl compound and
ammonium carbonate (28.8 g, 0.3 mol) in CH3CN (200 mL) was
heated under reflux for 10 h. The solvent was then removed in
vacuo and the residue treated with CH2Cl2 (200 mL) and H2O
(100 mL). The phases were separated, the organic layer was
washed with H2O (100 mL), dried over Na2SO4, and concentrated
under diminished pressure. After purification by column chro-
matography, (silica gel, CH2Cl2 / methanol, 95 : 5) compound 2
(7.0 g, 52%) was obtained as light yellow solid. M.p.: 217–2188C
(lit.: 215–2218C [15], 216-2178C [16]); RF: 0.50 (CH2Cl2 / MeOH,
95 : 5); IR (KBr) m: 3178m, 3042m, 2956w, 2361w, 1683s, 1606s,
1576m, 1509m, 1480s, 1446m, 1385s, 1360s, 1321s, 1285m,
The authors have declared no conflict of interest.
Experimental
General
Melting points are uncorrected (Leica hot stage microscope;
Leica, Wetzlar, Germany), NMR spectra were recorded using the
Varian spectrometers Gemini 200, Gemini 2000, or Unity 500 (d
given in ppm, J in Hz, internal Me4Si; Varian, Palo Alto, CA, USA),
optical rotations were obtained using a Perkin-Elmer 341 polar-
imeter (1 cm micro cell), IR spectra (film or KBr pellet) on a Per-
kin-Elmer FT-IR spectrometer Spectrum 1000 (Perkin Elmer,
USA), MS spectra were taken on a Intectra GmbH (Harpstedt, Ger-
many) AMD 402 (electron impact, 70 eV) or on a Finnigan MAT
TSQ 7000 (electrospray, voltage 4.5 kV, sheath gas nitrogen;
Thermo Electron Corporation, Bremen, Germany) instrument.
TLC was performed on silica gel (Merck 5554; Merck, Darmstadt,
Germany, detection by UV absorption). The solvents were dried
according to usual procedures.
1258m, 1234s, 1194m, 1180w, 1129w, 1098w, 1013m cm– 1; H-
1
NMR (500 MHz, CDCl3) d 9.43 (br s, 1H, NH), 7.52–7.37 (m, 6H,
Harom.), 7.28 (d, 4JH,H = 2.4 Hz, 1H, CH(6)), 7.13 (d, 3JH,H = 8.9 Hz, 1H,
CH(9)), 4.31 (br s, 2H, CH2(3)); 13C-NMR (125 MHz, CDCl3) d 171.7
(s, C=N), 169.8 (s, C=O), 138.7 (s, C(6a)), 137.3 (s, C(9a)), 131.9 (d,
CH(8)), 130.7 (d, CH(49)), 130.6 (d, CH(6)), 129.6 (d, CH(29)), 128.8 (s,
C(19)), 128.5 (s, C(7)), 128.3 (d, CH(39)), 122.6 (d, CH(9)), 56.6 (t,
CH2(3)); UV-vis (methanol) kmax (loge): 246 nm (4.52); MS (ESI,
MeOH) m/z: 271.1 [M(35Cl) + H]+ (100%), 273.1 [M(37Cl) + H]+ (33%).
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Arch. Pharm. Chem. Life Sci. 2009, 342, 445–452
Inhibitors of Amyloid Peptides Association
449
CH(39)), 127.5 (s, C(6)), 116.9 (s, C(5a)), 116.0 (d, CH(8)), 55.2 (t,
CH2(399)), 53.3 (t, piperazine), 42.5 (t, CH2(199)), 24.6 (t, CH2(299)); UV-
vis (methanol) kmax (loge): 252 nm (4.40); MS (ESI, MeOH) m/z:
679.2 [M(2 x35Cl) + H]+ (100%), 681.2 [M(35Cl, 37Cl) + H]+ (64%), 683.2
[M(2637Cl) + H]+ (13%), 701.3 [M(2635Cl) + Na]+ (20%), 703.3
[M(35Cl,37Cl) + Na]+ (13%).
6-Chloro-1-(3-iodopropyl)-4-phenylquinazolin-2(1H)-one
3
To a solution of 1 (6.0 g, 23.4 mmol) in DMF (50 mL), NaH (1.0 g,
60% dispersion in mineral oil, 25.0 mmol) was added in several
portions. After the evolution of hydrogen had ceased, 1,3-diiodo-
propane (10.8 g, 35.0 mmol) was added and and stirring at r.t.
was continued for 30 min. Finally, the solvent was evaporated in
vacuo and the residue purified by column chromatography
(silica gel, ethyl acetate). Compound 3 (7.0 g, 70%) was obtained
as a light yellow solid. M.p.: 177-1788C; RF: 0.75 (ethyl acetate); IR
(KBr) m 2924m, 1723w, 1646s, 1602s, 1538s, 1479m, 1457m,
1364m, 1280m, 1176m, 1103m cm– 1; 1H-NMR (400 MHz, CDCl3)
1,19-(1,4-Diazepane-1,4-diyldipropane-3,1-diyl)bis(6-
chloro-4-phenylquinazolin-2(1H)-one) 6
Compound
6 (0.09 g, 27%) was obtained from 3 (0.50 g,
1.18 mmol) and homopiperazine (49.00 mg, 0.49 mmol) follow-
ing the procedure described for compound 5 as an amorphous
slightly yellowish solid. RF: 0.74 (CH2Cl2 / MeOH, 8 : 2); IR (KBr)
m: 2925m, 1658s, 1606s, 1536s, 1477m, 1362m, 1280m,
4
d: 7.80 (d, JH,H = 2.5 Hz, 1H, CH(5)), 7.72–7.64 (m, 3H, Harom.),
7.57–7.48 (m, 4H, Harom.), 4.37 (t, 3JH,H = 7.0 Hz, 2H, CH2(199)), 3.33
(t, 3JH,H = 6.6 Hz, 2H, CH2(399)), 2.40–2.30 (m, 2H, CH2(299)); 13C-NMR
(100 MHz, CDCl3) d 174.0 (s, C=N), 155.0 (s, C=O), 141.8 (s, C(8a)),
135.8 (s, C(19)), 135.4 (d, CH(7)), 131.0 (d, CH(49)), 129.4 (d, CH(29)),
129.2 (d, CH(39)), 128.5 (d, CH(5)), 127.8 (s, C(6)), 116.9 (s, C(5a)),
115.4 (d, CH(8)), 45.1 (t, CH2(199)), 30.6 (t, CH2(299)), 2.0 (t, CH2(399));
UV-vis (methanol) kmax (loge): 252 nm (4.59); MS (ESI, MeOH) m/z:
424.9 [M(35Cl) + H]+ (100%), 426.9 [M(37Cl) + H]+ (33%), 447.0 [M(35Cl)
+ Na]+ (50%), 449.0 [M(37Cl) + Na]+ (16%).
1103w cm– 1
;
1H-NMR (500 MHz, DMSO-d6) d 7.90 (dd,
4
3JH,H = 9.1 Hz, JH,H = 2.5 Hz, 2H, CH(7)), 7.80 (d, 3JH,H = 9.1 Hz, 2H,
3
CH(8)), 7.66–7.56 (m, 12H, Harom.), 4.27 (t, JH,H = 7.0 Hz, 4H,
CH2(199)), 3.08–2.90 (m, 12H, CH2(399) + homopiperazine), 2.00–
1.86 (m, 6H, CH2(299) + homopiperazine); 13C-NMR (100 MHz,
DMSO-d6) d172.7 (s, C=N), 153.9 (s, C=O), 141.7 (s, C(3)), 135.5 (s,
C(19)), 135.0 (d, CH(7)), 130.4 (d, CH(49)), 128.8 (d, CH(29)), 128.4 (d,
CH(39)), 127.6 (d, CH(5)), 126.0 (s, C(6)), 117.0 (d, CH(8)), 116.1 (s,
C(5a)), 53.9 (t, CH2(399)), 52.9 (t, homopiperazine), 51.4 (t, homopi-
perazine), 41.3 (t, CH2(199)), 24.0 (t, homopiperazine), 23.6 (t, CH2
(299)); UV-vis (methanol) kmax (loge): 252 nm (4.81); MS (ESI,
MeOH): m/z: 693.2 [M(2635Cl) + H]+ (100%), 695.2 [M(35Cl, 37Cl) +
H]+ (67%), 697.2 [M(2637Cl) + H]+ (100%).
7-Chloro-1-(3-iodopropyl)-5-phenyl-1,3-dihydro-2H-1,4-
benzodiazepin-2-one 4
Compound
4 (3.6 g, 62%) was obtained from 2 (3.60 g,
13.30 mmol) following the procedure described for compound 3
as an orange-colored oil. RF: 0.92 (ethyl acetate); IR (KBr) m:
2931w, 1678s, 1607m, 1559m, 1480m, 1446m, 1405m, 1357m,
1322m, 1267m, 1226m, 1191m, 1191m, 1139m, 1100w,
1,19-(Piperazine-1,4-diyldipropane-3,1-diyl)bis(7-chloro-
5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one) 7
1075w cm– 1
;
1H-NMR (400 MHz, CDCl3) d 7.63–7.34 (m, 7H,
Compound
7 (0.1 g, 31%) was obtained from 4 (0.50 g,
4
Harom.), 7.27 (d, JH,H = 2.4 Hz, 1H, CH(6)), 4.78 (d, 2JH,H = 10.4 Hz,
1H, CHa(3)), 4.38 (ddd, JH,H = 13.8 Hz, JH,H = 7.5, 5.8 Hz, 1H,
1.14 mmol) and piperazine (39.20 mg, 0.46 mmol) following the
procedure described for compound 5 as a slightly yellowish
solid. M.p.: 128–1298C; RF: 0.56 (CH2Cl2 / MeOH, 9 : 1); IR (KBr) m:
2937m, 2813m, 2361w, 1735w, 1677s, 1446m, 1608m, 1562w,
1480m, 1446m, 1406m, 1360w, 1323m, 1270m, 1188w, 1139m,
1323m, 1270m, 1188m cm– 1; 1H-NMR (400 MHz, CDCl3) d: 7.60–
2
3
CHa(199)), 3.75–3.68 (m, 2H, CHb(3)
+ CHb(199)), 3.03 (ddd,
3
2JH,H = 10.1 Hz, JH,H = 12.5, 6.1 Hz, 1H, CHa(399)), 2.84 (ddd,
3
2JH,H = 10.1 Hz, JH,H = 8.3, 5.9 Hz, 1H, CHb(399)), 2.20–2.09 (m, 1H,
CHa(299)), 1.94–1.83 (m, 1 H, CHb(299)); 13C-NMR (125 MHz, CDCl3)
d 166.9 (s, C=N), 166.6 (s, C=O), 139.0 (s, C(6a)), 135.5 (s, C(9a)),
129.3 (d, CH(8)), 128.8 (s, C(19)), 128.5 (d, CH(49)), 127.6 (s, C(7)),
127.5 (d, CH(6)), 127.0 (d, CH(29)), 126.2 (d, CH(39)), 121.3 (d, CH(9)),
54.6 (t, CH2(3)), 45.3 (t, CH2(199)), 29.0 (t, CH2(299)), 0.0 (t, CH2(399));
UV-vis (methanol) kmax (loge): 244 nm (4.48); MS (ESI, MeOH) m/z:
311.1 [(M(35Cl) + H) – HI]+ (100%), 313.1 [(M(37Cl) + H) – HI]+ (34%),
461.1 [M(35Cl) + H]+ (100%), 463.1 [M(35Cl) + H]+ (32%).
4
7.34 (m, 14H, Harom.), 7.25 (d, JH,H = 2.4 Hz, 2H, CH(6)), 4.77 (d,
2JH,H = 10.4 Hz, 2H, CHa(3)), 4.30 (ddd, 2JH,H = 13.8 Hz, 3JH,H = 7.5, 2H,
5.8 Hz, CHa(199)), 3.72 (d, 2JH,H = 10.4 Hz, 2H, CHb(3)), 3.64–3.58 (m,
2H, CHb(199)), 2.50–2.20 (m, 12H, CH2(399) + piperazine), 1.83–1.72
(m, 2H, CHa(299)), 1.70–1.60 (m, 2H, CHb(299)); 13C-NMR (100 MHz,
CDCl3) d 169.2 (s, C=N), 168.7 (s, C=O), 140.8 (s, C(6a)), 137.8 (s,
C(9a)), 131.6 (d, CH(8)), 131.3 (s, C(19)), 130.9 (d, CH(49)), 130.0 (s,
C(7)), 129.8 (d, CH(6)), 129.3 (d, CH(29)), 128.5 (d, CH(39)), 123.6 (d,
CH(9)), 57.1 (t, CH2(3)), 54.5 (t, CH2(399)), 51.5 (t, piperazine), 44.5 (t,
CH2(199)), 24.6 (t, CH2(299)); UV-vis (methanol) kmax (loge): 244 nm
(4.73); MS (ESI, MeOH) m/z: 707.2 [M(2 x 35Cl) + H]+ (100%), 709.2
[M(35Cl,37Cl) + H]+ (64%), 711.2 [M(2637Cl) + H]+ (14%).
1,19-(Piperazine-1,4-diyldipropane-3,1-diyl)bis(6-chloro-
4-phenyl-quinazolin-2(1H)-one) 5
A mixture of 3 (0.50 g, 1.18 mmol), piperazine (42.00 mg,
0.49 mmol), and NaHCO3 (0.1 g, 1.2 mmol) in DMF (10 mL) was
heated to 408C for 24 h. The reaction mixture was concentrated
in vacuo and the residue purified by column chromatography
(silica gel, CH2Cl2 / MeOH, 95 : 5). Compound 5 (0.13 g, 40%) was
obtained as an off-white solid. M.p.: A2508C (decomp.); RF: 0.28
(CH2Cl2 / MeOH, 95 : 5); IR (KBr) m: 3039m, 2950m, 1658s, 1605s,
1539s, 1480m, 1460m, 1367m, 1280m, 1200w, 1158w, 1103w,
1014w cm-1;1H-NMR (400 MHz, CDCl3) d 7.79 (d, 4JH,H = 2.5 Hz, 2H,
CH(5)), 7.70–7.66 (m, 6H, Harom.), 7.58–7.50 (m, 8H, Harom.), 4.35 (t,
3JH,H = 7.0 Hz, 4H, CH2(199)), 2.53 (br s, 12H, CH2(399) + piperazine),
2.07–1.97 (m, 4H, CH2(299)); 13C-NMR (100 MHz, CDCl3) d 173.6 (s,
C=N), 155.0 (s, C=O), 142.3 (s, C(8a)), 135.9 (s, C(19)), 135.1 (d,
CH(7)), 130.8 (d, CH(49)), 129.5 (d, CH(29)), 128.9 (d, CH(5)), 128.5 (d,
1,19-(1,4-Diazepane-1,4-diyldipropane-3,1-diyl)bis(7-
chloro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-
one) 8
Compound
8 (0.25 g, 76%) was obtained from 4 (0.50 g,
1.14 mmol) and homopiperazine (45.60 mg, 0.46 mmol) follow-
ing the procedure as described for compound 5 as an amorphous
slightly yellowish solid. RF: 0.70 (CH2Cl2 / MeOH, 9 : 1); IR (KBr)
m: 2925m, 1672s, 1607m, 1480m, 1446m, 1406m, 1322m, 1183m,
1074w cm-1; 1H-NMR (400 MHz, CDCl3) d: 7.63–7.35 (m, 14 H,
4
2
Harom.), 7.26 (d, JH,H = 2.4 Hz, 2H, CH(6)), 4.72 (d, JH,H = 10.4 Hz,
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450
A. Barthel et al.
Arch. Pharm. Chem. Life Sci. 2009, 342, 445–452
2
3
2H, CHa(3)), 4.33 (ddd, JH,H = 13.8 Hz, JH,H = 7.5, 5.8 Hz, 2H,
CHa(199)), 3.73–3.60 (m, 4H, CHb(3) + CHb(199)), 2.76–2.40 (m, 12H,
CH2(399) + homopiperazine), 1.97–1.68 (m, 6H, CH2(299) + homopi-
perazine); 13C-NMR (100 MHz, CDCl3) d 169.4 (s, C=N), 168.7 (s,
C=O), 140.5 (s, C(6a)), 137.6 (s, C(9a)), 131.8 (d, CH(8)), 131.1 (s,
C(19)), 130.9 (d, CH(49)), 130.2 (s, C(7)), 129.8 (d, CH(6)), 129.3 (d,
CH(29)), 128.6 (d, CH(39)), 123.8 (d, CH(9)), 57.1 (t, CH2(3)), 54.5 (t,
CH2(399)), 52.6 (t, homopiperazine), 51.9 (t, homopiperazine), 44.0
(t, CH2(199)), 24.3 (t, CH2(299)), 23.6 (t, homopiperazine); UV-vis
(methanol) kmax (loge): 208 nm (5.19); MS (ESI, MeOH): m/z: 721.2
[M(2635Cl) + H]+ (100%), 723.2 [M(35Cl, 37Cl) + H]+ (63%), 725.2
[M(2637Cl) + H]+ (13%).
nol) kmax (loge): 263 nm (4.04); MS (ESI, MeOH) m/z: 194.2 [M + H]+
(100%), 437.1 [(M(M + Na)]+ (100%).
4-({4,5-Dimethyl-2-[(E)-phenyldiazenyl]phenyl}amino)-
butan-1-ol 11
To a solution of aniline (9.3 g, 0.1 mol) in glacial acetic acid
(150 mL), H2O (21 mL) and conc. hydrochloric acid (21 mL) a solu-
tion of sodium nitrite (6.21 g, 0.09 mol) in H2O (10 mL) was
added at 0–58C and stirring was continued for 15 min. Then, 10
(8.7 g, 45.0 mmol) was added, followed by NaOH (6.00 g,
0.15 mol) in H2O (30 mL) at 0-58C. After stirring for 2 h at 108C,
the reaction mixture was concentrated in vacuo and treated with
diethyl ether (250 mL) and saturated Na2CO3 solution (250 mL).
The phases were separated, the organic layer was washed with
H2O (100 mL) and brine (100 mL). The solution was dried over
Na2SO4 and concentrated in vacuo. The crude material was puri-
fied by column chromatography (silica gel, hexane / ethyl ace-
tate, 3 : 7) and 11 (6.4 g, 48%) was obtained as a red oil. IR (KBr)
m: 2928s, 1627m, 1566s, 1508s, 1458s, 1376s, 1278s, 1173s,
1054m, 1001m cm– 1; 1H-NMR (400 MHz, CDCl3) d: 7.74–7.71 (m,
2H, CH(8')), 7.59 (s, 1H, CH(5)), 7.44–7.42 (m, 2H, 4JHCH(9')), 7.36–
7.32 (m, 1H, CH(109)), 6.57 (s, 1H, CH(2)), 3.72 (t, 3JH,H = 6.2 Hz, 2H,
CH2(19)), 3.30 (t, 3JH,H = 6.6 Hz, 2H, CH2(49)), 2.27 (s, 3H, CH3), 2.22 (s,
3H, CH3), 1.85–1.67 (m, 4H, CH2(29 + 39); 13C-NMR (100 MHz,
CDCl3) d: 153.0 (s, C(79)), 142.5 (s, C(3)), 141.6 (s, C(1)), 134.8 (s,
C(6)), 131.4 (d, CH(5)), 128.9 (d, CH(99+109)), 123.9 (s, C(4)), 121.6 (d,
CH(89)), 112.6 (d, CH(2)), 62.4 (t, CH2(49)), 42.5 (t, CH2(19)), 30.3 (t,
CH2(39)), 25.7 (t, CH2(29)), 20.5 (q, CH3), 18.5 (q, CH3); UV-vis (metha-
nol) kmax (loge): 343 nm (4.24); MS (ESI, MeOH) m/z: 298.1 [M + H]+
(100%), 320.3 [M + Na]+ (70%), 617.0 [M(M + Na)]+ (70%).
4-[(3,4-Dimethylphenyl)amino]-4-oxo-butanoic acid 9
To a solution of 3,4-dimethylaniline (5.0 g, 41.3 mmol), TEA
(10 mL) and DMAP (0.05 g, 0.41 mmol) in CH2Cl2 (100 mL), suc-
cinic anhydride (5.4 g, 54.0 mmol) was added in several por-
tions; then, the mixture was stirred for 5 h at room temperature.
The reaction was quenched by the addition of an aq. saturated
solution of Na2CO3 (100 mL). The phases were separated and the
aqueous layer was washed with CH2Cl2 (100 mL). The product
was precipitated by the addition of hydrochloric acid and col-
lected by filtration. The residue was washed with H2O (2630 mL)
and dried in vacuo. Compound 9 was obtained (8.6 g, 95%) as a
colourless solid. M.p.: 142–1438C (lit.: 143 [17]); IR (KBr) m: 3309s,
3026m, 2931m, 1720s, 1659s, 1616m, 1534s, 1506m, 1448m,
1401s, 1371w, 1354m, 1304w, 1264m, 1236s, 1214w, 1194s,
1156w, 1118w, 1070w, 1020w cm– 1; H-NMR (400 MHz, acetone-
1
d6) d 9.00 (br s, 1H, NH), 7.40 (d, 4JH,H = 2.0 Hz, 1H, CH(2)), 7.35 (dd,
3JH,H = 8.1, JH,H = 2.0 Hz, 1H, CH(4)), 7.00 (d, JH,H = 7.9 Hz, 1H,
CH(5)), 2.67–2.61 (m, 4H, CH2(29 + 39)), 2.19 (s, 3H, CH3), 2.16 (s,
3H, CH3); 13C-NMR (100 MHz, acetone-d6) d: 173.8 (s, C=O(19)),
170.3 (s, C=O(49)), 138.0 (s, C(1)), 137.2 (s, C(3)), 131.8 (s, CH(6)),
130.3 (d, CH(2)), 121.2 (d, CH(4)), 117.5 (d, CH(5)), 30.3 (t, CH2(29 +
39)), 19.9 (q, CH3), 19.0 (q, CH3); UV-vis (methanol) kmax (loge):
263 nm (4.02); MS (ESI, MeOH) m/z: 220.8 [M – H]– (100%), 441.4
[M(M – H)]– (98%).
4
3
10-(4-Hydroxybutyl)-7,8-dimethylbenzo[g]pteridine-
2,4(3H, 10H)-dione 12
A mixture of 11 (4.5 g, 15.0 mmol), barbituric acid (3.8 g,
30.0 mmol) in 1,4-dioxane (50 mL) and glacial acetic acid (8 mL)
was heated under reflux for 5 h. After cooling to room tempera-
ture, the product was filtered off and washed with diethyl ether
until the filtrate was colourless. The crude material was purified
by column chromatography (silica gel, CH2Cl2 / MeOH, 8 : 2) and
afforded compound 12 (2.6 g, 55%) as an orange coloured solid.
M.p.: 305–3068C (lit.: 304–307 [18]); RF: 0.80 (CH2Cl2 / MeOH,
8 : 2); IR (KBr) m: 3511m, 3193m, 3060w, 2940w, 1710s, 1676s,
1582s, 1546s, 1508s, 1462m, 1400w, 1348m, 1320w, 1251m,
4-[(3,4-Dimethylphenyl)amino]butan-1-ol 10
To a suspension of LiAlH4 (2.7 g, 72.0 mmol) and AlCl3 (0.26 g,
2.00 mmol) in THF (50 mL), a solution of 9 (10.7 g, 48.3 mmol) in
THF (50 mL) was added dropwise and heated under reflux for
48 h. After cooling to room temperature, MeOH was added drop-
wise until the evolution of gas had ceased, H2O (20 mL) was
added and the precipitate was filtered off. The residue was
washed thoroughly with CHCl3 (36100 mL). Then, the combined
extracts were washed with brine (100 mL), dried over Na2SO4,
and evaporated to dryness. After column chromatography (silica
gel, hexane / ethyl acetate, 3 : 7) compound 10 (6.7 g, 72%) was
obtained as colourless solid. M.p.: 75–768C; RF: 0.75 (hexane /
ethyl acetate, 3 : 7); IR (KBr) m: 3283s, 3016w, 2950s, 2933s, 2864s,
1613s, 1583w, 1502s, 1479s, 1452m, 1418w, 1383w, 1311m,
1255m, 1227w, 1171m, 1125m, 1105m, 1082s, 1042w,
1
1206w, 1162w, 1104w, 1056w, 1027w cm– 1; H-NMR (400 MHz,
DMSO-d6) d 11.21 (br s, 1H, NH), 7.80 (s, 1H, CH(9)), 7.72 (s, 1H,
CH(6)), 4.53 (t, 3JH,H = 7.5 Hz, 2H, CH2(19)), 3.44 (t, 3JH,H = 6.2 Hz, 2H,
CH2(49)), 2.46 (s, 3H, CH3), 2.34 (s, 3H, CH3); 1.77–1.68 (m, 2H,
CH2(29)), 1.58–1.51 (m, 2H, CH2(39)); 13C-NMR (100 MHz, DMSO-d6)
d 159.9 (s, C=O), 155.7 (s, C=O), 149.9 (s, C=N(1a)), 146.7 (s, C(8)),
136.9 (s, C(6a)), 135.8 (s, C(7)), 133.7 (s, C(9a)), 131.0 (d, CH(9)),
130.6 (s, C=N(4a)), 116.0 (d, CH(6)), 60.4 (t, CH2(49)), 44.1 (t, CH2(19)),
29.3 (t, CH2(29)), 23.4 (t, CH2(39)), 20.2 (q, CH3), 18.8 (q, CH3); UV-vis
(methanol) kmax (loge): 240 nm (4.43); MS (ESI, MeOH) m/z: 315.2
[M + H]+ (20%), 337.2 [M + Na]+ (30%), 651.6 [M(M + Na)]+ (100%).
1023w cm– 1; H-NMR (400 MHz, CDCl3) d 6.92 (d, JH,H = 8.0 Hz,
1
3
4
3
1H, CH(5)), 6.45 (d, JH,H = 2.3 Hz, 1H, CH(2)), 6.39 (dd, JH,H = 8.0,
4JH,H = 2.3 Hz, 1H, CH(6)), 3.73 (t, 3JH,H = 6.0 Hz, 2H, CH2(19)), 2.49 (t,
3JH,H = 6.5 Hz, 2H, CH2(49)), 2.18 (s, 3H, CH3), 2.13 (s, 3H, CH3),
1.70–1.62 (m, 4H, CH2(29+39)); 13C-NMR (100 MHz, CDCl3) d 146.4
(s, C(3)), 137.2 (s, C(1)), 130.2 (d, CH(5)), 125.6 (s, C(6)), 115.0 (d,
CH(2)), 110.6 (d, CH(4)), 62.6 (t, CH2(19)), 44.3 (t, CH2(49)), 30.4 (t,
CH2(29)), 26.2 (t, CH2(39)), 20.0 (q, CH3), 18.6 (q, CH3); UV-vis (metha-
10-(4-Iodobutyl)-7,8-dimethyl-benzo[g]pteridine-2,4(3H,
10H)-dione 13
To a mixture of 12 (2.0 g, 6.4 mmol), iodine (3.4 g, 13.2 mmol)
und imidazole (0.9 g, 1.3 mmol) in CH2Cl2 (100 mL), PPh3 (3.3 g,
12.7 mmol) was added at 08C, stirring was continued for 1 h at
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Arch. Pharm. Chem. Life Sci. 2009, 342, 445–452
Inhibitors of Amyloid Peptides Association
451
3-(3-Iodopropyl)-O29,O39,O49,O59-tetraacetylriboflavin 16
room temperature. The solvent was evaporated and the residue
subjected to column chromatography (silica gel, CH2Cl2 / MeOH,
95 : 5). Compound 13 (1.6 g, 60%) was obtained as an orange col-
oured solid. M.p.: A2008C (decomp.); RF: 0.20 (CH2Cl2 / MeOH,
95 : 5); IR (KBr) m: 3446s, 1717m, 1654s, 1577s, 1538s, 1503m,
To a solution of 15 (5.0 g, 9.0 mmol) and Cs2CO3 (4.5 g,
13.5 mmol) in DMF (50 mL), 1,3-diiodopropane (7.5 g,
25.0 mmol) was added, then stirred for 1 h at room temperature.
The solvent was removed in vacuo, the residue dissolved in
CH2Cl2 (200 mL) and washed with H2O (26100 mL). The organic
layer was dried over Na2SO4 and evaporated to dryness. After
1
1459m, 1350m, 1262m cm– 1; H NMR (400 MHz, CDCl3) d: 9.00
(br s, 1H, NH), 7.99 (s, 1H, CH(9)), 7.49 (s, 1H, CH(6)), 4.70 (br, 2H,
CH2(1')), 3.29 (t, 3JH,H = 6.2 Hz, 2H, CH2(4')), 2.56 (s, 3H, CH3), 2.44 (s,
3H, CH3), 2.05-1.97 (m, 4H, CH2(2'+3')); 13C-NMR (100 MHz, CDCl3)
d: 160.0 (s, C=O), 156.4 (s, C=O), 149.8 (s, C=N(1a)), 148.6 (s, C(8)),
137.3 (s, C(6a)), 135.7 (s, C(7)), 134.8 (s, C(9a)), 131.8 (d, CH(9)),
130.7 (s, C=N(4a)), 115.4 (d, CH(6)), 43.9 (t, CH2(1')), 29.9 (t, CH2(2')),
27.6 (t, CH2(3')), 21.4 (q, CH3), 19.2 (q, CH3), 5.5 (t, CH2(4')); UV-vis
(methanol) kmax (loge): 240 nm (4.59); MS (ESI, MeOH) m/z: 425.0
[M + H]+ (10%), 447.0 [M + Na]+ (20%), 871.0 [M(M + Na)]+ (100%).
purification by column chromatography (silica gel, CH2Cl2
/
MeOH, 95 : 5), compound 16 (4.5 g, 70%) was obtained as an
orange coloured oil. [a]D: 88.28 (c = 4.1, CHCl3); RF: 0.60 (CH2Cl2 /
MeOH, 9 : 1); IR (KBr) m: 2930w, 1747s, 1709s, 1662s, 1587s, 1549s,
1437m, 1372m, 1219s, 1157w, 1092m, 1051m cm-1; 1H-NMR
(400 MHz, CDCl3) d 7.99 (s, 1H, CH(9)), 7.52 (s, 1H, CH(6)), 5.64 (br
s, 1H, CH (29)), 5.44 (dd, 3JH,H = 7.0, 3JH,H = 6.2 Hz, 1H, CH (39)), 5.39
(ddd, 3JH,H = 6.2, 3JH,H = 5.8, 3JH,H = 2.9 Hz, 1H, CH2(49)), 4.90 (br, 2H,
3
CH2(19)), 4.42 (dd, 2JH,H = 12.5, JH,H = 2.9 Hz, 1H, CHa(59)), 4.23 (dd,
3
3
2JH,H = 12.5, JH,H = 5.8 Hz, 1H, CHb(59)), 4.12 (t, JH,H = 7.0 Hz, 2H,
CH2(199)), 3.20 (t, 3JH,H = 7.5 Hz, 2H, CH2(399)), 2.53 (s, 3H, CH3), 2.42
(s, 3H, CH3), 2.33–2.22 (m, 5H, Ac + CH2(299)), 2.20 (s, 3H, Ac), 2.05
(s, 3H, Ac), 1.72 (s, 3H, Ac); 13C-NMR (100 MHz, CDCl3) d 170.3 (s,
C=O), 170.0 (s, C=O), 169.6 (s, C=O), 169.4 (s, C=O), 160.1 (s, C=O),
155.5 (s, C=O), 149.0 (s, C=N(1a)), 147.7 C(8)), 136.7 (s, C(6a)), 135.4
(s, C(7)), 134.8 (s, C(9a)), 132.9 (d, CH(9)), 131.1 (s, C=N(4a)), 115.5
(d, CH(6)), 70.5 (d, CH(39)), 69.5 (d, CH(29)), 69.1 (d, CH(49)), 61.9 (t,
CH2(59)), 44.7 (t, CH2(19)), 42.7 (t, CH2(199)), 32.0 (t, CH2(299)), 21.5 (q,
CH3), 21.0 (q, OAc), 20.7 (q, OAc), 20.6 (q, OAc), 20.3 (q, OAc), 19.4
(q, CH3), 1.6 (t, CH2(399)); UV-vis (methanol) kmax (loge): 240 nm
(4.46); MS (ESI, MeOH) m/z: 713.0 [M + H]+ (20%), 735.0 [M + Na]+
(100%), 1446.2 [M(M + Na)]+ (50%).
10,10'(Piperazine-1,4-diyldibutane-4,1-diyl)bis(7,8-
dimethylbenzo[g]pteridine-2,4(3H,10H)-dione) 14
Compound 14 (0.1 g, 31%) was obtained from 13 (0.50 g,
1.18 mmol) and piperazine (40.40 mg, 0.47 mmol) following the
procedure described for compound 3 as an orange coloured
solid. M.p.: A2508C (decomp.); RF: 0.33 (CH2Cl2 / MeOH, 7 : 3); IR
(KBr) m: 3447m, 1654m, 1578m, 1541s, 1458m, 1400m, 1350m,
1260m, 1008w cm– 1; 1H-NMR (400 MHz, DMSO-d6 + D2SO4) d 7.91
(s, 2H, CH(9)), 7.85 (s, 2H, CH(6)), 4.64 (br, 4H, CH2(1')), 3.48–3.30
(m, 12H, CH2(49) + piperazine), 2.51 (s, 6H, CH3), 2.39 (s, 6H, CH3),
1.86–1.76 (m, 8H, CH2(29+39)); UV-vis (methanol) kmax (loge):
240 nm (4.00); MS (ESI, MeOH) m/z: 679.3 [M + H]+ (100%).
1,4-Bis-[3-(O29,O39,O49,O59-tetraacetylriboflavin-3-
yl)propyl]piperazine 17
Compound 17 (0.2 g, 20%) was obtained from 16 (1.5 g,
2.1 mmol) following the procedure described for compound 2,
followed by column chromatography (silica gel, CH2Cl2 / MeOH,
95 : 5) as an amorphous orange coloured oil. [a]D: 65.68 (c = 3.4,
CHCl3); RF: 0.50 (CH2Cl2 / MeOH, 9 : 1);IR (KBr) m: 2926m, 1749s,
1709m, 1656s, 1587s, 1549s, 1437m, 1372m, 1217s, 1157w,
1049m cm– 1; 1H-NMR (400 MHz, CDCl3) d: 7.99 (s, 2H, CH(9)), 7.52
O29,O39,O49,O59-Tetraacetylriboflavin 15
To a mixture of glacial acetic acid (200 mL) and acetic anhydride
(200 mL), riboflavin (5.0 g, 13.3 mmol) was added followed by
HClO4 (1 mL). The reaction mixture was stirred for 30 min at
40 C, then cooled in an ice bath, diluted with water (400 mL),
and extracted with CHCl3 (3625 mL). The combined organic
extracts were washed with H2O (4625 mL) and brine (25 mL).
The solution was dried over Na2SO4 and evaporated to dryness.
After recrystallisation from EtOH, compound 15 (5.8 g, 80%) was
obtained as an orange colored solid. M.p.: 240–2418C (decomp.)
(lit.: 242 [19], 240 [20], 238–242 [21], 238-239 [22]); [a]D: 119.58 (c =
2.2, CHCl3) (lit.: 80.08 (c = 0.25, 0.1N NaOH) [23]); RF: 0.22 (CH2Cl2 /
MeOH, 95: 5); (IR (KBr) m: 3159w, 3040w, 2813w, 1749s, 1716s,
1663s, 1578s, 1538s, 1508m, 1439w, 1400s, 1374m, 1212s, 1157w,
3
(s, 2H, CH(6)), 5.64 (br s, 2H, CH (2k)), 5.43 (dd, JH,H = 7.0,
3
3
3JH,H = 6.2 Hz, 2H, CH(39)), 5.38 (ddd, JH,H = 6.2, JH,H = 5.8,
3JH,H = 2.9 Hz, 2H, CH2(49)), 4.90 (br, 4H, CH2(19)), 4.41 (dd,
3
2
2JH,H = 12.5, JH,H = 2.9 Hz, 2H, CHa(59)), 4.22 (dd, JH,H = 12.5,
3JH,H = 5.8 Hz, 2H, CHb(59)), 4.10 (t, 3JH,H = 7.0 Hz, 4H, CH2(199)), 3.60
(t, 3JH,H = 6.6 Hz, 4H, CH2(399)), 2.80 (br s, 8H, piperazine), 2.52 (s,
6H, CH3), 2.41 (s, 6H, CH3), 2.24 (s, 6H, Ac), 2.18 (s, 6H, Ac), 1.96–
2.08 (m, 10H, Ac + CH2(299)), 1.71 (s, 6H, Ac); 13C-NMR (100 MHz,
CDCl3) d: 170.5 (s, C=O), 170.2 (s, C=O), 169.8 (s, C=O), 169.6 (s,
C=O), 159.9 (s, C=O), 154.8 (s, C=O), 149.1 (s, C=N(1a)), 147.5 C(8)),
136.6 (s, C(6a)), 135.6 (s, C(7)), 134.7 (s, C(9a)), 133.0 (d, CH(3)),
131.2 (s, C=N(4a)), 115.4 (d, CH(6)), 70.5 (d, CH (39)), 69.3 (d, CH
(29)), 69.1 (d, CH (49)), 61.8 (t, CH2(59)), 55.0 (t, CH2(399)), 44.6 (t,
CH2(19)), 39.7 (t, CH2(199)), 34.8 (t, piperazine), 29.6 (t, CH2(299)), 21.4
(q, CH3), 21.0 (q, OAc), 20.7 (q, OAc), 20.6 (q, OAc), 20.3 (q, OAc),
19.4 (q, CH3); UV-vis (methanol) kmax (loge): 240 nm (4.83); MS
(ESI, MeOH) m/z: 1255.4 [M + H]+ (100%), 1277.4 [M + Na]+ (20%).
1056m cm– 1
;
1H-NMR (400 MHz, CDCl3) d: 8.93 (br s, 1H, NH),
7.96 (s, 1H, CH(9)), 7.52 (s, 1H, CH(6)), 5.62 (br s, 1H, CH (2')), 5.42
3
3
3
(dd, JH,H = 7.0, JH,H = 6.2 Hz, 1H, CH (3')), 5.37 (ddd, JH,H = 6.2,
3
3JH,H = 5.8, JH,H = 2.9 Hz, 1H, CH2(49)), 4.85 (br, 2H, CH2(19)), 4.40
2
3
2
(dd, JH,H = 12.5, JH,H = 2.9 Hz, 1H, CHa(59)), 4.20 (dd, JH,H = 12.5,
3JH,H = 5.8 Hz, 1H, CHb(59)), 2.53 (s, 3H, CH3), 2.40 (s, 3H, CH3), 2.25
(s, 3H, Ac), 2.18 (s, 3H, Ac), 2.04 (s, 3H, Ac), 1.71 (s, 3H, Ac); 13C-
NMR (100 MHz, CDCl3) d 170.5 (s, C=O), 170.1 (s, C=O), 169.7 (s,
C=O), 169.6 (s, C=O), 159.2 (s, C=O), 154.5 (s, C=O), 150.6 (s,
C=N(1a)), 147.9 C(8)), 136.8 (s, C(6a)), 136.0 (s, C(7)), 134.5 (s,
C(9a)), 132.8 (d, CH(9)), 131.1 (s, C=N(4a)), 115.5 (d, CH(6)), 70.5 (d,
CH(39)), 69.4 (d, CH(29)), 69.0 (d, CH(49)), 61.8 (t, CH2(59)), 45.0 (t,
CH2(19)), 21.4 (q, CH3), 21.0 (q, OAc), 20.7 (q, OAc), 20.6 (q, OAc), References
20.3 (q, OAc), 19.4 (q, CH3); UV-vis (methanol) kmax (loge): 240 nm
(4.47); MS (ESI, MeOH) m/z: 545.1 [M + H]+ (30%), 567.1 [M + Na]+
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