34
Müller and Breu
ether (25 mL) was cooled on an ice/NaCl bath to 0 °C. Ethyl chloroformate
(1.09 g, 10 mmol) was added slowly under stirring, and the temperature was
kept at 0 °C. Then the mixture was warmed to room temperature within 1 h
and filtered. The filtrate was washed with a solution of NaHCO3 (0 °C) and
then with water, dried over MgSO4, and evaporated. The crude N-acetyl-L-
phenylalanoylethylcarbonate (1.53 g, 5.50 mmol) in absolute acetone
(10 mL) was used in the subsequent acylation of 1 in acetone (48 h, room
temperature), as described for 2a. Purification by chromatography
(CH2Cl2/Et2O 9/1) afforded 2b as yellow crystals (10%): mp 162–164 °C;
1H-NMR (250 MHz, CDCl3) δ 12.63, 12.15 (2 × s, 2H, OH), 7.68–6.74 (m,
11H, Ar), 6.18, 5.43 (2 × d, J = 8 Hz, 1H, NH), 5.37, 4.39 (2 × s, 1H, 10-H),
the corresponding solvents. Our finding is that N-protected
2c is considerably more stable than anthralin, whereas depro-
tection (2e) dramatically decreased stability. For 2c and an-
thralin, decomposition was more favored in the protic solvent
ethanol than in the aprotic DMSO while 2e was also slightly
faster degraded in DMSO. Moreover, decomposition of 2c
resulted in formation of the corresponding anthracenedione,
dantron, as also observed with other 10-acylated an-
[28]
thracenones
. However, degradation products of 2e are
anthralin and the anthralin dimer, precursors of anthralin-
brown, which is somewhat unfortunate.
5.33–5.25, 5.11–5.02 (2 × m, 1H, CH), 3.57–3.49, 2.91–2.82 (2 × q, JAB
=
14 Hz, JBX = 7 Hz, 1H, HCH), 3.40–3.31, 2.74–2.65 (2 × q, JAB = 14 Hz, JAX
= 7 Hz, 1H, HCH), 2.17, 1.78 (2 × s, 3H, Me); FTIR 3363 (NH), 1763 (CON),
1717 (CO), 1630 cm–1 (CO HO). Anal. (C25H21NO5) C, H, N.
...
Conclusions
We have synthesized a small series of 10-α-aminoacyl-1,8-
dihydroxy-9(10H)-anthracenones and have determined their
biological activity in various assays. Appendage of an amino
acid group to anthralin results in an interesting in vitro profile.
Based on this limited data set, we found that the ability of the
compounds to inhibit 12(S)-HETE biosynthesis is quite vari-
able in this series, whereas their capacity to inhibit the growth
of keratinocytes is consistently high. With respect to both of
these features, analogue 2a is equipotent to anthralin and
compares favorably in further tests with this antipsoriatic
drug. In particular, hydroxyl-radical generation by 2a is
largely reduced and damage to cell membrane was not ob-
served at concentrations necessary forpotentantiproliferative
action. However, the observation that an α-aminoacyl substi-
tuent at the 10-position of the molecules only slightly in-
creases the stability as compared to anthralin is somewhat
disappointing.
1,8-Dihydroxy-10-[2-(1,1-dimethylethoxycarbonylamino)-1-oxo-3-phenyl-
propyl]-9(10H)-anthracenone (2c)
To a solution of 1 (1.00 g, 4.42 mmol) in absolute acetone (160 mL) under
N2 were added triethylamine (0.66 mL, 4.75 mmol) and Boc-L-phenylalan-
ine-N-carboxyanhydride (3.81 g, 12 mmol, Fluka), and the mixture was
stirred for 12 h under N2. Then the mixture was concentrated, and the residue
was purified by chromatography (CH2Cl2) to afford 2c as a yellow powder
(44%): mp 147–149 °C; 1H-NMR (CDCl3) δ 12.27 (s, 2H, OH), 7.50–6.71
(m, 11H, Ar), 5.38 (s, 1H, 10-H), 4.73–4.33 (m, 2H, CHNH), 2.87 (m, 2H,
CH2), 1.29 (s, 9H, tert-Bu); FTIR 3349 (NH), 1726 (CO), 1696 (OCONH),
•
+
1630 cm–1 (CO HO). MS m/z 400 (2) (M - Otert-Bu) , 226 (100). Anal.
...
(C28H27NO6) C, H, N.
1,8-Dihydroxy-10-[2-(1,1-dimethylethoxycarbonylamino)-1-oxopropyl]-9
(10H)-anthracenone (2d)
2d waspreparedfromBoc-L-alanine-N-carboxyanhydride as described for
2c. Purification by chromatography (CH2Cl2/Et2O 95/5) afforded 2d as a
1
yellow powder (25%): mp 150–151 °C; H-NMR (CDCl3) δ 12.24 (s, 2H,
OH), 7.63–6.88 (m, 6H, Ar), 5.47 (s, 1H, 10-H), 4.83–4.40 (m, 2H, CHNH),
1.39 (s, 9H, tert-Bu), 1.09 (d, J = 7 Hz, 3H, Me); FTIR 3363 (NH), 1725
(CO), 1674 (OCONH), 1632 cm–1 (CO HO). PI-FDMS m/z 397 (M+•).
...
Anal. (C22H23NO6) C, H, N.
Experimental Part
Melting points: Büchi 510 melting point apparatus (uncorrected). 1H-
NMR: Varian EM 390 (90 MHz) or Bruker Spectrospin WM 250 spectrome-
ter (250 MHz). Fourier-transform IR spectra (KBr): Nicolet 510M FTIR
spectrometer. UV spectra: Kontron 810 spectrometer. Mass spectra (EI,
unless otherwise stated): Varian MAT CH5 spectrometer (70 eV). HPLC:
Kontron 420, 735 LC UV detector, 250- × 4-mm column (4- × 4-mm
precolumn), LiChrospher 100 RP18 (5-µm particles; Merck, Darmstadt,
Germany). Data recording and analysis: MacLab data acquisition system
(WissTech, Germany), software Peaks (Apple Macintosh computer). Chro-
matography refers to column chromatography on silica gel (E. Merck,
70–230 mesh).
10-(2-Amino-1-oxo-3-phenylpropyl)-1,8-dihydroxy-9(10H)-anthracenone
Hydrochloride (2e)
To a solution of 2c (0.10 g, 0.21 mmol) in ethyl acetate (8 mL) was added,
dropwise over 30 min, 36% HCl (1 mL). The mixture was stirred until the
reaction was completed (TLC control). Then the solvent was evaporated, and
the residue was digested with small amounts of ether and filtered by suction
1
to afford 2e as a yellow powder (81%): mp 191–192 °C (dec); H-NMR
(CD3OD) δ 7.65–6.97 (m, 11H, Ar), 4.76 (q, JAX = 9.5 Hz, JMX = 5 Hz, 1H,
CH), 3.56 (q, JAM = 14.5 Hz, JMX = 5 Hz, 1H, HCH), 2.86 (q, JAM = 14.5 Hz,
JAX = 9.5 Hz, 1H, HCH), 10-H, 1,8-(OH)2, NH2 exchanged; FTIR 2855
(NH3+), 1721 (CO), 1630 cm–1 (CO HO). PI-LISIMS (DMSO, glycerol)
...
m/z 452 (M+H++DMSO), 374 M+H+). Anal. (C23H20ClNO4) C, H, N.
10-(2-Benzyloxycarbonylamino-1-oxo-3-phenylpropyl)-1,8-dihydroxy-
9(10H)-anthracenone (2a)
(2-Amino-1-oxopropyl)-1,8-dihydroxy-10-9(10H)-anthracenone Hydro-
chloride (2f)
To a solution of 1 [29] (1.00 g, 4.42 mmol) in absolute toluene (75 mL) and
dry pyridine (0.43 mL, 5.50 mmol) was added dropwise a solution of
N-benzyloxycarbonyl-L-phenylalanoyl chloride [11] (1.55 g, 5.50 mmol) in
absolute toluene (10 mL) under N2. The reaction mixture was stirred at room
temperature for 12 h, filtered, and the filtrate was evaporated. The residue
was purified by chromatography (CH2Cl2) to afford 2a as a yellow powder
(10%): mp 152–154 °C; 1H-NMR (CDCl3) δ 12.36 (s, 2H, OH), 7.61–6.62
(m, 16H, Ar), 5.34 (s, 1H, 10-H), 4.89–4.56 (m, 4H, CHNH, OCH2),
2.86–2.66 (m, 2H, CH2CH); FTIR 3332 (NH), 1705 (CO), 1674 (OCONH),
2f was preparedbydeprotectionof 2d as described for 2e. Recrystallization
from acetone afforded 2f as yellow crystals (76%): mp 193–194 °C (dec);
1H-NMR (250 MHz, CD3OD) δ 7.63–6.97 (m, 6H, Ar), 4.54 (q, J = 7 Hz,
1H, CH), 1.57 (d, J = 7 Hz, 3H, Me), 10-H, 1,8-(OH)2, NH2 exchanged; FTIR
2925 (NH3+), 1725 (CO), 1630 cm–1 (CO HO). PI-LISIMS (DMSO, glyc-
...
erol) m/z 390 (M+H++glycerol), 298 (M+H+). Anal. (C17H16ClNO4) C, H,
N.
1630 cm–1 (CO HO). Anal. (C31H25NO6) C, H, N.
...
Degradation of 2-Deoxy-D-ribose
10-(2-Acetylamino-1-oxo-3-phenylpropyl)-1,8-dihydroxy-9(10H)-anthra-
cenone (2b)
Mixed-anhydride coupling method:[13] A solution of N-acetyl-L-phenyl-
alanine (2.07 g, 10 mmol) and triethylamine (1.01 g, 10 mmol) in absolute
The deoxyribose assay was conducted as described [30]. The reaction
mixtures contained the following reagents at the final concentrations stated:
0.3 mL of KH2PO4-KOH buffer, pH 7.4 (30 mM), 0.2 mL of H2O (double
distilled), 0.2 mL of 2-deoxy-D-ribose (2 mM), 0.2 mL of FeCl3•6H2O
Arch. Pharm. Pharm. Med. Chem. 332, 31–35 (1999)