Hydrophobicity and glutathione peroxidase-like activity of substituted salicyloyl-5-seleninic acids: Re-investigations on aromatic selenium compounds based on their hydrophobicity

Article abstract of DOI:10.1016/j.jorganchem.2018.02.045

Previously we have shown that some of 5-selenized salicylic acid derivatives exhibit glutathione peroxidase (GPx)-like activities higher than or equal to ebselen [Yu et al., Chem. Eur. J., 2008, 14, 7066; Org. Biomol. Chem., 2010, 8, 828]. For understandi

Full text of DOI:10.1016/j.jorganchem.2018.02.045

Accepted Manuscript
Hydrophobicity and glutathione peroxidase-like activity of substituted salicyloyl-5-
seleninic acids: Re-investigations on aromatic selenium compounds based on their
hydrophobicity
Sun-Chol Yu, Dong-Myong Ri, Hartmut Kühn
PII:
S0022-328X(18)30144-X
10.1016/j.jorganchem.2018.02.045
JOM 20344
DOI:
Reference:
To appear in: Journal of Organometallic Chemistry
Received Date: 17 November 2017
Revised Date: 3 February 2018
Accepted Date: 26 February 2018
Please cite this article as: S.-C. Yu, D.-M. Ri, H. Kühn, Hydrophobicity and glutathione peroxidase-
like activity of substituted salicyloyl-5-seleninic acids: Re-investigations on aromatic selenium
compounds based on their hydrophobicity, Journal of Organometallic Chemistry (2018), doi: 10.1016/
j.jorganchem.2018.02.045.
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ACCEPTED MANUSCRIPT
Hydrophobicity and glutathione peroxidase-like activity of substituted salicyloyl-5-
seleninic acids: re-investigations on aromatic selenium compounds based on their
hydrophobicity
Sun-Chol Yua,b*, Dong-Myong Ria, Hartmut Kühnb
a. Faculty of Pharmacy, Pyongyang Medical College, Kim Il Sung University, Ryomyong Str., Pyongyang, DPR of Korea.
b. Institute of Biochemistry, University Medicine Berlin-Charité, Chariteplatz 1, D-10117 Berlin, Germany
Previously we have shown that some of 5-selenized salicylic acid derivatives exhibit glutathione peroxidase (GPx)-like activities higher than or equal to
ebselen [Yu et al., Chem. Eur. J., 2008, 14, 7066; Org. Biomol. Chem., 2010, 8, 828]. For understanding the absence of GPx-like activity of the homologue of 5-
seleninic anhydride of salicyloylglycine with a loger side chain, we have further synthesized 19 new derivatives (5-seleninic acids of methyl or phenyl
salicylates, N-salicyloyl ω-carboxyalkylamines or N-salicyloyl alkyl/phenyl amines, and some of their diselenides). Some of the 5-seleninic acids which carry
long side chains or cyclohexyl group have exerted no GPx–like activity, irrespective of whether they are derived from ω-carboxyalkylamines or simple
alkylamines. Such lacks of GPx-like activity let us quantitatively relate the GPx-like activities of the congeners of the above 3 series with their hydrophobicity
(ClogP), which showed satisfactory correlations in each series. The molecular hydrophobicity was then extensively applied to diverse known aromatic
selenium GPx mimics including diaryl diselenides and ebselen derivatives to explain their GPx-like activities in comparably quantitative mode, which could be
helpful in designing new improved GPx mimic analogues in each series.
Keywords: Organoselenium compound, Antioxidant, Glutathione peroxidase-like activity, Partition Coefficient, Hydrophobicity, QSAR
To our knowledge of structure-activity relationship in a
1. Introduction
Selenium, an essential trace element for human health [1],
series of homologues, elongation of a side chain might result in
steric and hydrophobic effect on certain biological activity.
has been of great significance in pathogenesis of many fatal
Steric effects of substituents in aromatic selenium GPx mimics
diseases such as Keshan disease [2], cancer [3], etc. Selenium
have been discussed mainly in the cases of ortho-substituted
is incorporated into selenocysteine which functions as a re-dox
analogues [7], but the effect of molecular hydrophobicity has
active site of many selenoenzymes [4] including GPx. GPx is
not been mentioned yet. Because the elongation of
one of the most important antioxidant enzymes in mammals,
substituents in our salicyloyl-derived GPx mimics occurs in
which catalyses reduction of hydrogen peroxide and lipid
meta-position to seleninic acid, their catalytic reactions might
peroxide, using glutathione (GSH) as a reductant [5,6]. During
not be affected by steric hindrance of substituents. Actually,
several decades, a variety of organoselenium compounds have
molecular hydrophobicity does not directly influence on GPx-
been appeared as possible GPx mimics, but there are only a
like reaction mechanism, but the reaction rate could depend
few leads superior to ebselen, a “standard” of organoselenium
on it as the catalytic assay runs in certain solvents (e.g.
GPx mimics [7].
phosphate buffer solution or CH2Cl2/MeOH). We, therefore,
We have previously synthesized
a new 5-seleninic
continued to synthesize 19 new derivatives with carbon side
chains of different lengths to relate their hydrophobicity with
their GPx-like activities.
anhydride of salicyloylglycine (1 in Fig. 1) which exhibited
higher GPx-like activity than ebselen and inhibited plant and
mammalian 12/15-lipoxygenase (LOX) [8]. Further synthesized
5-selenized salicylic acid derivatives showed not only selective
inhibition against 5-LOX but also GPx-like activities superior or
The result that not the simple side chain elongation but the
change in molecular hydrophobicity could affect the catalytic
reactivity of our GPx mimics has encouraged us to apply this
hydrophobic effect to some of known aromatic selenium GPx
mimics, including diaryl diselenides and ebselen derivatives.
similar to the lead compound (
1) [9]. Interestingly, only one
derivative (2) with a long side chain showed no detectable
GPx-like activity [9].
2. Experimental
2.1. Chemicals and instruments
Some starting reagents such as methyl salicylate, phenyl
salicylate (salol), salicylamide, salicylanilide and SeCl4 were
purchased from Merck and Sigma-Aldrich and commercially
unavailable reagents were synthesized by the reaction of
methyl salicylate with corresponding amines. All the solvents
were of extra pure grade from Roth (Germany). 1H and 13C
NMR spectra were recorded on a Brucker Biospin AV 300 (1H:
300 MHz; 13C: 75 MHz) or 400 (1H: 400 MHz; 13C: 100 MHz) by
using d6-DMSO as a solvent. For 3m and 4m, d6-D2O+KOH was
used as a solvent because of its getting dark in d6-DMSO.
Chemical shift values (δ) are reported in ppm downfield from
Fig. 1 5-seleninic anhydrides of N-salicyloyl ω-carboxyalkylamines published earlier.
* Corresponding author.
E-mail address: ryongnam34@yahoo.com

TMS (δ =0.0 ppm) as internal standard. 77Se
A
NM
C
R
C
sp
E
e
P
ct
T
ra
E
w
D
ereMA2.2
N
.3.
U
Sy
S
nt
C
he
R
sis
I
of 5,5'-diselanediyl-bis(2-hydroxybenzamide)
P
T
recorded by using a Brucker Avance II 300 instrument (57.2
(
4e
).
MHz) in d6-DMSO (dimethylselenide as external standard). HR-
Yield: 78%, mp: 288-90 °C, Found: C39.15, H2.75, N6.51.
MS recording was done on a Finnigan Thermo Scientific LTQ Calc. for C14H12N2O4Se2: C39.09, H2.81, N6.51%, δH 6.86(d, 3-
OrbitrapXL (ESI) in MeOH. Elemental analysis was carried out H), 7.55(dd, 4-H), 7.90(s, NH), 8.11(d, 6-H), 8.39(s, NH),
on HEKAtech EURO EA, vario EL. Some IR spectra were 13.16(OH), δC 115.43(C-1), 118.67(C-3), 118.94(C-6), 134.12(C-
recorded on a Nicolet Avatar 360 FT-IR. Kinetic measurements 4), 139.84(C-5), 161.65(C-2), 171.03(C=O), δSe 508, m/z (ESI)
were performed on a Shimadzu UV-2102 spectrophotometer.
430.90547 (M-. C14H12N2O480Se2 requires 430.90547).
2.2. General procedure for 5-selenization of salicyloylamines
2.2.4. Synthesis of 2,2'-((5,5'-diselanediyl-bis(2-
hydroxybenzoyl))-bis(azanediyl)) diacetic acid (4f).
Synthetic procedure followed Scheme 1. A solution of SeCl4
(5 mmol, 1.107 g) in THF (10mL) was added to a solution of
salicyloylamines (5 mmol) in THF (10 mL) and the mixture was
stirred for 1 hour at room temperature (RT). Then water (100
mL) was added to the reaction mixture, followed by stirring at
Yield: 72%, mp: 234-6°C(decomp.), Found: C39.35, H3.00,
N5.23. Calc. for C18H16N2O8Se2: C39.58, H2.95, N5.13%, δH
4.02(d, CH2-2H), 6.94(d, 3-H), 7.57(dd, 4-H), 8.18(d, 6-H),
9.15(t, NH), δC 41.41(CH2), 116.74(C-1), 118.88(C-3), 119.38(C-
5), 134.44(C-6), 139.35(C-4), 160.00(C-2), 167.65(C=O),
171.09(COOH), δSe 507, m/z (ESI) 546.91483 (M-.
C18H16N2O880Se2 requires 546.91483).
RT for additional 24 hours. White seleninic acid (3) precipitated
was filtered, washed with THF (3 x 30 mL) and dried in air.
When hydrazine hydrate (2mmol, 0.2mL) was added to a
solution of
stirred at RT for 24 hours followed by evaporation of THF to
produce yellow to orange diselenide ( ).
3 (2mmol) in THF (10mL) and the mixture was
2.2.5. Synthesis of 3-(2-hydroxy-5-
seleninobenzamido)propanoic acid (3g).
4
Yield: 32%, mp: 136-8°C(decomp.), Found: C37.24, H3.46,
N4.41. Calc. for C10H11NO6Se: C37.51, H3.46, N4.37%, δH
2.57(m, CH2-2H), 3.52(m, CH2-2H), 6.89(d, 3-H), 7.44(dd, 4-H),
8.09(d, 6-H), 8.92(t, NH), δC 33.55(CH2), 35.38(CH2), 116.81(C-
1), 118.95(C-3), 119.16(C-5), 133.24(C-6), 138.51(C-4),
159.35(C-2), 167.67(C=O), 172.98(COOH), δSe 1176, m/z (ESI)
319.98875 (M-. C10H11NO680Se requires 319.96788).
2.2.6. Synthesis of 3,3'-((5,5'-diselanediyl-bis(2-
hydroxybenzoyl))-bis(azanediyl)) dipropanoic acid (4g).
Yield: 75%, mp: 250-2°C(decomp.), Found: C41.60, H3.43,
N4.79. Calc. for C20H20N2O8Se2: C41.83, H3.51, N4.88%, δH
2.42(t, CH2-2H), 3.51(m, CH2-2H), 6.85(d, 3-H), 7.44(dd, 4-H),
8.08(d, 6-H), 9.56(s, NH), δC 33.88(CH2), 35.91(CH2), 116.40(C-
1), 118.22(C-5), 119.58(C-3), 135.46(C-6), 138.74(C-4),
162.54(C-2), 166.62(C=O), 175.10(COOH), δSe 515, m/z (ESI)
574.94623 (M-. C20H20N2O880Se2 requires 575.01249).
2.2.7. Synthesis of 5-(2-hydroxy-5-
Scheme
1 5-selenization of salicylic acid derivates (see ref. 8 and 9 for
3a,4a,3c,3e,3f,3i).
seleninobenzamido)pentanoic acid (3h).
Yield: 59%, mp: 130-2°C(decomp.), Found: C41.23, H4.47,
N4.05. Calc. for C12H15NO6Se: C41.39, H4.34, N4.01%, δH
1.57(m, CH2-4H), 2.27(t, CH2-2H), 3.33(m, CH2-2H), 7.11(d, 3-
H), 7.84(dd, 4-H), 8.33(d, 6-H), 9.04(t, NH), δC 22.08(CH2),
28.38(CH2), 33.39(CH2), 38.94(CH2), 115.95(C-1), 118.18(C-3),
2.2.1. Synthesis of 4-hydroxy-3-(methoxycarbonyl)benzeneseleninic
acid (3b).
Yield: 14%, mp: 136-138 °C, Found: C, 36.74; H, 3.02. Calc.
for C8H8O5Se: C, 36.52; H, 3.06%, δH 3.90(s, CH3), 7.15(d, 3-H),
7.90(dd, 4-H), 8.21(d, 6-H), δC 52.62(CH3), 113.84(C-1),
118.12(C-3), 128.29(C-6), 132.83(C-4), 139.34(C-5), 162.01(C-
126.51(C-6),
130.98(C-4),
138.52(C-5),
162.62(C-2),
167.94(C=O), 174.53(COOH), δSe 1177, m/z (ESI) 347.99946 (M-
2), 168.10(C=O), δSe 1175, m/z (ESI)
C8H8O580Se requires 262.94642).
:
262.94616 (M-.
. C12H15NO680Se requires 347.99918).
2.2.8. Synthesis of 5,5'-((5,5'-diselanediyl-bis(2-
2.2.2. Synthesis of 4-hydroxy-3-
hydroxybenzoyl))-bis(azanediyl)) dipentanoic acid (4h).
Yield: 75%, mp: 255-7°C(decomp.), Found: C45.86, H4.37,
N4.56. Calc. for C24H28N2O8Se2: C45.73, H4.48, N4.44%, δH
1.56(s, CH2-4H), 2.20(s, CH2-2H), 3.31(s, CH2-2H), 6.81(d, 3-H),
7.42(dd, 4-H), 8.10(d, 6-H), 9.60(s, NH), δC 22.87(CH2),
28.98(CH2), 35.13(CH2), 38.69(CH2), 116.19(C-1), 117.93(C-5),
(phenoxycarbonyl)benzeneseleninic acid (3d).
Yield: 12%, mp: 140-1°C(decomp.), Found: C48.24, H3.09.
Calc. for C13H10O5Se: C48.02, H3.10%, δH 7.26(d, 3-H), 7.34(dd,
2’,6’-2H), 7.38(d, 4’-H), 7.52(t, 3’,5’-2H), 8.05(dd, 4-H), 8.46(d,
6-H), δC 114.10(C-1), 118.30(C-3), 121.91(2’,6’-2C), 126.27(C-
5), 129.08(4’-C), 129.65(3’,5’-2C), 133.15(C-6), 139.31(1’-C),
150.13(C-4), 162.19(C-2), 165.55(C=O), δSe 1178, m/z (ESI)
324.96173 (M-. C13H10O580Se requires 324.96207).
119.72(C-3),
135.30(C-6),
138.94(C-4),
163.30(C-2),
167.18(C=O), 176.21(COOH), δSe 517, m/z (ESI) 631.00879 (M-.
C24H28N2O880Se2 requires 631.10314).

2.2.9. Synthesis of 6,6'-((5,5'-diselanediyl-bis(
A
2-CCEPTED MA38
N
.91
U
(C
S
H2
C
),
R
11
I
6.39(C-1), 118.86(C-3), 118.89(C-5), 132.67(C-6),
P
T
hydroxybenzoyl))-bis(azanediyl)) dihexanoic acid (4i).
138.37(C-4),159.82(C-2), 167.94(C=O), δSe 1177, m/z (ESI)
Yield: 83%, mp: 233-5°C(decomp.), Found: C47.17, H4.85, 332.04105 (M-. C13H19NO480Se requires 332.04065).
N3.98. Calc. for C26H32N2O8Se2: C47.43, H4.90, N4.25%, δH
2.2.15. Synthesis of 5,5'-diselanediyl-bis(N-hexyl-2-
1.29(m, CH2-2H), 1.52(m, CH2-4H), 2.20(t, CH2-2H), 3.25(m,
hydroxybenzamide) (4l).
CH2-2H), 6.86(d, 3-H), 7.53(dd, 4-H), 8.09(d, 6-H), 8.80(t, NH),
Yield: 72%, mp: 212-4°C, Found: C52.27, H6.10, N4.81. Calc.
12.91(s, COOH), δC 24.29(CH2), 26.09(CH2), 28.55(CH2),
for C22H28N2O4Se2: C52.18, H6.06, N4.68%, δH 0.63(t, CH3-3H),
33.67(CH2), 38.92(CH2), 116.16(C-1), 118.80(C-3), 118.85(C-5),
1.07(m, CH2-6H), 1.29(m, CH2-2H), 3.05(m, CH2-2H), 6.67(d, 3-
133.71(C-6),
139.36(C-4),
160.84(C-2),
167.97(C=O),
H), 7.33(dd, 4-H), 7.88(d, 6-H), 8.58(t, NH) 12.52(s, OH), δC
13.83(CH3), 22.00(CH2), 26.09(CH2), 28.76(CH2), 30.92(CH2),
39.02(CH2), 116.08(C-1), 118.37(C-5), 118.75(C-3), 133.50(C-6),
139.26(C-4), 160.23(C-2), 167.83(C=O), δSe 509, m/z (ESI)
599.09155 (M-. C22H28N2O480Se2 requires 599.19677).
174.48(COOH), δSe 509, m/z (ESI) 659.04173 (M-.
C26H32N2O880Se2 requires 659.04163).
2.2.10. Synthesis of 4-hydroxy-3-
(propylcarbamoyl)benzeneseleninic acid (3j).
Yield: 63%, mp: 117-8°C(decomp.), Found: C41.41, H4.52,
N4.90. Calc. for C10H13NO4Se: C41.39, H4.52, N4.83%, δH 0.90(t,
CH3-3H), 1.57(m, CH2-2H), 3.27(m, CH2-2H), 7.11(d, 3-H),
7.84(dd, 4-H), 8.34(d, 6-H), 9.04(t, NH), δC 11.38(CH3),
22.06(CH2), 40.85(CH2), 115.84(C-1), 118.05(C-3), 126.41(C-6),
130.84(C-4), 138.45(C-5), 162.55(C-2), 167.98(C=O), δSe 1178,
m/z (ESI) 289.99401 (M-. C10H13NO480Se requires 289.99370).
2.2.16. Synthesis of 3-(heptylcarbamoyl)-4-
hydroxybenzeneseleninic acid (3m).
Yield: 11%, mp: 118-20°C(decomp.), Found: C48.48, H6.13,
N4.08. Calc. for C14H21NO4Se: C48.56, H6.11, N4.04%, δH 0.84(t,
CH3-3H), 1.27(m, CH2-8H), 1.52(t, CH2-2H), 3.27(m, CH2-2H),
7.08(d, 3-H), 7.81(dd, 4-H), 8.30(d, 6-H), 9.02(t, NH), δC
13.93(CH3), 22.05(CH2), 26.40(CH2), 28.39(CH2), 28.73(CH2),
31.32(CH2), 38.97(CH2),115.73(C-1), 118.01(C-3), 118.90(C-5),
126.30(C-6), 130.83(C-4), 162.51(C-2), 167.78(C=O), δSe 1176,
2.2.11. Synthesis of 5,5'-diselanediyl-bis(2-hydroxy-N-
propylbenzamide) (4j).
Yield: 85%, mp: 247-8°C, Found: C46.86, H4.67, N5.50. Calc. m/z (ESI) 346.05566 (M-. C14H21NO480Se requires 346.05630).
for C20H24N2O4Se2: C46.70, H4.70, N5.45%, δH 0.90(t, CH3-3H),
2.2.17. Synthesis of 3-(cyclohexylcarbamoyl)-4-
1.56(m, CH2-2H), 3.26(m, CH2-2H), 6.89(d, 3-H), 7.56(dd, 4-H),
hydroxybenzeneseleninic acid (3n).
8.12(d, 6-H), 8.83(t, NH) 12.96(s, OH), δC 11.35(CH3),
Yield: 14%, mp: 133-5°C, Found: C47.21, H5.22, N4.27. Calc.
22.02(CH2), 40.80(CH2), 116.05(C-1), 118.73(C-3, C-5),
for C13H17NO4Se: C47.28, H5.19, N4.24%, δH 1.15(t, CH2-H),
133.66(C-6), 139.35(C-4), 160.80(C-2), 167.95(C=O), δSe 511,
1.32(t, CH2-2H), 1.38(d, CH2-2H), 1.59(d, CH2-H), 1.72(d, CH2-
m/z (ESI) 514.99784 (M-. C20H24N2O480Se2 requires 515.02898).
2H), 1.82(d, CH2-2H), 3.83(t, CH2-H), 7.08(d, 3-H), 7.81(d, 4-H),
2.2.12. Synthesis of 3-(butylcarbamoyl)-4-
8.35(s, 6-H), 8.81(d, NH), δC 24.81(CH2-2C), 25.20(CH2),
hydroxybenzeneseleninic acid (3k).
32.08(CH2-2C), 48.36(CH2), 115.91(C-1), 118.03(C-3), 126.72(C-
Yield: 73%, mp: 128-30°C(decomp.), Found: C43.56, H4.87, 6), 130.74(C-4), 138.54(C-5), 162.55(C-2), 166.92(C=O), δSe
N4.41. Calc. for C11H15NO4Se: C43.43, H4.97, N4.60%, δH 0.90(t, 1177, m/z (ESI) 330.02421 (M-. C13H17NO480Se requires
CH3-3H), 1.33(m, CH2-2H), 1.53(m, CH2-2H), 3.30(m, CH2-2H), 330.02500).
7.10(d, 3-H), 7.83(dd, 4-H), 8.32(d, 6-H), 8.99(t, NH), δC
2.2.18. Synthesis of 4-hydroxy-3-
13.74(CH3), 19.74(CH2), 30.98(CH2), 38.91(CH2), 116.06(C-1),
(phenylcarbamoyl)benzeneseleninic acid (3o).
118.19(C-3), 126.57(C-6), 130.94(C-4), 138.51(C-5), 162.58(C-
Yield: 17%, mp: 136-8°C(decomp.), Found: C48.23, H3.28,
2), 167.89(C=O), δSe 1177, m/z (ESI) 304.00955 (M-.
N4.39. Calc. for C13H11NO4Se: C48.16, H3.42, N4.32%, δH 7.14(t,
C11H15NO480Se requires 304.00935).
4’-H), 7.18(d, 3-H), 7.37(t, 3’,5’-2H), 7.71(d, 2’,6’-2H), 7.85(dd,
2.2.13. Synthesis of 5,5'-diselanediyl-bis(N-butyl-2-
4-H), 8.37(d, 6-H), 10.48(s, NH), 12.16(s, OH), δC 117.70(C-3),
hydroxybenzamide) (4k).
119.04(C-1), 120.81(2’,6’-2C), 124.23 (4’-C), 127.87(C-6),
Yield: 79%, mp: 245-7°C, Found: C48.80, H5.28, N5.08. Calc. 128.76(3’,5’-2C), 130.67(C-4), 138.14(C-5), 139.12(1’-C),
for C22H28N2O4Se2: C48.72, H5.20, N5.16%, δH 0.91(t, CH3-3H), 160.29(C-2), 165.04(C=O), δSe 1146 (KOH+D2O), m/z (ESI)
1.33(m, CH2-2H), 1.53(m, CH2-2H), 3.29(m, CH2-2H), 6.89(d, 3- 323.97753 (M-. C13H11NO480Se requires 323.97805).
H), 7.56(dd, 4-H), 8.12(d, 6-H), 8.82(t, NH), 12.97(s, OH), δC
2.2.19. Synthesis of 5,5'-diselanediylbis(2-hydroxy-N-
13.56(CH3), 19.58(CH2), 30.76(CH2), 38.68(CH2), 115.96(C-1),
phenylbenzamide) (4o).
118.65(C-5), 118.72(C-3), 133.58(C-6), 139.31(C-4), 160.80(C-
Yield: 73%, mp: 242-4°C, Found: C53.65, H3.31, N4.73. Calc.
2), 167.89(C=O), δSe 510, m/z (ESI) 543.02919 (M-.
for C26H20N2O4Se2: C53.62, H3.46, N4.81%, δH 7.01(d, 3-H),
C22H28N2O480Se2 requires 543.11197).
7.11(t, 4’-H), 7.33(t, 3’,5’-2H), 7.61(dd, 4-H), 7.67(d, 2’,6’-2H),
2.2.14. Synthesis of 3-(hexylcarbamoyl)-4-
8.20(d, 6-H), 10.37(s, NH), 12.05(s, OH), δC 118.62(C-3),
hydroxybenzeneseleninic acid (3l).
119.14(C-5), 119.33(C-1), 120.96(2’,6’-2C), 124.27(4’-C),
Yield: 43%, mp: 136-8°C(decomp.), Found: C47.10, H5.76, 128.78(3’,5’-2C), 134.70(C-6), 138.17(1’-C), 138.69(C-4),
N4.20. Calc. for C13H19NO4Se: C46.99, H5.76, N4.22%, δH 0.85(t, 158.69(C-2), 165.23(C=O), δSe 500, m/z (ESI) 582.96807 (M-.
CH3-3H), 1.28(m, CH2-6H), 1.52(m, CH2-2H), 3.29(m, CH2-2H), C26H20N2O480Se2 requires 582.96903).
6.87(d, 3-H), 7.44(dd, 4-H), 8.11(d, 6-H), 8.83(t, NH), δC
2.3. GPx-like activity [8].
13.84(CH3), 22.02(CH2), 26.11(CH2), 28.70(CH2), 30.94(CH2),

The catalytic reaction was run at 37 °C
A
C
a 1
C
m
E
L
P
r
T
ea
E
ct
D
ionMA3.2
N
. G
U
Px
S
-li
C
ke
R
ac
I
ti
P
vity.
T
mixture consisting of 100 mM Tris-HCl buffer (pH 7.4)
containing 5 mM EDTA and 0.1 % Triton X-100, 3 mM GSH, 0.2
mM NADPH, 1 U of glutathione reductase (GR) and 10 μM of
the test compound (DMSO solution). The assay sample was
equilibrated for 10 minutes in the absence of peroxide
substrate and GPx-like reaction was initiated by addition of 0.5
mM tert-butyl hydroperoxide (t-BuOOH). The time-dependent
decrease in absorbance at 340 nm (10 to 40 seconds after
addition of t-BuOOH) was recorded. During the GPx-like
reaction, reduced GSH is oxidized and the resulting disulfide
(GSSG) is back-reduced by the GR reaction consuming
stoichiometric amounts of NADPH. Since NADPH exhibits a
local absorbance maximum (Acat) at 340 nm but its oxidized
counterpart (NADP) does not, NADPH oxidation can be
quantified by measuring the decrease in absorbance at this
wavelength. A blank assay (solvent control, Ablank) was run in
GPx-like activities of new 5-seleninic acids were assayed in
coupled reductase model [9] with glutathione and tert-butyl
hydroperoxide (t-BuOOH) as substrates. Most of the 5-
seleninic acids (3a
GPx-like activities than ebselen (Table 1) and when normalized
to selenium content, the diselenides (4e 4k and 4o) also
exerted almost equivalent GPx-like activities to their
corresponding precursors, 5-seleninic acids (data not
, 3b, 3d-3h, 3j, 3k and 3o) showed higher
-
3
shown). Surprisingly, like in 3i [9], there were no detectable
GPx-like activities in 3l and 3m, where the number of carbon
atoms comprising the side chain bonded to the nitrogen of
salicyloylamine moiety exceeded more than 6, and so was it in
3n, which carries a cyclohexyl ring instead of a normal chain
bonded to the nitrogen of amide.
Table 1 The rate of NADPH oxidation (υ0) in the presence of compounds
μM) and their GPx-like activities relative to ebselen (n =3)
3 (10
.
the absence of catalysts. The rate of NADPH oxidation (υ ) was
₀
compound
ClogP
υ0 (μM min-1)
5.19 ± 0.51
16.40 ± 1.02
8.97 ± 0.85
5.21 ± 0.28
9.54 ± 0.82
12.05 ± 1.82
6.48 ± 0.47
8.92 ± 0.45
9.44 ± 0.42
no detectable
12.28 ± 1.12
6.67 ± 0.46
no detectable
no detectable
no detectable
6.14 ± 0.51
Relative Activity (RA)
calculated using a molar absorbance coefficient for NADPH of
6.22 x 103 M-1·cm-1.
Ebselen
3a
1
0.18
0.32
0.85
1.83
-0.72
-0.72
-0.66
-0.35
0.17
0.53
1.06
2.12
2.65
1.50
1.26
2.8
1.7
0.9
1.9
2.1
1.1
1.7
1.8
0
3b
3c
3. Results and discussion
3d
3e
3f
3.1. Synthesis.
Under stirring at RT for 1h yellow 5-selenium trichlorides
are formed, which are further hydrolyzed in water for 24 h to
3g
white 5-seleninic acids (
3
), followed by reduction by hydrazine
).
3h
3i
hydrate at RT for 24 h to yellow diselenides (
4
In the previous study [9] we reported that the seleninic
group of 3a was methyl esterified during monocrystallization
from methanol. Although we did not try to prepare any
3j
2.4
1.3
0
3k
3l
monocrystals of the new congeners
3, their methyl
3m
3n
3o
0
esterification were identified from their HR-MS spectra with
methanol as a solvent, for example as is seen for 3h in Fig. 2.
However, 5-seleninic acids of alkyl or phenyl salicylate esters
did not show the possibility of methyl esterification (see
Supplementary Data), the reason of which is unclear.
0
1.1
3.3. Hydrophobic effect on GPx-like activity.
To get further more meaningful understanding of these
lacks of GPx-like activity, logPs related to molecular
hydrophobicity were calculated (ClogP) with the use of
ChemBioDraw 2010 to correlate them with GPx-like activities
relative to that of ebselen. This software was selected because
of its superiority to other commercially available chemical
softwares including ACD/log P and HyperChem [10].

In N-salicyloyl ω-carboxy-n-alkylamines
A
(
3
C
f
-
3
C
i
),
E
t
P
heTEch
D
ainMAob
N
tai
U
ne
S
d
C
th
R
e
I
q
P
ua
ntitative relation equation (R2=0.88) for this
T
lengths and ClogPs are in proportion to GPX-like activities from series. From the graph of the equation (Fig. 4) one could
realize that there would exist a switching threshold of ClogP
Fig. 3 Plot of ClogPs and relative GPx-like activities of 5-seleninic acids of N-
salicyloyl ω-carboxyalkylamines.
Fig. 6 Plot of ClogPs and relative GPx-like activities of 5-selenino salicylic acid
and its esters
3f [8] to 3g, but as the number of carbon atoms of a side chain
increases from 5 to 6 (from 3h to 3i [9]), the increment of
ClogP gets much more (ΔClogP = 0.52) than ever (from 2 to 3:
ΔClogP = 0.06 and from 3 to 5: ΔClogP = 0.31) and, moreover,
GPx-like activity does not decrease but gets disappeared. We
have, therefore, plotted using Microsoft Excel the relative GPx-
like activities and ClogPs (Fig. 3), which resulted in satisfactory
quantitative relationship (R2=0.95). From the inversed
parabolic equation obtained (Fig. 3) we could get the
maximum relative GPx-like activity (1.87) corresponding to the
ClogP (-0.39). According to the above equation, ClogP of the
compound whose substituent R is aminobutyric acid in Scheme
1 is -0.30 and its GPx-like activity is calculated to be 1.82,
which suggests that this congener could be one of the optimal
derivatives in this series.
(about 2.20) for GPx-like activity. GPx-like activity of a phenyl
derivative (3o) similar to ebselen could be assigned to its ClogP
(1.27) which is beyond the threshold. Furthermore, although
we did not synthesize n-methyl and ethyl homologues (Fig. 5)
in this series, it could be expected that they might exert 6.48
and 4.31 times higher GPx-like activity than ebselen, for their
ClogP values are -0.522 and -0.007, which are far lower than
the threshold.
In addition, we have obtained a satisfactory quantitative
relationship (R2=0.91) between ClogPs and GPx-like activity for
5-selenino salicylic acid and its esters (Fig 6).
From these results, we could suggest that activities of a
series of organoselenium GPx mimics might have
a
quantitative relationship with their ClogPs, which could be
useful in designing better analogues or homologues in each
series. This concept would be connected with the suggestion
[11] that molecular hydrophobicity could improve cellular
uptake of GPx mimics.
On the contrary to the above series, in N-salicyloyl n-alkyl
amines (3j-3m), as the alkyl chain gets elongated from n-propyl
(3j) to n-butyl (3k), GPx-like activity gets lowered with the
3.4. Relationship between ClogPs and catalytic activities of known
aromatic selenium GPx mimics.
A number of reports have been published on development
of improved GPx mimics, where the explanations [12] were
focused mainly on structural novelty or superiority of newer
structures to older ones, but there have been only a few
researches [13] on structure-activity relationships in one series,
for example, the QSAR study of aromatic organochalcogens
with relation to their molecular orbital energies (LUMO and
electrochemical oxidation potential) and atomic electron
densities, preference of steric effect to electronic one in ortho-
substitution of ebselen, electronic contribution of substituents
(Hammett plot) in cyclic seleninates and spirodioxyselenuranes,
etc. We have, therefore, tried to delineate GPx-like activities of
some known aromatic selenium derivatives with respect to
their ClogPs in each series.
increase of ClogP. Interestingly, also in this series, as the
number of chain carbon atoms gets 6 (3l) or 7 (3m), GPx-like
activity is not detectable. A cyclohexyl derivative (3n) with
ClogP (1.51) between those of n-butyl derivative (3k) and n-
hexyl one (3l), exerts no GPx-like activity, too. We have also
Fig. 2 HR-MS spectrum of 3h in MeOH.

ACCEPTED MAby
N
6-
U
me
S
th
C
ox
R
yl
I
a
P
tio
T
n could be responsible for higher activities of
8
than those of
9
, we could sugget that it would be better to
add electonic effect instead of steric one to hydrophobic effect
to obtain more reliable relationship equation.
Wirth [16] measured GPx-like activities of some oxygen-
containing diselenides (Fig. 9) using GR coupled assay with
either hydrogen peroxide (H2O2) or t-BuOOH. He suggested
that significantly lower activity of bis-ortho substituted
diselenides (10b-10d) could be attributed to steric hindrance,
but actually 10c showed much lower activity than 10d, though
its substituent was less bulkier than that of 10d, for which he
mentioned a decrease of electron density at selenium atom by
electron withdrawing substituent CF3 of 10c. However, ClogP
of CF3 substitued compoud 10c is bigger than that of 1’-
hydroxypropyl substitued one 10d. The inferior activity of 10c
to the others could be responsible for its lowest ClogP, as
shown in Fig. 9. About 2 fold discrepancy in GPx-like activity
between hydroxyl substituted 10a and methoxy substituted
10e has not been tried to explain before, but higher
hydrophobicity of 10e might be attributed to its less activity.
ClogPs and GPx-like activities in this diselenide series are in
inverse parabolic relation (R2=0.87 for H2O2 and R2=0.85 for t-
BuOOH), which reveals that there might exist a ClogP for
maximal GPx-like activity. The optimum ClogPs from the above
equations are 4.42 and 4.43, when their GPx-like activities
Fig. 7 ClogPs and peroxidase activities of some aromatic diselenides.
Most of known aromatic selenium GPx mimics are diaryl
diselenides and ebselen derivatives. Mugesh et al. [14]
reported thiol peroxidase-like activities of some aromatic
diselenides, which might be grouped into alkyl-substituted
diphenyl diselenides, dinaphtyl diselenides and 4,5-
dihydrooxazol substituted diphenyl diselenides (Fig. 7). In the
case of diphenyl diselenides, inactivity of p-tert-butyl-o,o’-
dimethyl substituted derivative (5b) can be explained in some
measure on the point of ClogP. That is, because ClogP of 5b
(10.06) is much bigger than that of the non-substituted
compound 5a (4.41, υ0= 24.08μM min-1), 5b could not exert
activity. In dinaphtyl diselenides (6a-6c), peroxidase activities
are in quite a quantitative inverse proportion (R2=0.99) to
ClogPs. Such a trend can be seen also in 4,5-dihydrooxazol
substituted diphenyl diselenides (7a-7c), but if we consider the
fact that alkyl substituted derivatives (7b and 7c) were actually
inactive in lower concentration [14], we could suggest that
their excessive hydrophobicity compared to that of
unsubstituted one (7a) might lead to their inactivity.
Mugesh and Bhabak [15] suggested 6-methoxylation (o-
methoxylation) as a means for enhancement of GPx-like
activities of diselenides of N, N-dialkylbenzylamines.
Altogether, there exists a parabolic relationship between ClogP
and half-life of t-BuOOH (Fig. 8), and the correlation coefficient
is 0.70, which is relatively satisfied. Considering the authors’
Fig. 9 ClogPs and GPx-like activities of oxygen-containing diphenyl diselenides.
Fig. 4 Plot of ClogPs and relative GPx-like activities of 5-seleninic acids of N-
Fig. 10 Bis-(2,4,6-substituted phenyl)-diselenides with close to optimal ClogPs.
salicyloyl alkyl or phenyl amines.
would be 27.25 μM min-1 and 15.74 μM min-1 for H2O2 and t-
BuOOH, respectively. There might be exemplified compounds
with ClogPs close to the above optimal ones (Fig 10). For bis-
explanation, however, that the stabilization of selenium atom
(2-methyl-4-methoxy-6-hydroxypheny)
diselenide,
the
calculated activities are 27.04μM min-1 for H2O2 and 10.67μM
min-1 for t-BuOOH from its ClogP (4.27), and for bis-(2-amino-
Fig. 5 The congeners estimated to exert higher GPx-like activity.

4-methoxy-6-hydroxyphenyl) diselenide, th
A
eyCCareEP26
T
.7
E
4
D
μMMA17
N
4.3
U
9μ
S
M
CR
inI-P1 Tand 174.20μM min-1, respectively, from their
m
min-1 and 10.67μM min-1, respectively, according to its ClogP ClogPs (2.47, 2.48 and 2.44, respectively).
(4.19).
Elsherbini et al. [19] have recently synthesized several
chiral ebselen analogues as GPx-like mimics (Fig. 14), where
they indicated that the highest activity of 13g was due to its
higher solubility in the reaction medium compared to the
other compounds. As can be seen from Fig. 14, 13g has the
Fig. 11 ClogPs and GPx-like activities of p-tert-butyl-o-(N-alkyl/phenyl) carbamoyl
ebselen derivatives.
ClogP can also be applied to some ebselen derivatives.
Zade et al. [17] published a report on the synthesis and GPx-
like activities of p-tert-butyl-o-(N-alkyl/phenyl) carbamoyl
ebselen derivatives (11), when they indicated that the lower
activity of 11c relative to that of ebselen could be attributed to
its poor solubility, which could be due to its higher
hydrophobicity (ClogP = 6.04 in Fig. 11). There was a
pronounced reciprocal proportional relation (R2=0.97)
between ClogP values and GPx-like activities.
Mugesh and Bhabak [18] suggested that phenyl
substituents on the nitrogen atom were important for the GPx-
like activity of ebselen, but in fact, their experimental results
presented that non-N-phenyl substituted analogues (12a-12c
in Fig. 12) showed higher or much higher activity than p-
bromophenyl substituted one (12g). From the lower half of Fig.
12 one could note that 12g with the largest ClogP shows the
lowest GPx-like activity among N-phenyl derivatives tested,
when there exists a significant parabolic relation (R2=0.77)
Fig. 8 ClogPs and GPx-like activities of N,N-dialkylbenzylamine diselenides.
Fig. 12 ClogPs and GPx-like activities of N-substituted ebselen derivatives.
Fig. 13 N-substituted ebselen derivatives with close to optimal ClogPs.
between GPx-like activities and ClogPs in N-phenyl and non-
phenyl derivatives. The obtained equation reveals that ClogP
might have an optimal value (2.52) for maximal GPx-like
activity (174.46μM min-1), and we have estimated the
following compounds with ClogPs close to the above optimal
one (Fig 13). The estimated activities of 2-aminophenyl, ethyl
and 3,4-dihydroxyphenyl substituents are 174.36μM min-1,
Fig. 14 ClogPs and GPx-like activities of ebselen and its chiral analogues.

smallest ClogP among the compounds teste
A
d,
C
w
C
hic
E
h
P
co
T
u
E
ld
D
beMANCy
U
cl
S
ic
C
se
R
le
I
ninate/selenenate ester is well known to be a
P
T
regarded as another reasonable delineation of its highest GPx- lead of successful GPx mimics. Singh et al. [21] reported that o-
like activity. They also explained that steric hindrance in 13i nitro could stabilise aromatic cyclic selenenate/seleninate
could be the cause of its lower GPx-like activity in both assays esters to exert higher GPx-like activities in comparison to that
with GSH and PhSH as the substrate. Here we can make an of the analogue without o-nitro group (Fig. 16). Although the
additional remark that the higher ClogP of 13i (5.06) could introduction of o-nitro group enhanced the GPx-like activity,
but the increment was found to be not so great from the
comparison of 15a and 15e, and instead, electronic effects of
polar S=O and C=O groups were more significant (15d and 15e, 15c
and 15d), which was, of course, mentioned by authors. These polar
groups could directly be reflected to molecular hydrophobicity.
Indeed, GPx-like activities of these aromatic cyclic
selenenate/seleninate esters were in relatively good
relationship to ClogPs (R2=0.73). The parabolic graph obtained
reveals that such aromatic cyclic selenenate/seleninate esters
might certainly exert at least superior GPx-like activity to
ebselen.
4. Conclusions
We have synthesized 19 new 5-seleninic acids and some of
their diselenides of methyl or phenyl salicylates, N-salicyloyl ω-
carboxyalkylamines, or N-salicyloyl alkyl or phenyl amines, and
measured GPx-like activities of the 5-seleninic acids with
coulpled reductase assay. Structure-activity relationship study
using ClogP reflecting hydrophobic property of the mimics has
concluded that in each series observed there could exist its
own relationship between ClogPs and GPx-like activities of the
congeners and that it could have a switching threshold of
ClogP for the activity or its limited maximal activity. Not only
ClogP could, of course, account for the absence of GPx-like
activity of some derivatives, which should be further
elucidated in other ways. Applications of ClogP correlation to
diverse aromatic selenium GPx mimics including diaryl
diselenides and ebselen derivatives also showed some
meaningful or quantitative relationships between ClogPs and
GPx-like activities in each series. The series with R2 lower than
0.9 are thought to be further explored for other structural
factors on GPx-like activity. In addition, it should be pointed
out that the source of thiols could be significant for QSAR of
GPx mimics, because benzene thiol (PhSH) or benzyl thiol
(BnSH) might bring about confusion in QSAR analysis due to
their thiol exchange effect. In fact, we could not succeed in
relating ClogPs with GPx-like activities for data of many GPx
mimics with PhSH or BnSH as thiol source. Our results did not
cover aliphatic selenium GPx mimics, but were focused on
aromatic ones, which constituted majority of GPx mimics
reported until now. As in drug design field, further more
extensive QSAR studies are required for each series of not only
aromatic but also aliphatic selenium/tellurium GPx mimics to
get successive druggable GPx mimic candidates.
Fig. 15 ClogPs and GPx-like activities of ebselen derivatives inhibiting
acetylcholine esterase.
account for its lower activity. In GSH/GSSG assay ClogP values
are found to be in comparably reliable inverse proportion to
GPx-like activities (R2=0.80 for H2O2 and R2=0.76 for CumOOH).
Luo et al. [20] consulted the structures of ebselen and
donepezil to design and synthesize a new series of ebselen
derivatives (14) as hybrids of GPx mimics and cholinesterase
inhibitors against Alzheimer’s disease. As is seen in Fig. 15, the
relationship between ClogP and GPx-like activity in 11
derivatives follows inverse parabolic function (R2=0.63) which
means that there could also exist a ClogP for maximal activity
in this series like in 3
, but the low correlation coefficient, R2
highlights the additional contributions of other structural
factors on GPx-like activity to be further considered.
Acknowledgements
Financial support of the Alexander von Humboldt
Foundation and the European Commission (LSHM-CT-2004-
0050333) is acknowledged. The authors thank Drs. M.
Schlangen and R. Zeisberg, Profs. L. Ernst and T. Braun, and
Mmes. Kaetel and Klose for recording spectra.

2083; G. Mugesh, A. Panda, H. B. Singh, N. S. Punekar and R.
ACCEPTED MANUSCRIPT
Supplementary data related to this article can be found in
the online version at
Appendix A. Supplementary data
J. Butcher, Chem. Commun., 1998, 2227-2228; T. G. Back and
Z. Moussa, J. Amer. Chem. Soc., 2002, 124, 12104-12105; S.
S. Zade, H. B. Singh and R. J. Butcher, Angew. Chem. Int. Ed.,
2004, 43, 4513-4515; T. G. Back, Z. Moussa and M. Parvez,
Angew. Chem., 2004, 116, 1288-1290; P. P. Phadnis and G.
http://dx.doi.org/xx.xxxx/j.jorganchem.201x.xx.xxx.
Mugesh, Org. Biomol. Chem., 2005,
Mugesh, G. Roy, H. Sies, Z. Berente and K. Hideg, Org.
Biomol. Chem., 2005, , 3564-3569; K. P. Bhabak and G.
3, 2476-2481; T. Kálai, G.
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Fig. 16 ClogPs and GPx-like activities of aromatic cyclic seleninate
and selenenate esters.

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Synthesis and determination of GPx-like activity of 19 new compounds.
Quantitative relationships between hydrophobicity (ClogP) and GPx-like activity
of several 5-seleninic acids.
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Applying the relationship to the known GPx-mimics (aromatic diselenides,
ebselen derivatives, etc.).