Lead discovery of a guanidinyl tryptophan derivative on amyloid cascade inhibition
549
white powder. Compound TSR4 was purified by column (C]O, C]C, C]N), 1,456, 1,432 (C–C), 1,366, 1,341 (C–O
1
chromatography on silica gel (CHCl /EtOAc/MeOH 4:4:1) st), 1,204, 1,139 (C–N). H-NMR spectrum in DMSO-d (δ,
3
6
to yield yellow solid (hygroscopic). Yield 260.36 mg ppm): 10.85 (s, 1H, indole-NH), 9.36 (s, 1H, OH), 8.26 (s,
−1
(
3
60.06%). FTIR (ATR, υ, cm ): 3,392–3,216 (O–H, N–H), 1H, NH), 7.57 (d, 1H, J 7.6 Hz, H9′), 7.52 (s, 1H, NH), 7.34
2
3
,113 (sp C–H), 2,919 (sp C–H), 1,659, 1,516 (C]O, C] C) (s, 1H, NH), 7.34 (d, 1H, J 7.7 Hz, H6′), 7.35 (d, 2H, J
1
(
1
,457, 1,433 (C–C), 1,363, 1,336 (C–O), 1,229, 1,202, 1,180 8.9 Hz, H2″, H6″), 7.21 (d, 1H, J 2.2 Hz, H4′), 7.06 (t, 1H, J
1
C–N, C–O). H-NMR spectrum in DMSO-d (δ, ppm): 7.5 Hz, H7′), 6.97 (t, 1H, J 7.4 Hz, H8′), 6.70 (dd, 2H, J
6
0.81 (s, 2H, indole-NH), 7.87 (m, 2H, NH, NH), 7.60 (d, 8.8 Hz, H3″, H5″), 4.05 (m, 1H, H1′), 3.16 (dd, 1H, J1
H, J 7.6 Hz, H7″), 7.53 (d, 1H, J 7.7 Hz, H9′), 7.32 (d, 1H, J 4.1 Hz, J 14.6 Hz, H2b′), 2.93 (dd, 1H, J 6.1 Hz, J 14.6 Hz,
1
8
2
3
1
2
1
.0 Hz, H6′, H4″), 7.15 (m, 2H, H4′, H2″), 7.05 (t, 2H, J H2a′). C-NMR spectrum in DMSO-d6 (δ, ppm): 171.8
.4 Hz, H8′, H6″), 6.97 (t, 2H, J 7.3 Hz, H7′, H5″), 4.24 (m, (C1), 158.5 (C2), 154.5 (C4″), 136.4 (C5′), 129.9 (C1″), 128.1
H, H1′, H2), 3.60 (dd, 1H, J 9.9 Hz, H4b), 3.50 (dd, 1H, J1 (C2″, C6″), 127.9 (C10′), 123.9 (C4′), 121.2 (C7′), 119.1 (C9′),
.7 Hz, J 10.8 Hz, H4a), 3.09 (dd, 1H, J 4.7 Hz, J 14.2 Hz, 118.6 (C8′), 115.8 (C3″, C5″), 111.7 (C6′), 110.0 (C3′), 60.8
H2b′), 2.94 (m, 1H, H2a′), 2.76 (m, 4H, H9″, H10″). C- (C1′), 27.4 (C2′). HRMS (ESI) m/z: 360.1426 [M + Na].
NMR spectrum in DMSO-d6 (δ, ppm): 175.1 (C1), 170.3
7
2
5
2
1
2
1
3
(
C3), 136.9 (C3″), 136.7 (C5′), 127.9 (C8″), 127.6 (C10′), 123.2
(
C2″), 123.0 (C4′), 121.6 (C5″), 121.4 (C7′), 118.9 (C9′, C7″), 2.2.8 (S)-2-Amino-N-(N-(4-hydroxybenzyl)carbamimid
1
18.7 (C8′, C6″), 112.0 (C4″), 111.8 (C6′), 111.0 (C1″), 110.8
C3′), 62.3 (C1′), 55.7 (C4), 55.1 (C2), 44.9 (C10″), 31.2 (C9″),
6.1 (C2′). HRMS (ESI) m/z 434.2193 [M + H].
oyl)-3-(1H-indol-3-yl)propanamide (TGN2)
(
2
Compound Boc-TGN2 was purified by column chromato-
graphy on silica gel (EtOAc/CHCl /Hex 2:7:1) to yield
3
white powder. Compound TGN2 was purified by column
2
.2.6 General synthesis procedure of TGN1–TGN4
chromatography on silica gel (CHCl /EtOAc/MeOH 2:7:1)
3
to yield brown viscous (hygroscopic). Yield 487.40 mg
−1
A solution of compound T3 (1 mmol), NH –R (1 mmol), (53.33%). FTIR (ATR, υ, cm ): 3,394–3,111 (O–H, N–H),
2
2
2
3
HATU (1.5 mmol), and N-methylmorpholine (NMM) 3,065 (sp C–H), 2,925 (sp C–H), 1,674, 1,611, 1,515 (C]O,
3 mmol) in 5 mL of DMF was stirred at room tempera- C]C, C]N) 1,456, 1,431 (C–C), 1,357, 1,338 (C–O), 1,201,
(
1
ture. After 18 h stirring, water was added. The aqueous 1,136 (C–N). H-NMR spectrum in DMSO-d6 (δ, ppm):
phase was extracted with ethyl acetate. The combined 10.87 (s, 1H, indole-NH), 9.32 (s, 1H, OH), 8.10 (s, 1H, NH),
organic extracts were dried. The obtained residue was 7.55 (s, 1H, NH), 7.55 (d, 1H, J 7.7 Hz, H9′), 7.34 (s, 1H,
purified by column chromatography on silica gel to yield NH), 7.34 (d, 1H, J 7.6 Hz, H6′), 7.13 (s, 1H, H4′), 6.93 (d,
compound Boc-TGN1 to Boc-TGN4. The protecting 2H, J 8.4 Hz, H2″, H6″), 7.06 (t, 1H, J 7.5 Hz, H7′), 6.97 (t,
group of the obtained compound was removed by 50% 1H, J 7.5 Hz, H8′), 6.67 (d, 2H, J 8.4 Hz, H3″, H5″), 4.24 (m,
of TFA in ethyl acetate at room temperature for 1.5 h. The 2H, H7″), 4.06 (m, 1H, H1′), 3.14 (dd, 1H, J 4.0 Hz, J
1
2
1
3
reaction mixture was adjusted to pH 7 by saturated 14.6 Hz, H2b′), 2.83 (dd, 1H, J 6.9 Hz, J 14.6 Hz H2a′). C-
1
2
sodium bicarbonate solution and extracted with ethyl NMR spectrum in DMSO-d6 (δ, ppm): 171.9 (C1), 156.9
acetate. The combined organic layers were dried. The (C4″), 156.8 (C2), 136.5 (C5′), 129.1 (C1″), 128.9 (C2″, C6″),
residue was purified by column chromatography on 127.9 (C10′), 123.9 (C4′), 121.2 (C7′), 119.0 (C9′), 118.7 (C8′),
silica gel to yield TGN1–TGN4 (Scheme 1).
115.5 (C3″, C5″), 111.7 (C6′), 110.3 (C3′), 61.4 (C1′), 45.0
C7″), 27.9 (C2′). HRMS (ESI) m/z: 374.1590 [M + Na].
(
2
.2.7 (S)-2-Amino-N-(N-(4-hydroxyphenyl)carbamimid
oyl)-3-(1H-indol-3-yl)propanamide (TGN1)
2.2.9 (S)-2-Amino-N-(N-(4-hydroxyphenethyl)carbamimid
oyl)-3-(1H-indol-3-yl)propanamide (TGN3)
Compound Boc-TGN1 was purified by column chroma-
tography on silica gel (EtOAc/CHCl /Hex 2:7:1) to yield Compound Boc-TGN3 was purified by column chroma-
3
white powder. Compound TGN1 was purified by column tography on silica gel (EtOAc/CHCl /EtOAc 2:7:1) to yield
3
chromatography on silica gel (CHCl /EtOAc/MeOH 6:3:1) white powder. Compound TGN3 was purified by column
3
to yield white powder. Yield 190.75 mg (56.54%); m.p. = chromatography on silica gel (CHCl /EtOAc/MeOH 3:6:1)
3
−1
2
08 (d) °C. FTIR (ATR, υ, cm ): 3,417–3,018 (O–H, N–H), to yield yellow viscous (hygroscopic). Yield 266.68 mg
2 3 −1
3
,080 (sp C–H), 2,923 (sp C–H), 1,678, 1,588, 1,511 (62.03%). FTIR (ATR, υ, cm ): 3,387–3,120 (O–H, N–H),