Synthesis and Biological Evaluation of Acetylcholinesterase Inhibitor Macakurzin C and Its Derivatives

Abstract

The derivatives of macakurzin C containing a modified D ring and protected C(3)/C(5)-hydroxyl groups were synthesized and their in vitro AChE inhibitory activity and neurotoxicity were evaluated to identify the structural requirements for the activities. The results indicated that C(3)-benzyl-protected derivative has a more potent AChE inhibitory activity (IC₅₀, 2.6 μM) and a less neurotoxicity (GI₅₀, >100 μM) than synthetic macakurzin C (IC₅₀, 9.1 μM; GI₅₀, 16.6 μM).

Key words

natural products - macakurzin C - aromatic Claisen rearrangement - acetylcholinesterase inhibitors - tandem reaction

• References and Notes

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• 4 Macakurzin C was synthesized in very poor yield (<3% overall yield) by a prenylation of glalangin and DDQ-mediated oxidative cyclization of the resultant C(6)-prenylated galangin, see: Jain AC, Zutshi MK. Tetrahedron 1973; 29: 3347
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For a recent aromatic Claisen rearrangement, see:
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• 7 Preparation of 4a A solution of aryl propargyl ether 9 (280.4 mg, 0.658 mmol) in diethylaniline (20 mL) was stirred at 270 °C for 3 h. The reaction mixture was concentrated in vacuo and purified by column chromatography (silica gel; hexanes–EtOAc, 10:1 to 5:1) to afford Claisen adduct (159.8 mg, 57%) as a yellow solid (mp 132–133 °C). ¹H NMR (400 MHz, CDCl₃): δ = 12.72 (s, 1 H), 7.98–7.95 (m, 2 H), 7.51–7.43 (m, 3 H), 7.31–7.24 (m, 5 H), 6.72 (d, J = 9.6 Hz, 1 H), 6.28 (s, 1 H), 5.58 (d, J = 10.0 Hz, 1 H), 5.08 (s, 2 H), 1.48 (s, 6 H). ¹³C NMR (100 MHz, CDCl₃): δ = 178.8, 161.5, 159.4, 156.1, 151.0, 137.9, 136.2, 130.74, 130.57, 128.72, 128.53, 128.36, 128.20, 128.15, 127.3, 114.7, 105.9, 101.2, 100.0, 78.2, 74.4, 28.4. To a cooled solution (–30 °C) of the above Claisen adduct (159.8 mg, 0.375 mmol) in CH₂Cl₂ (5 mL) was added BCl₃ (0.75 mL, 1.0 M solution in toluene, 0.750 mmol), and the resulting mixture was stirred for 1 h at the same temperature before quenched with H₂O (100 mL) and diluted with EtOAc (30 mL). The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated in vacuo. The residue was purified by column chromatography (silica gel; hexanes–EtOAc, 4:1 to 2:1) to afford C(7)/C(8)-derivative 4a (109.3 mg, 87%) as a yellow solid (mp 223–224 °C). ¹H NMR (400 MHz, CDCl₃): δ = 11.72 (s, 1 H), 8.20–8.17 (m, 2 H), 7.56–7.46 (m, 3 H), 6.82 (d, J = 10.0 Hz, 1 H), 6.66 (s, 1 H), 6.30 (s, 1 H), 5.62 (d, J = 10.0 Hz, 1 H), 1.49 (s, 6 H). ¹³C NMR (100 MHz, CDCl₃): δ = 175.4, 160.4, 159.9, 151.0, 144.8, 136.6, 131.9, 130.3, 128.7, 127.50, 127.40, 114.8, 103.8, 101.5, 99.9, 78.4, 28.5. Preparation of 5a A solution of aryl propargyl ether 10 (194.9 mg, 0.382 mmol) in diethylaniline (20 mL) was stirred at 270 °C for 4 h. The reaction mixture was concentrated in vacuo and purified by column chromatography (silica gel; hexanes–EtOAc, 10:1 to 5:1) to afford Claisen adduct (170.2 mg, 87%) as a light red solid (mp 205–206 °C). ¹H NMR (400 MHz, CDCl₃): δ = 7.97–7.93 (m, 2 H), 7.42–7.36 (m, 3 H), 7.34–7.30 (m, 2 H), 7.28–7.22 (m, 3 H), 6.72 (s, 1 H), 6.68 (dd, J = 10.0, 0.8 Hz, 1 H), 5.61 (d, J = 10.0 Hz, 1 H), 5.55 (s, 1 H), 5.09 (s, 2 H), 3.86 (ddd, J = 10.8, 10.8, 2.4 Hz, 1 H), 3.68 (ddd, J = 11.2, 11.2, 4.0 Hz, 1 H), 2.05–1.90 (m, 3 H), 1.77–1.54 (m, 3 H), 1.59 (s, 6 H). ¹³C NMR (100 MHz, CDCl₃): δ = 173.7, 157.3, 155.6, 154.0, 153.5, 139.7, 136.8, 130.8, 129.9, 128.6, 128.3, 128.2, 128.0, 127.9, 127.7, 116.0, 108.0, 96.2, 94.6, 77.4, 74.1, 62.0, 30.1, 27.86, 27.77, 25.1, 18.5. To a cooled solution (–30 °C) of the above Claisen adduct (104.3 mg, 0.204 mmol) in CH₂Cl₂ (5 mL) was added BCl₃ (0.62 mL, 1.0 M solution in toluene, 0.620 mmol), and the resulting mixture was stirred for 2 h at the same temperature before quenched with H₂O (100 mL) and diluted with EtOAc (100 mL). The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated in vacuo. The residue was purified by column chromatography (silica gel; hexanes–EtOAc, 4:1 to 2:1) to afford C(5)/C(6)-derivative 5a (49.5 mg, 72%) as a yellow solid (mp 189–190 °C). ¹H NMR (400 MHz, DMSO): δ = 8.98 (s, 1 H), 8.10 (d, J = 8.4 Hz, 2 H), 7.53 (dd, J = 7.2, 7.2 Hz, 2 H), 7.45 (dd, J = 5.2, 5.2 Hz, 1 H), 7.30 (s, 1 H), 6.57 (d, J = 10.0 Hz, 1 H), 6.48 (s, 1 H), 5.66 (d, J = 10.0 Hz, 1 H), 1.44 (s, 6 H).
• 8 Liu J, Li L, Suo WZ. Life Sci. 2009; 84: 267