Osthole: an overview of its sources, biological activities, and modification development

Abstract

Osthole, also known as osthol, is a coumarin derivative found in several medicinal plants such as Cnidium monnieri and Angelica pubescens. It can be obtained via extraction and separation from plants or total synthesis. Plenty of experiments have suggested that osthole exhibited multiple biological activities covering antitumor, anti-inflammatory, neuroprotective, osteogenic, cardiovascular protective, antimicrobial, and antiparasitic activities. In addition, there has been some research done on the optimization and modification of osthole. This article summarizes the comprehensive information regarding the sources and modification progress of osthole. It also introduces the up-to-date biological activities of osthole, which could be of great value for its use in future research.

Keywords: Biological activity; Modification; Osthole; Source; Synthesis.

Fig. 1

Structure of osthole

Fig. 2

Proposed pathway of osthole biosynthesis. PLA phenylalanine ammonia-lyase, C4H cinnamate-4-hydroxylase, 4CL 4-coumarate-CoA ligase, C2’H 4-Coumaroyl CoA 2′-hydroxylase, PT prenyltransferase, DMAPP dimethylallyl diphosphate, OMT O-methyltransferase

Scheme 1

Synthesis of osthole. Reagents and conditions: a ClCH₂COOC₂H₅, Ph₃P⁺-CH₂COOC₂H₅, CH₃CH₂OH, 80 °C, 2 h, 72%; b 3-Chloropropene, K₂CO₃, KI, acetone, 60 °C, 22 h, 90.6%; c ethylene glycol, reflux, 6 h; d (CH₃O)₂SO₂, K₂CO₃, KI, acetone, rt, 5 h, 94.6%; e 2-methyl-2-butylene, Grubbs 2nd catalyst, DCM, 45 °C, 2 h, 77.6%

Scheme 2

Synthesis of osthole. Reagents and conditions: a I₂/KI, 20% NH₃^.H₂O, rt; b MeI, K₂CO₃, acetone; c for reference [21]: tributyl(3-methylbut-2-en-1-yl)stannane (1.5 equiv), Pd(PPh₃)₄ (5 mol%), PPh₃(5 mol%), LiCl (4.0 equiv), DMF, 80 °C; for reference [22]: (1) i-PrMgCl, THF, −20 °C; (2) 1-bromo-3-methylbut-2-ene, CuI, LiCl, −20 °C to rt, 80%

Scheme 3

Synthesis of osthole. Reagents and conditions: a (1) AlCl₃, DCM, −20 °C; (2) NIS, −20 °C to rt, overnight, 88%; b PPh₃MeBr, NaH, THF, rt, 12 h, 46%; c [Cp*RhCl₂]₂ (2.5 mol%), Cu(OAc)₂^.H₂O (1.2 equiv), MeCN, 85 °C, 16 h, 37%; d tributyl(3-methylbut-2-en-1-yl)stannane, Pd(dppf)Cl₂, DMF, 125 °C, 5 h, 32%

Scheme 4

Synthesis of osthole. Reagents and conditions: a tert-butyl (2-methylbut-3-en-2-yl) carbonate, [Pd(PPh₃)₄] (1.0 mol%), THF, 0 °C, 87%; b 2-methylbut-3-yn-2-ol, TFAA, Cu(acac), DBU, MeCN, −5 to 0 °C, 5 h; c H₂ (1 atm), Pd/CaCO₃, EtOAc, rt; d for reference [24]: ethyl 2-(triphenylphosphoranylidene) acetate, N,N-diethylaniline (0.15 M), MW, 250 °C, 1 h, 68%; for reference [25]: methyl 2-(triphenylphosphoranylidene)acetate, MW (300 W), toluene, 185 °C, 1 h. (TFAA = trifluoroacetic anhydride, acac = acetylacetonate, DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene)

Scheme 5

Synthesis of osthole analogs 15. Reagents and conditions: a Lawesson reagent, THF, reflux, 24 h, 76%; b NH₂OH^.HCl, pyridine, reflux, 5 h, 70%; c RCOOH, DCC, DMAP, DCM, rt, 1–3 h, 32–98%

Scheme 6

Synthesis of osthole analogs 17. Reagents and conditions: a NaOH/DMSO, propargyl bromide, rt, 2 h; b RN₃, t-butanol/H₂O, CuSO₄^.5H₂O, sodium ascorbate, rt, 0.5–1 h

Scheme 7

Synthesis of osthole analog 20. Reagents and conditions: a (1) NaOH, EtOH, Δ, N₂, 6 h; (2) Dis-H₂O, 1 N HCl, pH 4-5; b 4-methoxy benzyl chloride, K₂CO₃, acetone, Δ, N₂, overnight; c (1) NH₂OH^.HCl, 10% KOH/MeOH, reflux, N₂, overnight; (2) Dis-H₂O, 1 N HCl, pH 5–6

Scheme 8

Synthesis of osthole analogs 24–27. Reagents and conditions: a Cys, NaH, DMF, reflux, 3 h, 82.38%; b 1,2-dibromoethane, K₂CO₃, DMF, rt, 48 h, 42.3%; c 1-bromo-3-chloropropane, K₂CO₃, DMF, 60 °C, 48 h, 82.3%; d 1-arylpiperazine, K₂CO₃, KI, DMF, rt, 48 h; e 1-arylpiperazine, K₂CO₃, KI, DMF, 70 °C, 48 h

Scheme 9

Synthesis of osthole analogs 30 and 31. Reagents and conditions: a BBr₃, DCM, −40 °C to rt, 3 h, 92%; b 2-bromoacetyl bromide, K₂CO₃, DCM, rt, 3 h; c K₂CO₃, DMF, 90 °C, 4 h, 65% (30), 59% (31)

Scheme 10

Synthesis of osthole analogs 32 and 33. Reagents and conditions: a Cys, NaH, DMF; b R₁NH₂, BTC, DIPEA; c R₂COCH₂Cl, K₂CO₃, MeCN, reflux

Fig. 3

Predicted binding modes of compound 33a with Aβ₄₂ (1IYT)

Scheme 11

Synthesis of osthole analogs 35a–35e. Reagents and conditions: a SeO₂, DMSO, EtOH, 90 °C, 3 h; b RNH₂/hydroxylamine hydrochloride, EtOH, reflux, 2–5 h

Scheme 12

Synthesis of osthole analogs 41a–41g. Reagents and conditions: a m-CPBA, DCM, rt, 24 h; b NaIO₄, acetone/H₂O, 80 °C, 6 h; c Jones reagent, acetone, rt, 1 h; d (1) SOCl₂, reflux, 2 h; (2) R₁R₂C₆H₄, AlCl₃, nitrobenzene, 10–15 °C, 1 h; (3) 10% HCl solution; e solution of NaBH₄ in EtOH, pyridine, DCM, 60 °C, 6 h; f P₂O₅, toluene/CHCl₃, 15 °C; g 12 mol/L HCl, MeOH/CHCl₃; h HOAc, H₂O

Scheme 13

Synthesis of osthole analogs 42–44. Reagents and conditions: a SeO₂, dioxane, EtOH, 60–80 °C, 1.5 h; b R₁NHNH₂, AcOH, EtOH, reflux, 0.5–1 h; c R₂CONHNH₂, AcOH, EtOH, reflux, 0.5–1 h; d R₃SO₂NHNH₂, EtOH, rt, 1–2 h

Scheme 14

Synthesis of osthole analogs 46. Reagents and conditions: a NH₂OH^.HCl, NaOH, EtOH/H₂O, rt, 24 h, 74%; b RCOOH, DCC or EDC/DMAP, DCM, rt, 8 h, 15–95%

Scheme 15

Synthesis of osthole analogs 48, 50, and 51. Reagents and conditions: a NaClO₂, NaH₂PO₄, t-BuOH, 2-methyl-2-butene, 40 °C; b R₁NH₂, DCC, DCM, rt; c NaBH₃, EtOH, rt; d R₂COOH, DCC, DMAP, DCM, rt; e R₃SO₂Cl, TEA, DCM, rt

Scheme 16

Synthesis of osthole analogs 52a and 52b. Reagents and conditions: a HBr in CCl₄ or NaBr/EtOH for 52a, HI in CCl₄ or NaI/EtOH for 52b

Scheme 17

Synthesis of osthole analogs 53. Reagents and conditions: a I₂, KI, K₂CO₃, H₂O, 30 °C; b MeI, K₂CO₃, acetone, 55 °C; c ArB(OH)₂, Pd(PPh₃)Cl₂, Cs₂CO₃, toluene, 110 °C

Scheme 18

Synthesis of osthole analogs 57–62. Reagents and conditions: a H₂, Pd/C, DCM/EtOH, 21%; b Pd/C, mesitylene, reflux, 72%; c BBr₃, DCM, −78 °C, 69%; d ROH, Ph₃P, diethyl azodicarboxylate, toluene. rt, e RCOCl, Et₃N, DCM, rt; f (1) (CF₃SO₂)₂O, Et₃N, DCM, 0 °C; (2)1,1-bis(diphenylphosphino)ferrocene, Pd(OAc)₂, HCOOH, DMF, 60 °C, 50%; g m-CPBA, DCM, 0 °C, 88%; h H₂SO₄, THF/H₂O, rt, 73%; i BF₃^.OEt₂, H₂O/DCM, rt, 52%; j Br₂, DCM, 0 °C, 34%

Scheme 19

Synthesis of osthole analog 64. Reagents and conditions: a AlCl₃, ethanethiol, DCM, 0 °C to rt, 24 h, 76%; b dimethyl sulfide, AlCl₃, DCM, 0 °C to rt, 24 h, 62%

Scheme 20

Synthesis of osthole analogs 66 and 67. Reagents and conditions: a PtO₂, H₂, 24 h, 80%; b NBS, NaOAc, CH₃CN, MW, 2 h, 60%; c Pd(PPh₃)₄, phenylboronic acid, K₃PO₄, dioxane, 60–90%; d BBr₃, DCM, −78 °C, 40–70%

Scheme 21

Synthesis of osthole analogs 71. Reagents and conditions: a H₂, EtOAc, rt, 16 h, 92%; b BBr₃, DCM, N₂, 0 °C to rt, 2.5 h, 92%; c 1-bromo-2-chloroethane/1-bromo-3-chloropropane/1-bromo-4-chlorobutane, K₂CO₃, acetone, N₂, 56 °C, 16 h, 81–85%; d methyl 4/3/2-hydroxycinnamate, K₂CO₃, DMF, N₂, rt, 16 h, 51–60%; e LiOH, MeOH, N₂, 63 °C, 16 h, 93–97%; f (1) ClCO₂Et, Et₃N, THF, rt, 1 h; (2) NH₂OH^.HCl, KOH, MeOH, rt, 3 h, 52–64%

Fig. 4

Molecular modeling results of compounds 71d (blue) and SAHA (magenta) docked to HDLP (PDB code: 1C3R; surface representation)

Scheme 22

Synthesis of osthole analogs 76–78. Reagents and conditions: a Pd-C, mesitylene, Δ, 16 h, 81%; b BBr₃, DCM, N₂, 0 °C to rt, 2.5 h, 89–92%; c for 72, bromo-substituted methyl aliphatic acid esters, NaH, 18-crown-6, TBAI, DMF, rt, 74–85%; for 73, bromo-substituted methyl aliphatic acid esters, K₂CO₃, 18-crown-6, TBAI, acetone, Δ, 2 h, 81–89%; d LiOH, MeOH, Δ, 2 h, 91–95%; e (1) ClCO₂Et, Et₃N, THF, rt, 1 h; (2) 2 equiv NH₂OH, KOH, MeOH, rt, 3 h, 38–65%; f (1) ClCO₂Et, Et₃N, THF, rt, 1 h; (2) 8 equiv NH₂OH, KOH, MeOH, rt, 3 h, 59–65%

Fig. 5

Molecular modeling results of compounds 76c (magenta) and 78c (green) docked to HDAC8. SAHA is shown in gray sticks

Scheme 23

Synthesis of osthole analogs 82 and 84. Reagents and conditions: a ClCH₂COOC₂H₅, Ph₃P⁺-CH₂COOC₂H₅, CH₃CH₂OH, 80 °C, 2 h, 72%; b 3-chloropropene/3-chloro-3-methyl-1-butylene/3-chloro-2-methyl-1-propene, K₂CO₃, KI, acetone, 60 °C, 22–24 h, 83–90%; c ethylene glycol, reflux, 6 h; d 3-chloropropene/3-chloro-2-methyl-1-propene/3-chloro-3-methyl-1-butylene/(CH₃O)₂SO₂, K₂CO₃, KI, acetone, rt - 60 °C, 5–22 h, 60–98%; e ethyl acetoacetate, H₂SO₄, ice bath, 16 h, 90%

Fig. 6

Structure of compounds 83 and 84

Scheme 24

Synthesis of osthole analogs 86a–86k. Reagents and conditions: a (1) i-PrMgCl, THF, −20 °C; (2) 1-bromo-3-methylbut-2-ene, CuI, LiCl, −20 °C to rt, 43–83%

Fig. 7

Reported modifications of osthole