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Article

Synthesis of ∆3-2-Hydroxybakuchiol Analogues and Their Growth Inhibitory Activity against Rat UMR106 Cells

by
Qun Zhao
1,
Qianqian Xu
1,
Guangsheng Shan
1,
Chao Dong
1,
Hong Zhang
2,* and
Xinsheng Lei
1,3,*
1
School of Pharmacy, Fudan University, Shanghai 201203, China
2
Department of Pharmaceutical Botany, School of Pharmacy, Second Military Medical University, Shanghai 200433, China
3
Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
*
Authors to whom correspondence should be addressed.
Molecules 2014, 19(2), 2213-2225; https://doi.org/10.3390/molecules19022213
Submission received: 17 January 2014 / Revised: 9 February 2014 / Accepted: 11 February 2014 / Published: 20 February 2014
(This article belongs to the Section Medicinal Chemistry)
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Versions Notes

Abstract

:
A series of ∆3-2-hydroxybakuchiol analogues have been synthesized and tested for their growth inhibitory activity against rat UMR106 cells by using the MTT method. Some of them exhibit enhanced activities compared with the natural product, and the preliminary SAR profile shows that the chain tail on the natural product could be subtly modified to enhance the activity and the aromatic moiety or the terminal olefin on the main chain can also be modified without any evident loss of activity. The stereo-configuration of the quaternary chiral center has an important influence on the activity.

1. Introduction

Natural products from plants are an important source of potential therapeutic agents for human health. The medicinal plant Psoralea coryliforlia L., a member of the Leguminosae family, has been used for a long time as a Traditional Chinese Medicine for the treatment of premature ejaculation, knee pain, pollakiuria, callus, psoriasis, vitiligo and psoriasis [1]. The seed extract has been suggested as a useful remedy for bone fractures, osteomalacia and osteoporosis [2]. A number of monoterpene phenols occurring in the plant have been isolated and demonstrated to possess interesting biological activities [3,4,5,6,7], and among them, bakuchiol (15b, Figure 1), one of the major components in the plant seed, has attracted great attention due to its diverse activities, such as antibacterial, antihelminthic, antioxidant, and especially antitumor properties [8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23]. In contrast to that, ∆3-2-hydroxybakuchiol (15a), a congener of bakuchiol, has not attracted much interest among medicinal chemists, probably due to its scarcity and lability [24,25]. To the best of our knowledge, only Guo and co-workers have recently investigated its inhibitory effects against monoamine transporters, suggesting that it might be a potential psychopharmacologic agent for the treatment of psychogenic disorders [26].
Given the fact that the analog bakuchiol shows various biological activities, we have put ∆3-2-hydroxybakuchiol into our natural product-based drug discovery program [27,28,29,30]. Recently, a facile asymmetric synthesis of ∆3-2-hydroxybakuchiol was established and the compound was tested for antiosteoporosis effects [31,32]. Unexpectedly, this natural product did not show the desired activity, but it exhibited growth inhibitory activity against osteosarcoma cells (rat UMR106 cell) with an IC50 value of 69 µM, suggesting that it was worthy of further investigation [33].
Molecules 19 02213 g001 550
Figure 1. The structures of bakuchiol (15b) and ∆3-2-hydroxybakuchiol (15a) and the proposed modifications.
Figure 1. The structures of bakuchiol (15b) and ∆3-2-hydroxybakuchiol (15a) and the proposed modifications.
Molecules 19 02213 g001
Herein the synthesis of ∆3-2-hydroxybakuchiol analogues was described and their growth inhibitory activity against rat UMR106 cells was demonstrated. The preliminary structure-activity relationship knowledge of this natural product has been obtained by modifying the substituent (G) on the aromatic ring and the R1 group on the chain, while keeping the main chain unchanged. In addition, we would also replace the terminal olefin with an ethyl moiety (R2) in order to probe the effect of this moiety on the activity (Figure 1).

2. Results and Discussion

2.1. Chemistry

Our synthetic approach to the analogues of ∆3-2-hydroxybakuchiol is depicted in Scheme 1. Starting from (E)-2-methylbut-2-enoyl chloride and (R)-4-isopropyloxazolidin-2-one, the α,β-unsaturated imide 3 bearing an Evans’ auxiliary was prepared in excellent yield. Then, the a-alkylation of 3 with tert-butyl iodoacetate afforded the fragment 4 in a moderate yield with an excellent diastereoselectivity (dr > 20: 1). After selective reduction of the imide group, the key chiral intermediate 5 was obtained in an acceptable yield. To avoid the formation of the volatile lactone from 5, the free hydroxyl group in 5 was protected with a TBS group to afford compound 6. Upon reduction of the ester group and subsequent oxidation, compound 8a was prepared in 94% yield (over two steps).
Molecules 19 02213 g002 550
Scheme 1. Synthetic approach to the analogues of ∆3-2-hydroxybakuchiol.
Scheme 1. Synthetic approach to the analogues of ∆3-2-hydroxybakuchiol.
Molecules 19 02213 g002
Reagents and conditions: (a) n-BuLi, THF, 96%; (b) NaHMDS, −78 ○C, 1.5 h; ICH2CO2But, −50 ○C, 6 h, 68%; (c) LiBH4, THF, 0 ○C, 3 h, 70%; (d) TBSCl, imidazole, CH2Cl2, rt, 3 h, 84%; (e) DIBALH, CH2Cl2, −78 ○C, 2 h; (f) IBX, DMSO, rt, 5 h, for 8a: 94%; for 8b: 100%; two steps; (g) Ph3P=CHCO2Et, toluene, reflux, 2 h, for 9a: 92%; for 9b: 81%; (h) HCl, EtOH, 0 ○C, 7 h, for 10a: 97%; for 10b: 86%; (i) IBX, DMSO, rt, 5 h, for 11a: 95%; for 11b: 97%; (j) CHI3, CrCl2, THF, 0 ○C, 3 h, for 12a: 86%; for 12b: 80%; (k) ArBr, n-BuLi/ZnCl2; Pd(OAc)2/PPh3, THF, 60%–98%; (l) RLi, THF, rt, 5 h, up to 34%–100%; for 14b, 14h–j, additional step required for deprotection of TBDPS group: Bu4NF, THF, quantitative yield; (m) H2, Pd/C (10%), rt, overnight, 100%.
Compound 8a successfully underwent a Wittig reaction to afford the α,β-unsaturated ester 9a. Next, the TBS group was removed and oxidized to afford the corresponding aldehyde 11a in 92% yield (over two steps). Through a Takai-Utimoto reaction with CrCl2 and CHI3, the trans-iodo-olefin 12a was obtained in up to 86% yield. The iodo-olefin was coupled with different substituted aryl zinc species via the Negishi reaction to give the desired cross-coupling product 13a,c–f, respectively. After selective 1,2-addition reactions of the esters 13a, c–g with alkyllithiums, the corresponding products 14a, c–j were obtained in acceptable (up to 73%) yields.
In order to assess the effect of the terminal olefin moiety in ∆3-2-hydroxybakuchiol on the biological activity, compound 14b was prepared. Hydrogenation of 7a provided saturated alcohol 7b in a quantitative yield which was successfully transformed into 14b by a method similar to that shown in Scheme 1. As positive control, bakuchiol (15b) and its methyl ether (15c), together with their corresponding enantiomers 15d and 15e, were also prepared according to our recently reported method [31].

2.2. Activity against Rat UMR106 Cell

With the various analogues of ∆3-2-hydroxybakuchiol in hand, their cytotoxic activity against rat UMR106 osteosarcoma cells was tested by the MTT assay after two days of treatment [34] and the results are shown in Table 1.
Among those compounds, ∆3-2-hydroxybakuchiol (15a) displayed the expected [33] cytotoxic activity with an IC50 value of 69 µM (Entry 21, Table 1). When the chain tail was modified with an α,β-unsaturated ester (compound 13a), the activity increased (IC50: 27 µM, Entry 1) compared with 14a (IC50: 66 µM, Entry 7). When the methoxy group was replaced with other substituent (compounds 13c–g), the corresponding activity was significantly reduced (IC50: > 263 µM, Entries 2–6), suggesting that the substituent on the aromatic ring had an important influence on the activity in the case of α,β-unsaturated ester analogues.
When the modifications were performed only on the aromatic moiety of ∆3-2-hydroxybakuchiol, the substituent effect seemed to have somewhat of an effect on the activity (compounds 14a, c, d, f). For example, the activity was still retained in the case of a para-methoxy (14a; Entry 7), but other groups such as H and para-methyl led to slightly reduced activities (14c, 14d; Entries 8 and 9). Notably, a strong electron-withdrawing group gave a slightly increased activity (14f, Entry 11). When a larger bulky group was used (compounds 14e,g; Entries 10 and 12), the activity was just slightly decreased. Surprisingly, if the phenolic hydroxyl was moved to the meta-position (14h), its IC50 value was still up to 123 µM, with about one-fold reduced activity in contrast to ∆3-2-hydroxybakuchiol (Entry 13). Modification on the R1 group (14i,j) in the tertiary alcohol moiety suggested that this domain could accommodate a bulky hydrophobic space, and 14j gave the best result (IC50: 17 µM; Entries 14 and 15). In addition, the terminal double bond could be saturated without influence on the activity, implied by the almost identical activities of 14b (IC50: 71 µM; Entry 16) and ∆3-2-hydroxybakuchiol.
On the other hand, bakuchiol (15b), with a slight structural difference on the chain tail of ∆3-2-hydroxybakuchiol, showed almost the same potency (IC50: 62 µM, Entry 18). Interestingly, ent-bakuchiol (15d) had a one-fold enhanced activity (IC50: 33 µM, Entry 20). However, in comparison with (S- or R)bakuchiol methyl ether showed different influences on the activity, namely, (S)-bakuchiol methyl ether (15c) maintained the activity (IC50: 60 µM, Entry 17) but (R)-bakuchiol methyl ether (15e) gave less activity (IC50: 161 µM, Entry 19), indicating that the stereochemistry played an important role to the activity.
Table
Table 1. Cytotoxic activities of ∆3-2-hydroxybakuchiol and its analogues against rat UMR106 osteosarcoma cell.
Table 1. Cytotoxic activities of ∆3-2-hydroxybakuchiol and its analogues against rat UMR106 osteosarcoma cell.
Molecules 19 02213 i001
EntryComp.ArR1R2IC50 (µM)
113a4-MeO-C6H4CO2EtCH=CH227
213cC6H5CO2EtCH=CH2330
313d4-Me-C6H4CO2EtCH=CH2263
413e2-C10H7CO2EtCH=CH2>500
513f4-CF3-C6H4CO2EtCH=CH2242
613g3,4-OCH2O-C6H4CO2EtCH=CH2511
714a4-MeO-C6H4Me2CH(OH)CH=CH266
814cC6H5Me2CH(OH)CH=CH2107
914d4-Me-C6H4Me2CH(OH)CH=CH287
1014e2-C10H7Me2CH(OH)CH=CH2128
1114f4-CF3-C6H4Me2CH(OH)CH=CH246
1214g3,4-OCH2O-C6H4Me2CH(OH)CH=CH2115
1314h3-HO-C6H4Me2CH(OH)CH=CH2123
1414i4-HO-C6H4Et2CH(OH)CH=CH257
1514j4-HO-C6H4n-Bu2CH(OH)CH=CH217
1614b4-HO-C6H4Me2CH(OH)CH2CH371
17bakuchiol methyl ether (15c) Molecules 19 02213 i00260
18bakuchiol (15b) Molecules 19 02213 i00362
19ent-bakuchiol methyl ether (15e) Molecules 19 02213 i004161
20ent-bakuchiol (15d) Molecules 19 02213 i00533
21∆3-2-hydroxybakuchiol (15a) Molecules 19 02213 i00669

3. Experimental

3.1. General Information

Solvents were distilled from the appropriate drying agents before use. All the reagents were purchased from Acros (Shanghai, China), Alfa Aesar (Shanghai, China), and National Chemical Reagents Group Co. Ltd (Shanghai, China). Unless otherwise stated, all the reactions were performed under argon. Column chromatography: commercial silica gel (Qingdao Haiyang Chemical Group Co.; 300–400 mesh, Qingdao, China). Spots on the TLC plates (GF 254, Yantai Jiangyou Silica R&D Co. Ltd., Yantai, China) were detected under UV light or with iodine, KMnO4, and H3PO4·12MoO3·xH2O. 1H and 13C-NMR spectra (400 MHz for 1H, and 100 MHz for 13C): Varian Mercury-Plus (Palo Alto, CA, USA) spectrometer; chemical shifts δ in parts per million, with residual CHCl3 [d (H) 7.26; d (C) 77.0] as internal standard; J in Hertz. ESI-MS and HR-APCI/ESI-MS: Finnigan Mat-95 mass spectrometer (Waltham, MA, USA); in m/z. Compounds 3–7a, 8–14a, ∆3-2-hydroxybakuchiol, (S)-bakuchiol and (R)-bakuchiol as well as their corresponding methyl ethers (15a–e) were prepared by our previously reported method [32].

3.2. Synthetic Procedures for the New Compounds

(R)-3-(((tert-Butyldimethylsilyl)oxy)methyl)-3-methylpentan-1-ol (7b). A mixture of (S)-3-(((tert-butyldimethylsilyl)oxy)methyl)-3-methylpent-4-en-1-ol (1.0 g, 4.09 mmol) and Pd/C (100 mg, 10% w/w) in methanol (20 mL) was purged with H2 gas and was stirred overnight at room temperature under H2. The reaction mixture was directly passed through a pad of silica gel with ethyl acetate and the solvent was removed under vacuum. The residue was purified by column chromatography (petroleum ether/ethyl acetate 10:1) to afford 7b (1.01 g, 100%) as a colorless oil. Rf = 0.26 (petroleum ether/ethyl acetate 10:1), Molecules 19 02213 i007 +4.8 (c 0.65, CHCl3). 1H-NMR (CDCl3) δ 3.64 (t, J = 5.6 Hz, 2H), 3.41 (brs, 1H), 3.39 (d, J = 10.0 Hz, 1H), 3.34 (d, J = 10.0 Hz, 1H), 1.64–1.48 (m, 2H), 1.39–1.20 (m, 2H), 0.91 (s, 9H), 0.85–0.78 (m, 6H), 0.08 (s, 6H). 13C-NMR (CDCl3) δ 70.6, 58.8, 41.2, 37.4, 29.6, 25.8, 21.7, 18.2, 7.7, −5.6. ESI-MS: 247.1 [M+H], HRMS (ESI): Calcd. for C13H30O2Si [M+H]: 247.2088, found: 247.2091.
(R)-3-(((tert-Butyldimethylsilyl)oxy)methyl)-3-methylpentanal (8b). IBX (1.71 g, 4.9 mmol) was added to a solution of 7b (1.01 g, 4.09 mmol) in DMSO (20 mL). The mixture was stirred overnight at room temperature. Then the mixture was diluted with ethyl acetate (200 mL) and washed successively with saturated NaHCO3 aq. solution (30 mL × 2), water (30 mL), brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate 20:1) to afford 8b (1.00 g, 99%) as a colorless oil. Rf = 0.74 (petroleum ether/ethyl acetate = 10:1), Molecules 19 02213 i007 −2.6 (c 0.50, CHCl3). 1H-NMR (CDCl3) δ 9.84 (t, J = 3.1 Hz, 1H), 3.42 (d, J = 9.7 Hz, 1H), 3.35 (d, J = 9.7 Hz, 1H), 2.32–2.21 (m, 2H), 1.46–1.37 (m, 2H), 0.96 (s, 3H), 0.92–0.83 (m, 12H), 0.03 (s, 6H). 13C-NMR (CDCl3) δ 203.8, 69.6, 51.0, 42.2, 37.8, 29.4, 25.8, 21.3, 7.9, −5.6. ESI-MS: 283.7 [M+K].
(R,E)-Ethyl 5-(((tert-butyldimethylsilyl)oxy)methyl)-5-methylhept-2-enoate (9b). To a solution of 8b (0.978 g, 4.0 mmol) in toluene (10 mL) was added a solution of ethyl-2-(triphenyl-phosphoranylidene)acetate (1.71 g, 4.9 mmol) in toluene (10 mL). The mixture was stirred for 2 h under argon at reflux and then cooled to rt. The reaction mixture was concentrated under reduced pressure, diluted with ether (50 mL) and filtered. The filter cake was washed successively with ether (10 mL) and petroleum ether (10 mL). The combined filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate 80:1) to afford 9b (0.953 g, 81%) as a colorless oil. Rf = 0.60 (petroleum ether/ethyl acetate = 20:1), Molecules 19 02213 i007 −11.5 (c 0.60, CHCl3). 1H-NMR (CDCl3) δ 6.97 (dt, J = 15.7, 7.9 Hz, 1H), 5.81 (d, J = 15.7 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H), 3.28 (d, J = 9.7 Hz, 1H), 3.23 (d, J = 9.7 Hz, 1H), 2.14 (d, J = 7.9 Hz, 2H), 1.28 (t, J = 7.1 Hz, 3H), 0.89 (s, 9H), 0.85–0.76 (m, 6H), 0.02 (s, 6H). 13C-NMR (CDCl3) δ 166.6, 146.8, 123.2, 68.6, 60.1, 39.4, 38.8, 29.0, 3.82, 21.1, 18.2, 14.3, 7.8, −5.6. ESI-MS: 315.2 [M+H], HRMS(ESI): Calcd. for C17H35O3Si [M+H]: 315.2350, found: 315.2356.
(R,E)-Ethyl-5-(hydroxymethyl)-5-methylhept-2-enoate (10b). To a solution of 9b (950 mg, 3.02 mmol) in methanol (10 mL) at 0 ○C was added concentrated hydrochloric acid (0.75 mL). The mixture was stirred for 7 h at rt. The reaction was quenched with saturated NaHCO3 (10 mL). The mixture was concentrated under reduced pressure. The residue was extracted with ethyl acetate (15 mL × 3). The organic phase was combined, washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate 20:1) to afford 10b (517 mg, 86%) as a colorless oil. Rf = 0.81 (petroleum ether/ethyl acetate = 5:1), Molecules 19 02213 i007 −14.7 (c 0.60, CHCl3). 1H-NMR (CDCl3) δ 7.10–6.88 (m, 1H), 5.86 (ddd, J = 15.5, 3.0, 1.7 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 3.40 (d, J = 10.8 Hz, 1H), 3.36 (d, J = 10.8 Hz, 1H), 2.18 (dd, J = 7.9, 1.3 Hz, 2H), 1.37–1.25 (m, 5H), 0.91–0.81 (m, 6H). 13C-NMR (CDCl3) δ 166.4, 146.0, 123.6, 68.9, 60.2, 39.1, 38.6, 28.8, 21.1, 14.33, 7.8. ESI-MS: 201.1 [M+H], HRMS(ESI): Calcd. for C11H21O3 [M+H]: 201.1485, found: 201.1489.
(R,E)-Ethyl 5-formyl-5-methylhept-2-enoate (11b). Compound 10b (447 mg, 2.23 mmol) and IBX (938 mg, 3.4 mmol) in a 100 mL flask was dissolved with DMSO (20 mL). The mixture was stirred overnight at rt. Then the mixture was diluted with ethyl acetate (300 mL), washed successively with saturated NaHCO3 aq. solution (40 mL × 2), water (40 mL), brine (40 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate 20:1) to afford 11b (430 mg, 97%) as a colorless oil. Rf = 0.74 (petroleum ether/ethyl acetate = 5:1), Molecules 19 02213 i007 −21.6 (c 0.45, CHCl3) 1H-NMR (CDCl3) δ 7.04–6.89 (m, 1H), 5.86 (ddd, J = 15.5, 3.0, 1.7 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 3.40 (d, J = 10.8 Hz, 1H), 3.36 (d, J = 10.8 Hz, 1H), 2.18 (dd, J = 7.9, 1.3 Hz, 2H), 1.44–1.22 (m, 5H), 0.92–0.79 (m, 6H). 13C-NMR (CDCl3) δ 205.3, 166.0, 143.6, 124.6, 60.4, 49.3, 36.7, 27.9, 18.6, 14.2, 8.3. ESI-MS: 237.1, [M+K] HRMS(ESI): Calcd. for C11H19O3 [M+H]: 199.1329, found: 199.1331.
(R,2E,6E)-Ethyl 5-ethyl-7-iodo-5-methylhepta-2,6-dienoate (12b). To a suspension of anhydrous CrCl2 (1.85 g, 8.82 mmol) in THF (20 mL) at 0 ○C was added dropwise a solution of 11b (388 mg, 2.0 mmol) and CHI3 (1.16 g, 2.9 mmol) in THF (10 mL). After 3 h, the mixture was quenched with 10% Na2S2O3 aq. solution (20 mL). The mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate 50:1) to afford 12b (504 mg, 80%) as a colorless oil. Rf = 0.61 (petroleum ether/ethyl acetate = 10:1), Molecules 19 02213 i007 −39.2 (c 0.65, CHCl3) 1H-NMR (CDCl3) δ 6.96–6.75 (m, 1H), 6.44 (d, J = 14.7 Hz, 1H), 5.97 (d, J = 14.7 Hz, 1H), 5.82 (d, J = 15.5 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 2.26–2.13 (m, 2H), 1.43–1.24 (m, 5H), 0.98 (s, 3H), 0.82 (t, J = 7.1 Hz, 3H). 13C-NMR (CDCl3) δ 166.2, 153.2, 144.8, 124.0, 74.3, 60.2, 44.3, 42.6, 32.6, 22.1, 14.2, 8.4. ESI-MS: 323.0 [M+H], HRMS(ESI): Calcd. for C12H20IO2 [M+H]: 323.0502, found: 323.0511.
General procedure for the synthesis of compounds 13b–g, exemplified by (R,2E,6E)-ethyl 7-(4-((tert-butyldiphenylsilyl)oxy)phenyl)-5-ethyl-5-methylhepta-2,6-dienoate (13b). A dried flask was charged with ZnCl2 (300 mg, 2.2 mmol), and heated by a hot gun under vacuum until the ZnCl2 was melted. Then the flask was filled with Ar gas and cooled to rt. Anhydrous THF (5 mL) was added into the flask to dissolve the ZnCl2. Another dried flask was charged with 1-bromo-4-(t-BuPh2SiO)-C6H4Br (823 mg, 2.0 mmol) and THF (5 mL) under argon, and then cooled to −78 ○C. n-BuLi (0.8 mL, 2.0 mmol) was added dropwise to the bromoarene solution over 30 min, and stirring was continued for 30 min. Then the organolithium solution was added dropwise to the ZnCl2 solution at −78 ○C over 15 min, and the resulting solution was stirred at rt for 1 h. Meanwhile, a mixture of [Pd(OAc)2] (22 mg, 0.1 mmol), PPh3 (26 mg, 0.1 mmol) and THF (2 mL) was stirred at rt for about 30 min until the brown solution was formed, and this solution was added to the organozinc solution, followed by a solution of the 12b (322 mg, 1.0 mmol) in THF (2 mL). The mixed solution was stirred overnight at rt. The reaction solution was quenched with saturated NH4Cl aq. solution (15 mL), and extracted with ethyl acetate (15 mL × 3). The extract was washed with brine (15 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate 80:1) to afford 13b (463 mg, 88%) as a colorless oil. Rf = 0.43 (petroleum ether/ethyl acetate = 20:1), Molecules 19 02213 i007 −40.4 (c 0.50, CHCl3). 1H-NMR (CDCl3) δ 7.77–7.66 (m, 4H), 7.46–7.31 (m, 6H), 7.10 (d, J = 8.4 Hz, 2H), 6.91 (dt, J = 15.4, 7.6 Hz, 1H), 6.70 (d, J = 8.4 Hz, 2H), 6.16 (d, J = 16.3 Hz, 1H), 5.90 (d, J = 16.3 Hz, 1H), 5.81 (d, J = 15.5 Hz, 1H), 4.16 (q, J = 7.1 Hz, 2H), 2.31–2.18 (m, 2H), 1.49–1.33 (m, 2H), 1.26 (t, J = 7.1 Hz, 3H), 1.09 (s, 9H), 1.03 (s, 3H), 0.80 (t, J = 7.4 Hz, 3H). 13C-NMR (CDCl3) δ 166.4, 154.8, 146.2, 135.7, 135.5, 132.9, 130.6, 129.9, 127.8, 127.2, 126.9, 123.4, 119.6, 60.1, 43.7, 39.6, 33.5, 26.5, 19.4, 14.3, 8.5. ESI-MS: 527.2 [M+H].
(S,2E,6E)-Ethyl 5-methyl-7-phenyl-5-vinylhepta-2,6-dienoate (13c). Yield: 98%, Rf = 0.43 (petroleum ether/ethyl acetate = 20:1), Molecules 19 02213 i007 −3.1 (c 0.55, CHCl3). 1H-NMR (CDCl3) δ 7.39–7.17 (m, 5H), 6.93 (dt, J = 15.4, 7.6 Hz, 1H), 6.36 (d, J = 16.2 Hz, 1H), 6.20 (d, J = 16.2 Hz, 1H), 5.93–5.82 (m, 2H), 5.11 (d, J = 10.7 Hz, 1H), 5.06 (d, J = 17.5 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 2.41 (d, J = 7.6 Hz, 2H), 1.28 (t, J = 7.1 Hz, 3H), 1.23 (s, 3H). 13C-NMR (CDCl3) δ 166.3, 145.3, 144.4, 137.3, 136.4, 128.5, 128.1, 127.2, 126.2, 123.9, 113.1, 60.2, 43.8, 42.62, 23.7, 14.2. ESI-MS: 271.2 [M+H], 293.1 [M+Na], HRMS (ESI): Calcd. for C18H22O2Na [M+H]: 293.1512, found: 293.1518.
(S,2E,6E)-Ethyl-5-methyl-7-(p-tolyl)-5-vinylhepta-2,6-dienoate (13d) Yield: 82%, Rf = 0.41 (petroleum ether/ethyl acetate =20:1), Molecules 19 02213 i007 +3.3 (c 0.55, CHCl3). 1H-NMR (CDCl3) δ 7.25 (d, J = 7.7 Hz, 2H), 7.11 (d, J = 7.7 Hz, 2H), 6.92 (dt, J = 15.4, 7.6 Hz, 1H), 6.32 (d, J = 16.2 Hz, 1H), 6.14 (d, J = 16.2 Hz, 1H), 5.94–5.77 (m, 2H), 5.12–5.01 (m, 2H), 4.17 (q, 7.2 Hz, 2H), 2.40 (d, J = 7.4 Hz, 2H), 2.33 (s, 3H), 1.28 (t, J = 7.2 Hz, 3H), 1.21 (s, 3H). 13C-NMR (CDCl3) δ 166.3, 145.5, 144.6, 137.0, 135.4, 134.5, 129.2, 127.9, 126.1, 123.8, 113.0, 60.2, 43.8, 42.6, 23.7, 21.1, 14.2. ESI-MS: 307.1 [M+Na], HRMS(ESI): Calcd. for C19H25O2 [M+H]: 285.1849, found: 285.1855.
(S,2E,6E)-ethyl 5-methyl-7-(naphthalen-2-yl)-5-vinylhepta-2,6-dienoate (13e) Yield: 60%, Rf = 0.34 (petroleum ether/ethyl acetate =20:1), Molecules 19 02213 i007 −4.4 (c 0.50, CHCl3). 1H-NMR (CDCl3) δ 7.84–7.74 (m, 3H), 7.71 (s, 1H), 7.59 (d, J = 8.6 Hz, 1H), 7.50–7.37 (m, 2H), 6.96 (dt, J = 15.4, 7.5 Hz, 1H), 6.52 (d, J = 16.2 Hz, 1H), 6.33 (d, J = 16.2 Hz, 1H), 6.00–5.82 (m, 2H), 5.17–5.05 (m, 2H), 4.18 (q, 7.1 Hz, 2H), 2.46 (d, J = 7.5 Hz, 2H), 1.30–1.23 (m, 6H). ESI-MS: 343.3 [M+Na], HRMS (ESI): Calcd. for C22H25O2 [M+H]: 321.1849, found: 321.1857.
(S,2E,6E)-Ethyl-5-methyl-7-(4-(trifluoromethyl)phenyl)-5-vinylhepta-2,6-dienoate (13f). Yield: 90%, Rf = 0.41 (petroleum ether/ethyl acetate = 20:1), Molecules 19 02213 i007 +9.8 (c 0.50, CHCl3). 1H-NMR (CDCl3) δ 7.55 (d, J = 8.2 Hz, 2H), 7.45 (d, J = 8.2 Hz, 2H), 6.98–6.84 (m, 1H), 6.39 (d, J = 16.2 Hz, 1H), 6.29 (d, J = 16.2 Hz, 1H), 5.96–5.82 (m, 2H), 5.20–5.11 (m, 1H), 5.08 (dd, J = 17.4, 0.8 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H), 2.43 (dd, J = 7.6, 1.3 Hz, 2H), 1.28 (t, J = 7.1 Hz, 3H), 1.24 (s, 3H). 13C-NMR (CDCl3) δ 166.2 (C4), 144.9 (C7), 143.9 (C11), 140.8 (C15), 139.1 (C14), 128.9 (C18), 127.0 (C10), 126.3 (C16), 125.5 (C17), 124.1 (C5), 113.6 (13), 60.3 (C2), 43.6 (C8), 42.8 (C9), 23.5 (C12), 14.2 (C1).ESI-MS: 361.2 [M+Na], HRMS(ESI): Calcd. for C19H22F3O2 [M+H]: 339.1566, found: 339.1575.
(S,2E,6E)-Ethyl-7-(benzo[d] [1,3] dioxol-5-yl)-5-methyl-5-vinylhepta-2,6-dienoate (13g). Yield: 96%, Rf = 0.30 (petroleum ether/ethyl acetate = 20:1), Molecules 19 02213 i007 −15.0 (c 0.50, CHCl3). 1H-NMR (CDCl3) δ 6.97–6.86 (m, 2H, C(7)H, C(20)H), 6.81–6.71 (m, 2H, C(16)H, C(17)H), 6.26 (d, J = 16.2 Hz, 1H, C(14)H), 6.02 (d, J = 16.2 Hz, 1H, C(10)H), 5.94 (s, 2H, C(22)H), 5.92–5.81 (m, 2H, C(5)H, C(11)H), 5.10 (dd, J = 10.7, 0.7 Hz, 1H, C(13)H), 5.05 (d, J = 17.5 Hz, 1H, C(13)H), 4.18 (q, J = 7.1 Hz, 2H, C(2)H2), 2.42–2.36 (m, 2H, C(8)H), 1.28 (t, J = 7.1 Hz, 3H, C(1)H), 1.20 (s, 3H, C(12)H3). 13C-NMR (CDCl3) δ 166.3 (C(4)), 147.9 (C(19)), 146.9 (C(18)), 145.4 (C(7)), 144.5 (C(11)), 134.7 (C(14)), 131.8 (C(15)), 127.6 (C(10)), 123.8 (C(5)), 120.7, 113.0 (C(13)), 108.2, 105.5, 101.0 (C(16), C(17), C(20)), 60.2 (C(2)), 43.8 (C(8)), 42.5 (C(9)), 23.7 (C(12)), 14.2 (C(1)). ESI-MS: 315.2[M+H], 337.2 [M+Na], HRMS(ESI): Calcd. for C19H23O4 [M+H]: 315.1591, found: 315.1602.
General procedure for the synthesis for 14b–g, exemplified by 4-((R,1E,5E)-3-ethyl-7-hydroxy-3,7-dimethylocta-1,5-dien-1-yl)phenol (14b). To a stirred solution of 13b (267 mg, 0.51 mmol,) in THF (5 mL) at 0 ○C was added MeLi (1.0 mL, 1.5 mmol). The mixture was stirred overnight at rt. The reaction was quenched with saturated NH4Cl (10 mL). The mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate 5:1) to afford the silyl protected 14b (124 mg, 48%) together with 14b (47 mg, 34%) as a colorless oil. The protected compound could be deprotected quantitatively into 14b by n-Bu4NF in THF at rt for 3–4 h.
Silyl protected 14b: Rf = 0.45 (petroleum ether/ethyl acetate = 5:1), Molecules 19 02213 i007 −65.5 (c 0.20, CHCl3). 1H-NMR (CDCl3) δ 7.76–7.67 (m, 4H), 7.46–7.31 (m, 6H), 7.09 (d, J = 8.6 Hz, 2H), 6.69 (d, J = 8.6 Hz, 2H), 6.12 (d, J = 16.3 Hz, 1H), 5.90 (d, J = 16.2 Hz, 1H), 5.64–5.50 (m, 2H), 2.12–1.98 (m, 2H), 1.40–1.32 (m, 2H), 1.27 (s, 6H), 1.09 (s, 9H), 0.98 (s, 3H), 0.79 (t, J = 7.4 Hz, 3H). 13C-NMR (CDCl3) δ 154.6, 140.6, 136.9, 135.5, 132.9, 130.9, 129.8, 127.7, 126.8, 126.5, 123.4, 119.6, 70.7, 43.6, 39.4, 33.3, 29.9, 26.5, 22.9, 19.4, 8.6. ESI-MS: 530.2 [M+NH4].
14b: Rf = 0.09 (petroleum ether/ethyl acetate = 5:1), Molecules 19 02213 i007 −36.3 (c 0.07, CHCl3). 1H-NMR (CDCl3) δ 7.23 (d, J = 8.6 Hz, 2H), 6.77 (d, J = 8.6 Hz, 2H), 6.18 (d, J = 16.3 Hz, 1H), 5.96 (d, J = 16.3 Hz, 1H), 5.68–5.49 (m, 2H), 2.17–2.03 (m, 2H), 1.46–1.34 (m, 2H), 1.30 (s, 6H), 1.02 (s, 3H), 0.82 (t, J = 7.5 Hz, 3H). 13C-NMR (CDCl3) δ 154.7, 140.5, 136.8, 130.8, 127.2, 126.4, 123.5, 115.3, 70.9, 43.6, 39.5, 33.3, 29.8, 22.8, 8.6. ESI-MS: 530.2 [M+NH4].
(S,3E,7E)-2,6-Dimethyl-8-phenyl-6-vinylocta-3,7-dien-2-ol (14c) Yield: 73%, Rf = 0.42 (petroleum ether/ethyl acetate = 5:1), Molecules 19 02213 i007 −9.5 (c 0.55, CHCl3). 1H-NMR (CDCl3) δ 7.36 (d, J = 8.0 Hz, 2H), 7.33–7.25 (m, 2H), 7.20 (t, J = 6.6 Hz, 1H), 6.32 (d, J = 16.2 Hz, 1H), 6.20 (d, J = 16.2 Hz, 1H), 5.89 (dd, J = 17.4, 10.7 Hz, 1H), 5.70–5.55 (m, 2H), 5.09–4.98 (m, 2H), 2.23 (d, J = 6.3 Hz, 2H), 1.38 (s, 1H), 1.30 (s, 6H), 1.18 (s, 3H). 13C-NMR (CDCl3) δ 145.3, 141.2, 137.6, 137.4, 128.5, 127.4, 127.0, 126.1, 122.9, 112.3, 70.7, 43.8, 42. 7, 29.9, 23.4. ESI-MS: 274.2 [M+NH4], HRMS (ESI): Calcd. for C18H25O [M+H]: 257.1900, found: 257.1899.
(S,3E,7E)-2,6-Dimethyl-8-(p-tolyl)-6-vinylocta-3,7-dien-2-ol (14d) Yield: 98%, Rf = 0.46 (petroleum ether/ethyl acetate = 5:1), Molecules 19 02213 i007 −9.1 (c 0.55, CHCl3). 1H-NMR (CDCl3) δ 7.25 (d, J = 7.3 Hz, 2H), 7.10 (d, J = 7.3 Hz, 2H), 6.28 (d, J = 16.2 Hz, 1H), 6.14 (d, J = 16.2 Hz, 1H), 5.88 (dd, J = 17.4, 10.7 Hz, 1H), 5.70–5.53 (m, 2H), 5.11–4.94 (m, 2H), 2.32 (s, 3H), 2.22 (d, J = 5.9 Hz, 2H), 1.42 (brs, 1H), 1.29 (s, 6H), 1.17 (s, 3H). 13C-NMR (CDCl3) δ 145.4, 141.1, 136.7, 136.4, 134.9, 129.2, 127.3, 126.0, 123.0, 112.2, 70.7, 43.8, 42.6, 29.8, 23.4, 21.1. ESI-MS: 293.2 [M+Na].
(S,3E,7E)-2,6-Dimethyl-8-(naphthalen-2-yl)-6-vinylocta-3,7-dien-2-ol (14e) Yield: 100%, Rf = 0.41 (petroleum ether/ethyl acetate = 5:1), Molecules 19 02213 i007 −13.7 (c 0.35, CHCl3). 1H-NMR (CDCl3) δ 7.83–7.74 (m, 3H), 7.70 (s, 1H), 7.59 (d, J = 8.6 Hz, 1H), 7.48–7.38 (m, 2H), 6.49 (d, J = 16.2 Hz, 1H), 6.34 (dd, J = 16.2, 2.0 Hz, 1H), 5.93 (ddd, J = 17.4, 10.7, 2.0 Hz, 1H), 5.72-5.57 (m, 2H), 5.14–5.01 (m, 2H), 2.26 (dd, J = 5.9, 1.7 Hz, 2H), 1.41 (s, 1H), 1.30 (s, 6H), 1.23 (s, 3H). 13C-NMR (CDCl3) δ 145.3, 141.2, 137.9, 135.1, 133.6, 132.7, 128.0, 127.8, 127.6, 126.1, 125.68, 125.5, 123.5, 122.9, 112.4, 70.8, 43.8, 42.8, 29.9, 23.4. ESI-MS: 293.2 [M+Na], HRMS (ESI): Calcd. for C22H26ONa [M+Na]: 329.1876, found: 329.1885.
(S,3E,7E)-2,6-Dimethyl-8-(4-(trifluoromethyl)phenyl)-6-vinylocta-3,7-dien-2-ol (14f) Yield: 96%, Rf = 0.42 (petroleum ether/ethyl acetate = 5:1), Molecules 19 02213 i007 +2.0 (c 0.75, CHCl3). 1H-NMR (CDCl3) δ 7.54 (d, J = 8.2 Hz, 2H), 7.44 (d, J = 8.2 Hz, 2H), 6.35 (d, J = 16.3 Hz, 1H), 6.30 (d, J = 16.3 Hz, 1H), 5.89 (dd, J = 17.5, 10.7 Hz, 1H), 5.70–5.53 (m, 2H), 5.09 (dd, J = 10.7, 1.0 Hz, 1H), 5.03 (dd, J = 17.5, 1.0 Hz, 1H), 2.24 (d, J = 6.6 Hz, 2H), 1.37 (brs, 1H), 1.30 (s, 6H), 1.20 (s, 3H). 13C-NMR (CDCl3) δ 144.7, 141.4, 141.1, 140.2, 126.3, 126.2, 125.4, 125.4, 122.5, 112.8, 70.7, 43.7, 42.9, 29.9, 23.2. ESI-MS: 347.2 [M+Na], HRMS(ESI): Calcd. for C19H24F3O [M+H]: 325.1774, found: 325.1774.
(S,3E,7E)-8-(Benzo[d][1,3]dioxol-5-yl)-2,6-dimethyl-6-vinylocta-3,7-dien-2-ol (14g) Yield: 38%, Rf = 0.26 (petroleum ether/ethyl acetate = 5:1), Molecules 19 02213 i007 −10.2 (c 0.50, CHCl3). 1H-NMR (CDCl3) δ 6.91 (s, 1H), 6.77 (d, J = 8.0 Hz, 1H), 6.73 (d, J = 8.0 Hz, 1H), 6.22 (d, J = 16.2 Hz, 1H), 6.03 (d, J = 16.2 Hz, 1H), 5.93 (d, J = 1.0 Hz, 2H), 5.87 (dd, J = 17.5, 10.7 Hz, 1H), 5.68–5.52 (m, 2H), 5.05 (d, J = 10.7 Hz, 1H), 5.00 (d, J = 17.5 Hz, 1H), 2.21 (d, J = 6.5 Hz, 2H), 1.42 (brs, 1H), 1.29 (s, 6H), 1.16 (s, 3H). 13C-NMR (CDCl3) δ 147.9, 146.7, 145.3, 141.1, 135.7, 132.2, 127.0, 122. 9, 120.5, 112.3, 108.2, 105.4, 100.9, 70.7, 43.8, 42.6, 29.9, 29.7, 23.4. ESI-MS: 318.4 [M+NH4], HRMS (ESI): Calcd. for C19H24O3Na [M+Na]: 323.1618, found: 323.1639.

3.3. Activity Tests

The MTT assay was used to measure cell viability. All the tested compounds were dissolved in 0.5% DMSO. Before analysis, UMR 106 cells (rat osteosarcoma cell line) were cultured with or without different concentrations of compounds for 48 h, respectively. At the end of incubation 0.5% MTT (20 μL) was added to each well, followed by incubation at 37 °C in 5% CO2 atmosphere for 4 h. The medium was then removed carefully, and DMSO (150 μL) was added to each well. The plates were shaken gently for 10 min to dissolve the blue formazan crystals. Absorbance was measured at 570 nm using an ELx-800 universal microplate reader (Bio-Tek, Winooski, VT, USA).

4. Conclusions

In summary, a series of the analogues of ∆3-2-hydroxybakuchiol have been synthesized, and some of them have been found to possess evident cytotoxic activity against rat UMR106 cells. Furthermore, the SAR study gives a preliminary profile, including: (1) the chain tail on the natural product could be somewhat modified to enhance the activity; (2) the aromatic moiety or the terminal olefin attached on the main chain are allowed to be modified without evident loss of activity; (3) the stereoconfiguration at the quaternary chiral center has an important influence on the activity.

Acknowledgments

We thank National Natural Foundation of China (21242008) and National High-tech R&D Program of China (2013AA092903) for the financial support. We are grateful to Luyan Zhang for his helpful discussion.

Conflicts of Interest

The authors declare no conflict of interest.
Sample Availability: Samples of the compounds are available from the authors.

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  • Sample Availability: Samples of the compounds are available from the authors.

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MDPI and ACS Style

Zhao, Q.; Xu, Q.; Shan, G.; Dong, C.; Zhang, H.; Lei, X. Synthesis of ∆3-2-Hydroxybakuchiol Analogues and Their Growth Inhibitory Activity against Rat UMR106 Cells. Molecules 2014, 19, 2213-2225. https://doi.org/10.3390/molecules19022213

AMA Style

Zhao Q, Xu Q, Shan G, Dong C, Zhang H, Lei X. Synthesis of ∆3-2-Hydroxybakuchiol Analogues and Their Growth Inhibitory Activity against Rat UMR106 Cells. Molecules. 2014; 19(2):2213-2225. https://doi.org/10.3390/molecules19022213

Chicago/Turabian Style

Zhao, Qun, Qianqian Xu, Guangsheng Shan, Chao Dong, Hong Zhang, and Xinsheng Lei. 2014. "Synthesis of ∆3-2-Hydroxybakuchiol Analogues and Their Growth Inhibitory Activity against Rat UMR106 Cells" Molecules 19, no. 2: 2213-2225. https://doi.org/10.3390/molecules19022213

APA Style

Zhao, Q., Xu, Q., Shan, G., Dong, C., Zhang, H., & Lei, X. (2014). Synthesis of ∆3-2-Hydroxybakuchiol Analogues and Their Growth Inhibitory Activity against Rat UMR106 Cells. Molecules, 19(2), 2213-2225. https://doi.org/10.3390/molecules19022213

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