KR100890521B1 - Hypoxia-Inducible Factor-1 and Nuclear Factor-?B Inhibitory Meroterpene Analogues of Bakuchiol - Google Patents

Abstract

The present invention relates to formulas (I)-(II), wherein cytotoxicity is reduced while maintaining hypoxia-inducing factor-I (HIF-1) and nuclear factor-κB (Nuclear Factor-κB, hereinafter referred to as NF-κB) inhibitory activity. Provided are the merotter analogs of bakuchiol.

Bone Golgi, Bakuchiol, Merlotenoid, HIF-1, NF-κB

Description

Hypoxia-Inducible Factor-1 and Nuclear Factor-κB Inhibitory Meroterpene Analogues of Bakuchiol} having hypoxia-inducing factor-1 and nuclear factor-κＢ inhibitory activity

The present invention relates to a merotter analog of bakuchiol having hypoxia-inducible factor-1 (hereinafter referred to as HIF-1) inhibitory activity. More specifically, the present invention relates to a novel methterpene analogue of bakuchiol with reduced cytotoxicity while maintaining HIF-1 and nuclear factor-κB (Nuclear Factor-κB, hereinafter referred to as NF-κB) inhibitory activity.

Corrugated beams (Psoraleae fructus) has hazel pool (Psoralea coylifolia ) is the fruit of the fruit, which is traditionally used as a tonic in Chinese medicine. Bone Golgi contains many chemicals known to have pharmaceutical activity in the literature. The main chemicals contained in Bogol Gol include, in addition to lipids, psoralens, isopsolalens and bakuchiols.

Among these components, Bakuchiol of the meroterpenoid family isolated from the bones of Golgi was anti-diabetic (Kim Y.-C., Oh H., Kim BS, Kang T.-H., Ko E. -K., Han YM, Kim BY, Ahn JS, Planta Med . 87-89 (2005); Krenisky JM, Luo J., Reed MJ, Carney JR, Biol . Pharm . Bull . , 22 , 1137-1140 (1999).), Anti-inflammatory (Pae H.-O., Cho H., Oh G.-S., Kim N.-Y., Song E.-K., Kim Y. -C., Yun Y.-G., Kang C.-L. , Kim J.-D., Kim J.-M., Chung H.-T., Int. Immunopharmacol., 1, 1849 (2001) ), antimicrobial (Katsura H., Tsukiyama R.-I., Suzuki A., Kobayashi M., Antimicrob. Agents Chemother . , 45 , 3009-3013 (2001)), antioxidant (Adhikari S., Joshi R., Patro BS, Ghanty TK, Chintalwar GJ, Sharma A., Chattopadhyay S., Mukherjee T., Chem . Res . Toxicol . , 16 , 1062-1069 (2003)), anti-tumor (K. Bapat, Chintalwar GJ, Pandey U., Thakur VS, Sarma HD, Samuel G., MRA Pillai, S. Chattopadhyay, Venkatesh M., Appl. Radiat. Isot. , 62 , 389-393 (2005)), hepatoprotective activity (Park E.-J., Zhao Y.-Z., Kim Y.-C., Sohn DH, Eur . J. Pharmacol . , 559 , 115- 123 (2007); Park E.-J., Zhao Y.-Z., Kim Y.-C., Sohn DH, Planta Med . , 508 (2005)), various pharmacological properties have been reported.

Korean Patent Publication No. 10-0686469 discloses that bakuchiol can be used to prepare female osteoporosis pharmaceutical compositions. Korean Patent Publication No. 10-068470 discloses a pharmaceutical composition for treating female breast cancer comprising bakuchiol.

 It is an object of the present invention to provide a novel chelterpene analogue of bakuchiol with reduced cytotoxicity while maintaining HIF-1 and nuclear factor-κB (Nuclear Factor-κB, hereinafter referred to as NF-κB) inhibitory activity. .

The present invention is a merocer of bakuchiol represented by formula (I) or (II) with reduced cytotoxicity while maintaining HIF-1 and nuclear factor-κB (Nuclear Factor-κB, hereinafter referred to as NF-κB) inhibitory activity. Provide pen analogs.

The present invention provides a pharmaceutical composition for the prophylaxis or treatment of cancer, which comprises a merotter analog of bakuchiol represented by the formula (I) or (II) as an active ingredient.

The present invention provides a pharmaceutical composition for treating inflammation, which comprises a merotter analog of bakuchiol represented by the formula (I) or (II) as an active ingredient.

Preferably the pharmaceutical composition may be formulated in topical, oral, injection or sustained release dosage forms.

Furthermore, the pharmaceutical composition of the present invention contains a meteropenen analog of bakuchiol represented by the formula (I) or (II) in a therapeutically effective amount as an active ingredient, and is a pharmaceutically acceptable carrier used in combination with the active ingredient. Or in a pharmaceutical composition comprising a diluent.

The present invention provides a health food for preventing or treating cancer, or for treating inflammation, which comprises a merotter analog of bakuchiol represented by the formula (I) or (II) as an active ingredient.

EMBODIMENT OF THE INVENTION Hereinafter, this invention is demonstrated more concretely.

The inventors of the hazelnut ( Psoralea) 12,13-dihydro-12,13-dihydroxybakuchiol (12,13-dihydro-12,13-), two new meroterpenoids from Bogolchi , the seed of corylifolia L. dihydroxybakuchiol, compound 2) and (12 'R) - bis Baku chiol D ((12' R) -bisbakuchiol D, were isolated compound 3), each of the structures was determined using the spectroscopic data and chemical methods. HIF-1 and NF-κB activity was measured for 7 meroterpenoids and 3 semisynthetic derivatives isolated from Bogol Gum. As a result, O -methyl and O -ethylbakuchichiol (Compounds 6 and 7) were AGS The present invention was found to inhibit the activity of HIF-1 and NF-κB without reducing the survival rate of HeLa and HeLa cell lines.

In the course of studying the physiological activity of natural origin, the present inventors have observed that methanol extracts of Bulgogi seeds may be depleted of oxygen deficiency (HIF-1-mediated reporter gene assay) for AGS (Human Gastric Cancer Cell Line). It was found to strongly inhibit the activity of hypoxia inducer-1 (HIF-1) that induces% inhibition at 20 μg / mL). Since HIF-1 regulates a large number of cellular events required for cancer cell adaptation to hypoxia, HIF-1 inhibitors can be thought of as potent therapeutics for cancer. The present inventors also found plant chemistry such as bakuchiol (compound 1), which is an inhibitor of HIF-1 in plants, as well as three new meroterenoid dimers, bisbakuchiol AC, which were not active in HIF-1 mediated reporter gene analysis. Ingredient and bioactivity studies were conducted. The inventors have continued to work on two new meroterpenes (compounds 2 and 3 ) and 12,13-dihydro-12,13-epoxynathithiol (12,13-dihydro), a previously reported meroterpene-based component. -12,13-epoxynakuchiol, compound 4), and a bakuchiol semisynthetic material were obtained and their biological activities were investigated.

Compound 2 was found to have a molecular formula of C ₁₈ H ₂₆ O ₃ from positive high-resolution FABMS ( m / z [M + Na] ⁺ , 313.1776) as yellow oil, with ¹ H and ¹³ C-NMR spectra. As a result of comparison with thiol (Compound 1), Compound 2 could be assumed to be a merocterol type bakuchiol analog. AA 'from ¹ H-NMR spectrum at δ _H 6.71 (2H, d, J = 8.8 Hz, H-3 and H-5) and 7.19 (2H, d, J = 8.8 Hz, H-2 and H-6) Check the XX'-type proton signal and the vinyl group signal at δ _H 5.02 (overlap, H-18) and 5.91 (1H, m, H-17). In addition, three methyl signals were observed at δ _H 1.11 (3H, s, H-14), 1.15 (3H, s, H-15), and 1.20 (3H, s, H-16).

However, the absence of signals due to olefinic methine (H-12) of bakuchiol (Compound 1) and δ _H 3.21 (1H, dd, J = 2.0 and 10.8 Hz, H-12), δ _C 74.0 ( s, C-13) and the presence of δ _C 80.6 (d, C-12) could be inferred from the oxidative modification of the double bonds of C-12 and C-13 in bakuchiol (Compound 2). .

Compound 2 was confirmed to be 12,13-dihydroxylated bakuchiol (12,13-dihydroxylated bakuchiol) based on a comparison with the spectroscopic data of bakuchiol (Formula 1 ) by 2D NMR experiment. Therefore, the structure of new compound 2 was determined to be 12,13-dihydro-12,13-dihydroxybakuchiol (2,13-dihydro-12,13-dihydroxybakuchiol).

Compound 3 was obtained as a yellow oil, the molecular formula of positive ₃₆ H ₄₈ O ₃ from positive HRFABMS ( m / z [M + Na] ⁺ , 551.3498). ¹ H the compound 3 and ¹³ C-NMR spectrum δ from the two characteristic was the signal is appeared respectively, ¹ H-NMR spectrum of compound 3 is similar with respect to Baku chiol (Compound 1) and compound 2 _H 6.91 (2H, d, J = 8.4 Hz, H-3 and H-5) and 7.28 (2H, d, J = 8.4 Hz, H-2 and H-6); 2 sets of AA'XX at 6.78 (2H, d, J = 8.4 Hz, H-3 'and H-5') and 7.24 (2H, d, J = 8.4 Hz, H-2 'and H-6') The AA'XX'-type proton signal is converted into δ _H 6.13 (1H, d, J = 16.0 Hz, H-8) and 6.30 (1H, d, J = 16.0 Hz, H-7). ; 6.06 (1H, d, J = 16.0 Hz, H-8 ') and 6.28 (1H, d, J = 16.0 Hz, H-7') 2 of trans (trans) portion signals (proton signal) of the double bond in the Δ _H 5.90 (1H, doublet of doublets, J = 10.4 and 17.2 Hz, H-17) and 5.04 (overlap, H-18); Two vinyl group signals were observed at 5.89 (1H, dd, J = 10.4 and 17.2 Hz, H-17 ') and 5.04 (overlap, H-18').

In Ali patik (Aliphatic) region _{δ H 3.61 (1H, dd,} J = 1.6 and 9.2 Hz, H-12 ') from the observed oxidation methine signals _{(oxygenated methine signal) δ H 1.20} (3H, s, H-15 '), 1.21 (3H, s, H-14'), 1.22 (6H, s, H-16 and H-16 '), 1.60 (3H, s, H-14), 1.69 (3H, s, H- Six methyl signals were identified in 15).

Therefore, compound 3 could be estimated to be a meroterpene dimer in which bakuchiol (compound 1) and compound 2 were connected by a phenyl ether bond, which was confirmed by 2D NMR experiment and molecular formula measurement. Absolute coordination of C-12 'and C-9 (C-9') positions was clearly determined by the Mosher's method and biogenetic considerations.

The chemical shift (Δδ _{S - R} ) values are negative for H-10 'and H-11' and positive for H-14 'and H-15' in the Mosher's esters (3s and 3r). It was found that C-12 'is the R configuration, and based on biogenetic considerations (naturally, 9 S -bakuchiol can be obtained), the stereogenic center of C-9 and C-9' is the stereogenic center. Chemistry could be estimated. Thus, the new pen methoxy rotor structure of the dimer (12 'R) - bis Baku thiol -D ((12' decided R) -bisbakuchiol D, compound 3).

The AGS (human gastric cancer cell line), the HIF-1- mediated reporter gene analysis of HIF-1 activity by inducing hypoxia to the use of (HIF-1-mediated reporter gene assay) with respect to - the pure compound was isolated (42) It was measured and found to have no inhibitory activity (IC ₅₀ values> 20 μg / ml). Only bakuchiol (Compound 1) isolated from Bogolgol was found to be an HIF-1 inhibitory active substance (IC ₅₀ value 1.6 μg / ml) (Table 1).

To determine whether it inhibits the activity of NF-κB, which regulates a large number of genes involved in inflammation and cancer, the NF-κB activity of meroterpene compounds obtained from Bogolgol was measured. Bakuchiol (Compound 1) and bisbakuchiol D (Compound 3 ) were able to convert HeLa (human cervical gland carcinoma cell line) into TNF-α-induced NF-κB activity with IC ₅₀ of 1.8 and 6.4 μg / ml, respectively. In contrast, compounds 2 and 4 and bisbakuchiols AC showed no activity (Table 1).

However, bakuchiol (Compound 1) showed strong cytotoxicity to AGS and HeLa cell lines at a concentration of 20 μg / ml by MTT assay (83% and 95% inhibition, respectively). These results may increase HIF-1 and NF-κB inhibitory ability while reducing cytotoxicity, and promoted the preparation of bakuchiol analogs to elucidate the structure-activity correlation of bakuchiol (Compound 1).

Acetyl Baku chiol (Acetylakuchiol, compound 5), and O - methyl (O -methyl) and O - ethyl Baku chiol (O -ethylbakuchiols) (compounds 6 and 7) was prepared as described in the Examples. These derivatives were measured for both assay systems. As a result, acetylbakuchiol (Compound 5 ) showed almost the same physiological activity as Bakuchiol (Compound 1 ), but O -methyl ( O -methyl) and O -Ethyl Baku O- ethylbakuchiols (compounds 6 and 7) showed inhibitory effects on HIF-1 (IC ₅₀ values, 2.4 and 7.5, respectively) with little effect on viability at 20 μg / ml for AGS and HeLa cell lines. Μg / ml) and NF-κB inhibitory activity (IC ₅₀ values, 1.5 and 4.1 μg / ml, respectively) were maintained (Table 1).

As described above, the phenolic hydroxyl group and 12,13-double bond of bakuchiol (Compound 1) can be assumed to play a structurally important role in HIF-1 and NF-κB activity. As in Bisbakuchiols AD, the substitution of the hydroxyl group of bakuchiol (Compound 1) reduced or inactivated HIF-1 and NF-κB activity, while acetylbakuchiol (Compound 5) ) is Baku chiol (showed the physiological activity of the compound 1), O - methyl (O -methyl) and O - ethyl (O -ethyl) the analog (6 and 7) is in a state which does not affect the cell viability HIF-1 and NF-κB activity was maintained. In addition, it was found that 12,13-double bond of bakuchiol (Compound 1) is required for HIF-1 and NF-κB inhibitory activity (2 and 4).

As described above, the merotter analogs of bakuchiol represented by formulas (I) to (II) according to the present invention are HIF-1 and nuclear factor-κB (Nuclear Factor-κB, hereinafter referred to as NF-κB). It appears that the cytotoxicity is reduced while maintaining the inhibitory activity, and thus can be usefully used as a material for medicines and functional foods for preventing or treating cancer or for treating inflammation, which may be very useful in the pharmaceutical industry.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto.

Optical rotations and UV spectra were measured with a Jasco P-1020 polarimeter and Shimazu UV-1601 UV-VIS spectrophotometer, respectively. NMR experiments were performed with Bruker DRX 500 and Varian Unity Ionva-400 instruments. EIMS and ESIMS spectra were recorded by HP 5989A and Platform quadruple mass spectrometers, respectively. HRFABMS data were obtained by JMS-HX / HX 110A tandem mass spectrometer.

Example  One. Bongol  Methanol Extract Preparation and Separation

Bogolgol seeds were purchased from Daejeon Herbal Medicine Market and Gyeongdong Market, and samples were stored in Korea Biotechnology Research Institute and Korea University Natural Metabolism Laboratory.

2.3 Kg of golgol seeds were ground and extracted with methanol. The concentrate was suspended with water, and the solvent was partitioned with hexane to obtain 27.6 g of hexane fraction. The aqueous layer was further fractionated with chloroform to obtain 106 g of CHCl ₃ fraction.

CHCl ₃ The fraction (100 g) was subjected to silica gel column chromatography using a CHCl ₃ -MeOH gradient as a mobile phase, and then seven fractions (F01 to F07) were obtained based on TLC analysis. Fraction F05 was divided into seven subfractions (F08-F14) based on TLC analysis by silica gel column chromatography using hexane-EtOAc.

Sephadex LH-20 was carried out using CHCl ₃ -MeOH (1: 1) as a mobile phase for the fraction F09, followed by preparative HPLC (Waters system, YMC Pack Pro C ₁₈ , 250 × 20 mm id, MeCN-H _2). Compound 3 (44 mg) and Compound 4 (21 mg) were separated purely using O gradient, flow rate 10 ml / min. Compound 2 was purified by silica gel on fraction F11 and separated using preparative HPLC (MeCN-H ₂ O gradient, flow rate 10 ml / min).

Physical and chemical properties and the results of the instrumental analysis of the compound 2 are as follows.

Appearance: Yellow Oil

Proton Nuclear Magnetic Resonance Spectrum:

¹ H-NMR (400 MHz, CD ₃ OD) δ: 1.11 (3H, s, H-14), 1.15 (3H, s, H-15), 1.20 (3H, s, H-16), 1.27 (1H , m, H-11), 1.45 (1H, m, H-10), 1.63 (1H, m, H-11), 1.87 (1H, m, H-10), 3.21 (1H, dd, J = 2.0 and 10.8 Hz, H-12), 5.02 (2H, overlap, H-18), 5.91 (1H, m, H-17), 6.04 (1H, brd, J = 16.4 Hz, H-8), 6.25 (1H , d, J = 16.4 Hz, H-7), 6.71 (2H, d, J = 8.8 Hz, H-3 and H-5), 7.19 (2H, d, J = 8.8 Hz, H-2 and H- 6).

Carbon Nuclear Magnetic Resonance Spectrum:

¹³ C-NMR (100 MHz, CD ₃ OD) δ: 24.2 (q, C-16), 25.0 (q, C-14), 26.0 (q, C-15), 27.4 (t, C-11), 40.2 (t, C-10), 43.5 (s, C-9), 74.0 (s, C-13), 80.6 (d, C-12), 112.7 (t, C-18), 116.4 (d, C -3 and C-5), 128.4 (d, C-2, C-6 and C-7), 131.1 (s, C-1), 136.1 (d, C-8), 147.8 (d, C-17 ), 157.9 (s, C-4).

HMBC correlations H-12 / C-11, C-13, C-14, C-15; H-14 / C-12, C-13, C-15; H-15 / C-12, C-13, C-14.

UV λ _max (MeOH) nm (log e ): 262 (3.93), 206 (3.99).

ESIMS m / z: [M + Na] + 313.4, [2M + Na] + 603.6, [M - H] - 289.4, [2M - H] - 579.6. [α] _D ²⁵ +7.0 ( c = 0.1, MeOH).

HRFABMS m / z [M + Na] ⁺ 313.1776 (Calcd for C ₁₈ H ₂₆ O ₃ Na: 313.1780).

Physical and chemical properties and the results of the instrumental analysis of the compound 3 are as follows.

Appearance: Yellow Oil

Proton Nuclear Magnetic Resonance Spectrum:

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.20 (3H, s, H-15 ′), 1.21 (3H, s, H-14 ′), 1.22 (6H, s, H-16 and H-16 '), 1.60 (3H, s, H-14), 1.69 (3H, s, H-15), 3.61 (1H, dd, J = 1.6 and 9.2 Hz, H-12'), 5.04 (overlap, H- 18 and H-18 '), 5.12 (1H, brt, H-12), 5.89 (1H, dd, J = 10.4 and 17.2 Hz, H-17'), 5.90 (1H, dd, J = 10.4 and 17.2 Hz , H-17), 6.06 (1H, d, J = 16.0 Hz, H-8 '), 6.13 (1H, d, J = 16.0 Hz, H-8), 6.28 (1H, d, J = 16.0 Hz, H-7 '), 6.30 (1H, d, J = 16.0 Hz, H-7), 6.78 (2H, d, J = 8.4 Hz, H-3' and H-5 '), 6.91 (2H, d, J = 8.4 Hz, H-3 and H-5), 7.24 (2H, d, J = 8.4 Hz, H-2 'and H-6'), 7.28 (2H, d, J = 8.4 Hz, H-2 and H-6).

Carbon Nuclear Magnetic Resonance Spectrum:

¹³ C-NMR (100 MHz, CDCl ₃ ) δ: 17.9 (q, C-14), 20.8 (q, C-14 '), 23.35 (q, C-15'), 23.44 (t, C-11) , 23.5 (q, C-16), 23.8 (q, C-16 '), 25.9 (q, C-15), 26.4 (t, C-11'), 38.6 (t, C-10 '), 41.5 (t, C-10), 42.6 (s, C-9 '), 42.8 (s, C-9), 78.9 (d, C-12'), 83.8 (s, C-13 '), 112.2 (t , C-18 'or C-18), 112.4 (t, C-18' or C-18), 115.6 (d, C-3 'and C-5'), 124.5 (d, C-3 and C- 5), 125.0 (d, C-12), 126.7 (d, C-7), 126.89 (d, C-2 and C-6), 127.01 (d, C-7 '), 127.6 (d, C- 2 'and C-6'), 130.8 (s, C-1 '), 131.6 (s, C-13), 134.0 (s, C-1), 135.8 (d, C-8'), 137.4 (d , C-8), 146.0 (d, C-17 and C-17 '), 153.4 (s, C-4), 155.1 (s, C-4').

HMBC correlations H-12 '/ C-10', C-11 ', C-13', C-14 '; H-14 '/ C-12', C-13 ', C-15'; H-15 '/ C-12', C-13 ', C-14'.

UV λ _max (MeOH) nm (log e ): 262 (4.58), 207 (4.65).

ESIMS m / z: [M + Na] + 551.6, [M - H] - 527.7.

[a] _D ²⁵ +25.2 ( c = 0.1, CHCl ₃ ).

HRFABMS m / z [M + Na] ⁺ 551.3498 (Calcd for C ₃₆ H ₄₈ O ₃ Na: 551.3501).

Example  2. In Mercer Law  Of compound 3 ( R )- and  ( S )- MTPA  ester( Esters ) Produce

( R )-and ( S ) -MTPA esters of compound 3 were prepared using the Mercer method described previously. 4-dimethyl-aminopyridine (0.5 mg) and ( S )-(-)-a-methoxy-a- (trifluoromethyl) phenylacetyl chloride in a solution of compound 3 in an NMR tube (( S )-(-)-a-methoxy-a- (trifluoromethyl) phenylacetyl chloride, 10 μl) is added. The reaction is confirmed by NMR while heating the mixture to 40 ° C. over 4 hours on nitrogen gas. After completion of the reaction, the mixture is purely obtained with ( R ) -MTPA ester ( 3r ) using chloroform as a mobile phase on a small silica gel column.

Compound 3 was also treated with ( R )-(-)-a-methoxy-a- (trifluoromethyl) phenylacetyl chloride. In a similar way ( S ) -MTPA ester ( 3s ) was obtained.

3r : ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.994 (H-10 '), 1.366 (H-11'), 3.553 (H-12 '), 1.167 (H-14'), 1.152 (H -15 ').

3s : ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.990 (H-10 '), 1.358 (H-11'), 3.559 (H-12 '), 1.184 (H-14'), 1.171 (H -15 ').

Example  3. Of acetylbakuchiol  Produce

Pyridine _{-Ac 2 O (Pyridine-Ac 2} O) Baku chiol acetate (kuchiol acetate, compound 5) was obtained 11 mg to acetylation (acetylation) of compound 1 in the usual way using.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.19 (3H, s, H-16), 1.57 (3H, s, H-14), 1.66 (3H, s, H-15), 2.28 (3H, s, H-2 '), 5.00 (1H, d, J = 17.2 Hz, H-18), 5.03 (1H, d, J = 10.8 Hz, H-18), 5.09 (1H, t, J = 6.6 Hz , H-12), 5.86 (1H, dd, J = 10.8 and 17.2 Hz, H-17), 6.14 (1H, d, J = 16.0 Hz, H-8), 6.29 (1H, d, J = 16.0 Hz , H-7), 7.00 (2H, d, J = 8.4 Hz, H-3 and H-5) and 7.34 (2H, d, J = 8.4 Hz, H-2 and H-6).

EIMS m / z : 298 [M] ⁺ _, 256, 213, 173.

[α] _D ²⁵ +15.2 ( c = 0.1, MeOH).

Example  4. O - methyl  And O -ethyl Bakuchiol  pharmacy

Compound 1 was prepared in two parts (each-50 mg), and CH ₃ I (30 ml) and CH were added to a solution in which K ₂ CO ₃ (100 mg) was added to dimethylformamide (DMF) (3 ml). ₃ CH ₂ was added Br (35 ml) overnight at room temperature, each was O - methyl Baku chiol (O -methylbakuchiol, compound 6) and 10 mg O - ethyl Baku chiol (O -ethylbakuchiol, compound 7) was obtained 10 mg.

Compound 6: ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.21 (3H, s, H-16), 1.59 (3H, s, H-14), 1.69 (3H, s, H-15), 3.81 (3H, s, H-1 '), 5.89 (1H, dd, J = 10.8 and 17.2 Hz, H-17), 6.08 (1H, d, J = 16.0 Hz, H-8), 6.28 (1H, d , J = 16.0 Hz, H-7), 6.85 (2H, d, J = 8.4 Hz, H-3 and H-5) and 7.31 (2H, d, J = 8.4 Hz, H-2 and H-6) .

EIMS m / z : 270 [M] ⁺ _, 227, 187.

Compound 7: ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.21 (3H, s, H-16), 1.42 (3H, t, J = 7.0 Hz, H-2 ′), 1.60 (3H, s, H-14), 1.69 (3H, s, H-15), 4.04 (2H, q, J = 7.0 Hz, H-1 '), 5.89 (1H, dd, J = 10.4 and 17.2 Hz, H-17) , 6.07 (1H, d, J = 16.0 Hz, H-8), 6.27 (1H, d, J = 16.0 Hz, H-7), 6.84 (2H, d, J = 8.4 Hz, H-3 and H- 5) and 7.30 (2H, d, J = 8.4 Hz, H-2 and H-6).

EIMS m / z : 284 [M] ⁺ _, 269, 241,201.

Example  5. HIF -1 reporter analysis ( HIF -One reporter assay )

The activity of HIF-1 was measured according to known methods (Cai XF, Jin X., Lee D., Yang YT, Lee K., Hong YS, Lee JH, Lee JJ, J. Nat . Prod . , 69 , 1095- 1097 (2006) / Jin W., Cai XF, Na M., Lee JJ, Bae K., Arch. Pharm. Res., 30, 412-418 (2007) / Lee K., Lee JH, Boovanahalli SK, Jin Y., Lee M., Jin X., Kim JH, Hong YS, Lee JJ, J. Med . Chem . , 50 , 1675-1684 (2007)).

Transfection, compound treatment, hypoxia (1% O ₂ , 94% N ₂ , and 5% CO ₂ ), and luciferase activity were measured in AGS cells. The results are shown in Table 1. Table 1 shows the biological activity of compounds 1-7 (IC ₅₀ values, μg / ml).

AGS ^a HeLa ^b HIF-1 MTT NF-κB MTT One 1.6 3.9 1.8 2.8 2 ^-c - - - 3 - - 6.4 - 4 - - - - 5 1.7 7.9 1.7 5.4 6 2.4 15.1 1.5 - 7 7.5 - 4.1 -

^a AGS: human gastric cancer cell;

^b HeLa: human cervical adenocarcinoma cell;

^c IC ₅₀ value> 20 μg / ml

Example  6. NF -κB reporter activity ( reporter activity )

The activity of NF-κB was measured according to known methods (Hwang BY, Lee J.-H., Jung HS, Kim K.-S., Nam JB, Hong YS, Paik S.-G., Lee JJ, Planta Med) ., 69, 1096-1101 (2003) ; Jin HZ, Lee D., Lee JH, Lee K., Hong Y.-S., Choung D.-H., Kim YH, Lee JJ, Planta Med . , 72 , 40-45 (2006); Jin HZ, Lee JH, Lee D., Hong YS, Kim YH, Lee JJ, Phytochemistry , 65 , 2247-2253 (2004); Lee J.-H., Koo TH, Yoon H., Jung HS, Jin HZ, Lee K., Hong Y.-S., Lee JJ, Biochem . Pharmacol . , 72 , 1311 (2006).

HeLa cells were eukaryotic transfected with a plasmid with eight copies of the κB element linked to the secreted alkaline phosphatase (SEAP) gene. Induction of LPS in the presence of various concentrations of the compound according to the invention and the SEAP gene expression in the medium was measured. The results are shown in Table 1.

Example  7. Cytotoxicity Assay ( Cytotoxicity assay)

Cytotoxicity was measured by MTT [3- (4,5-dimethylthiazole-2-yl) -2,5-diphenyl tetrazolium bromide] method in AGS and HeLa cells (Hwang BY, Lee J.-H., Jung HS , Kim K.-S., Nam JB, Hong YS, Paik S.-G., Lee JJ, Planta Med. , 69 , 1096-1101 (2003); Lee J.-H., Koo TH, Yoon H. , Jung HS,. Jin HZ, Lee K., Hong Y.-S., Lee JJ, Biochem. Pharmacol, 72, 1311 (2006)). The results are shown in Table 1.

Claims (14)

delete delete delete delete A pharmaceutical composition for the prevention or treatment of cancer, comprising a merotter analog of bakuchiol represented by the formula (I) as an active ingredient. Formula (I)

A pharmaceutical composition for treating inflammation, comprising a merotter analog of bakuchiol represented by formula (I) as an active ingredient. Formula (I)

The pharmaceutical composition of claim 5 or 6, wherein the pharmaceutical composition is in topical, oral, injection or sustained release dosage form. A pharmaceutical composition for preventing or treating cancer, which comprises a merotter analog of bakuchiol represented by the formula (II) as an active ingredient. Formula (II)

A pharmaceutical composition for treating inflammation comprising a merotter analog of bakuchiol represented by the formula (II) as an active ingredient. Formula (II)

The pharmaceutical composition of claim 8 or 9, wherein the pharmaceutical composition is in a topical, oral, injectable or sustained release dosage form. delete delete delete delete