CN106045881A - Resveratrol derivative, preparation method thereof and application of resveratrol derivative serving as LSD1 inhibitor - Google Patents
Resveratrol derivative, preparation method thereof and application of resveratrol derivative serving as LSD1 inhibitor Download PDFInfo
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- C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
- C07C257/18—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to carbon atoms of six-membered aromatic rings
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
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- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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Abstract
The invention discloses a resveratrol derivative, a synthesizing method thereof and application of the resveratrol derivative serving as a histone lysine specificity demethylase 1 inhibitor and belongs to the field of medicinal chemistry. The formula of the resveratrol derivative is as shown in the specification, wherein R is preferably hydrogen, hydroxyl, methoxy, nitro or halogen, and X represents N atom and C atom. The resveratrol derivative has good inhibitory effect on the histone lysine specificity demethylase 1 and can be used as the candidate for further development or the lead compound to develop medicine for treating diseases such as tumors and AIDS.
Description
Technical field
Present invention relates particularly to resveratrol analog derivative, preparation method and as istone lysine specificity
The application of demethylase 1 inhibitor, belongs to field of pharmaceutical chemistry technology.
Background technology
Istone lysine specificity demethylase 1 (Histone Lysine Specific Demethylase 1,
LSD1) be first istone lysine demethylase being found (Y.Shi et al, Cell, 2004,29,941
953).LSD1 is the demethylase of a flavine-adenine-dinucleotide-dependent, by combining from different molecular chaperoneses
Act on different substrates, thus produce different biological functions.LSD1 is combined with target gene by CoREST, it is possible to special
Single or double the methylating of the removal H3K4 (Histone 3, Lysine 4) of property, causes genetic transcription to suppress.When LSD1 and hero swash
When element receptor or estrogen receptor combine, the single or double methyl of specific removal H3K9 (Histone 3, Lysine 9) of energy
Change, cause the gene transcriptional activation that hormone receptor relies on.LSD1 is by the interaction of regulation histone with other albumen, impact
The activation of genetic transcription and suppression, the important life process such as x chromosome inactivation (Lee MG et al, Nature, 2005,437,
432–435)。
Current research finds the generation development of the diseases such as LSD1 and tumor, viral infection, metabolic disease, inflammation all
There is close relationship.LSD1 is all that overexpression is the most abnormal the most sharp in the Several Kinds of Malignancies such as gastric cancer, carcinoma of prostate, breast carcinoma
Live, cause antioncogene abnormal reticent, suppress its activity or downward expression can suppress the growth of tumor, attack and shift, be
The focus target of antitumor drug research and development at present.The tranylcypromine class LSD1 inhibitor of Oryzon company of Spain report, at present
Carrying out II clinical trial phase, be used for treating leukemia (Zheng YC et al, Med Res Rev, 2015,35,1032
1071)；LSD1/CoREST complex can transcribing, with little point by demethylation Tat albumen K51 site activation inhibition of HIV
Sub-inhibitor suppression LSD1 activity can suppress to infect activation (Sakane N et al, the PLoS of inhibition of HIV in T cell
Pathog, 2011,7, e1002184).In people's cell of varicella zoster virus and herpes simplex infections, reduce
The expression of LSD1 or suppress its activity, can reduce virus mRNA and virus protein expression (Liang Y et al,
Nat Med, 2009,15,1,312 1317)；LSD1 is by synergism mutual with histon deacetylase (HDAC) HDACs, suppression
IL1 α, IL1 β, the expression of the proinflammatory cytokines such as IL6 (Janzer A et al, Biochem Biophys Res Commun,
2012,18,665 670).
The LSD1 type of report is the deficientest at present, and major part remains in laboratory research and faces
Bed conceptual phase, therefore, it is thus achieved that LSD1 inhibitor novel, highly active, for research LSD1 biological function, develop novel
Antitumor, the disease therapeuticing medicine such as antiviral, be of great significance.
Resveratrol (Resveratrol) is derived from the natural polyphenol compounds in the plant such as Fructus Vitis viniferae, Fructus Mori, due to
It has the multiple biological activity such as antitumor, antioxidation, causes the extensive concern of people.Research finds that resveratrol is to LSD1
There is certain inhibitory activity.In the active appraisal experiment of enzyme level, resveratrol can suppress LSD1 to methylate p53 with
And the demethylation of H3K4me2 substrate, IC50Being 15 μ Μ, activity is better than positive control tranylcypromine.
In order to find novel LSD1 micromolecular inhibitor, by the further structure optimization to resveratrol, obtain a class
Verakanol derivative, this compounds has significant LSD1 inhibitory activity, has not yet to see the synthesis of this compounds
And the report of LSD1 inhibitory activity.
Summary of the invention
It is an object of the present invention to provide resveratrol derivant, providing for novel drugs screening may.
Further object is that and provide the preparation method of this type of Verakanol derivative and as histone
The application of lysine specificity demethylase 1 (LSD1) inhibitor.
For achieving the above object, the resveratrol derivant structure formula that the present invention provides is:
In general formula III, R is positioned on A ring other any position removing link position, for monosubstituted or take on A ring more
In generation, substituent group refers to: hydrogen, hydroxyl, methoxyl group, nitro or halogen, and wherein, halogen includes F, Cl, Br, I.
In general formula III, substituent groupB ring is monosubstituted.
In general formula III, X represents atom N or C atom.
Preferably, R represents substituent group and the atom of the position of substitution, X representative are as follows:
(1) R group is 3,4-diOH, and B ring is 3 replacements, X=C；
(2) R group is 3,4-diOH, and B ring is 4 replacements, X=C；
(3) R group be 4-OH, B ring be 3 replacements, X=C；
(4) R group be 4-OH, B ring be 4 replacements, X=C；
(5) R group is 3,4-diF, and B ring is 4 replacements, X=C；
(6) R group is 2-F-4, and 5-diOH, B ring is 3 replacements, X=C；
(7) R group is 2-F-4, and 5-diOH, B ring is 4 replacements, X=C；
(8) R group is 2-Br-4, and 5-diOH, B ring is 3 replacements, X=C；
(9) R group is 2-Br-4, and 5-diOH, B ring is 4 replacements, X=C；
(10) R group is 3,5-diOH, and B ring is 3 replacements, X=C；
(11) R group be 3-F-4-OH, B ring be 3 replacements, X=C；
(12) R group be 3-F-4-OH, B ring be 4 replacements, X=C；
(13) R group be H, B ring be 3 replacements, X=N；
For realizing above-mentioned second purpose, the synthetic reaction flow process of the compounds of this invention is as shown below:
Concretely comprise the following steps:
Benzaldehyde or substituted benzaldehyde and cyano group substituted benzyl diethyl phosphonate, in dry DMF, strongly alkaline compound is deposited
Under, reaction being stirred at room temperature, generate compound I, wherein, described strongly alkaline compound is selected from potassium tert-butoxide, Feldalat NM, hydrogenation
Sodium, sodium tert-butoxide；Do not have methoxy substitution in compound I, then compound I is in methanol solution, in the presence of triethylamine, with salt
Acid oxyammonia back flow reaction obtains R not for the compound III of hydroxyl.
Compound I containing methoxy substitution is dissolved in dichloromethane ,-20～-80 DEG C of cryogenic conditions under, add tribromide
Boron, demethylation obtains the compound II that R is hydroxyl.Compound II is in methanol solution, in the presence of triethylamine, refluxes with oxammonium hydrochloride
React to obtain compound III containing hydroxyl in structure.
The invention have the advantages that the compound that the present invention synthesizes is respectively provided with the strongest LSD1 inhibitory activity, majority of compounds
LSD1 suppresses IC50Being respectively less than 1 μM, activity is all better than positive control medicine tranylcypromine.The compounds represented of the present invention a class
The LSD1 inhibitor that structure is brand-new, the research and development for LSD1 inhibitor class medicine provide the foundation, and the biological function for LSD1 grinds
Study carefully and provide effective tool.Can be used for developing antitumor, anti-AIDS as the candidate of exploitation further or lead compound
Deng disease therapeuticing medicine, and synthetic method is simple, and yield is high, and total recovery reaches more than 62%, beneficially popularization and application.
Accompanying drawing explanation
Fig. 1 is that the compounds of this invention cellular level LSD1 inhibitory activity evaluates block diagram, and in figure, * * represents p < 0.05, tool
Statistically significant.
Detailed description of the invention
Name embodiment technical solution of the present invention is elaborated.
The preparation of embodiment 1 (E)-4-(3,4 dimethoxy styrene base) benzene first cyanogen (I-1)
By compound Veratraldehyde (1.66g, 10mmol) and 4-cyanobenzyls diethyl phosphonate (2.79g,
11mmol) it is dissolved in dry DMF (10mL), is slowly added into potassium tert-butoxide (2.24g, 20mmol) under ice bath stirring, finishes room temperature
React 3 hours, reaction system is slowly added in frozen water (40mL), has white solid to wash out, sucking filtration, washing, collect solid,
With acetone recrystallization, sucking filtration, vacuum drying, obtain white solid 2.21g, yield 83.4%.Mp:102-103℃.1H NMR
(400MHz,CDCl3) δ 7.64 (d, 2H, J=8.0Hz), 7.58 (d, 2H, J=8.0Hz), 7.19 (d, 1H, J=16.4Hz),
7.10 (m, 2H), 6.98 (d, 1H, J=16.4Hz), 6.90 (d, 1H, J=8.0Hz), 3.97 (s, 3H), 3.93 (s, 3H).13C
NMR(101MHz,CDCl3)δ149.76,149.22,142.11,132.48,132.22,129.36,126.59,124.74,
120.76,119.17,111.19,110.10,108.88,55.98,55.93.HRMS(ESI)calcd for C17H16NO2[M+
H]+:266.1176,Found:266.1179.
The preparation of embodiment 2 (E)-4-(2-fluoro-4,5-dimethoxy-styryl) benzene first cyanogen (I-2)
As described in Example 1, with 2-fluoro-4,5-dimethoxy benzaldehyde (1.84g, 10mmol) replaces 3,4-methoxyl group
Benzaldehyde, obtains white solid 2.12g, yield 74.9%.Mp:130-131℃.1H NMR(400MHz,CDCl3)δ7.66(d,2H,J
=8.0Hz), 7.61 (d, 2H, J=8.0Hz), 7.36 (d, 1H, J=16.0Hz), 7.06 (d, 1H, J=8.0Hz), 7.04 (d,
1H, J=16.0Hz), 6.69 (d, 1H, J=12.0Hz), 3.95 (s, 3H), 3.92 (s, 3H).13C NMR(101MHz,CDCl3)
δ156.68,154.24,150.50,150.40,145.64,145.62,142.00,132.51,126.37,126.32,
124.47,124.44,119.09,115.29,115.16,110.44,108.35,108.30,100.30,100.02,56.46,
56.24.HRMS(ESI)calcd for C17H15FNO2[M+H]+:284.1081,Found:284.1081.
The preparation of embodiment 3 (E)-4-(2-bromo-4,5-dimethoxy-styryl) benzene first cyanogen (I-3)
As described in Example 1,3 are replaced with 2-bromo-4,5-dimethoxy benzaldehyde (1.23g, 5mmol), 4-dimethoxy
Benzaldehyde, obtains white solid 1.31g, yield 76.3%.Mp:149-151℃.1H NMR(400MHz,CDCl3)δ7.67(d,
2H, J=8.0Hz), 7.63 (d, 2H, J=8.0Hz), 7.55 (d, 1H, J=16.0Hz), 7.16 (s, 1H), 7.08 (s, 1H),
6.95 (d, 1H, J=16.0Hz), 3.97 (s, 3H), 3.92 (s, 3H).13C NMR(101MHz,CDCl3)δ150.10,
148.74,141.70,132.55,130.93,128.19,127.31,126.97,119.04,115.74,115.54,110.69,
108.68,56.25,56.16.HRMS(ESI)calcd for C17H14BrNNaO2[M+Na]+:366.0106,Found:
366.0101.
The preparation of embodiment 4 (E)-4-(3-fluoro-4-methoxyl-styrene) benzene first cyanogen (I-4)
As described in Example 1,3 are replaced with the fluoro-4-methoxybenzaldehyde of 3-(1.54g, 10mmol), 4-dimethoxy benzene
Formaldehyde, obtains white solid 2.02g, yield 80.1%.Mp:103-104℃.1H NMR(400MHz,DMSO)δ7.82(d,2H,J
=8.0Hz), 7.74 (d, 2H, J=8.0Hz), 7.59 (d, 1H, J=16.4Hz), 7.41 (d, 1H, J=8.0Hz), 7.37 (s,
1H), 7.27 (d, 1H, J=16.4Hz), 7.21 (t, 1H, J=8.8Hz).13C NMR(101MHz,DMSO)δ153.34,
150.91,147.89,147.79,142.36,133.06,131.38,130.26,130.20,127.37,126.37,124.80,
124.77,119.53,114.27,113.93,113.75,109.72,56.48.HRMS(ESI)calcd for C16H11FNO
[M-H]-:252.0830,Found:252.0830.
The preparation of embodiment 5 (E)-4-(4-methoxyl-styrene) benzene first cyanogen (I-5)
As described in Example 1, replace Veratraldehyde with 4-methoxybenzaldehyde (1.36g, 10mmol),
Obtain white solid 1.70g, yield 72.7%.Mp:113-114℃.1H NMR(400MHz,CDCl3) δ 7.64 (d, 2H, J=
8.0Hz), 7.58 (d, 2H, J=8.0Hz), 7.51 (d, 2H, J=8.8Hz), 7.21 (d, 1H, J=16.4Hz), 6.93-6.99
(m,3H),3.87(s,3H).13C NMR(101MHz,CDCl3)160.09,142.24,132.48,131.97,129.07,
128.30,126.58,124.55,119.21,114.32,110.04,55.39.HRMS(ESI)calcd for C16H13NNaO
[M+Na]+:258.0889,Found:258.0893.
The preparation of embodiment 6 (E)-3-(3,4 dimethoxy styrene base) benzene first cyanogen (I-6)
As described in Example 1, replace 4-cyanobenzyls diethyl phosphonate with 3-cyanobenzyls diethyl phosphonate, obtain white
Solid 2.34g, yield 88.3%.Mp:147-148℃.HRMS(ESI)calcd for C17H16NO2[M+H]+:266.1176,
Found:266.1177.
The preparation of embodiment 7 (E)-3-(3,5-dimethoxy-styryl) benzene first cyanogen (I-7)
By compound 3,5-dimethoxy benzaldehyde (1.66g, 10mmol) and 3-cyanobenzyls diethyl phosphonate (2.79g,
11mmol) it is dissolved in dry DMF (10mL), is slowly added into potassium tert-butoxide (2.24g, 20mmol) under ice bath stirring, finishes room temperature
React 3 hours, reaction system is slowly added in frozen water (40mL), has white solid to wash out, sucking filtration, washing, collect solid,
With acetone recrystallization, sucking filtration, vacuum drying, obtain white solid 2.10g, yield 79.2%.Mp:114-115℃.1H NMR
(400MHz,CDCl3) δ 7.78 (s, 1H), 7.73 (d, 1H, J=8.0Hz), 7.56 (d, 1H, J=8.0Hz), 7.49 (t, 1H, J
=8.0Hz), 7.12 (d, 1H, J=16.0Hz), 7.06 (d, 1H, J=16.0Hz), 6.69 (d, 2H, J=2.4Hz), 6.46
(t, 1H, J=2.4Hz), 3.86 (s, 6H).13C NMR(101MHz,CDCl3)δ161.07,138.41,138.34,131.29,
130.81,130.60,129.93,129.50,126.69,118.81,112.93,104.87,100.64,55.43.HRMS
(ESI)calcd for C17H16NO2[M+H]+:266.1176,Found:266.1179.
The preparation of embodiment 8 (E)-3-(2-fluoro-4,5-dimethoxy-styryl) benzene first cyanogen (I-8)
As described in Example 7, with 2-fluoro-4,5-dimethoxy benzaldehyde (1.84g, 10mmol) replaces 3,5-methoxyl group
Benzaldehyde, obtains white solid 2.14g, yield 75.5%.Mp:130-132℃.1H NMR(400MHz,CDCl3)δ7.78(s,
1H), 7.75 (d, 1H, J=8.0Hz), 7.55 (d, 1H, J=8.0Hz), 7.49 (t, 1H, J=8.0Hz), 7.30 (d, 1H, J=
16.0Hz), 7.05 (d, 1H, J=8.0Hz), 7.01 (d, 1H, J=16.0Hz), 6.96 (d, 1H, J=12.0Hz), 3.95 (s,
3H),3.91(s,3H).13C NMR(101MHz,CDCl3)δ156.53,154.10,150.27,150.17,145.61,
145.58,138.76,130.63,130.31,129.83,129.49,125.92,125.87,123.43,123.40,118.82,
115.32,115.19,112.93,108.36,108.31,100.31,100.02,56.45,56.23.HRMS(ESI)calcd
for C17H15FNO2[M+H]+:284.1081,Found:284.1081.
The preparation of embodiment 9 (E)-3-(2-bromo-4,5-dimethoxy-styryl) benzene first cyanogen (I-9)
As described in Example 7,3 are replaced with 2-bromo-4,5-dimethoxy benzaldehyde (1.23g, 5mmol), 5-dimethoxy
Benzaldehyde, obtains white solid 2.38g, yield 69.1%.Mp:138-140℃.1H NMR(400MHz,CDCl3)δ7.80(s,
1H), 7.78 (d, 1H, J=8.0Hz), 7.57 (d, 1H, J=8.0Hz), 7.50 (t, 1H, J=8.0Hz), 7.48 (d, 1H, J=
16.4Hz), 7.14 (s, 1H), 7.07 (s, 1H), 6.91 (d, 1H, J=16.4Hz), 3.97 (s, 3H), 3.92 (s, 3H).13C
NMR(101MHz,CDCl3)δ149.94,148.72,138.47,130.84,130.52,130.07,129.88,129.55,
128.26,126.84,118.80,115.52,115.49,112.98,108.64,56.24,56.15.HRMS(ESI)calcd
for C17H14BrNNaO2[M+Na]+:366.0106,found:366.0109.
The preparation of embodiment 10 (E)-3-(3-fluoro-4-methoxyl-styrene) benzene first cyanogen (I-10)
As described in Example 7,3 are replaced with the fluoro-4-methoxybenzaldehyde of 3-(1.54g, 10mmol), 5-dimethoxy benzene
Formaldehyde, obtain white solid 2.03g, yield 80.3%.Mp:90-92℃.1H NMR(400MHz,DMSO)δ8.04(s,1H),
7.88 (d, 1H, J=2.0Hz), 7.71 (d, 1H, J=2.0Hz), 7.59 (t, 1H, J=8.0Hz), 7.55 (d, 1H, J=
16.4Hz),7.35-7.39(m,2H),7.17-7.22(m,2H),3.87(s,3H).13C NMR(101MHz,DMSO)δ
153.36,150.94,147.70,147.59,138.96,131.39,131.08,130.39,130.17,130.15,129.95,
125.88,124.48,124.45,119.26,114.39,114.37,113.77,113.59,112.35,56.51.HRMS
(ESI)calcd for C16H11FNO[M-H]-:252.0830,Found:252.0830.
The preparation of embodiment 11 (E)-3-(4-methoxyl-styrene) benzene first cyanogen (I-11)
As described in Example 7, replace 3 with 4-methoxybenzaldehyde (1.36g, 10mmol), 5-dimethoxy benzaldehyde,
Obtain white solid 2.10g, yield 89.2%.Mp:137-139℃.1H NMR(400MHz,CDCl3)δ7.76(s,1H),7.72
(d, 1H, J=8.0Hz), 7.44-7.53 (m, 4H), 7.15 (d, 1H, J=16.0Hz), 6.92-6.96 (m, 3H), 3.86 (s,
3H).13C NMR(101MHz,CDCl3)δ159.92,138.95,130.84,130.29,129.60,129.44,129.14,
128.12,124.03,118.93,114.29,112.85,55.38.HRMS(ESI)calcd for C16H13NNaO[M+Na]+:
258.0889,Found:258.0891.
The preparation of embodiment 12 (E)-3-(2-(pyridin-4-yl) vinyl)-benzene first cyanogen (I-12)
3-cyanobenzyls diethyl phosphonate (2.79g, 11mmol) is dissolved in the tert-butyl alcohol (10mL), under ice bath stirring slowly
Add potassium tert-butoxide (2.24g, 20mmol), finish and stir 20 minutes under ice bath, then, be slowly added into the uncle of Pyridine-4-Carboxaldehyde
Butanol solution (1.07g, 10mmol, 5mL), finishes and changes room temperature reaction into 1 hour.After reaction terminates, reaction system is slowly added
Enter in frozen water (40mL), have white solid to wash out, sucking filtration, washing, collect solid, with acetone recrystallization, sucking filtration, vacuum is done
Dry, obtain white solid 1.88g, yield 91.2%.Mp:144-145℃.1H NMR(400MHz,CDCl3) δ 8.65 (d, 2H, J=
6.0Hz), 7.83 (s, 1H), 7.78 (d, 1H, J=8.0Hz), 7.63 (d, 1H, J=8.0Hz), 7.54 (t, 1H, J=
8.0Hz), 7.40 (d, 2H, J=6.0Hz), 7.30 (d, 1H, J=16.4Hz), 7.12 (d, 1H, J=16.4Hz).13C NMR
(101MHz,CDCl3)δ150.45,143.57,137.44,131.77,131.01,130.61,130.34,129.72,
128.72,121.00,118.49,113.23.HRMS(ESI)calcd for C14H11N2[M+H]+:207.0917,Found:
207.0918
The preparation of embodiment 13 (E)-4-(the fluoro-styryl of 3,4-bis-) benzene first cyanogen (I-13)
As described in Example 1, with 3,4-difluorobenzaldehyde (1.42g, 10mmol) replaces Veratraldehyde,
Obtain white solid 2.0g, yield 83.3%.Mp:103-105℃.1H NMR(400MHz,CDCl3)δ7.74-7.85(m,5H),
7.41-7.53 (m, 3H), 7.37 (d, 1H, J=16.0Hz).13C NMR(101MHz,DMSO)δ151.52,151.37,
151.08,150.92,149.06,148.91,148.58,148.42,141.86,134.89,134.86,134.79,133.12,
130.48,128.63,128.04,127.66,124.83,124.79,124.76,124.73,119.41,118.38,118.21,
115.59,115.42,110.27.HRMS(ESI)calcd for C15H10F2N[M+H]+:242.0776,Found:
242.0773.
The preparation of embodiment 14 (E)-4-(3,4-dihydroxystyryl) benzene first cyanogen (II-1)
Being dissolved by compound I-1 (398mg, 1.5mmol) anhydrous methylene chloride (10mL), nitrogen is protected ,-35 DEG C of stirrings
Under, it being slowly added into the dichloromethane solution (2.25g, 9mmol, 5mL) of Boron tribromide, finish, reaction system is slowly warmed to room temperature,
Stirred overnight at room temperature is reacted.Reaction system is slowly added in frozen water (30mL), has white-yellowish solid to separate out, filter, washing,
Collect solid, vacuum drying, obtain white-yellowish solid.1H NMR(400MHz,DMSO)δ9.28(br,1H),9.03(br,1H),
7.79 (d, 2H, J=8.0Hz), 7.74 (d, 2H, J=8.0Hz), 7.32 (d, 1H, J=16.4Hz), 7.05 (d, 1H, J=
2.0Hz), 7.03 (d, 1H, J=16.4Hz), 6.95 (dd, 1H, J1=2.0Hz, J2=8.0Hz), 6.77 (d, 1H, J=
8.0Hz).13C NMR(101MHz,DMSO)δ146.96,145.97,142.96,133.23,132.97,128.44,127.11,
123.75,119.87,119.66,116.21,114.26,109.05.HRMS(ESI)calcd for C15H10NO2[M-H]-:
236.0717,Found:236.0716.
The preparation of embodiment 15 (E)-4-(2-fluoro-4,5-dihydroxystyryl) benzene first cyanogen (II-2)
As described in Example 14, replace compound I-1 with compound I-2, obtain white-yellowish solid 286mg, yield
74.7%.Mp:234-235℃.1H NMR (400MHz, DMSO) δ 9.84 (br, 1H), 8.98 (br, 1H), 7.80 (d, 2H, J=
8.0Hz), 7.76 (d, 2H, J=8.0Hz), 7.35 (d, 1H, J=16.0Hz), 7.11 (d, 1H, J=8.0Hz), 7.09 (d,
1H, J=16.0Hz), 6.63 (d, 1H, J=12.0Hz).13C NMR(101MHz,DMSO)δ155.50,153.11,147.96,
147.85,142.68,142.66,142.60,133.02,127.33,126.07,126.02,125.03,119.57,114.51,
114.38,113.14,113.09,109.54,103.72,103.46.HRMS(ESI)calcd for C15H9FNO2[M-H]-:
254.0623,Found:254.0622.
The preparation of embodiment 16 (E)-4-(2-bromo-4,5-dihydroxystyryl) benzene first cyanogen (II-3)
As described in Example 14, replace compound I-1 with compound I-3, obtain white-yellowish solid 395mg, yield
83.3%.Mp:196-197℃.1H NMR (400MHz, DMSO) δ 9.88 (br, 1H), 9.37 (br, 1H), 7.83 (d, 2H, J=
8.0Hz), 7.75 (d, 2H, J=8.0Hz), 7.42 (d, 1H, J=16.0Hz), 7.24 (s, 1H), 7.07 (d, 1H, J=
16.0Hz),7.00(s,1H).13C NMR(101MHz,DMSO)δ148.10,146.06,142.25,133.15,130.60,
127.46,127.10,126.81,119.51,119.46,113.81,113.28,109.85.HRMS(ESI)calcd for
C15H9BrNO2[M-H]-:313.9822,Found:313.9822.
The preparation of embodiment 17 (E)-4-(3-fluoro-4-Vinyl phenol base) benzene first cyanogen (II-4)
As described in Example 14, replace compound I-1 with compound I-4, obtain white-yellowish solid 276mg, yield
76.9%.Mp:162-163℃.1H NMR (400MHz, DMSO) δ 10.18 (br, 1H), 7.81 (d, 2H, J=8.4Hz), 7.73
(d, 2H, J=8.4Hz), 7.52 (dd, 1H, J1=2.0Hz, J2=8.4Hz), 7.38 (d, 1H, J=16.4Hz), 7.28 (dd,
1H,J1=1.6Hz, J2=8.4Hz), 7.20 (d, 1H, J=16.4Hz), 6.99 (t, 1H, J=8.8Hz).13C NMR
(101MHz,DMSO)δ152.87,150.47,145.98,145.86,142.55,133.05,131.77,131.75,128.93,
128.86,127.26,125.47,124.65,124.63,119.57,118.33,118.30,114.52,114.34,
109.51.HRMS(ESI)calcd for C15H9FNO[M-H]-:238.0674,Found:238.0669.
The preparation of embodiment 18 (E)-4-(4-Vinyl phenol base) benzene first cyanogen (II-5)
As described in Example 14, replace compound I-1 with compound I-5, obtain white-yellowish solid 265mg, yield
79.8%.Mp:180-181℃.1H NMR (400MHz, DMSO) δ 9.76 (br, 1H), 7.80 (d, 2H, J=8.0Hz), 7.73
(d, 2H, J=8.0Hz), 7.49 (d, 2H, J=8.4Hz), 7.39 (d, 1H, J=16.4Hz), 7.12 (d, 1H, J=
16.4Hz), 6.81 (d, 2H, J=8.4Hz).13C NMR(101MHz,DMSO)δ158.57,142.95,133.01,132.81,
129.03,127.89,127.09,123.87,119.64,116.14,109.13.HRMS(ESI)calcd for C15H10NO
[M-H]-:220.0768,Found:220.0769.
The preparation of embodiment 19 (E)-3-(3,4-dihydroxystyryl) benzene first cyanogen (II-6)
As described in Example 14, replace compound I-1 with compound I-6, obtain khaki solid 294mg, yield
82.6%.Mp:142-143℃.1H NMR (400MHz, DMSO) δ 9.11 (br, 2H), 8.03 (s, 1H), 7.88 (d, 1H, J=
8.0Hz), 7.66 (d, 1H, J=8.0Hz), 7.55 (t, 1H, J=8.0Hz), 7.28 (d, 1H, J=16.0Hz), 7.03 (d,
1H, J=2.0Hz), 6.98 (d, 1H, J=16.0Hz), 6.91 (dd, 1H, J1=2.0Hz, J2=8.0Hz), 6.77 (d, 1H, J
=8.0Hz).13C NMR(101MHz,DMSO)δ146.66,145.93,139.48,131.88,131.05,130.50,
130.26,129.76,128.54,123.19,119.53,119.38,116.20,114.07,112.25.HRMS(ESI)calcd
for C15H10NO2[M-H]-:236.0717,Found:236.0709.
The preparation of embodiment 20 (E)-3-(3,5-dihydroxystyryl) benzene first cyanogen (II-7)
As described in Example 14, replace compound I-1 with compound I-7, obtain khaki solid 271mg, yield
76.1%.Mp:187-189℃.1H NM7R (400MHz, DMSO) δ 9.34 (br, 2H), 8.09 (s, 1H), 7.93 (d, 1H, J=
8.0Hz), 7.71 (d, 1H, J=8.0Hz), 7.58 (t, 1H, J=8.0Hz), 7.28 (d, 1H, J=16.0Hz), 7.11 (d,
1H, J=16.0Hz), 6.47 (s, 2H), 6.20 (s, 1H).13C NMR(101MHz,DMSO)δ159.05,138.93,138.67,
131.97,131.53,131.14,130.30,130.25,126.18,119.31,112.29,105.44,103.33.HRMS
(ESI)calcd for C15H10NO2[M-H]-:236.0717,Found:236.0712.
The preparation of embodiment 21 (E)-3-(2-fluoro-4,5-dihydroxystyryl) benzene first cyanogen (II-8)
As described in Example 14, replace compound I-1 with compound I-8, obtain white solid 317mg, yield 82.7%.
Mp:186-187℃。1H NMR(400MHz,DMSO)δ9.77(br,1H),9.06(br,1H),8.07(s,1H),7.91(d,
1H, J=8.0Hz), 7.69 (d, 1H, J=8.0Hz), 7.57 (t, 1H, J=8.0Hz), 7.32 (d, 1H, J=16.0Hz),
7.07 (d, 1H, J=8.0Hz), 7.05 (d, 1H, J=16.0Hz), 6.62 (d, 1H, J=12.0Hz).13C NMR(101MHz,
DMSO)δ155.34,152.95,147.62,147.51,142.62,142.60,139.18,131.18,130.97,130.31,
130.10,125.65,125.60,123.89,119.30,114.60,114.47,113.10,113.05,112.32,103.74,
103.48.HRMS(ESI)calcd for C15H9FNO2[M-H]-:254.0623,Found:254.0619.
The preparation of embodiment 22 (E)-3-(2-bromo-4,5-dihydroxystyryl) benzene first cyanogen (II-9)
As described in Example 14, replace compound I-1 with compound I-9, obtain white solid 361mg, yield 76.2%.
Mp:168-169℃。1H NMR(400MHz,DMSO)δ9.81(br,1H),9.38(br,1H),8.01(s,1H),7.90(d,
1H, J=8.0Hz), 7.71 (d, 1H, J=8.0Hz), 7.58 (t, 1H, J=8.0Hz), 7.36 (d, 1H, J=16.0Hz),
7.19(s,1H),7.00(m,3H).13C NMR(101MHz,DMSO)δ147.83,146.00,138.82,131.28,131.12,
130.41,130.37,129.49,127.03,126.72,119.45,119.23,113.75,112.96,112.39.HRMS
(ESI)calcd for C15H9BrNO2[M-H]-:313.9822,Found:313.9822.
The preparation of embodiment 23 (E)-3-(3-fluoro-4-Vinyl phenol base) benzene first cyanogen (II-10)
As described in Example 14, replace compound I-1 with compound I-10, obtain white solid 264mg, yield
73.7%.Mp:127-129℃.1H NMR (400MHz, DMSO) δ 10.13 (s, 1H), 8.02 (s, 1H), 7.85 (d, 1H, J=
8.0Hz), 7.69 (d, 1H, J=8.0Hz), 7.58 (t, 1H, J=8.0Hz), 7.44 (dd, 1H, J1=2.0Hz, J1=
12.8Hz), 7.35 (d, 1H, J=16.0Hz), 7.25 (dd, 1H, J1=2.0Hz, J1=8.0Hz), 7.15 (d, 1H, J=
16.0Hz), 6.99 (t, 1H, J=8.0Hz).13C NMR(101MHz,DMSO)δ152.87,150.47,145.72,145.59,
139.11,131.26,130.89,130.50,130.48,130.35,129.84,129.05,128.99,124.94,124.33,
124.30,119.30,118.34,118.31,114.31,114.13,112.32.HRMS(ESI)calcd for C15H9FNO
[M-H]-:238.0674,Found:238.0667.
The preparation of embodiment 24 (E)-3-(4-Vinyl phenol base) benzene first cyanogen (II-11)
As described in Example 14, replace compound I-1 with compound I-11, obtain white-yellowish solid 259mg, yield
77.8%.Mp:189-191℃.1H NMR (400MHz, DMSO) δ 9.70 (br, 1H), 8.02 (s, 1H), 7.87 (d, 1H, J=
8.0Hz), 7.67 (d, 1H, J=8.0Hz), 7.54 (t, 1H, J=8.0Hz), 7.46 (d, 2H, J=8.0Hz), 7.35 (d, 1H,
J=16.0Hz), 7.07 (d, 1H, J=16.0Hz), 6.81 (d, 2H, J=8.0Hz).13C NMR(101MHz,DMSO)δ
158.30,139.48,131.49,131.07,130.56,130.30,129.72,128.74,128.00,123.32,119.36,
116.10,112.28.HRMS(ESI)calcd for C15H10NO[M-H]-:220.0768,Found:220.0766.
The preparation of embodiment 25 (Z)-4-((E)-3,4-dihydroxystyryl)-N'-hydroxy benzenes carbonamidine (III-1)
Compound II-1 (237mg, 1mmol) and oxammonium hydrochloride. (209mg, 3mmol) methanol (10mL) are dissolved, room temperature
Add triethylamine (303mg, 3mmol) under stirring, finish, back flow reaction 6 hours.After reaction terminates, by reaction system vacuum
Concentrate, concentrate ethyl acetate, water dissolution, divide and take ethyl acetate layer, successively with water (2 × 20mL), saturated aqueous common salt (1 ×
20mL) washing.Anhydrous sodium sulfate is dried, decompression distillation after, crude product with silica gel column chromatography separating purification (petroleum ether: acetone=1:
1), compound as white solid 169mg, yield 62.5% are obtained.Mp:167-168℃.1H NMR(400MHz,DMSO)δ9.65(br,
1H), 9.09 (br, 2H), 7.66 (d, 2H, J=8.0Hz), 7.54 (d, 2H, J=8.0Hz), 7.14 (d, 1H, J=16.4Hz),
7.01 (s, 1H), 6.95 (d, 1H, J=16.4Hz), 6.89 (d, 1H, J=8.0Hz), 6.75 (d, 1H, J=8.0Hz), 5.81
(s,2H).13C NMR(101MHz,DMSO)δ151.06,146.22,145.91,138.55,132.07,129.76,129.02,
126.17,126.02,124.86,119.20,116.19,113.83.HRMS(ESI)calcd for C15H14N2O2[M-H]-:
269.0932,Found:269.0931.
The system of embodiment 26 (Z)-4-((E)-2-fluoro-4,5-dihydroxystyryl)-N'-hydroxy benzenes carbonamidine (III-2)
Standby
By the method for embodiment 25, replace compound II-1 with compound II-2, obtain white solid 202mg, yield
70.4%.Mp:193-194℃.1H NMR (400MHz, DMSO) δ 9.68 (br, 2H), 9.01 (br, 1H), 7.68 (d, 2H, J=
8.0Hz), 7.57 (d, 2H, J=8.0Hz), 7.19 (d, 1H, J=16.0Hz), 7.08 (d, 1H, J=8.0Hz), 7.02 (d,
1H, J=16.0Hz), 6.61 (d, 1H, J=12.0Hz), 5.84 (s, 2H).13C NMR(101MHz,DMSO)δ155.11,
152.73,151.04,147.14,147.03,142.59,138.27,132.48,127.23,127.18,126.36,126.09,
121.57,115.03,114.90,112.81,112.76,103.71,103.45.HRMS(ESI)calcd for C15H12FN2O3
[M-H]-:287.0837,Found:287.0832.
The system of embodiment 27 (Z)-4-((E)-2-bromo-4,5-dihydroxystyryl)-N'-hydroxy benzenes carbonamidine (III-3)
Standby
By the method for embodiment 25, replace compound II-1 with compound II-3, obtain white solid 288mg, yield
82.5%.Mp:184-185℃.1H NMR (400MHz, DMSO) δ 9.69 (br, 2H), 9.34 (br, 1H), 7.70 (d, 2H, J=
8.0Hz), 7.56 (d, 2H, J=8.0Hz), 7.29 (d, 1H, J=16.0Hz), 7.21 (s, 1H), 6.98 (s, 1H), 6.94 (d,
1H, J=16.0Hz), 5.83 (s, 2H).13C NMR(101MHz,DMSO)δ150.98,147.45,146.01,137.96,
132.80,128.23,127.39,127.36,126.49,126.19,119.42,113.48,112.71.HRMS(ESI)calcd
for C15H15BrN2O3[M+H]+:349.0183,Found:349.0187.
The preparation of embodiment 28 (Z)-4-((E)-3-fluoro-4-Vinyl phenol base)-N'-hydroxy benzenes carbonamidine (III-4),
By the method for embodiment 25, replace compound II-1 with compound II-4, obtain white solid 201mg, yield
73.6%.Mp:184-186℃.1H NMR(400MHz,DMSO)δ9.69(br,2H),7.36-7.67(m,5H),6.95-7.23
(m,4H),5.83(s,2H).13C NMR(101MHz,DMSO)δ168.02,152.90,151.03,150.51,145.32,
145.20,138.20,132.46,129.54,129.47,128.40,126.58,126.34,126.08,123.95,118.31,
114.12,113.94.HRMS(ESI)calcd for C15H14FN2O2[M+H]+:273.1034,Found:273.1031.
The preparation of embodiment 29 (Z)-4-((E)-4-Vinyl phenol base)-N'-hydroxy benzenes carbonamidine (III-5)
By the method for embodiment 25, replace compound II-1 with compound II-5, obtain white solid 208mg, yield
81.9%.Mp:192-194℃.1H NMR (400MHz, DMSO) δ 9.66 (br, 1H), 9.62 (br, 1H), 7.67 (d, 2H, J=
8.0Hz), 7.55 (d, 2H, J=8.0Hz), 7.45 (d, 2H, J=8.0Hz), 7.21 (d, 1H, J=16.4Hz), 7.05 (d,
1H, J=16.4Hz), 6.79 (d, 2H, J=8.0Hz), 5.83 (s, 2H).13C NMR(101MHz,DMSO)δ157.90,
151.10,138.58,132.10,129.40,128.44,126.16,126.06,124.99,116.05.HRMS(ESI)calcd
for C15H15N2O2[M+H]+:255.1128,Found:255.1127.
The preparation of embodiment 30 (Z)-3-((E)-3,4-dihydroxystyryl)-N'-hydroxy benzenes carbonamidine (III-6)
By the method for embodiment 25, replace compound II-1 with compound II-6, obtain white solid 192mg, yield
71.0%.Mp:210-211℃.1H NMR(400MHz,DMSO)δ9.65(br,1H),9.08(br,2H),7.84(s,1H),
7.54 (d, 2H, J=8.0Hz), 7.35 (t, 1H, J=8.0Hz), 7.14 (d, 1H, J=16.0Hz), 7.01 (d, 1H, J=
2.0Hz), 6.95 (d, 1H, J=16.0Hz), 6.90 (dd, 1H, J1=2.0Hz, J2=8.0Hz), 6.75 (d, 1H, J=
8.0Hz),5.87(s,2H).13C NMR(101MHz,DMSO)δ151.24,146.19,145.91,137.85,134.15,
129.67,128.99,128.87,127.16,125.18,124.47,123.25,119.13,116.20,113.80.HRMS
(ESI)calcd for C15H14N2O2[M-H]-:269.0932,Found:269.0925.
The preparation of embodiment 31 (Z)-3-((E)-3,5-hydroxy styrenes base)-N'-hydroxy benzenes carbonamidine (III-7)
By the method for embodiment 25, replace compound II-1 with compound II-7, obtain white solid 217mg, yield
80.4%.Mp:85-87℃.1H NMR(400MHz,DMSO)δ9.67(br,1H),9.30(br,2H),7.88(s,1H),7.58
(d, 2H, J=8.0Hz), 7.38 (t, 1H, J=8.0Hz), 7.14 (d, 1H, J=16.4Hz), 7.07 (d, 1H, J=
16.4Hz), 6.46 (d, 2H, J=2.4Hz), 6.19 (t, 1H, J=2.4Hz), 5.89 (s, 2H).13C NMR(101MHz,
DMSO)δ159.04,151.16,139.12,137.35,134.18,129.81,128.92,128.09,127.62,125.05,
123.63,105.18,102.90.HRMS(ESI)calcd for C15H15N2O3[M+H]+:271.1077,Found:
271.1079.
The preparation of embodiment 32 (Z)-3-((E)-2-fluoro-4,5-hydroxy styrenes base)-N'-hydroxy benzenes carbonamidine (III-8)
By the method for embodiment 25, replace compound II-1 with compound II-8, obtain white solid 223mg, yield
77.4%.Mp:171-172℃.1H NMR(400MHz,DMSO)δ9.66(br,2H),9.02(br,1H),7.87(s,1H),
7.58 (d, 1H, J=8.0Hz), 7.53 (d, 1H, J=8.0Hz), 7.37 (t, 1H, J=8.0Hz), 7.22 (d, 1H, J=
16.0Hz), 7.08 (d, 1H, J=8.0Hz), 7.02 (d, 1H, J=16.0Hz), 6.62 (d, 1H, J=12.0Hz), 5.89 (s,
2H).13C NMR(101MHz,DMSO)δ155.10,152.72,151.14,147.13,147.01,142.61,137.61,
134.17,128.96,127.49,124.86,123.20,121.52,114.99,114.86,112.73,112.68,103.71,
103.45.HRMS(ESI)calcd for C15H12FN2O3[M-H]-:287.0837,Found:287.0832.
The preparation of embodiment 33 (Z)-3-((E)-2-bromo-4,5-hydroxy styrenes base)-N'-hydroxy benzenes carbonamidine (III-9)
By the method for embodiment 25, replace compound II-1 with compound II-9, obtain white solid 303mg, yield
86.7%.Mp:66-68℃.1H NMR (400MHz, DMSO) δ 9.67 (br, 3H), 7.87 (s, 1H), 7.59 (d, 1H, J=
8.0Hz), 7.54 (d, 1H, J=8.0Hz), 7.40 (t, 1H, J=8.0Hz), 7.30 (d, 1H, J=16.0Hz), 7.21 (s,
1H), 6.98 (s, 1H), 6.94 (d, 1H, J=16.0Hz), 5.89 (s, 2H).13C NMR(101MHz,DMSO)δ151.19,
147.46,146.02,137.30,134.31,129.08,128.55,127.70,127.39,127.36,125.17,123.34,
119.41,113.52,112.64.HRMS(ESI)calcd for C15H15BrN2O3[M+H]+:349.0183,Found
349.0180.
The preparation of embodiment 34 (Z)-3-((E)-3-fluoro-4-Vinyl phenol base)-N'-hydroxy benzenes carbonamidine (III-10)
By the method for embodiment 25, replace compound II-1 with compound II-10, obtain white solid 204mg, yield
75.1%.Mp:189-190℃.1H NMR(400MHz,DMSO)δ10.05(br,1H),9.67(br,1H),7.87(s,1H),
7.57 (t, 2H, J=8.0Hz), 7.47 (dd, 1H, J1=1.6Hz, J2=12.4Hz), 7.38 (t, 1H, J=8.0Hz), 7.25
(dd,1H,J1=2.0Hz, J2=8.0Hz), 7.20 (d, 1H, J=16.4Hz), 7.13 (d, 1H, J=16.4Hz), 6.98 (t,
1H, J=8.0Hz), 5.88 (s, 2H).13C NMR(101MHz,DMSO)δ152.90,151.24,150.51,145.25,
145.13,137.51,134.24,129.55,129.49,128.94,128.28,127.31,126.95,124.86,123.91,
123.51,118.31,118.28,114.12,113.93.HRMS(ESI)calcd for C15H14FN2O2[M+H]+:
273.1034,Found:273.1030.
The preparation of embodiment 35 (Z)-3-((E)-4-Vinyl phenol base)-N'-hydroxy benzenes carbonamidine (III-11)
By the method for embodiment 25, replace compound II-1 with compound II-11, obtain white solid 171mg, yield
67.6%.Mp:184-186℃.1H NMR(400MHz,DMSO)δ9.65(br,1H),9.62(br,1H),7.86(s,1H),
7.54 (d, 2H, J=8.0Hz), 7.45 (d, 2H, J=8.0Hz), 7.36 (t, 1H, J=8.0Hz), 7.21 (d, 1H, J=
16.0Hz), 7.05 (d, 1H, J=16.0Hz), 6.80 (d, 2H, J=8.0Hz), 5.87 (s, 2H).13C NMR(101MHz,
DMSO)δ157.87,151.26,137.86,134.18,129.29,128.89,128.45,128.40,127.14,125.32,
124.52,123.30,116.06.HRMS(ESI)calcd for C15H15N2O2[M+H]+:255.1128,Found:
255.1126.
The preparation of embodiment 36 (Z)-3-((E)-4-Vinyl phenol base)-N'-hydroxy benzenes carbonamidine (III-12)
By the method for embodiment 25, replace compound II-1 with compound I-12, obtain white solid 207mg, yield
86.7%.Mp:185-187℃.1H NMR (400MHz, DMSO) δ 9.71 (s, 1H), 8.57 (d, 2H, J=6.0Hz), 7.98
(s, 1H), 7.56-7.67 (m, 5H), 7.42 (t, 1H, J=8.0Hz), 7.32 (d, 1H, J=16.4Hz), 5.92 (s, 2H).13C
NMR(101MHz,DMSO)δ151.07,150.53,144.63,136.49,134.38,133.29,129.11,128.15,
126.81,126.13,124.35,121.38.HRMS(ESI)calcd for C14H14N3O[M+H]+240.1131,Found
240.1139
The preparation of embodiment 37 (Z)-4-(the fluoro-styryl of (E)-3,4-two)-N'-hydroxy benzenes carbonamidine (III-13)
By the method for embodiment 25, replace compound II-1 with compound II-13, obtain white solid 193mg, yield
70.4%.Mp:192-194℃.1H NMR(400MHz,DMSO)δ9.71(br,1H),7.70-7.75(m,3H),7.70(d,
2H, J=8.0Hz), 7.42-7.46 (m, 2H), 7.29 (s, 2H), 5.84 (s, 2H).13C NMR(101MHz,DMSO)δ
151.50,151.38,150.94,149.07,148.94,148.15,148.03,137.58,135.48,133.13,129.77,
127.20,126.76,126.12,124.17,118.28,118.10,115.18,115.01.HRMS(ESI)calcd for
C15H13F2N2O[M+H]+:275.0990,Found:275.0997.
The LSD1 inhibitory activity of the Verakanol derivative synthesized by embodiment 38 present invention is evaluated
(1) enzyme level LSD1 inhibitory activity is evaluated:
1, experimental technique: sample is that the above-claimed cpd synthesized by embodiment, purification obtain；Stock sample solution: weigh 3-
5mg sample is placed in 1.5mL EP pipe, is then configured to the solution that concentration is 20mM, 4 liquid with DMSO, preserves and place, during experiment
Dilute according to desired concn DMSO.By testing sample and LSD1 albumen after incubated at room, add LSD1 reaction substrate
H3K4me2 incubation reaction, be eventually adding fluorescent dye Amplex and horseradish peroxidase HRP incubated at room, in microplate reader
Exciting light 530nm, transmitting light 590nm detection fluorescence values:
Result of the test uses SPSS computed in software IC50Value.
2, experimental result
LSD1 inhibitory activity measurement result
aTables of data is shown as: mean+SD；bN.t.: undetermined
From upper table experimental result it can be seen that most compound is respectively provided with the strongest LSD1 inhibitory activity, major part
The LSD1 of compound suppresses IC50Being respectively less than 1 μM, activity is all better than positive control medicine tranylcypromine.The change that wherein activity is the strongest
Compound III-3 and III-9, LSD1 inhibitory activity is 230 times of 2-PCPA.It is brand-new that the compounds represented of the present invention a class formation
LSD1 inhibitor, the research and development for LSD1 inhibitor class medicine provide the foundation, for LSD1 biological function study provide
Effective tool.
(2) cellular level LSD1 inhibitory activity is evaluated:
1, experimental technique
2000/hole of gastric carcinoma cell lines MGC-803 cell is inoculated in saturating 96 orifice plates at the bottom of black wall, adds variable concentrations chemical combination
Cultivate 5 days after thing III-9；Utilize H3K4me2 antibody and green fluorescence two to resist and do immunofluorescence dyeing, contaminate cell with DAPI simultaneously
Core adds up cell number as internal reference；Utilize the every hole of high intension to choose 16 visuals field, take pictures and green fluorescence with 4 Bei Jingming factories respectively
Taking pictures statistics, wherein H3K4me2 fluorescence intensity/cell number is this hole individual cells H3K4me2 fluorescence intensity parameter.With
Control, as comparison, calculates drug treating group individual cells H3K4me2 fluorescence intensity and does figure.
2, experimental result
From accompanying drawing it can be seen that compound III-9 can raise MGC-803 cell by dose dependent under variable concentrations effect
The amount of interior LSD1 substrate H3K4me2, the compound III-9 of 2.5 μm ol/L can make the amount of H3K4me2 improve more than 5 times, explanation
Compound III-9 also can significantly suppress the activity of LSD1 at cellular level.
Claims (5)
1. resveratrol derivant, it is characterised in that there is structure shown in logical formula (III):
R is monosubstituted or polysubstituted on A ring, and substituent group is selected: hydrogen, hydroxyl, methoxyl group, nitro or halogen；
On B ring monosubstituted；X represents atom N or C atom.
2. resveratrol analog derivative as claimed in claim 1, it is characterised in that in logical formula (III) preferably: R be hydrogen,
Hydroxyl or F, Cl, Br, R is monosubstituted or polysubstituted on A ring；X represents atom N or C atom.
3. resveratrol analog derivative as claimed in claim 2, it is characterised in that preferred following compound:
III-1:R group is 3,4-diOH, and B ring is 4 replacements, the derivant of X=C；
III-2:R group is 2-F-4, and 5-diOH, B ring is 4 replacements, the derivant of X=C；
III-3:R group is 2-Br-4, and 5-diOH, B ring is 4 replacements, the derivant of X=C；
III-4:R group be 3-F-4-OH, B ring be 4 replacements, the derivant of X=C；
III-5:R group be 4-OH, B ring be 4 replacements, the derivant of X=C；
III-6:R group is 3,4-diOH, and B ring is 3 replacements, the derivant of X=C；
III-7:R group is 3,5-diOH, and B ring is 3 replacements, the derivant of X=C；
III-8:R group is 2-F-4, and 5-diOH, B ring is 3 replacements, the derivant of X=C；
III-9:R group is 2-Br-4, and 5-diOH, B ring is 3 replacements, the derivant of X=C；
III-10:R group be 3-F-4-OH, B ring be 3 replacements, the derivant of X=C；
III-11:R group be 4-OH, B ring be 3 replacements, the derivant of X=C；
III-12:R group is 3,4-diF, and B ring is 4 replacements, the derivant of X=C；
III-13:R group be H, B ring be 3 replacements, the derivant of X=N.
4. the method preparing resveratrol analog derivative as claimed in claim 1 or 2, it is characterised in that by as follows
Step realizes:
Benzaldehyde or substituted benzaldehyde and cyano group substituted benzyl diethyl phosphonate, in dry DMF, strongly alkaline compound exists
Under, reaction be stirred at room temperature, generate compound I, wherein, described strongly alkaline compound selected from potassium tert-butoxide, Feldalat NM, sodium hydride,
Sodium tert-butoxide；If not having methoxy substitution in compound I, then compound I is in methanol solution, in the presence of triethylamine, with hydrochloric acid
Oxyammonia back flow reaction obtains R not for the compound III of hydroxyl；
Compound I containing methoxy substitution is dissolved in dichloromethane, under-20 ~-80 DEG C of cryogenic conditions, adds Boron tribromide, de-
Methyl obtains the compound II that R is hydroxyl；Compound II is in methanol solution, in the presence of triethylamine, with oxammonium hydrochloride back flow reaction
Must be containing the compound III of hydroxyl.
5., such as the application in prepared by medicine of the claim 1-3 resveratrol analog derivative as described in one of them, it is special
Levy and be, be used for the preparation of LSD1 inhibitor class medicine as active component.
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| WO2017157825A1 (en) | 2016-03-15 | 2017-09-21 | F. Hoffmann-La Roche Ag | Combinations of lsd1 inhibitors for use in the treatment of solid tumors |
| CN107474011A (en) * | 2017-08-25 | 2017-12-15 | 新乡医学院 | A kind of the stibazole class LSD1 inhibitor of 2 phenyl 4, its preparation method and application |
| CN107501169A (en) * | 2017-08-25 | 2017-12-22 | 新乡医学院 | A kind of trans diarylethene LSD1 inhibitor, its preparation method and application |
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