AU2021105895A4

AU2021105895A4 - Lycoline B-aryl acrylate derivatives, preparation method and application thereof

Info

Publication number: AU2021105895A4
Application number: AU2021105895A
Authority: AU
Inventors: Huanying CAO; Shuwang HE; Yajun JING; Peng Wang; Wensheng Wang; Shiqiang YAN; Jie Yang
Original assignee: Shandong Dyne Marine Biopharmaceutical Co Ltd
Current assignee: Shandong Dyne Marine Biopharmaceutical Co Ltd
Priority date: 2021-07-20
Filing date: 2021-08-19
Publication date: 2021-10-21
Anticipated expiration: 2029-08-19
Also published as: WO2023000398A1; CN113416199B; CN113416199A

Abstract

The present applictaion provides a lycolinep-aryl acrylate derivative, preparation method and application thereof. The lycorine p-aryl acrylate derivative has the structure shown in formula I: 0 H OH 0 N 5 0N wherein, Ar is C6- 12 aromatic or C3-10 aromatic heterocycle, and the heteroatom in the aromatic heterocycle is selected from N, 0 and S; R is a substituent on Ar, which is monosubstituted or polysubstituted, R is independently selected from hydrogen, halogen, halogenated C 1-6 alkyl, halogenated Ci-6 alkoxy, nitro, hydroxyl, C1-6 alkyl, C1 -6 alkoxy, 10 C2-6 alkenyloxy, C2-6 alkenyl, C3-6 cycloalkyl and phenyl. The lycorine p-aryl acrylate derivative with the brand new structure has better anti-tumor activity, and has a good prospect for medicinal application. 94

Description

LYCOLINE /-ARYL ACRYLATE DERIVATIVES, PREPARATION METHOD AND APPLICATION THEREOF TECHNICAL FIELD

The application relates to the field of biomedicine, in particular to a lycoline P-aryl

acrylate derivative, a preparation method and application thereof.

BACKGROUND

The information disclosed in the background of the application is intended to

enhance the understanding of the overall background of the application, and the

disclosure should not necessarily be regarded as an acknowledgement or in any form

implying that the information has become prior art known to those of ordinary skill in

the art.

In recent years, the incidence and mortality of tumors have been on the rise, and

malignant tumors are seriously threatening human health and life safety. According to

statistics, more than 14 million people worldwide suffer from tumors each year, and

tumors are currently the second cause of death in the world. Traditional tumor treatment

uses a combination of radiotherapy and chemotherapy, which causes greater damage to

normal cells, and patients will have many adverse reactions in the middle and late stages,

which will cause the disease to further aggravate. Therefore, it is particularly important

to find new tumor treatment targets and develop new tumor treatment drugs. Compared with traditional drugs, small-molecule targeted drugs have the advantages of fewer side effects, higher specificity and higher efficacy, and are currently the research hotspots of anti-tumor medicines. Traditional Chinese medicine has obvious advantages in the treatment of malignant tumors because of its mild effect, good therapeutic effect and few adverse reactions. In recent years, the extraction of effective antineoplastic compounds from natural drugs is an important research direction for the development of new antineoplastic drugs.

Lycorine is a kind of alkaloid isolated from the bulb of traditional Chinese

medicine Lycoris radiata, which has good antiviral, anti-inflammatory and anti-tumor

activities and has a variety of mechanisms. As early as 1976, Jimenez et al. discovered

the anti-tumor activity of lycorine for the first time. Lycoline and its derivatives have

varying degrees of inhibitory effects on leukemia (K562, HL-60, L-1210), bladder

cancer (T24), prostate cancer (PC-3, DU145, LNCaP, 22RV1, CRPC), ovarian cancer

(Hey1B), lung cancer (A549, H460), esophageal cancer (Eca-109), multiple myeloma

(KM3, ARH-77), gastric cancer (hGCC), hepatic cancer (HCC), kidney cancer (786-0)

and other malignant tumors. A large number of studies have shown that lycoline can

induce tumor cell apoptosis, regulate tumor cell cycle, affect tumor cell autophagy, and

inhibit tumor cell invasion and metastasis by regulating most tumor molecular targets

and signal pathways.

SUMMARY

The present applictaion provides a lycoline p-aryl acrylate derivative, and a

preparation method and appliction thereof. According to the lycorine p-aryl acrylate

derivative provided by the application, hydroxy group at the position 1 of lycorine is

modified on the basis of lycorine, and the result shows that a compound obtained when

the 8-aryl acrylate is modified at the position generally shows excellent anti-tumor

activity, the activity of the compound is generally superior to that of 5-fluorouracil

(5-FU), most of the compounds show the anti-tumor activity superior to that of lycorine,

and the compound shows a good anti-tumor application prospect.

In particular, the present application provides the following technical features, one

or more of which in combination constitute a solution of the present application.

In the first aspect of the application, there is provided a lycorine 8-aryl acrylate

derivative or a pharmaceutically acceptable salt or solvate thereof, which has the

structure as shown in formula I:

R O OH O / N

Wherein Ar is C6-12 aromatic or C 3 -10 aromatic heterocycle, and the heteroatom in

the aromatic heterocycle is selected from N, 0 and S;

R is a substituent on Ar, which is monosubstituted or polysubstituted (i.e., there can

be one or more substituents on Ar). R is independently selected from hydrogen, halogen, halogenated C1.6 alkyl, halogenated C1.6 alkoxy, nitro, hydroxyl, C1-6 alkyl, C1-6 alkoxy,

C 2 -6alkenyloxyC 2-6alkenyl,C3-6cycloalkyl and phenyl.

In some embodiments of the present application, Ar is selected from phenyl,

naphthyl, biphenyl, pyridyl, furanyl, thienyl, pyrrolyl, imidazolyl, benzofuranyl,

benzothienyl and benzodioxol.

In some embodiments of the present application, R is monosubstituted or

polysubstituted, R is independently selected from hydrogen, halogen, trihalogenated

C1-3 alkyl, trihalogenated C1-3 alkoxy, nitro, hydroxyl, C14 alkyl, C14 alkoxy, C 2 -6

alkenyloxy,C2-4alkenyl, and phenyl.

In the embodiments of the present application, the compounds exhibit different

degrees of inhibitory activity on tumor cells, especially, it shows relatively excellent

anti-tumor activity against human tumor cell lines A549, HepG2, Hs683, HGC27 and

HCT116, and the anti-tumor activity is comparable to 5-fluorouracil (5-FU) and most of

them are better than 5-FU.

Further, Ar is selected

from R-C ,- 3 C- -; N S 0 R is

monosubstituted or polysubstituted, the polysubstituted preferably includes

disubstituted or trisubstituted; when R is monosubstituted, the substitution position is

C-4 or C-3; when R is disubstituted, the substitution position is preferably C-2 and C-4,

C-3 and C-4, C-2 and C-5, C-2 and C-6, more preferably C-3 and C-4, C-2 and C-5;

when R is trisubstituted, the substitution position is preferably C-2, C-4 and C-5, or C-3,

C-4 and C-5. The above substitution positions are all positioned based on the position

where Ar is connected to the general formula as the C-1 position (the same applies

hereinafter).

According to the present application, thef#-aryl acrylate structure in formula I of 0 RA the present application, i.e., is an essential group for maintaining

the anti-tumor activity of the present application. In the course of research, the inventors

found that compounds with only an ester group, an aryl group or an alkenyl group at the

position 1 of lycorine are hard to achieve the excellent anti-tumor effect of the present

application. For example, in the preliminary screening process of the application, it is

0 0

found that when the group at the position is - o\, (n is 1-3) 0

or 0 , these compounds showed certain degree of inhibitory activity

against tumor cell lines A549 and HS683, but their activities are weaker than that of

lycorine. In addition, these compounds had no obvious inhibitory activity or only weak

inhibitory activity against HCT116, HGC27 and HEPG2 cell lines at the same dose.

Further, in some embodiments of the present application, the compound has the

structure as shown in formula II:

R0 OH

O y O N II

wherein X is C or N; R is as defined in any one of the embodiments hereinbefore.

Preferably, R is monosubstituted or disubstituted, wherein R is independently

selected from hydrogen, halogen, halogenated C 1 .6 alkyl, halogenated C1.6 alkoxy, nitro,

100 hydroxyl, C1.6 alkyl, C 1 .6 alkoxy, C 2 -6 alkenyloxy, C 2 .6 alkenyl, C 3 -6 cycloalkyl and

phenyl.

In the embodiments, the compounds of the present application have relatively

excellent anti-tumor activities, their anti-tumor activities against human tumor cell lines

A549, HepG2, Hs683, HGC27 and HCT116 are significantly better than 5-FU, and

105 most of the them showed anti-tumor activity comparable to or even better than that of

lycorine, especially, they showed extremely excellent inhibitory activity against Hs683.

Further, in some embodiments of the present application, R is monosubstituted or

disubstituted, wherein when R is monosubstituted, R is selected from hydrogen,

halogenated C1.6 alkyl, halogenated C1.6 alkoxy, nitro, C1.6 alkyl, C 1 .6 alkoxy, C 2 -6

110 alkenyloxy, phenyl; and when R is disubstituted, R is independently selected from

halogen and nitro. The halogen is selected from F, Cl and Br.

Further, in some embodiments of the present application, when X is N, R is

preferably hydrogen. And, in some further embodiments, the compounds of the present application have the structure shown in formula II':

0 -~. ~ o,,OH R4

0 N II' 115

R is as defined hereinbefore; further, in some embodiments of the present

application, in the structure of formula II', when R is monosubstituted, R is attached to

the para-position (C-4 position) or meta-position (C-3 position) of the phenyl group;

when R is disubstituted, R is attached to the orthon-position and meta-position (i.e., C-2

120 and C-5 position), or para-position and meta-position (C-3 and C-4 position).

In particular, in some embodiments of the present application, in the structure of

formula II', R is independently selected from halogen, halogenated C1.6 alkyl,

halogenated C1.6 alkoxy, nitro, C1.6 alkyl , C1.6 alkoxy, C 2 -6 alkenyloxy, phenyl. Further,

when R is monosubstituted, R is selected from halogenated C1.6 alkyl, halogenated C 1.6

125 alkoxy, nitro, C 1 .6 alkyl, C 1.6 alkoxy, C 2 -6 alkenyloxy and phenyl; and when R is

disubstituted, R is independently selected from halogen and nitro. Preferably, the

halogen is selected from F, Cl and Br; the halogenated C1.6 alkyl is fluorinated C 1 -3alkyl,

and is preferably trifluoromethyl; the halogenated C 1 .6 alkoxy is fluorinated C1.3 alkoxy,

and is preferably trifluoromethoxy; the C 1 .6 alkyl group is preferably methyl, ethyl or

130 propyl.

Further, the present application provides a series of exemplary compounds, which are selected from the following compounds S1-S40:

Si: 1-(2-fluorocinnamoyl)-lycorine;

S2: 1-(3-fluorocinnamoyl)-lycorine;

135 S3: 1-(4-fluorocinnamoyl)-lycorine;

S4: 1-(2,4-difluorocinnamoyl)-lycorine;

S5: 1-(3,4-difluorocinnamoyl)-lycorine;

S6: 1-(2-trifluoromethylcinnamoyl)-lycorine;

S7: 1-(3-trifluoromethylcinnamoyl)-lycorine;

140 S8: 1-(4-trifluoromethylcinnamoyl)-lycorine;

S9: 1-(3-trifluoromethoxycinnamoyl)-lycorine;

S10: 1-(4-trifluoromethoxycinnamoyl)-lycorine;

Sll: 1-(2-chlorocinnamyl)-lycorine;

S12: 1-(3-chlorocinnamyl)-lycorine;

145 S13: 1-(4-chlorocinnamyl)-lycorine;

S14: 1-(2,5-dichlorocinnamoyl)-lycorine;

S15: 1-(2,6-dichlorocinnamoyl)-lycorine;

S16: 1-(3,4-dichlorocinnamoyl)-lycorine;

S17: 1-4-fluoro-2-chlorocinnamyl)-lycorine;

150 S18: 1-(2-fluoro-4-chlorocinnamyl)-lycorine;

S19: 1-(4-bromocinnamoyl)-lycorine;

S20: 1-(2-nitrocinnamoyl)-lycorine;

S21: 1-(3-nitrocinnamoyl)-lycorine;

S22: 1-(4-nitrocinnamoyl)-lycorine;

155 S23: 1-(2-chloro-5-nitrocinnamoyl)-lycorine;

S24: 1-(4-chloro-3-nitrocinnamoyl)-lycorine;

S25: 1-(4,5-dimethoxy-2-nitrocinnamoyl)-lycorine;

S26: 1-cinnamoyl-lycorine;

S27: 1-(4-methylcinnamoyl)-lycorine;

160 S28: 1-(4-methoxycinnamoyl)-lycorine;

S29: 1-(4-propoxycainnamoyl)-lycorine;

S30: 1-(4-allyloxycinnamoyl)-lycorine;

S31: 1-(4-hydroxycinnamoyl)-lycorine;

S32: 1-(3-methoxy-4-hydroxycinnamoyl)-lycorine;

165 S33: 1-(3,4-methylenedioxycinnamoyl)-lycorine;

S34: 1-(3,4,5-trimethoxycinnamoyl)-lycorine;

S35: 1-[3-(1-biphenyl) acryloyl)]-lycorine;

S36: 1-[3-(2-furan) acryloyl)]-lycorine;

S37: 1-[3-(2-thiophene)acryloyl)]-lycorine;

170 S38: 1-[3-(3-pyridine)acryloyl)]-lycorine;

S39: 1-[3-(2-pyridine)acryloyl)]-lycorine;

S40: 1- [3- (1-naphthyl)acryloyl)]-lycorine.

The pharmaceutically acceptable salts referred to herein refer to acidic and/or basic

salts of the above compounds or stereoisomers thereof, formed with inorganic and/or

175 organic acids and bases, as well as zwitterionic (inner) salts, and also quaternary

ammonium salts, such as alkylammonium salts. These salts can be obtained directly in

the final isolation and purification of the compounds. It can also be obtained by

appropriately mixing the above-mentioned compound, or its stereoisomers, with a

certain amount of acid or base (e.g., an equivalent amount). These salts may form

180 precipitates in the solution which are collected by filtration, or they may be recovered

by evaporation of the solvent, or they may be prepared by reaction in an aqueous

medium followed by lyophilization. In some embodiments of the present application,

the pharmaceutically acceptable salt described herein can be a hydrochloride,

hydrobromide, sulfate, bisulfate, nitrate, phosphate, biphosphate, formate, acetate,

185 propionate, benzoate, succinate, fumarate, maleate, lactate, citrate, tartrate, succinate,

gluconate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate salt

of a compound described herein above.

Solvate refers to the form of a compound of the present application that forms a

complex by coordination with solvent molecules, which is in the solid or liquid state,

190 wherein hydrate is one specific form of solvate that coordinates with water. The solvates

described herein include hydrates. In some embodiments of the present application, the solvate includes a solvate formed by the compound of formula I with any one of water, ethanol, isopropanol, or acetone.

In the second aspect of the present application, there is provided a process for

195 preparing the lycorine p-aryl acrylate derivative or the pharmaceutically acceptable salt

or solvate thereof as described in the first aspect above, which comprises: lycorine was

taken as an initial compound, hydroxy at position 2 of lycorine was selectively

protected by adopting tert-butyldimethylchlorosilane to obtain an intermediate INB;

intermediate INB and p-aryl acrylic acid, i.e.R Ar COOH are subjected to

200 esterification reaction to obtain intermediate INC; the silane protecting group at the

position 2 of the intermediate INC is removed to obtain the lycorine 8-aryl acrylate

derivative shown in the formula I;

Wherein INB and INC have the following structures, Ar or R is defined as above: OTBS 0 HO,,RO TB 0 <0 O / N INB N INC N ~ 0 [NC

205 Specifically, the process comprises the following steps:

In the presence of acid-binding agent imidazole, hydroxy at position 2 of lycorine

was selectively protected by adopting tert-butyldimethylchlorosilane to obtain an

intermediate INB;

The intermediate INB and different p-aryl acrylic acid are subjected to

210 esterification reaction in the presence of a condensing agent and a catalyst to obtain an intermediate INC;

Under heating conditions, the silane protecting group at the position 2 of the

intermediate INC is removed by adopting concentrated hydrochloric acid to obtain a

lycorinefp-aryl acrylate derivative.

215 The process relates to the following reaction scheme, wherein Ar or R is defined as

the above: OH0 OH OHOTBS R- ~ COACH OTBS R OH TBSCI /Im/DMFED MCAOOHM con. HCI EtOH

o N EIDCIHCIDMAP /DCM KN :~< INA INB INC

In the third aspect of the present application, the present application provides a

pharmaceutical composition comprising the lycorine 8-aryl acrylate derivative or

220 thepharmaceutically acceptable salt or solvate thereof described in the first aspect

above.

In the fourth aspect of the application, the application provides a pharmaceutical

preparation comprising the lycorine p-aryl acrylate derivative or the pharmaceutically

acceptable salt or solvate thereof described in the first aspect above, and at least one

225 pharmaceutically acceptable adjuvant or pharmaceutical carrier.

The pharmaceutical composition or the pharmaceutical preparation referred to

herein may contain one or more of the lycorine p-aryl acrylate derivatives or the

pharmaceutically acceptable salts or solvates thereof described herein.

In some embodiments of the present application, the pharmaceutical composition

230 or pharmaceutical preparation described herein may be administered gastrointestinally

or parenterally, and the formulation includes but not limited to tablets, capsules, pills,

injections, and the like.

Common pharmaceutically acceptable adjuvants are excipients, such as binders,

fillers, wetting agents, disintegrants, etc., which can be used in tablets, capsules and

235 pills for oral administration. If necessary, further adjuvants such as flavouring agents,

colouring agents, stabilisers, lubricants and the like may be added, or the appropriate

formulations may be coated using methods known in the art of pharmacy.

In some embodiments, there is provided a method of producing a pharmaceutical

composition or pharmaceutical preparation comprising admixing one or more of the

240 lycorine f-aryl acrylate derivatives, or the pharmaceutically acceptable salts or solvates

thereof described herein with pharmaceutically acceptable adjuvants or pharmaceutical

carriers. For example, in some embodiments, solid or liquid formulations can be

prepared by uniformly mixing the active compound with a liquid and/or finely divided

solid adjuvants in the desired ratio, and then, if necessary, forming the resulting mixture

245 into the desired shape. Formulations for parenteral administration are prepared, for

example, as follows: the compounds of the present application are dissolved in a

suitable liquid solvent, the solution is filter sterilized and then filled into suitable vials

or ampoules and sealed.

Of course, in addition to this, the compounds of the present application may also

250 be formulated into pharmaceutical compositions or pharmaceutical preparations by

those skilled in the art using other techniques well known in the art. For example, the

pharmaceutical preparation can be prepared according to the modern pharmaceutical

preparation series written by Shenyang pharmaceutical university. And, in addition to

those mentioned in the present application, suitable pharmaceutical adjuvants may also

255 be of other types known in the art, for example as described in the Handbook of

Pharmaceutical Excipients by the authors Paul J Sheskey et al, which has been revised

to the eighth edition. The first edition was published in 1986 and the eighth edition was

published in 2017.

In the fifth aspect of the present application, there is provided an application of the

260 lycorine P-arylacrylate derivative or the pharmaceutically acceptable salt or solvate

thereof as described in the first aspect above in the preparation of an anti-tumor

medicine. In some embodiments of the present application, the tumor includes, but is

not limited to, lung cancer, hepatic cancer, glioma, gastric cancer, and colon cancer.

In the sixth aspect of the present application, there is provided a method for

265 treating cancer, which comprises administering to a subject a therapeutically effective

amount of the lycoline P-aryl acrylate derivative or the pharmaceutically acceptable salt

or solvate thereof as described in the first aspect above, or a pharmaceutical

composition or a pharmaceutical preparation containing such as ubstances. Such cancers

include, but are not limited to, lung cancer, hepatic cancer, glioma, gastric cancer, and

270 colon cancer.

The term "subject" refers to an animal, preferably a mammal, most preferably a

human, who has been the object of treatment, observation or experiment. The term

"therapeutically effective amount" is meant an amount of an active compound or

pharmaceutical agent including the compound of the present application, that elicits the

275 biological or medicinal response in a tissue system, animal or human that is being

sought by a researcher, veterinarian, medical doctor or other medical professional,

which includes alleviation or partial alleviation of the symptoms of the disease,

syndrome, condition, or disorder being treated.

The optimal dosage and interval of administration of a compound of the present

280 application will be determined by the nature of the compound and external conditions

such as the form, route and site of administration and the particular mammal being

treated, and such optimal dosage can be determined by conventional techniques. It

should also be recognized that the optimal course of treatment, i.e., the daily dosage of

the compound over the nominal time period, may be determined by methods known in

285 the art. Although the dosage varies with the symptoms and age of the patient, the nature

and severity of the disease or disorder and the route and mode of administration, for oral

administration to adult patients, the compounds of the present application are normally

administered in a total dose of from 1 to 1000 mg, preferably from 5 to 500 mg, per day,

in single or divided doses, e.g. twice or three times daily; in the case of intravenous

290 injection, a dose of 0.1 to 100 mg, preferably 0.5 to 50 mg, may be administered in one

to three times a day.

Compared with the prior art, the present application has the advantages that:

The present application provides a lycoline f-aryl acrylate derivative shown in

formula I. The primary activity screening experiment showed that most of the

295 compounds have good inhibitory activity on lung cancer cells A549, hepatocellular

carcinoma cells HepG2, glioma Hs683, stomach cancer cells HGC27 and colon cancer

cells HCT116, the tumor inhibitory activity of the compounds is obviously superior to

that of a positive control drug 5-fluorouracil, the inhibitory activity of some of the

compounds to the tumor cells is equivalent to that of lycorine, and the inhibitory activity

300 of some of the compounds is superior to that of the lycorine. This shows that the

lycorine f-aryl acrylate derivative with the brand new structure has better anti-tumor

application prospect.

DETAILED DESCRIPTION

The present application is further illustrated below with reference to specific

305 examples. It should be understood that these examples are for illustrative purposes only

and are not intended to limit the scope of the present application. Experimental

procedures without specific conditions noted in the following examples, generally

according to conventional conditions or according to conditions recommended by the

manufacturers.

310 Unless defined otherwise, all technical and scientific terms used herein have the

same meaning as commonly understood by one of ordinary skill in the art to which this

invention belongs. The reagents or starting materials used in the present application can

be purchased from conventional sources, and unless otherwise specified, the reagents or

starting materials used in the present application can be used in a manner conventional

315 in the art or in accordance with the product specifications. In addition, any methods and

materials similar or equivalent to those described herein can be used in the methods of

the present application. The preferred embodiments and materials described herein are

exemplary only.

Unless otherwise specified, the starting materials are generally available from

320 commercial sources. Commercial solvents or reagents are generally used without further

purification. The structure of the compound was determined by nuclear magnetic

resonance spectroscopy (NMR). The hydrogen and carbon spectral shifts (6) of nuclear

magnetic resonance are given in parts per million (ppm). Hydrogen spectrum and

carbon spectrum of nuclear magnetic resonance deuterated chloroform (CDCl 3) or

325 deuterated dimethyl sulfoxide (DMSO-d) are used as solvents, and tetramethylsilane

(TMS) is used as an internal standard. The column chromatography generally uses

200-300 mesh silica gel as a carrier and n-hexane--ethyl acetate as an elution solvent.

The abbreviations referred to in this application are as follows:

TBSCl: tert-butyldimethylsilyl chloride; Im: imidazole; DMF:

330 N,N-dimethylformamide; EDCI: 1-ethyl-(3-dimethylaminopropyl)carbonyldiimine

hydrochloride; DMAP: 4-dimethylaminopyridine; Con, HCl: concentrated hydrochloric

acid; EtOH: ethanol.

Examples: preparation of exemplary compounds

Example 1: 2-tert-butyldimethylsilyl-lycorine (INB)

OTBS HO,,,

335 The structure of INB: / N

Lycorine (100.0 mmol) and Im (150.0 mmol) were dissolved in 300 mL DMF in a

2000 mL round-bottom flask, and TBSCl (150.0 mmol) was added slowly with

vigorous stirring at room temperature. The reaction system was heated to 40 °C to

dissolve completely, kept the temperature and stirred for 4 h. The residual quantity of

340 the starting material lycorine was traced and detected by HIPLC, when it was less than 5

percent, post-treatment was performed. 500 mL ethyl acetate and 800 mL purified water

were added into the reaction system in sequence, stirred for 10 min at room temperature,

and then separated the liquid. The organic phase was washed by 500 mL 10% sodium

chloride solution, and then dried over 100.0 g anhydrous sodium sulfate, filtered,

345 concentrated under reduced pressure, and separated and purified by column

chromatography to obtain the white solid INB. 1H NMR (500 MHz, CDCl3 ) 6 6.80 (s,

1H), 6.56 (s, 1H), 5.89 (d, J= 1.1 Hz, 2H), 5.39 (s, 1H), 4.38 (s, 1H), 4.25 (s, iH), 4.10

(d, J= 14.0 Hz, 1H), 3.45 (d, J= 14.0 Hz, 1H), 3.38 - 3.25 (m, 1H), 2.78 (d, J= 10.6

Hz, 1H), 2.69 (d, J= 10.6 Hz, 1H), 2.59 (dd, J= 15.9, 7.9 Hz, 2H), 2.31 (q, J= 8.8 Hz,

350 1H), 0.88 (s, 9H), 0.13 (s, 3H), 0.10 (s, 3H); 1 3 C NMR (126 MHz, CDC 3)6 146.50,

146.15, 141.81, 130.35, 128.02, 118.35, 107.72, 104.53, 100.95, 72.30, 60.94, 57.15,

53.92, 40.92, 28.59, 25.87, 25.70, 18.14, -4.41, -4.70.

Example 2: 1-(2-fluorocinnamoyl)-lycorine (Si)

F OH

0 N,

The structure of Sl: 0 N

355 a: 2-tert-butyldimethylsilyl-lycorine, i.e., INB (10.0 mmol) and 2-fluorocinnamic

acid (12.0 mmol) were dissolved in 50 mL of dichloromethane in a 250 mL

round-bottom reaction flask and EDCI.HCl (18.0 mmol), DMAP (1.0 mmol) were

added successively at room temperature under nitrogen. After the addition, the reaction

was kept at the temperature of 35 °C and stirred. The residual quantity of INB was

360 traced and detected by HPLC, when it was less than 8 percent, post-treatment was

performed. The reaction solution was washed once with 100 mL of purified water and

100 mL of 10% sodium chloride solution in turn, and then concentrated under reduced

pressure for later use.

b: the above product dissolved in 50 mL absolute ethanol in a 250 mL

365 round-bottom reaction flask, and 5.0 mL concentrated HCl was slowly added dropwise with stirring at room temperature. After the addition was completed, the reaction was stirred at 80 °C for 1.0 h, the heating was turned off and the temperature was naturally cooled to 25 °C, and then 5.0 mL ammonia water was slowly added dropwise. 80 mL of ethyl acetate and 80 mL of purified water were added to the reaction system

370 successively, and the liquids were extracted and separated. The organic phase was

washed with saturated sodium bicarbonate solution and saturated sodium chloride

solution respectively, dried over anhydrous sodium sulfate, concentrated, and separated

by column chromatography to obtain white Solid SI. 1 H NMR (400 MHz, CDC 3) 6

7.71 (d, J= 16.2 Hz, 1H), 7.46 (td, J= 7.6, 1.2 Hz, 1H), 7.32 (td, J= 7.3, 1.5 Hz, 1H),

375 7.08 (dt, J= 19.0, 8.0 Hz, 2H), 6.70 (s, 1H), 6.57 (s, 1H), 6.38 (d, J= 16.2 Hz, 1H),

5.89 (d, J= 1.2 Hz, 1H), 5.88 (d, J= 1.2 Hz, 1H), 5.88 (d, J= 1.2 Hz, 1H), 5.75 (s, 1H),

5.58 (s, 1H), 4.26 (s, 1H), 4.17 (d, J= 14.1 Hz, 1H), 3.54 (d, J= 14.0 Hz, 1H), 3.38 (dt,

J= 9.1, 4.7 Hz, 1H), 2.94 (d, J= 10.5 Hz, 1H), 2.85 (d, J= 10.4 Hz,1H), 2.65 (s, 2H),

2.41 (q, J= 8.7 Hz,1H); 13C NMR (101 MHz, CDC 3) 6 166.45, 162.59, 160.06, 146.51,

380 146.26, 143.98, 138.05, 131.80 (d, J= 8.9 Hz), 129.24 (d, J= 2.7 Hz), 127.02, 124.38

(d, J= 3.2 Hz), 122.32 (d, J= 11.6 Hz), 120.27 (d, J= 6.1 Hz), 117.42, 116.16 (d, J=

21.9 Hz), 107.30, 105.0, 100.93, 72.89, 69.61, 61.73, 56.91, 53.76, 39.50, 28.64.

Example 3: 1-(3-fluorocinnamoyl)-lycorine (S2)

0 OH F

K0 The structure of S2: 0 N

385 a: 2-tert-butyldimethylsilyl-lycorine, i.e., INB (10.0 mmol) and 3-fluorocinnamic

acid (12.0 mmol) were dissolved in 50 mL of dichloromethane in a 250 mL

round-bottom reaction flask and EDCI.HCl (18.0 mmol), DMAP (1.0 mmol) were

390 traced and detected by HPLC, when it was less than 8 percent, post-treatment was

pressure for later use.

b: the above product dissolved in 50 mL absolute ethanol in a 250 mL

395 round-bottom reaction flask, and 5.0 mL concentrated HCl was slowly added dropwise

with stirring at room temperature. After the addition was completed, the reaction was

stirred at 80 °C for 1.0 h, the heating was turned off and the temperature was naturally

cooled to 25 °C, and then 5.0 mL ammonia water was slowly added dropwise. 80 mL of

ethyl acetate and 80 mL of purified water were added to the reaction system

400 successively, and the liquids were extracted and separated. The organic phase was

washed with saturated sodium bicarbonate solution and saturated sodium chloride solution respectively, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain white Solid S2. 1 H NMR (400 MHz, CDCl 3 ) 6

7.54 (d, J= 16.0 Hz, 1H), 7.36 - 7.27 (m, 1H), 7.22 (d, J= 7.7 Hz, 1H), 7.14 (d, J= 9.7

405 Hz, 1H), 7.04 (td, J= 8.2, 1.9 Hz, 1H), 6.70 (s, 1H), 6.57 (s, 1H), 6.27 (d, J= 16.0 Hz,

1H), 5.89 (s, 1H), 5.88 (s, 1H), 5.75 (s, 1H), 5.58 (s, 1H), 4.26 (s, 1H), 4.18 (d, J= 14.1

Hz, 1H), 3.54 (d, J= 14.0 Hz, 1H), 3.38 (dt, J= 9.0, 4.6 Hz, 1H), 2.95 (d, J= 10.5 Hz,

1H),2.85(d,J=10.3Hz,1H),2.66(s,2H),2.42(dd,J=17.1,8.4Hz,1H); 13CNMR

(101 MHz, CDCl 3) 6 166.21, 164.14, 161.69, 146.50, 146.27, 143.94, 136.44 (d, J= 7.7

410 Hz), 130.36 (d, J= 8.2 Hz), 129.29, 126.99, 124.17 (d, J= 2.7 Hz), 119.13, 117.37 (d, J

= 7.2 Hz), 117.12, 114.30 (d, J= 22.1 Hz), 107.31, 104.97, 100.93, 72.94, 69.54, 61.70,

56.89, 53.75, 39.45, 28.64.

Example 4: 1-(4-fluorocinnamoyl)-lycorine (S3)

F O OH

FI Ko The structure of S3: 0 / N

415 a: 2-tert-butyldimethylsilyl-lycorine NB (10.0 mmol) and 4-fluorocinnamic acid

(12.0 mmol) were dissolved in 50 mL of dichloromethane in a 250 mL round-bottom

reaction flask and EDCI.HCl (18.0 mmol), DMAP (1.0 mmol) were added successively

at room temperature under nitrogen. After the addition, the reaction was kept at the

temperature of 35 °C and stirred. The residual quantity of INB was traced and detected

420 by HPLC, when it was less than 8 percent, post-treatment was performed. The reaction

solution was washed once with 100 mL of purified water and 100 mL of 10% sodium

chloride solution in turn, and then concentrated under reduced pressure for later use.

b: the above product dissolved in 50 mL absolute ethanol in a 250 mL

round-bottom reaction flask, and 5.0 mL concentrated HCl was slowly added dropwise

425 with stirring at room temperature. After the addition was completed, the reaction was

ethyl acetate and 80 mL of purified water were added to the reaction system

successively, and the liquids were extracted and separated. The organic phase was

430 washed with saturated sodium bicarbonate solution and saturated sodium chloride

by column chromatography to obtain white Solid S3. 1 H NMR (400 MHz, CDCl 3) 6

7.55 (d, J= 16.0 Hz, 1H), 7.44 (dd, J= 8.7, 5.4 Hz, 2H), 7.02 (t, J= 8.6 Hz, 2H), 6.70

(s, 1H), 6.57 (s, 1H), 6.21 (d, J= 16.0 Hz, 1H), 5.89 (d, J= 1.3 Hz, 1H), 5.87 (d, J= 1.3

435 Hz, 1H), 5.75 (s, 1H), 5.57 (s, 1H), 4.25 (s, 1H), 4.17 (d, J= 14.1 Hz, 1H), 3.54 (d, J=

14.0 Hz, 1H), 3.38 (dt, J= 9.1, 4.7 Hz, 1H), 2.95 (d, J= 10.5 Hz, 1H), 2.85 (d, J= 10.4

Hz, 1H), 2.65 (s, 2H), 2.42 (q, J= 8.7 Hz, 1H); 13C NMR (101 MHz, CDCl 3) 6 166.48,

165.16, 162.66, 146.49, 146.24, 144.07, 143.92, 130.46 (d, J= 3.4 Hz), 130.07, 129.98,

129.28, 127.06, 117.4, 116.08, 115.86, 107.29, 104.99, 100.92, 72.80, 69.56, 61.70,

440 56.88, 53.76, 39.45, 28.65.

Example 5: 1-(2,4-difluorocinnamoyl)-lycorine (S4)

F 0 OH

FO

The structure of S4: O N

a: 2-tert-butyldimethylsilyl-lycorine, i.e., INB (10.0 mmol) and

2,4-difluorocinnamic acid (12.0 mmol) were dissolved in 50 mL of dichloromethane in

445 a 250 mL round-bottom reaction flask and EDCI.HCl (18.0 mmol), DMAP (1.0 mmol)

were added successively at room temperature under nitrogen. After the addition, the

reaction was kept at the temperature of 35 °C and stirred. The residual quantity of INB

was traced and detected by HPLC, when it was less than 8 percent, post-treatment was

450 100 mL of 10% sodium chloride solution in turn, and then concentrated under reduced

pressure for later use.

b: the above product dissolved in 50 mL absolute ethanol in a 250 mL

455 stirred at 80 °C for 1.0 h, the heating was turned off and the temperature was naturally

cooled to 25 °C, and then 5.0 mL ammonia water was slowly added dropwise. 80 mL of ethyl acetate and 80 mL of purified water were added to the reaction system successively, and the liquids were extracted and separated. The organic phase was washed with saturated sodium bicarbonate solution and saturated sodium chloride

460 solution respectively, dried over anhydrous sodium sulfate, concentrated, and separated

by column chromatography to obtain white Solid S4. 1 H NMR (400 MHz, CDCl 3) 6

7.65 (d, J= 16.2 Hz, 1H), 7.45 (dd, J= 15.0, 8.2 Hz, 1H), 6.92 - 6.77 (m, 2H), 6.71 (s,

1H), 6.57 (s, 1H), 6.33 (d, J= 16.2 Hz, 1H), 5.89 (d, J= 5.3 Hz, 2H), 5.76 (s, 1H), 5.58

(s, 1H), 4.27 (s, 1H), 4.17 (d, J= 14.1 Hz, 1H), 3.54 (d, J= 13.9 Hz, 1H), 3.45 - 3.29

465 (m, 1H), 2.94 (d, J= 10.4 Hz, 1H), 2.84 (d, J= 10.1 Hz, 1H), 2.66 (s, 2H), 2.49 - 2.35

(m, 1H); "C NMR (101 MHz, CDCl 3 ) 6 166.37, 146.51, 146.27, 144.13, 137.06, 130.37

(dd, J= 9.9, 4.5 Hz), 129.31, 126.97, 119.80 (d, J= 4.5 Hz), 118.80 (dd, J= 11.6, 3.8

Hz), 117.33, 112.05 (dd, J = 21.8, 3.4 Hz), 107.33, 104.98, 104.89, 104.64, 104.38,

100.96, 72.88, 69.64, 61.69, 56.89, 53.76, 39.49, 28.66.

470 Example 6: 1-(3,4-difluorocinnamoyl)-lycorine (S5)

0 OH F

F II The structure of S5: 0 N

a: 2-tert-butyldimethylsilyl-lycorine, i.e., INB (10.0 mmol) and

3,4-difluorocinnamic acid (12.0 mmol) were dissolved in 50 mL of dichloromethane in

a 250 mL round-bottom reaction flask and EDCI.HCl (18.0 mmol), DMAP (1.0 mmol)

475 were added successively at room temperature under nitrogen. After the addition, the

480 pressure for later use.

b: the above product dissolved in 50 mL absolute ethanol in a 250 mL

485 cooled to 25 °C, and then 5.0 mL ammonia water was slowly added dropwise. 80 mL of

ethyl acetate and 80 mL of purified water were added to the reaction system

washed with saturated sodium bicarbonate solution and saturated sodium chloride

490 by column chromatography to obtain white Solid S5. 1 H NMR (400 MHz, CDCl 3) 6

7.49 (d, J= 16.0 Hz, 1H), 7.31 - 7.23 (m, 1H), 7.15 (ddd, J= 18.0, 14.1, 8.5 Hz, 2H),

6.68 (s, 1H), 6.57 (s, 1H), 6.19 (d, J= 16.0 Hz, 1H), 5.89 (d, J= 1.1 Hz, 1H), 5.88 (s,

1H), 5.74 (s, 1H), 5.57 (s, 1H), 4.24 (s, 1H), 4.18 (d, J= 14.1 Hz, 1H), 3.54 (d, J= 14.0

Hz, 1H), 3.38 (dt, J= 9.0, 4.6 Hz, 1H), 2.95 (d, J= 10.5 Hz, 1H), 2.85 (d, J= 10.3 Hz,

495 IH), 2.65 (s, 2H), 2.43 (q, J= 8.6 Hz, 1H); 13 C NMR (101 MHz, CDCl 3) 6 166.08,

150.98 (ddd, J= 110.8, 99.7, 13.0 Hz), 146.49, 146.25, 143.69, 142.98, 131.41 (dd, J=

5.8,4.1 Hz), 129.21,126.96,124.94(dd,J=6.4,3.4Hz), 118.81 (d,J=2.0Hz), 117.75

(d, J= 17.6 Hz), 117.49, 116.40, 116.22, 107.31, 104.93, 100.94, 72.93, 69.39, 61.68,

56.82, 53.74, 39.29, 28.60 .

500 Example 7: 1-(2-trifluoromethylcinnamoyl)-lycorine (S6)

CF 3 OH

0,, 0

The structure of S6: 0 / N

a: 2-tert-butyldimethylsilyl-lycorine,i.e., INB (10.0 mmol) and

2-trifluoromethylcinnamic acid (12.0 mmol) were dissolved in 50 mL of

dichloromethane in a 250 mL round-bottom reaction flask and EDCI.HCl (18.0 mmol),

505 DMAP (1.0 mmol) were added successively at room temperature under nitrogen. After

the addition, the reaction was kept at the temperature of 35 °C and stirred. The residual

quantity of INB was traced and detected by HPLC, when it was less than 8 percent,

post-treatment was performed. The reaction solution was washed once with 100 mL of

purified water and 100 mL of 10% sodium chloride solution in turn, and then

510 concentrated under reduced pressure for later use.

b: the above product dissolved in 50 mL absolute ethanol in a 250 mL

round-bottom reaction flask, and 5.0 mL concentrated HCl was slowly added dropwise with stirring at room temperature. After the addition was completed, the reaction was stirred at 80 °C for 1.0 h, the heating was turned off and the temperature was naturally

515 cooled to 25 °C, and then 5.0 mL ammonia water was slowly added dropwise. 80 mL of

ethyl acetate and 80 mL of purified water were added to the reaction system

washed with saturated sodium bicarbonate solution and saturated sodium chloride

520 by column chromatography to obtain white Solid S6. 1 H NMR (500 MHz, CDC 3 ) 6

8.02 (d, J= 15.4 Hz, 1H), 7.68 (d, J= 7.7 Hz, 2H), 7.49 (dt, J= 28.0, 7.5 Hz, 2H), 6.73

(s, iH), 6.61 (s, 1H), 6.33 (d, J= 15.7 Hz, iH), 5.95 (s, 1H), 5.91 (s, iH), 5.77 (s, 2H),

4.36 (s, 1H), 4.12 (dd, J= 14.2, 7.1 Hz, 2H), 3.87 - 3.65 (m, 1H), 3.36 (t, J= 19.9 Hz,

3H), 2.87 (s, 1H), 2.78 (d, J= 15.6 Hz, iH); 13 C NMR (126 MHz, CDC 3 ) 6 165.46,

525 148.11, 146.91, 141.52, 132.66, 132.13, 130.00, 128.97, 128.73, 127.91, 126.25, 126.20,

126.16, 126.12, 124.97, 122.79, 121.10, 120.58 (d, J= 5.6 Hz), 108.12, 104.55, 101.43,

71.51, 68.09, 54.10, 36.52.

Example 8: 1-(3-trifluoromethyleinnamoyl)-lycorine (S7)

F3C 0 OH

The structure of S7: 0 I/ N

530 a: 2-tert-butyldimethylsilyl-lycorine, i.e., INB (10.0 mmol) and

3-trifluoromethylcinnamic acid (12.0 mmol) were dissolved in 50 mL of

DMAP (1.0 mmol) were added successively at room temperature under nitrogen. After

535 quantity of INB was traced and detected by HPLC, when it was less than 8 percent,

purified water and 100 mL of 10% sodium chloride solution in turn, and then

concentrated under reduced pressure for later use.

b: the above product dissolved in 50 mL absolute ethanol in a 250 mL

540 round-bottom reaction flask, and 5.0 mL concentrated HCl was slowly added dropwise

ethyl acetate and 80 mL of purified water were added to the reaction system

545 successively, and the liquids were extracted and separated. The organic phase was

washed with saturated sodium bicarbonate solution and saturated sodium chloride

by column chromatography to obtain white Solid S7. 1 H NMR (500 MHz, CDCl 3) 6

7.70 (s, 1H), 7.62 (s, 1H), 7.61 (s, 1H), 7.59 (s, 1H), 7.47 (t, J= 7.8 Hz, 1H), 6.72 (s,

550 1H), 6.57 (s, 1H), 6.35 (d, J= 16.0 Hz, 1H), 5.89 (d, J= 1.2 Hz, 1H), 5.87 (d, J= 1.2 Hz,

IH), 5.78 (s, 1H), 5.58 (s, 1H), 4.27 (s, 1H), 4.18 (d, J= 14.1 Hz, 1H), 3.55 (d, J= 14.0

Hz, 1H), 3.39 (dt, J= 9.2, 4.7 Hz, 1H), 2.95 (d, J= 10.5 Hz, 1H), 2.86 (d, J= 10.4 Hz,

13 1H), 2.66 (d, J= 1.8 Hz, 2H), 2.43 (q, J= 8.8 Hz, H); CNMR (126 MHz, CDC3) 6

166.11, 146.54, 146.32, 144.11, 143.57,135.03, 131.53, 131.35, 131.27, 129.42, 129.39,

555 126.99, 126.76 (d, J= 3.5 Hz), 124.52 (d, J= 3.5 Hz), 119.73, 117.37, 107.37, 105.00,

100.97, 73.07, 69.61, 61.73, 56.93, 53.78, 39.52, 28.67.

Example 9: 1-(4-trifluoromethylcinnamoyl)-lycorine (S8)

0 OH

F 3C O

The structure of S8: 0 N

a: 2-tert-butyldimethylsilyl-lycorine, i.e., INB (10.0 mmol) and

560 4-trifluoromethylcinnamic acid (12.0 mmol) were dissolved in 50 mL of

quantity of INB was traced and detected by HIPLC, when it was less than 8 percent,

565 post-treatment was performed. The reaction solution was washed once with 100 mL of

purified water and 100 mL of 10% sodium chloride solution in turn, and then

concentrated under reduced pressure for later use.

b: the above product dissolved in 50 mL absolute ethanol in a 250 mL

570 with stirring at room temperature. After the addition was completed, the reaction was

ethyl acetate and 80 mL of purified water were added to the reaction system

575 washed with saturated sodium bicarbonate solution and saturated sodium chloride

by column chromatography to obtain white Solid S8. 1 H NMR (500 MHz, CDCl 3) 6

7.66 - 7.47 (m, 5H), 6.69 (s, 1H), 6.57 (s, 1H), 6.35 (d, J= 16.0 Hz, 1H), 5.88 (s, 1H),

5.87 (s, 1H), 5.76 (s, 1H), 5.58 (s, 1H), 4.26 (s, 1H), 4.18 (d, J= 14.1 Hz, 1H), 3.54 (d,

580 J= 14.0 Hz, 1H), 3.38 (dt, J= 9.0, 4.6 Hz, 1H), 2.96 (d, J= 10.5 Hz, 1H), 2.86 (d, J=

10.3 Hz, 1H), 2.66 (s, 2H), 2.42 (q, J= 8.7 Hz, 1H); 13 C NMR (126 MHz, CDCl 3) 6

166.06, 146.54, 146.30, 143.74, 143.49, 137.57, 131.81 (d, J= 32.6 Hz), 129.29, 128.25,

126.99, 125.77 (dd, J= 7.3, 3.6 Hz), 124.86, 122.69, 120.30, 117.52, 107.34, 104.97,

100.96,73.10, 69.43, 61.73, 56.88, 53.77, 39.36,28.63.

585 Example 10: 1-(3-trifluoromethoxycinnamoyl)-lycorine (S9)

0 OH F 3CO O,

0 s

The structure of S9: 0 I/ N

a: 2-tert-butyldimethylsilyl-lycorine, i.e., INB (10.0 mmol) and

3-trifluoromethoxycinnamic acid (12.0 mmol) were dissolved in 50 mL of

590 DMAP (1.0 mmol) were added successively at room temperature under nitrogen. After

post-treatment was performed. The reaction solution was washed once with 100 mLmL

of purified water and 100 mL of 10% sodium chloride solution in turn, and then

595 concentrated under reduced pressure for later use.

b: the above product dissolved in 50 mL absolute ethanol in a 250 mL

600 cooled to 25 °C, and then 5.0 mL ammonia water was slowly added dropwise. 80 mL of

ethyl acetate and 80 mL of purified water were added to the reaction system

washed with saturated sodium bicarbonate solution and saturated sodium chloride solution respectively, dried over anhydrous sodium sulfate, concentrated, and separated

605 by column chromatography to obtain white Solid S9. 1 H NMR (400 MHz, CDC 3 ) 6

7.56 (d, J= 16.0 Hz, 1H), 7.37 (s, 1H), 7.36 (s,1H), 7.29 (s, 1H), 7.19 (s, 1H), 6.69 (s,

1H), 6.58 (s, 1H), 6.29 (d, J= 16.0 Hz, 1H), 5.89 (s, 1H), 5.87 (s, 1H), 5.76 (s, 1H),

5.58 (s, 1H), 4.25 (s, 1H), 4.18 (d, J= 14.1 Hz, 1H), 3.54 (d, J= 14.0 Hz, 1H), 3.38 (dt,

J= 9.0, 4.6 Hz, 1H), 2.96 (d, J= 10.5 Hz, 1H), 2.86 (d, J= 10.3 Hz, 1H), 2.65 (s, 2H),

610 2.42 (q, J= 8.6 Hz,1H); 1C NMR (101 MHz, CDCl 3 ) 6 166.08, 149.53 (d, J= 1.8 Hz),

146.51, 146.26, 143.66, 143.56, 136.28, 130.24, 129.23, 126.96, 126.67, 122.55, 120.02,

119.52, 117.52, 107.32, 104.97, 100.93, 72.98, 69.37, 61.72, 56.86, 53.76, 39.31, 28.60.

Example 11: 1-(4-trifluoromethoxycinnamoyl)-lycorine (S10)

0 OH O

F 3CO

The structure of S1O: 0N

615 a: 2-tert-butyldimethylsilyl-lycorine, i.e., INB (10.0 mmol) and

4-trifluoromethoxycinnamic acid (12.0 mmol) were dissolved in 50 mL of

620 quantity of NB was traced and detected by HPLC, when it was less than 8 percent,

post-treatment was performed. The reaction solution was washed once with 100 mL of purified water and 100 mL of 10% sodium chloride solution in turn, and then concentrated under reduced pressure for later use.

b: the above product dissolved in 50 mL absolute ethanol in a 250 mL

625 round-bottom reaction flask, and 5.0 mL concentrated HCl was slowly added dropwise

ethyl acetate and 80 mL of purified water were added to the reaction system

630 successively, and the liquids were extracted and separated. The organic phase was

washed with saturated sodium bicarbonate solution and saturated sodium chloride

by column chromatography to obtain white Solid S10. 1 H NMR (400 MHz, CDCl 3) 6

7.56 (d, J= 16.0 Hz, 1H), 7.49 (s, 1H), 7.46 (s, 1H), 7.18 (s, 1H), 7.16 (s, 1H), 6.70 (s,

635 1H), 6.57 (s, 1H), 6.25 (d, J= 16.0 Hz, 1H), 5.89 (d, J= 1.3 Hz, 1H), 5.87 (d, J= 1.3

Hz, 1H), 5.75 (s, 1H), 5.58 (s, 1H), 4.26 (s, 1H), 4.17 (d, J= 14.1 Hz, 1H), 3.54 (d, J=

13.9 Hz, 1H), 3.38 (dt, J= 9.1, 4.7 Hz, 1H), 2.95 (d, J= 10.5 Hz, 1H), 2.86 (d, J= 10.4

Hz, 1H), 2.66 (s, 2H), 2.43 (q, J= 8.6 Hz, 1H); 13C NMR (101 MHz, CDC 3)6 166.29,

150.45, 146.53, 146.28, 143.84, 143.62, 132.80, 129.58, 129.26, 127.04, 121.03, 118.67,

640 117.49, 107.32, 104.98, 100.95, 72.93, 69.52, 61.70, 56.85, 53.76, 39.39, 28.65.

Example 12: 1-(2-chlorocinnamyl)-lycorine (S11)

CI 0 O OH

0 s

The structure of S11: O / N

a: 2-tert-butyldimethylsilyl-lycorine, i.e., INB (10.0 mmol) and 2-chlorocinnamic

acid (12.0 mmol) were dissolved in 50 mL of dichloromethane in a 250 mL

645 round-bottom reaction flask and EDCI.HCl (18.0 mmol), DMAP (1.0 mmol) were

traced and detected by HPLC, when it was less than 8 percent, post-treatment was

650 100 mL of 10% sodium chloride solution in turn, and then concentrated under reduced

pressure for later use.

b: the above product dissolved in 50 mL absolute ethanol in a 250 mL

655 stirred at 80 °C for 1.0 h, the heating was turned off and the temperature was naturally

ethyl acetate and 80 mL of purified water were added to the reaction system

washed with saturated sodium bicarbonate solution and saturated sodium chloride

660 solution respectively, dried over anhydrous sodium sulfate, concentrated, and separated

by column chromatography to obtain white Solid S11. 'H NMR (400 MHz, CDC 3) 6

7.99 (d, J= 16.0 Hz, 1H), 7.53 (d, J= 7.7 Hz, 1H), 7.37 (d, J= 7.9 Hz, 1H), 7.30 - 7.24

(m, 1H), 7.20 (t, J= 7.2 Hz, 1H), 6.71 (s, 1H), 6.57 (s, 1H), 6.28 (d, J= 16.0 Hz, 1H),

5.89 (s, 1H), 5.88 (d, J= 0.9 Hz, 1H), 5.74 (s, 1H), 5.58 (s, 1H), 4.30 (s, IH), 4.17 (d, J

665 = 14.1 Hz, 1H), 3.55 (d, J= 14.0 Hz, 1H), 3.37 (dd, J= 8.7, 4.4 Hz, 1H), 2.96 (d, J=

3 10.3 Hz, 1H), 2.88 (d, J= 9.8 Hz, 1H), 2.66 (s, 2H), 2.43 (d, J= 7.3 Hz,1H); C NMR

(101 MHz, CDCl 3) 8 166.09, 146.57, 146.31, 143.99, 141.15, 135.02, 132.47, 131.11,

130.15, 129.29, 127.62, 127.07, 126.96, 120.24, 117.41, 107.29, 105.00, 100.94, 73.07,

69.64, 61.74, 56.89, 53.78, 39.52, 28.67.

670 Example 13: 1-(3-chlorocinnamyl)-lycorine (S12)

0 C1 , OH

The structure of 12: o N

a: 2-tert-butyldimethylsilyl-lycorine, i.e., INB (10.0 mmol) and 3-chlorocinnamic

acid (12.0 mmol) were dissolved in 50 mL of dichloromethane in a 250 mL

round-bottom reaction flask and EDCI.HCl (18.0 mmol), DMAP (1.0 mmol) were

675 added successively at room temperature under nitrogen. After the addition, the reaction

traced and detected by HPLC, when it was less than 8 percent, post-treatment was performed. The reaction solution was washed once with 100 mL of purified water and

680 pressure for later use.

b: the above product dissolved in 50 mL absolute ethanol in a 250 mL

685 cooled to 25 °C, and then 5.0 mL ammonia water was slowly added dropwise. 80 mL of

ethyl acetate and 80 mL of purified water were added to the reaction system

washed with saturated sodium bicarbonate solution and saturated sodium chloride

690 by column chromatography to obtain white Solid S12. 1 H NMR (400 MHz, CDCl 3) 6

7.52 (d, J= 16.0 Hz, 1H), 7.44 (s, 1H), 7.36 - 7.28 (m, 3H), 6.70 (s, 1H), 6.58 (s, 1H),

6.29 (d, J= 16.0 Hz, 1H), 5.90 (d, J= 1.3 Hz, 1H), 5.88 (d, J= 1.3 Hz,1H), 5.75 (s,

1H), 5.59 (s, 1H), 4.28 (s, 1H), 4.17 (d, J= 14.1 Hz, 1H), 3.58 (d, J= 12.2 Hz, 1H),

3.43 - 3.29 (m, 1H), 2.96 (d, J= 10.1 Hz, 1H), 2.67 (s, 2H), 2.46 (s, 1H); 13C NMR

695 (101 MHz, CDCl 3) 6 166.16, 146.60, 146.34, 143.78, 136.03, 134.89, 130.24, 130.06,

127.78, 127.05, 126.38, 119.18, 107.38, 104.95, 100.96, 72.89, 69.63, 61.61, 56.38,

53.76, 39.46, 28.73.

Example 14: 1-(4-chlorocinnamyl)-lycorine (S13)

0 OH

The structure of S13: <0 N

700 a: 2-tert-butyldimethylsilyl-lycorine, i.e., INB (10.0 mmol) and 4-chlorocinnamic

acid (12.0 mmol) were dissolved in 50 mL of dichloromethane in a 250 mL

round-bottom reaction flask and EDCI.HCl (18.0 mmol), DMAP (1.0 mmol) were

was kept at the temperature of 35 °C and stirred. The residual quantity of NB was

705 traced and detected by HPLC, when it was less than 8 percent, post-treatment was

pressure for later use.

b: the above product dissolved in 50 mL absolute ethanol in a 250 mL

710 round-bottom reaction flask, and 5.0 mL concentrated HCl was slowly added dropwise

ethyl acetate and 80 mL of purified water were added to the reaction system

715 successively, and the liquids were extracted and separated. The organic phase was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution respectively, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain white Solid S13. 'H NMR (400 MHz, CDCl 3 ) 6

7.53 (d, J= 16.0 Hz, 1H), 7.37 (d, J= 8.4 Hz, 2H), 7.30 (d, J= 8.4 Hz, 2H), 6.69 (s,

720 1H), 6.57 (s, 1H), 6.25 (d, J= 16.0 Hz, 1H), 5.89 (s, 1H), 5.87 (s, 1H), 5.74 (s, 1H),

5.57 (s, 1H), 4.25 (s, 1H), 4.17 (d, J= 14.1 Hz, 1H), 3.53 (d, J= 14.0 Hz, 1H), 3.38 (dt,

J= 8.9, 4.5 Hz, 1H), 2.94 (d, J= 10.5 Hz, 1H), 2.85 (d, J= 10.3 Hz,1H), 2.65 (s, 2H),

2.41 (dd, J= 17.3, 8.5 Hz,1H); 13 C NMR (101 MHz, CDC 3 )6 166.35, 146.52, 146.27,

143.91, 136.29, 132.73, 129.29, 129.10, 127.07, 118.32, 117.45, 107.30, 105.00, 100.93,

725 72.92, 69.58, 61.71, 56.90, 53.77, 39.49, 28.66.

Example 15: 1-(2,5-dichlorocinnamoyl)-lycorine(S4)

C1 0 OH

The structure of Sl4: 0 / N

a: 2-tert-butyldimethylsilyl-lycorine, i.e., INB (10.0 mmol) and

2,5-dichlorocinnamic acid (12.0 mmol) were dissolved in 50 mL of dichloromethane in

730 a 250 mL round-bottom reaction flask and EDCI.HCl (18.0 mmol), DMAP (1.0 mmol)

was traced and detected by HPLC, when it was less than 8 percent, post-treatment was performed. The reaction solution was washed once with 100 mL of purified water and

735 100 mL of 10% sodium chloride solution in turn, and then concentrated under reduced

pressure for later use.

b: the above product dissolved in 50 mL absolute ethanol in a 250 mL

740 stirred at 80 °C for 1.0 h, the heating was turned off and the temperature was naturally

ethyl acetate and 80 mL of purified water were added to the reaction system

washed with saturated sodium bicarbonate solution and saturated sodium chloride

745 solution respectively, dried over anhydrous sodium sulfate, concentrated, and separated

by column chromatography to obtain white Solid S14. 1 H NMR (400 MHz, CDCl 3) 6

7.90 (d, J= 16.0 Hz, 1H), 7.49 (s, 1H), 7.30 (d, J= 8.5 Hz, 1H), 7.22 (d, J= 8.4 Hz,

1H), 6.67 (s, 1H), 6.57 (s, 1H), 6.26 (d, J= 16.0 Hz, 1H), 5.90 (s, 1H), 5.88 (s, 1H),

5.73 (s, 1H), 5.58 (s, 1H), 4.27 (s, 1H), 4.18 (d, J= 14.1 Hz, 1H), 3.62 - 3.26 (m, 3H),

750 2.95 (d, J= 10.2 Hz, 1H), 2.86 (d, J= 9.9 Hz, 1H), 2.65 (s, 2H), 2.51 - 2.30 (m, 1H);

13 C NMR (101 MHz, CDCl 3) 6 165.71, 146.54, 146.30, 143.80, 139.85, 133.87, 133.14,

132.97, 131.22, 130.93, 129.27, 127.34, 126.89, 121.44, 117.44, 107.33, 104.94, 100.98,

73.19, 69.43, 61.78, 56.91, 53.80, 39.36, 28.61.

Example 16: 1-(2,6-dichlorocinnamoyl)-lycorine(S15)

CI 0 OH o1 o10

755 The structure of S15: < / N

a: 2-tert-butyldimethylsilyl-lycorine, i.e., INB (10.0 mmol) and

2,6-dichlorocinnamic acid (12.0 mmol) were dissolved in 50 mL of dichloromethane in

a 250 mL round-bottom reaction flask and EDCI.HCl (18.0 mmol), DMAP (1.0 mmol)

760 reaction was kept at the temperature of 35 °C and stirred. The residual quantity ofINB

pressure for later use.

765 b: the above product dissolved in 50 mL absolute ethanol in a 250 mL

770 ethyl acetate and 80 mL of purified water were added to the reaction system

successively, and the liquids were extracted and separated. The organic phase was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution respectively, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain white Solid S15. 'H NMR (400 MHz, CDCl 3 ) 6

775 7.70 (d, J= 16.4 Hz, 1H), 7.32 (s, 1H), 7.30 (s, 1H), 7.19 - 7.09 (m, 1H), 6.73 (s, 1H),

6.57 (s, 1H), 6.50 (d, J= 16.4 Hz, iH), 5.91 (d, J= 1.2 Hz, 1H), 5.90 (d, J= 1.3 Hz,

iH), 5.74 (s, iH), 5.59 (s, iH), 4.34 (s, 1H), 4.17 (d, J= 14.0 Hz, 1H), 3.54 (d, J= 13.9

Hz, 1H), 3.38 (dt, J= 9.1, 4.7 Hz, 1H), 2.96 (d, J= 10.4 Hz, 1H), 2.86 (d, J= 10.3 Hz,

1H), 2.66 (s, 2H), 2.49 - 2.36 (m, 1H); 13 C NMR (101 MHz, CDCl 3 ) 8 165.99, 146.52,

780 146.26, 144.13, 138.84, 135.08, 131.47, 129.93, 129.30, 128.80, 126.94, 125.93, 117.28,

107.26, 105.01, 100.95, 73.37, 69.65, 61.68, 56.85, 53.73, 39.56, 28.64.

Example 17: 1-(3,4-dichlorocinnamoyl)-lycorine (S16)

0 OH o," CI ,

0 s

The structure of S16: <0 N

a: 2-tert-butyldimethylsilyl-lycorine, i.e., INB (10.0 mmol) and

785 3,4-dichlorocinnamic acid (12.0 mmol) were dissolved in 50 mL of dichloromethane in

a 250 mL round-bottom reaction flask and EDCI.HCl (18.0 mmol), DMAP (1.0 mmol)

790 performed. The reaction solution was washed once with 100 mL of purified water and

pressure for later use.

b: the above product dissolved in 50 mL absolute ethanol in a 250 mL

795 with stirring at room temperature. After the addition was completed, the reaction was

ethyl acetate and 80 mL of purified water were added to the reaction system

800 washed with saturated sodium bicarbonate solution and saturated sodium chloride

by column chromatography to obtain white Solid S16. 1 H NMR (400 MHz, CDCl 3) 6

7.52 (d, J= 1.8 Hz, 1H), 7.46 (d, J= 16.0 Hz, 1H), 7.39 (d, J= 8.3 Hz, 1H), 7.27 - 7.23

(m, 1H), 6.68 (s, 1H), 6.57 (s, 1H), 6.25 (d, J= 16.0 Hz, 1H), 5.89 (d, J= 1.0 Hz, 1H),

805 5.87 (d, J= 1.1 Hz, 1H), 5.74 (s, 1H), 5.57 (s, 1H), 4.25 (s, 1H), 4.18 (d, J= 14.1 Hz,

1H), 3.55 (d, J= 13.8 Hz, 1H), 3.37 (dt, J= 9.0, 4.6 Hz, 1H), 2.95 (d, J= 10.4 Hz, 1H),

2.86 (d, J= 9.2 Hz, 1H), 2.65 (s, 2H), 2.43 (d, J= 7.6 Hz, 1H); 13C NMR (101 MHz,

CDC 3) 6 165.99, 146.55, 146.29, 142.60, 134.28, 134.23, 133.17, 130.81, 129.59,

127.13, 127.00, 119.58, 117.56, 107.36, 104.94, 100.96, 73.04, 69.34, 61.68, 56.81,

810 53.77, 39.25, 28.63.

Example18:1-4-fluoro-2-chlorocinnamyl)-lycorine(S17)

C O OH F O

, The structure of S17: o / N

a: 2-tert-butyldimethylsilyl-lycorine, i.e., INB (10.0 mmol) and

4-fluoro-2-chlorocinnamic acid (12.0 mmol) were dissolved in 50 mL of

815 dichloromethane in a 250 mL round-bottom reaction flask and EDCI.HCl (18.0 mmol),

820 purified water and 100 mL of 10% sodium chloride solution in turn, and then

concentrated under reduced pressure for later use.

b: the above product dissolved in 50 mL absolute ethanol in a 250 mL

825 stirred at 80 °C for 1.0 h, the heating was turned off and the temperature was naturally

ethyl acetate and 80 mL of purified water were added to the reaction system successively, and the liquids were extracted and separated. The organic phase was washed with saturated sodium bicarbonate solution and saturated sodium chloride

830 solution respectively, dried over anhydrous sodium sulfate, concentrated, and separated

by column chromatography to obtain white Solid S17. 'H NMR (400 MHz, CDCl 3) 6

7.92 (d, J= 16.0 Hz, 1H), 7.53 (dd, J= 8.8, 6.0 Hz, 1H), 7.13 (dd, J= 8.4, 2.5 Hz, 1H),

6.95 (td, J= 8.4, 2.5 Hz, 1H), 6.71 (s, 1H), 6.57 (s, 1H), 6.23 (d, J= 16.0 Hz, 1H), 5.90

(s, 1H), 5.89 (s, 1H), 5.74 (s, 1H), 5.58 (s, 1H), 4.30 (s, 1H), 4.17 (d, J= 14.2 Hz, 1H),

835 3.54 (d, J= 13.9 Hz, 1H), 3.38 (dt, J= 9.1, 4.7 Hz, 1H), 2.95 (d, J= 10.4 Hz,1H), 2.85

(d, J= 9.8 Hz, 1H), 2.66 (s, 2H), 2.41 (d, J= 8.4 Hz, H); 13 CNMR (101 MHz, CDC3

) 6 166.00,146.55, 146.31, 140.02,136.03, 135.93, 128.96 (d, J= 9.1 Hz), 128.87 (d, J=

3.9 Hz), 127.02, 119.98 (d, J= 1.5 Hz),117.61, 117.36, 117.32, 114.81, 114.60, 107.30,

104.98, 100.95, 73.11, 69.66, 61.74, 56.92, 53.78, 39.55, 28.67.

840 Example 19: 1-(2-fluoro-4-chlorocinnamyl)-lycorine (S18)

F 0 CI o~OH

The structure of S18: O / N

a: 2-tert-butyldimethylsilyl-lycorine, i.e., INB (10.0 mmol) and

2-fluoro-4-chlorocinnamic acid (12.0 mmol) were dissolved in 50 mL of

845 DMAP (1.0 mmol) were added successively at room temperature under nitrogen. After the addition, the reaction was kept at the temperature of 35 °C and stirred. The residual quantity of INB was traced and detected by HPLC, when it was less than 8 percent, post-treatment was performed. The reaction solution was washed once with 100 mL of purified water and 100 mL of 10% sodium chloride solution in turn, and then

850 concentrated under reduced pressure for later use.

b: the above product dissolved in 50 mL absolute ethanol in a 250 mL

855 cooled to 25 °C, and then 5.0 mL ammonia water was slowly added dropwise. 80 mL of

ethyl acetate and 80 mL of purified water were added to the reaction system

washed with saturated sodium bicarbonate solution and saturated sodium chloride

860 by column chromatography to obtain white Solid S18. 1 H NMR (400 MHz, CDCl 3) 6

7.64 (d, J= 16.2 Hz, 1H), 7.39 (t, J= 8.2 Hz, 1H), 7.12 (s, OH), 7.10 (d, J= 3.9 Hz, 1H),

6.72 (s, 1H), 6.57 (s, 1H), 6.36 (d, J= 16.2 Hz, 1H), 5.89 (s, 1H), 5.88 (s, 1H), 5.76 (s,

1H), 5.58 (s, 1H), 4.28 (s, 1H), 4.16 (d, J= 14.0 Hz, 1H), 3.55 (d, J= 13.8 Hz, 1H),

3.38 (dt, J= 9.1, 4.7 Hz, 1H), 2.94 (d, J= 10.5 Hz, 1H), 2.84 (d, J= 10.3 Hz, 1H), 2.66

865 (s, 2H), 2.42 (dd, J= 17.2, 8.4 Hz, 1H); 13C NMR (101 MHz, CDCl 3) 6 166.20, 146.52,

146.30, 144.34, 136.88 (d, J= 9.5 Hz,), 129.84 (d, J= 3.8 Hz), 129.42 (d, J= 4.6 Hz),

127.00, 124.99 (d, J= 3.5 Hz), 121.13, 121.01, 120.69 (d, J= 7.8 Hz), 117.26 (d, J=

2.8 Hz), 117.14 (d, J= 2.0 Hz), 116.90 (d, J= 1.2 Hz), 107.32, 104.99, 100.95, 72.99,

69.75, 61.66, 56.90, 53.74 , 39.59, 28.68.

870 Example 20: 1-(4-bromocinnamoyl)-lycorine (S19)

0 OH

Br O

The structure of S19: 0 N

a: 2-tert-butyldimethylsilyl-lycorine, i.e., INB (10.0 mmol) and 4-bromocinnamic

acid (12.0 mmol) were dissolved in 50 mL of dichloromethane in a 250 mL

round-bottom reaction flask and EDCI.HCl (18.0 mmol), DMAP (1.0 mmol) were

875 added successively at room temperature under nitrogen. After the addition, the reaction

880 pressure for later use.

b: the above product dissolved in 50 mL absolute ethanol in a 250

mLround-bottom reaction flask, and 5.0 mL concentrated HCl was slowly added

dropwise with stirring at room temperature. After the addition was completed, the reaction was stirred at 80 °C for 1.0 h, the heating was turned off and the temperature

885 was naturally cooled to 25 °C, and then 5.0 mL ammonia water was slowly added

dropwise. 80 mL of ethyl acetate and 80 mL of purified water were added to the

reaction system successively, and the liquids were extracted and separated. The organic

phase was washed with saturated sodium bicarbonate solution and saturated sodium

chloride solution respectively, dried over anhydrous sodium sulfate, concentrated, and

890 separated by column chromatography to obtain white Solid S19. 1 H NMR (400 MHz,

CDCl3 ) 6 7.51 (d, J= 16.0 Hz, 1H), 7.47 (s, 1H), 7.45 (s, 1H), 7.32 (s, 1H), 7.30 (s, 1H),

6.70 (s, 1H), 6.57 (s, 1H), 6.27 (d, J= 16.0 Hz, 1H), 5.89 (d, J= 1.3 Hz, 1H), 5.87 (d, J

= 1.3 Hz, 1H), 5.74 (s, 1H), 5.57 (s, 1H), 4.25 (s, 1H), 4.17 (d, J= 14.1 Hz, 1H), 3.53 (d,

J= 14.0 Hz, 1H), 3.38 (dt, J= 9.0, 4.6 Hz, 1H), 2.94 (d, J= 10.5 Hz, 1H), 2.84 (d, J=

895 10.3 Hz, 1H), 2.65 (s, 2H), 2.41 (q, J= 8.6 Hz, 1H); 1 3 C NMR (101 MHz, CDCl 3) 6

166.37, 146.51, 146.26, 144.01, 143.94, 133.11, 132.07, 129.52, 129.29, 127.01, 124.67,

118.38, 117.43, 107.32, 104.98, 100.95, 72.89, 69.53, 61.71, 56.89, 53.77, 39.43, 28.65.

Example 21: 1-(2-nitrocinnamoyl)-lycorine (S20)

NO 2 0 ~ OH

The structure of S20: 0 N

900 a: 2-tert-butyldimethylsilyl-lycorine, i.e., INB (10.0 mmol) and 2-nitrocinnamic

acid (12.0 mmol) were dissolved in 50 mL of dichloromethane in a 250 mL round-bottom reaction flask and EDCI.HCl (18.0 mmol), DMAP (1.0 mmol) were added successively at room temperature under nitrogen. After the addition, the reaction was kept at the temperature of 35 °C and stirred. The residual quantity of INB was

905 traced and detected by HPLC, when it was less than 8 percent, post-treatment was

pressure for later use.

b: the above product dissolved in 50 mL absolute ethanol in a 250 mL

910 round-bottom reaction flask, and 5.0 mL concentrated HCl was slowly added dropwise

ethyl acetate and 80 mL of purified water were added to the reaction system

915 successively, and the liquids were extracted and separated. The organic phase was

washed with saturated sodium bicarbonate solution and saturated sodium chloride

by column chromatography to obtain white Solid S20. 1 H NMR (400 MHz, CDCl 3) 6

8.01 (d, J= 3.3 Hz, 1H), 7.98 (d, J= 4.0 Hz, 1H), 7.62 - 7.54 (m, 2H), 7.50 (ddd, J=

920 8.6, 6.5, 2.4 Hz, 1H), 6.69 (s, 1H), 6.57 (s, 1H), 6.23 (d, J= 15.8 Hz, 1H), 5.90 (s, 1H),

5.89 (s, 1H), 5.74 (s, 1H), 5.58 (s, 1H), 4.30 (s, 1H), 4.17 (d, J= 14.1 Hz, 1H), 3.55 (d,

J= 13.8 Hz, 1H), 3.38 (dt, J= 9.2, 4.7 Hz, 1H), 2.95 (d, J= 10.4 Hz, 1H), 2.86 (d, J=

9.2 Hz, 1H), 2.66 (s, 2H), 2.43 (d, J= 6.5 Hz, 1H); 13 C NMR (101 MHz, CDCl 3 ) 6

165.34, 148.31, 146.58, 146.33, 143.99, 140.45, 133.34, 130.34, 130.28, 129.06, 126.91,

925 124.89, 122.78, 117.36, 107.3, 104.97, 100.95, 73.29, 69.51, 61.73, 56.85, 53.75, 39.51,

28.64.

Example 22: 1-(3-nitrocinnamoyl)-lycorine (S21)

0 OH 0 2N

The structure of S21: 0 I N

a: 2-tert-butyldimethylsilyl-lycorine, i.e., INB (10.0 mmol) and 3-nitrocinnamic

930 acid (12.0 mmol) were dissolved in 50 mL of dichloromethane in a 250 mL

round-bottom reaction flask and EDCI.HCl (18.0 mmol), DMAP (1.0 mmol) were

935 performed. The reaction solution was washed once with 100 mL of purified water and

pressure for later use.

b: the above product dissolved in 50 mL absolute ethanol in a 250 mL

940 with stirring at room temperature. After the addition was completed, the reaction was

ethyl acetate and 80 mL of purified water were added to the reaction system

945 washed with saturated sodium bicarbonate solution and saturated sodium chloride

by column chromatography to obtain white Solid S21. 'H NMR (400 MHz, CDCl 3 ) 6

8.31 (s, 1H), 8.20 (dd, J= 8.2, 1.3 Hz, 1H), 7.76 (d, J= 7.8 Hz, 1H), 7.63 (d, J= 16.0

Hz, 1H), 7.54 (t, J= 8.0 Hz, iH), 6.72 (s, iH), 6.58 (s, iH), 6.42 (d, J= 16.0 Hz,1H),

950 5.90 (d, J= 1.2 Hz, 1H), 5.88 (d, J= 1.2 Hz, 1H), 5.78 (s, iH), 5.59 (s, iH), 4.27 (s,

IH), 4.19 (d, J= 14.1 Hz, 1H), 3.71 (q, J= 7.0 Hz, 1H), 3.57 (d, J= 14.0 Hz,1H), 3.47

- 3.33 (m, iH), 2.97 (d, J= 10.4 Hz,1H), 2.87 (d, J= 10.3 Hz,1H), 2.67 (s, 2H), 2.45

(dd, J = 17.4, 8.7 Hz, 1H); 13 C NMR (101 MHz, CDCl 3 ) 6 165.75, 148.54, 146.50,

146.28, 143.92, 142.42, 135.92, 133.84, 129.92, 129.30, 126.86, 124.60, 122.33, 120.89,

955 117.35, 107.37, 104.91, 100.95, 73.16, 69.42, 61.70, 53.74, 39.35, 28.61, 18.41.

Example 23: 1-(4-nitrocinnamoyl)-lycorine (S22)

0

02 N O- OH 0 s

The structure of S22: 0 / N a: 2-tert-butyldimethylsilyl-lycorine, i.e., INB (10.0 mmol) and 4-nitrocinnamic acid (12.0 mmol) were dissolved in 50 mL of dichloromethane in a 250 mL

960 round-bottom reaction flask and EDCI.HCl (18.0 mmol), DMAP (1.0 mmol) were

965 100 mL of 10% sodium chloride solution in turn, and then concentrated under reduced

pressure for later use.

b: the above product dissolved in 50 mL absolute ethanol in a 250 mL

970 stirred at 80 °C for 1.0 h, the heating was turned off and the temperature was naturally

ethyl acetate and 80 mL of purified water were added to the reaction system

washed with saturated sodium bicarbonate solution and saturated sodium chloride

975 solution respectively, dried over anhydrous sodium sulfate, concentrated, and separated

by column chromatography to obtain white Solid S22. 1 H NMR (400 MHz, CDCl 3) 6

8.21 (s, 1H), 8.19 (s, 1H), 7.62 (dd, J= 12.5, 5.6 Hz, 3H), 7.27 (s, 1H), 6.70 (s, 1H),

6.58 (s, 1H), 6.41 (d, J= 16.0 Hz, 1H), 5.90 (s, 1H), 5.88 (s, 1H), 5.77 (s, 1H), 5.58 (s,

1H), 4.26 (s, 1H), 4.18 (d, J= 14.1 Hz, 1H), 3.55 (d, J= 13.9 Hz, 1H), 3.39 (dt, J= 8.7,

980 4.4 Hz, 1H), 2.96 (d, J= 10.4 Hz, 1H), 2.85 (d, J= 9.9 Hz, 1H), 2.66 (s, 2H), 2.43 (d, J

= 8.6 Hz, 1H); 1 C NMR (101 MHz, CDCl 3 ) 6 165.61, 148.51, 146.50, 146.30, 144.16,

142.35, 140.30,129.33, 128.66, 126.82,124.04,121.98, 117.24, 107.33, 104.86, 100.93,

73.16, 69.58, 61.61, 56.83, 53.68, 39.47, 28.61.

Example 24: 1-(2-chloro-5-nitrocinnamoyl)-lycorine (S23)

CI 0 OH

NOK N 985 The structure of S23: O0 N

a: 2-tert-butyldimethylsilyl-lycorine, i.e., INB (10.0 mmol) and

2-chloro-5-nitrocinnamic acid (12.0 mmol) were dissolved in 50 mL of dichloromethane

in a 250 mL round-bottom reaction flask and EDCI.HCl (18.0 mmol), DMAP (1.0

mmol) were added successively at room temperature under nitrogen. After the addition,

990 the reaction was kept at the temperature of 35 °C and stirred. The residual quantity of

INB was traced and detected by HPLC, when it was less than 8 percent, post-treatment

was performed. The reaction solution was washed once with 100 mL of purified water

and 100 mL of 10% sodium chloride solution in turn, and then concentrated under

reduced pressure for later use.

995 b: the above product dissolved in 50 mL absolute ethanol in a 250 mL

1000 ethyl acetate and 80 mL of purified water were added to the reaction system

washed with saturated sodium bicarbonate solution and saturated sodium chloride

by column chromatography to obtain white Solid S23. 1 H NMR (400 MHz, CDCl 3) 6

1005 8.38 (d, J= 2.4 Hz, 1H), 8.11 (dd, J= 8.8, 2.5 Hz, 1H), 7.95 (d, J= 16.0 Hz, 1H), 7.56

(d, J= 8.8 Hz, 1H), 6.67 (s, 1H), 6.57 (s, 1H), 6.41 (d, J= 16.0 Hz, 1H), 5.89 (s, 1H),

5.87 (s, 1H), 5.76 (s, 1H), 5.58 (s, 1H), 4.27 (s, 1H), 4.18 (d, J= 14.1 Hz, 1H), 3.54 (d,

J= 14.0 Hz, 1H), 3.38 (dd, J= 8.4, 4.0 Hz, 1H), 2.96 (d, J= 10.5 Hz, 1H), 2.87 (d, J=

10.4 Hz, 1H), 2.65 (s, 2H), 2.42 (q, J= 8.7 Hz, 1H); 13 C NMR (101 MHz, CDCl 3) 6

1010 165.27, 146.58, 146.50, 146.28, 143.69, 141.19, 138.72, 133.94, 131.17, 129.25, 126.73,

125.05, 123.18, 122.40, 117.39, 107.35, 104.85, 100.95, 73.36, 69.29, 61.76, 56.87,

53.75, 39.26, 28.54.

Example 25: 1-(4-chloro-3-nitrocinnamoyl)-lycorine (S24)

02 N OH

The structure of S24: / N

1015 a: 2-tert-butyldimethylsilyl-lycorine, i.e., INB (10.0 mmol) and

4-chloro-3-nitrocinnamic acid (12.0 mmol) were dissolved in 50 mL of dichloromethane

in a 250 mL round-bottom reaction flask and EDCI.HCl (18.0 mmol), DMAP (1.0

the reaction was kept at the temperature of 35 'C and stirred. The residual quantity of

1020 INB was traced and detected by HPLC, when it was less than 8 percent, post-treatment

and 100 mL of 10% sodium chloride solution in turn, and then concentrated under

reduced pressure for later use.

b: the above product dissolved in 50 mL absolute ethanol in a 250 mL

1025 round-bottom reaction flask, and 5.0 mL concentrated HCl was slowly added dropwise

ethyl acetate and 80 mL of purified water were added to the reaction system

1030 successively, and the liquids were extracted and separated. The organic phase was

washed with saturated sodium bicarbonate solution and saturated sodium chloride solution respectively, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain white Solid S24. 'H NMR (400 MHz, CDCl 3) 6

7.94 (d, J= 1.8 Hz, 1H), 7.62 - 7.44 (m, 3H), 6.70 (s, 1H), 6.57 (s, 1H), 6.35 (d, J=

1035 16.0 Hz, 1H), 5.89 (d, J= 1.2 Hz, 1H), 5.86 (d, J= 1.2 Hz, 1H), 5.77 (s, 1H), 5.56 (s,

1H), 4.25 (s, 1H), 4.17 (d, J= 14.1 Hz, 1H), 3.54 (d, J= 14.0 Hz, 1H), 3.38 (dt, J= 9.1,

4.7 Hz, 1H), 2.95 (d, J= 10.5 Hz, 1H), 2.85 (d, J= 10.2 Hz, 1H), 2.65 (s, 2H), 2.43 (d, J

= 8.2 Hz, 1H); 13C NMR (101 MHz, CDC1 3) 6 165.52, 148.17, 146.53, 146.31, 143.81,

141.16, 134.37, 132.40, 131.95, 129.34,128.32, 126.93, 124.49, 121.36, 117.42, 107.37,

1040 104.93, 100.95, 73.34, 69.37, 61.68, 56.85, 53.74, 39.37, 28.62.

Example 26: 1-(4,5-dimethoxy-2-nitrocinnamoyl)-lycorine (S25)

NO 2 0 OH

00

The structure of S25: - N

a: 2-tert-butyldimethylsilyl-lycorine, i.e., INB (10.0 mmol) and

4,5-dimethoxy-2-nitrocinnamic acid (12.0 mmol) were dissolved in 50 mL of

1045 dichloromethane in a 250 mL round-bottom reaction flask and EDCI.HCl (18.0 mmol),

1050 purified water and 100 mL of 10% sodium chloride solution in turn, and then

concentrated under reduced pressure for later use.

b: the above product dissolved in 50 mL absolute ethanol in a 250 mL

1055 stirred at 80 °C for 1.0 h, the heating was turned off and the temperature was naturally

ethyl acetate and 80 mL of purified water were added to the reaction system

washed with saturated sodium bicarbonate solution and saturated sodium chloride

1060 solution respectively, dried over anhydrous sodium sulfate, concentrated, and separated

by column chromatography to obtain white Solid S25. 1 H NMR (400 MHz, CDCl 3) 6

8.11 (d, J= 15.8 Hz, 1H), 7.59 (s, 1H), 6.90 (s, 1H), 6.73 (s, 1H), 6.58 (s, 1H), 6.15 (d,

J= 15.7 Hz, 1H), 5.90 (d, J= 1.2 Hz,1H), 5.89 (s,1H), 5.76 (s, 1H), 5.59 (s, 1H), 4.31

(s, 1H), 4.17 (d, J= 14.0 Hz, 1H), 3.96 (s, 3H), 3.95 (s, 3H), 3.55 (d, J= 13.8 Hz, 1H),

1065 3.37 (dt, J= 9.0, 4.7 Hz, 1H), 2.96 (d, J= 10.4 Hz, 1H), 2.87 (d, J= 9.9 Hz, 1H), 2.66

(s, 2H), 2.43 (d, J= 8.4 Hz, 1H); 13C NMR (101 MHz, CDC3) 6 165.61, 153.06, 149.95,

146.55, 146.29, 144.09, 141.30, 141.21, 129.38, 127.03, 124.81, 121.34, 117.36, 109.83,

107.89, 107.29, 105.07, 100.97, 73.17, 69.57, 61.69, 56.87, 56.60, 56.49, 53.73, 39.56,

28.66.

1070 Example 27: 1-cinnamoyl-lycorine (S26)

0 OH 0

The structure of S26: o / N

a: 2-tert-butyldimethylsilyl-lycorine, i.e., NB (10.0 mmol) and cinnamic acid

(12.0 mmol) were dissolved in 50 mL of dichloromethane in a 250 mL round-bottom

reaction flask and EDCI.HICl (18.0 mmol), DMAP (1.0 mmol) were added successively

1075 at room temperature under nitrogen. After the addition, the reaction was kept at the

by HPLC, when it was less than 8 percent, post-treatment was performed. The reaction

solution was washed once with 100 mL of purified water and 100 mL of 10% sodium

1080 b: the above product dissolved in 50 mL absolute ethanol in a 250 mL

1085 ethyl acetate and 80 mL of purified water were added to the reaction system

washed with saturated sodium bicarbonate solution and saturated sodium chloride solution respectively, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain white Solid S26. 'H NMR (400 MHz, CDCl 3) 6

1090 7.59 (d, J= 16.0 Hz, 1H), 7.45 (dd, J= 7.1, 2.4 Hz, 2H), 7.38 - 7.29 (m, 3H), 6.71 (s,

1H), 6.71 (s, 1H), 6.56 (s, 1H), 6.28 (d, J= 16.0 Hz, 1H), 5.88 (d, J= 1.4 Hz, 1H), 5.86

(d, J= 1.4 Hz, 1H), 5.75 (s, 1H), 5.57 (s, 1H), 4.26 (s, 1H), 4.17 (d, J= 14.1 Hz, 1H),

3.54 (d, J= 14.0 Hz, 2H), 3.37 (dt, J= 9.1, 4.7 Hz, 1H), 2.95 (d, J= 10.5 Hz, 1H), 2.86

(d, J= 10.4 Hz, 1H), 2.65 (d, J= 1.9 Hz, 2H), 2.42 (q, J= 8.8 Hz, 1H); 13 C NMR (101

1095 MHz, CDCl 3 ) 6 166.59, 146.48, 146.22, 145.37, 143.80, 134.19, 130.35, 129.24, 128.79,

128.13, 127.09, 117.69, 117.49, 107.26, 105.01, 100.90, 72.78, 69.53, 61.71, 56.88,

53.75, 39.42, 28.64.

Example 28: 1-(4-methylcinnamoyl)-lycorine (S27)

0 OH

~N 0/N

The structure of S27: / N

1100 a: 2-tert-butyldimethylsilyl-lycorine, i.e., INB (10.0 mmol) and 4-methylcinnamic

acid (12.0 mmol) were dissolved in 50 mL of dichloromethane in a 250 mL

round-bottom reaction flask and EDCI.HCl (18.0 mmol), DMAP (1.0 mmol) were

1105 traced and detected by HPLC, when it was less than 8 percent, post-treatment was performed. The reaction solution was washed once with 100 mL of purified water and

pressure for later use.

b: the above product dissolved in 50 mL absolute ethanol in a 250 mL

1110 round-bottom reaction flask, and 5.0 mL concentrated HCl was slowly added dropwise

ethyl acetate and 80 mL of purified water were added to the reaction system

1115 successively, and the liquids were extracted and separated. The organic phase was

washed with saturated sodium bicarbonate solution and saturated sodium chloride

by column chromatography to obtain white Solid S7. 1 H NMR (400 MHz, CDCl 3) 6

7.55 (d, J= 16.0 Hz, 1H), 7.34 (s, 1H), 7.32 (s, 1H), 7.13 (s, 1H), 7.11 (s, 1H), 6.69 (s,

1120 1H), 6.56 (s, 1H), 6.22 (d, J= 16.0 Hz, 1H), 5.87 (d, J= 1.2 Hz, 1H), 5.85 (d, J= 1.2

Hz, 1H), 5.73 (s, 1H), 5.57 (s, 1H), 4.24 (s, 1H), 4.17 (d, J= 14.1 Hz, 1H), 3.53 (d, J=

13.9 Hz, 1H), 3.37 (dt, J= 9.0, 4.6 Hz, 1H), 2.95 (d, J= 10.5 Hz, 1H), 2.87 (d, J= 10.5

Hz, 1H), 2.64 (s, 2H), 2.41 (d, J = 8.7 Hz, 1H), 2.33 (s, 3H); 13C NMR (101 MHz,

CDC 3) 6 166.76, 146.44, 146.15, 145.34, 143.37, 140.75, 131.42, 129.49, 129.13,

1125 128.11, 127.13, 117.65, 116.52, 107.22, 105.00, 100.86, 72.65, 69.33, 61.72, 56.84,

53.75, 39.24, 28.58, 21.43.

Example 29: 1-(4-methoxycinnamoyl)-lycorine (S28)

0 OH

00 N

The structure of S28: 0 N

a: 2-tert-butyldimethylsilyl-lycorine, i.e., INB (10.0 mmol) and

1130 4-methoxycinnamic acid (12.0 mmol) were dissolved in 50 mL of dichloromethane in a

250 mL round-bottom reaction flask and EDCI.HCl (18.0 mmol), DMAP (1.0 mmol)

1135 performed. The reaction solution was washed once with 100 mL of purified water and

pressure for later use.

b: the above product dissolved in 50 mL absolute ethanol in a 250 mL

1140 with stirring at room temperature. After the addition was completed, the reaction was

cooled to 25 °C, and then 5.0 mL ammonia water was slowly added dropwise. 80 mL of ethyl acetate and 80 mL of purified water were added to the reaction system successively, and the liquids were extracted and separated. The organic phase was

1145 washed with saturated sodium bicarbonate solution and saturated sodium chloride

by column chromatography to obtain white Solid S28. 'H NMR (400 MHz, CDCl 3) 6

7.54 (d, J= 15.9 Hz, 1H), 7.41 (s, 1H), 7.39 (s, 1H), 6.85 (s, 1H), 6.83 (s, iH), 6.70 (s,

1H), 6.57 (s, 1H), 6.15 (d, J= 15.9 Hz, 1H), 5.88 (s, 1H), 5.86 (s, 1H), 5.73 (s, 1H),

1150 5.57 (s, 1H), 4.25 (s, 1H), 4.17 (d, J= 14.1 Hz, 1H), 3.80 (s, 3H), 3.54 (d, J= 14.0 Hz,

1H), 3.43 - 3.30 (m, 1H), 2.94 (d, J= 10.4 Hz, 1H), 2.87 (d, J= 10.3 Hz, 1H), 2.65 (s,

2H), 2.42 (dd, J= 17.0, 8.4 Hz,1H); 13C NMR (101 MHz, CDC 3)6 166.96), 161.39,

146.46, 146.17, 145.05, 143.60, 129.82, 129.18, 127.19, 126.91, 117.58, 115.08, 114.20,

107.24, 105.02, 100.89, 72.58, 69.48, 61.70, 56.85, 55.33, 53.75, 39.33, 28.63, 18.37.

1155 Example 30: 1-(4-propoxycainnamoyl)-lycorine (S29)

0 OH

The structure of S29: 0 N

a: 2-tert-butyldimethylsilyl-lycorine, i.e., INB (10.0 mmol) and 4-propoxycinnamic

acid (12.0 mmol) were dissolved in 50 mL of dichloromethane in a 250 mL

round-bottom reaction flask and EDCI.HCl (18.0 mmol), DMAP (1.0 mmol) were

1160 added successively at room temperature under nitrogen. After the addition, the reaction was kept at the temperature of 35 °C and stirred. The residual quantity of INB was traced and detected by HPLC, when it was less than 8 percent, post-treatment was performed. The reaction solution was washed once with 100 mL of purified water and

1165 pressure for later use.

b: the above product dissolved in 50 mL absolute ethanol in a 250 mL

1170 cooled to 25 °C, and then 5.0 mL ammonia water was slowly added dropwise. 80 mL of

ethyl acetate and 80 mL of purified water were added to the reaction system

washed with saturated sodium bicarbonate solution and saturated sodium chloride

1175 by column chromatography to obtain white Solid S29. 1 H NMR (400 MHz, CDCl 3) 6

7.54 (d, J= 15.9 Hz, 1H), 7.40 (s, 1H), 7.38 (s, 1H), 6.85 (s, 1H), 6.83 (s, 1H), 6.71 (s,

1H), 6.57 (s, 1H), 6.14 (d, J= 15.9 Hz, 1H), 5.89 (d, J= 1.1 Hz,1H), 5.87 (s, 1H), 5.74

(s, 1H), 5.58 (s, 1H), 4.26 (s, 1H), 4.17 (d, J= 14.1 Hz, 1H), 3.92 (t, J= 6.6 Hz, 2H),

3.55 (d, J= 14.0 Hz, 1H), 3.37 (dd, J= 8.8, 4.6 Hz, 1H), 2.94 (d, J= 10.5 Hz, 1H), 2.86

1180 (d, J= 10.2 Hz, 1H), 2.66 (s, 2H), 2.43 (d, J= 8.6 Hz, 1H), 1.80 (dd, J= 14.1, 6.9 Hz,

2H), 1.02 (t, J= 7.4 Hz, 3H); 'C NMR (101 MHz, CDC 3) 6 167.01, 161.04, 146.47,

146.19, 145.17, 143.88, 129.82, 129.22, 127.17, 126.67, 117.46, 114.86, 114.70, 107.25,

105.03, 100.90, 72.53, 69.62, 69.56, 61.68, 56.85, 53.75, 39.43, 28.66, 22.46, 10.47.

Example 31: 1-(4-allyloxycinnamoyl)-lycorine (S30)

OH

0 0

1185 The structure of S30: 0 N

a: 2-tert-butyldimethylsilyl-lycorine, i.e., INB (10.0 mmol) and 4-allyloxycinnamic

acid (12.0 mmol) were dissolved in 50 mL of dichloromethane in a 250 mL

round-bottom reaction flask and EDCI.HCl (18.0 mmol), DMAP (1.0 mmol) were

1190 was kept at the temperature of 35 °C and stirred. The residual quantity of INB was

pressure for later use.

1195 b: the above product dissolved in 50 mL absolute ethanol in a 250 mL

stirred at 80 °C for 1.0 h, the heating was turned off and the temperature was naturally cooled to 25 °C, and then 5.0 mL ammonia water was slowly added dropwise. 80 mL of

1200 ethyl acetate and 80 mL of purified water were added to the reaction system

washed with saturated sodium bicarbonate solution and saturated sodium chloride

by column chromatography to obtain white Solid S30. 'H NMR (400 MHz, CDCl 3) 6

1205 7.54 (d, J= 15.9 Hz, 1H), 7.40 (s, 1H), 7.38 (s, 1H), 6.87 (s, 1H), 6.85 (s,1H), 6.71 (s,

1H), 6.57 (s, 1H), 6.15 (d, J= 15.9 Hz, 1H), 6.03 (ddd, J= 22.5, 10.5, 5.3 Hz, 1H), 5.89

(d, J= 1.1 Hz, 1H), 5.87 (s, 1H), 5.74 (s, 1H), 5.57 (s, 1H), 5.40 (dd, J= 17.3, 1.4 Hz,

1H), 5.29 (dd, J= 10.5, 1.2 Hz, 1H), 4.54 (d, J= 5.3 Hz, 2H), 4.26 (s, iH), 4.17 (d, J=

14.1 Hz, 1H), 3.54 (d, J= 13.9 Hz, 1H), 3.37 (dt, J= 8.9, 4.5 Hz, 1H), 2.94 (d, J= 10.4

1210 Hz, 1H), 2.86 (d, J= 10.2 Hz, 1H), 2.65 (s, 2H), 2.42 (q, J= 8.5 Hz,1H); 13 C NMR

(101 MHz, CDCl 3) 8 166.94, 160.39, 146.45, 146.18, 145.01, 143.84, 132.67, 129.80,

129.22, 127.15, 127.04, 118.04, 117.47, 115.15, 114.93, 107.24, 105.02, 100.89, 72.57,

69.58, 68.78, 61.69, 56.87, 53.75, 39.43, 28.64.

Example 32: 1- (4-hydroxycinnamoyl)-lycorine (S31) 0 OH O0,,, O HO HOJ[ 0 sN

1215 The structure of S31: 0 I/ N

a: 2-tert-butyldimethylsilyl-lycorine, i.e., INB (10.0 mmol) and

4-tert-butyldimethylsilylcinnamic acid (12.0 mmol) were dissolved in 50 mL of

1220 the addition, the reaction was kept at the temperature of 35 °C and stirred. The residual

purified water and 100 mL of 10% sodium chloride solution in turn, and then

concentrated under reduced pressure for later use.

1225 b: the above product dissolved in 50 mL absolute ethanol in a 250 mL

1230 ethyl acetate and 80 mL of purified water were added to the reaction system

washed with saturated sodium bicarbonate solution and saturated sodium chloride

by column chromatography to obtain white Solid S31. 1 H NMR (400 MHz, CDCl 3) 6

1235 7.53 (d, J= 16.0 Hz, 1H), 7.35 (s, 1H), 7.33 (s, 1H), 6.77 (s, 1H), 6.75 (s, 2H), 6.58 (s,

1H), 6.14 (d, J= 15.9 Hz, 1H), 5.90 (s, 1H), 5.88 (s, 1H), 5.75 (s, 1H), 5.59 (s, 1H),

4.31 (s, 1H), 4.15 (d, J= 14.0 Hz, 1H), 3.59 (d, J= 13.6 Hz, 1H), 3.41 - 3.34 (in, 1H),

2.97 - 2.85 (in, 2H), 2.67 (s, 211), 2.54 - 2.44 (in, 1H); 13 C NMR (101 MHz, DMSO) 6

166.61, 160.45, 146.24, 146.19, 145.78, 142.45, 130.96, 130.29, 127.93, 125.30, 118.71,

1240 116.18, 114.23, 107.86, 104.73, 101.26, 72.06, 69.24, 61.67, 56.90, 53.57, 28.58.

Example 33: 1- (3-methoxy-4-hydroxycinnamoyl)-lycorinee (S33)

0 0 o OH

HO' 0 s

The structure of S32: / N

a: 2-tert-butyldimethylsilyl-lycorine, i.e., INB (10.0 mmol) and

3-methoxy-4-tert-butyldimethylsilylcinnamic acid (12.0 mmol) were dissolved in 50 mL

1245 of dichloromethane in a 250 mL round-bottom reaction flask and EDCI.HC (18.0

mmol), DMAP (1.0 mmol) were added successively at room temperature under nitrogen.

After the addition, the reaction was kept at the temperature of 35 °C and stirred. The

residual quantity of INB was traced and detected by HPLC, when it was less than 8

percent, post-treatment was performed. The reaction solution was washed once with 100

1250 mL of purified water and 100 mL of 10% sodium chloride solution in turn, and then

concentrated under reduced pressure for later use.

b: the above product dissolved in 50 mL absolute ethanol in a 250 mL

1255 stirred at 80 °C for 1.0 h, the heating was turned off and the temperature was naturally

ethyl acetate and 80 mL of purified water were added to the reaction system

washed with saturated sodium bicarbonate solution and saturated sodium chloride

1260 solution respectively, dried over anhydrous sodium sulfate, concentrated, and separated

by column chromatography to obtain white Solid S32. 'H NMR (400 MHz, CDCl 3) 6

7.51 (d, J= 15.9 Hz, 1H), 7.00 - 6.95 (m, 1H), 6.94 (d, J= 1.4 Hz, 1H), 6.84 (d, J= 8.2

Hz, 1H), 6.69 (s, 1H), 6.58 (s, 1H), 6.11 (d, J= 15.9 Hz, 1H), 5.88 (s, 1H), 5.86 (d, J=

1.0 Hz, 1H), 5.74 (s, 1H), 5.59 (s, 1H), 4.27 (s, 1H), 4.17 (d, J= 14.1 Hz, 1H), 3.85 (s,

1265 3H), 3.60 (d, J= 13.9 Hz, 1H), 3.36 (dd, J= 9.0, 4.7 Hz, 1H), 3.03 -2.88 (m, 2H), 2.66

(s, 2H), 2.57 - 2.42 (m, 1H); 13 C NMR (101 MHz, CDCl 3) 6 166.98, 148.26, 146.89,

146.61, 146.26, 145.67, 143.35, 128.96, 127.32, 126.65, 123.33, 117.76, 114.81, 114.77,

109.40, 107.31, 105.03, 100.95, 72.48, 69.45, 61.50, 56.58, 55.90, 53.75, 39.04, 28.74.

Example 34: 1- (3,4-methylenedioxycinnamoyl)-lycorine (S33)

0 O o '- OH

1270 The structure of S33: 0 N

a: 2-tert-butyldimethylsilyl-lycorine, i.e., INB (10.0 mmol) and

3,4-methylenedioxycinnamic acid (12.0 mmol) were dissolved in 50 mL of dichloromethane in a 250 mL round-bottom reaction flask and EDCI.HCl (18.0 mmol),

1275 the addition, the reaction was kept at the temperature of 35 °C and stirred. The residual

purified water and 100 mL of 10% sodium chloride solution in turn, and then

concentrated under reduced pressure for later use.

1280 b: the above product dissolved in 50 mL absolute ethanol in a 250 mL

1285 ethyl acetate and 80 mL of purified water were added to the reaction system

washed with saturated sodium bicarbonate solution and saturated sodium chloride

by column chromatography to obtain white Solid S33. 1 H NMR (400 MHz, CDCl 3) 6

1290 7.49 (d, J= 15.9 Hz, 1H), 6.94 (d, J= 6.6 Hz, 2H), 6.76 (d, J= 8.5 Hz, 1H), 6.70 (s,

1H), 6.57 (s, 1H), 6.10 (d, J= 15.9 Hz, 1H), 5.97 (s, 2H), 5.89 (d, J= 1.3 Hz, 1H), 5.87

(d, J= 1.3 Hz, 1H), 5.73 (s, 1H), 5.57 (s, 1H), 4.26 (s, 1H), 4.17 (d, J= 14.2 Hz, 1H),

3.54 (d, J= 14.0 Hz, 1H), 3.37 (dt, J= 9.0, 4.7 Hz, 1H), 2.93 (d, J= 10.5 Hz, 1H), 2.85

(d, J= 10.2 Hz, 1H), 2.65 (s, 2H), 2.48 - 2.34 (m, 1H); 13 C NMR (101 MHz, CDCl 3) 6

1295 166.80, 149.68, 148.28, 146.48, 146.22, 145.10, 143.92, 129.26, 128.64, 127.14, 124.63,

117.44, 115.57, 108.46, 107.27, 106.48, 105.02, 101.55, 100.91, 72.65, 69.62, 61.68,

56.87, 53.75, 39.45, 28.65.

Example 35: 1- (3,4,5-trimethoxycinnamoyl)-lycorine (S34)

1 0 OH U

The structure of S34: <0 N

1300 a: 2-tert-butyldimethylsilyl-lycorine, i.e., INB (10.0 mmol) and

3,4,5-trimethoxycinnamic acid (12.0 mmol) were dissolved in 50 mL of

1305 quantity of INB was traced and detected by HPLC, when it was less than 8 percent,

purified water and 100 mL of 10% sodium chloride solution in turn, and then

concentrated under reduced pressure for later use.

b: the above product dissolved in 50 mL absolute ethanol in a 250 mL

1310 round-bottom reaction flask, and 5.0 mL concentrated HCl was slowly added dropwise with stirring at room temperature. After the addition was completed, the reaction was stirred at 80 °C for 1.0 h, the heating was turned off and the temperature was naturally cooled to 25 °C, and then 5.0 mL ammonia water was slowly added dropwise. 80 mL of ethyl acetate and 80 mL of purified water were added to the reaction system

1315 successively, and the liquids were extracted and separated. The organic phase was

washed with saturated sodium bicarbonate solution and saturated sodium chloride

by column chromatography to obtain white Solid S34. 'H NMR (500 MHz, CDCl 3 ) 6

7.52 (d, J= 15.9 Hz, 1H), 6.71 (s, 1H), 6.68 (s, 2H), 6.58 (s, 1H), 6.18 (d, J= 15.9 Hz,

1320 1H), 5.89 (s, 1H), 5.88 (s, 1H), 5.75 (s, 1H), 5.58 (s, 1H), 4.26 (s, 1H), 4.17 (d, J= 14.1

Hz, 1H), 3.86 (s, 3H), 3.85 (s, 3H), 3.83 (s, 3H), 3.56 (d, J= 13.9 Hz, 1H), 3.37 (dt, J=

9.1, 4.6 Hz, 1H), 2.96 (d, J= 10.5 Hz, 1H), 2.89 (d, J= 10.4 Hz, 1H), 2.66 (s, 2H), 2.45

(dd, J = 17.1, 8.5 Hz, 1H); 13 C NMR (126 MHz, CDCl 3 ) 6 166.67, 153.36, 146.55,

146.27, 145.50, 143.75, 140.20, 129.68, 129.23, 127.22, 117.59, 116.84, 107.29, 105.34,

1325 105.04, 100.97, 72.76, 69.55, 61.61, 60.97, 56.80, 56.17, 56.08, 53.76, 39.36, 28.71.

Example 36: 1- [3-(1-biphenyl) acryloyl)]-lycorine (S35)

0 ~ OH

DID 0 - The structure of S35: 0 / N

a: 2-tert-butyldimethylsilyl-lycorine, i.e., IN (10.0 mmol) and 3-(1-biphenyl) acrylic acid (12.0 mmol) were dissolved in 50 mL of dichloromethane in a 250 mL

1330 round-bottom reaction flask and EDCI.HCl (18.0 mmol), DMAP (1.0 mmol) were

1335 100 mL of 10% sodium chloride solution in turn, and then concentrated under reduced

pressure for later use.

b: the above product dissolved in 50 mL absolute ethanol in a 250 mL

1340 stirred at 80 °C for 1.0 h, the heating was turned off and the temperature was naturally

ethyl acetate and 80 mL of purified water were added to the reaction system

washed with saturated sodium bicarbonate solution and saturated sodium chloride

1345 solution respectively, dried over anhydrous sodium sulfate, concentrated, and separated

by column chromatography to obtain white Solid S35. 1 H NMR (400 MHz, CDCl 3) 6

7.58 (m, 7H), 7.43 (t, J= 7.5 Hz, 2H), 7.36 (t, J= 7.3 Hz, 1H), 6.75 (s, 1H), 6.58 (s, 1H),

6.32 (d, J= 16.0 Hz, 1H), 5.89 (s, 1H), 5.88 (s, 1H), 5.78 (s, 1H), 5.59 (s, 1H), 4.31 (s,

IH), 4.17 (d, J= 13.9 Hz, IH), 3.57 (d, J= 13.3 Hz, IH), 3.38 (d, J= 4.1 Hz,1H), 2.96

1350 (d, J= 10.3 Hz, 1H), 2.89 (s, 1H), 2.67 (s, 2H), 2.44 (d, J= 6.8 Hz, H); 13C NMR (101

MHz, CDC13 ) 6 166.64, 146.32, 144.95, 143.16, 140.08, 133.19, 128.88, 128.65, 127.86,

127.45, 127.20, 127.02, 117.53, 107.33, 105.05, 100.95, 72.77, 69.85, 61.65, 56.88,

53.78, 39.57, 28.76.

Example 37: 1-[3-(2-furan) acryloyl)]-lycorine (S36)

0 O,, OH KOOH

1355 The structure of S36: 0 / N

a: 2-tert-butyldimethylsilyl-lycorine, i.e., INB (10.0 mmol) and 3-(2-furan) acrylic

acid (12.0 mmol) were dissolved in 50 mL of dichloromethane in a 250 mL

round-bottom reaction flask and EDCI.HCl (18.0 mmol), DMAP (1.0 mmol) were

1360 was kept at the temperature of 35 °C and stirred. The residual quantity of INB was

pressure for later use.

1365 b: the above product dissolved in 50 mL absolute ethanol in a 250 mL

round-bottom reaction flask, and 5.0 mL concentrated HCl was slowly added dropwise with stirring at room temperature. After the addition was completed, the reaction was stirred at 80 °C for 1.0 h, the heating was turned off and the temperature was naturally cooled to 25 °C, and then 5.0 mL ammonia water was slowly added dropwise. 80 mL of

1370 ethyl acetate and 80 mL of purified water were added to the reaction system

washed with saturated sodium bicarbonate solution and saturated sodium chloride

by column chromatography to obtain white Solid S36. 'H NMR (400 MHz, CDCl 3 ) 6

1375 7.42 (s, 1H), 7.33 (d, J= 15.7 Hz, 1H), 6.72 (s, 1H), 6.64 - 6.50 (m, 2H), 6.43 (dd, J=

3.3, 1.8 Hz, 1H), 6.17 (d, J= 15.7 Hz, 1H), 5.92 - 5.80 (m, 2H), 5.74 (s, 1H), 5.58 (s,

1H), 4.27 (s, 1H), 4.16 (d, J= 8.5 Hz, 1H), 3.58 (d, J= 11.8 Hz, 1H), 3.42 - 3.30 (m,

IH), 2.92 (t, J= 14.8 Hz, 2H), 2.66 (s, 2H), 2.47 (s, 2H); C NMR (101 MHz, CDC 3) 6

166.60, 150.83, 146.30, 144.79, 131.62, 127.18, 115.36, 115.01, 112.31, 107.31, 105.01,

1380 100.93, 72.61, 69.72, 61.54, 53.74, 39.45, 28.73.

Example 38: 1- [3- (2-thiophene) acryloyl) ] -lycorine (S37)

0 o,, H

The structure of S37: 0 / N

a: 2-tert-butyldimethylsilyl-lycorine, i.e., INB (10.0 mmol) and 3-(2-thiophene)

acrylic acid (12.0 mmol) were dissolved in 50 mL of dichloromethane in a 250 mL

1385 round-bottom reaction flask and EDCI.HCl (18.0 mmol), DMAP (1.0 mmol) were

1390 100 mL of 10% sodium chloride solution in turn, and then concentrated under reduced

pressure for later use.

b: the above product dissolved in 50 mL absolute ethanol in a 250 mL

1395 stirred at 80 °C for 1.0 h, the heating was turned off and the temperature was naturally

ethyl acetate and 80 mL of purified water were added to the reaction system

washed with saturated sodium bicarbonate solution and saturated sodium chloride

1400 solution respectively, dried over anhydrous sodium sulfate, concentrated, and separated

by column chromatography to obtain white Solid S37. 1 H NMR (400 MHz, CDCl 3) 6

7.69 (d, J= 15.7 Hz, 1H), 7.34 (d, J= 5.0 Hz, 1H), 7.21 (d, J= 3.3 Hz, 1H), 7.05 - 6.90

(m, 1H), 6.71 (s, 1H), 6.58 (s, 1H), 6.08 (d, J= 15.7 Hz, 1H), 5.90 (s, 1H), 5.88 (d, J=

1.0 Hz, 1H), 5.75 (s, 1H), 5.58 (s, 1H), 4.27 (s, 1H), 4.16 (d, J= 13.7 Hz, 1H), 3.58 (d, J

1405 = 12.7 Hz, 1H), 3.43 - 3.27 (m, IH), 2.95 (d, J= 9.9 Hz, 1H), 2.89 (s,1H), 2.66 (s, 2H),

2.46 (s, 1H); 1 3 C NMR (101 MHz, CDC 3) 6 166.47, 146.30, 139.38, 137.84, 131.23,

128.67, 128.06, 127.14, 117.47), 116.37, 107.33, 105.01, 100.95, 72.66, 69.69, 61.58,

56.77, 53.74, 39.44, 28.72.

Example 39: 1-[3-(3-pyridine) acryloyl)]-lycorine (S38)

0 o,,OH

N 0

1410 The structure of S38: . N

a: 2-tert-butyldimethylsilyl-lycorine INB (10.0 mmol) and 3-(3-pyridine) acrylic

acid (12.0 mmol) were dissolved in 50 mL of dichloromethane in a 250 mL

round-bottom reaction flask and EDCI.HCl (18.0 mmol), DMAP (1.0 mmol) were

1415 was kept at the temperature of 35 °C and stirred. The residual quantity of INB was

pressure for later use.

1420 b: the above product dissolved in 50 mL absolute ethanol in a 250 mL

with stirring at room temperature. After the addition was completed, the reaction was stirred at 80 °C for 1.0 h, the heating was turned off and the temperature was naturally cooled to 25 °C, and then 5.0 mL ammonia water was slowly added dropwise. 80 mL of

1425 ethyl acetate and 80 mL of purified water were added to the reaction system

washed with saturated sodium bicarbonate solution and saturated sodium chloride

by column chromatography to obtain white Solid S38. 'H NMR (400 MHz, CDCl 3) 6

1430 8.69 (d, J= 1.4 Hz, 1H), 8.62 - 8.39 (m, 1H), 7.76 (d, J= 8.0 Hz,1H), 7.58 (d, J= 16.1

Hz, 1H), 7.31 - 7.28 (m, 1H), 6.72 (s, 1H), 6.57 (s, 1H), 6.37 (d, J= 16.1 Hz, 1H), 5.89

(s, iH), 5.88 (s, 1H), 5.78 (s, iH), 5.59 (s, 1H), 4.28 (s, iH), 4.17 (d, J= 14.1 Hz, 1H),

3.55 (d, J= 14.1 Hz, 1H), 3.38 (dt, J= 9.1, 4.7 Hz, 1H), 2.97 (d, J= 10.5 Hz, 1H), 2.86

(d, J= 10.2 Hz, 1H), 2.66 (s, 2H), 2.43 (q, J= 8.7 Hz, H); 13 CNMR (101 MHz, CDC 3

) 1435 6 165.91, 150.99, 149.65, 146.53, 146.30, 143.97, 141.63, 134.38, 130.04, 129.35,

127.02, 123.67, 119.97, 117.44, 107.33, 104.97, 100.94, 73.07, 69.58, 61.67, 56.87,

53.74, 39.49, 28.66.

Example 40: 1- [3- (2-pyridine) acryloyl) ] -lycorine (S39)

0 ~ OH

KN N The structure of S39: 0 N

1440 a: 2-tert-butyldimethylsilyl-lycorine, i.e., INB (10.0 mmol) and 3-(2-pyridine) acrylic acid (12.0 mmol) were dissolved in 50 mL of dichloromethane in a 250 mL round-bottom reaction flask and EDCI.HCl (18.0 mmol), DMAP (1.0 mmol) were added successively at room temperature under nitrogen. After the addition, the reaction was kept at the temperature of 35 °C and stirred. The residual quantity of INB was

1445 traced and detected by HPLC, when it was less than 8 percent, post-treatment was

pressure for later use.

b: the above product dissolved in 50 mL absolute ethanol in a 250 mL

1450 round-bottom reaction flask, and 5.0 mL concentrated HCl was slowly added dropwise

ethyl acetate and 80 mL of purified water were added to the reaction system

1455 successively, and the liquids were extracted and separated. The organic phase was

washed with saturated sodium bicarbonate solution and saturated sodium chloride

by column chromatography to obtain white Solid S39. 1 H NMR (400 MHz, CDCl 3) 6

8.58 (d, J= 4.0 Hz, 1H), 7.68 (td, J= 7.7, 1.7 Hz, 1H), 7.58 (d, J= 15.7 Hz, 1H), 7.38

1460 (d, J= 7.8 Hz, 1H), 7.24 (dd, J= 6.8, 4.9 Hz, 1H), 6.77 (d, J= 15.7 Hz, 1H), 6.68 (s,

IH), 6.56 (s, 1H), 5.89 (d, J= 1.3 Hz, 1H), 5.86 (d, J= 1.3 Hz,1H), 5.74 (s, 1H), 5.57

(s, 1H), 4.26 (s, 1H), 4.18 (d, J= 14.1 Hz, 1H), 3.55 (d, J= 13.9 Hz, 1H), 3.37 (dd, J=

9.0, 4.6 Hz, 1H), 2.96 (d, J= 10.6 Hz, 1H), 2.89 (d, J= 10.3 Hz, 1H), 2.65 (s, 2H), 2.43

13 (d, J= 8.3 Hz, 1H); C NMR (101 MHz, CDC 3 ) 6 166.23, 152.71, 150.05, 146.52,

1465 146.27, 143.78, 136.82, 129.15, 127.00, 124.34, 122.05, 117.44, 107.32, 104.93, 100.91,

72.89, 69.45, 61.67, 56.79, 53.73, 39.31, 28.59.

Example 41: 1-[3-(1-naphthyl) acryloyl)]-lycorine (S40)

0 OH

The structure of S40: 0 / N

a: 2-tert-butyldimethylsilyl-lycorine, i.e., INB (10.0 mmol) and 3-(1-naphthyl)

1470 acrylic acid (12.0 mmol) were dissolved in 50 mL of dichloromethane in a 250 mL

round-bottom reaction flask and EDCI.HCl (18.0 mmol), DMAP (1.0 mmol) were

1475 performed. The reaction solution was washed once with 100 mL of purified water and

pressure for later use.

b: the above product dissolved in 50 mL absolute ethanol in a 250 mL

1480 with stirring at room temperature. After the addition was completed, the reaction was

ethyl acetate and 80 mL of purified water were added to the reaction system

1485 washed with saturated sodium bicarbonate solution and saturated sodium chloride

by column chromatography to obtain white Solid S40. 1 H NMR (400 MHz, CDCl 3) 6

8.42 (d, J= 15.7 Hz, 1H), 8.05 (d, J= 8.2 Hz, 1H), 7.84 (dd, J= 7.4, 4.2 Hz, 2H), 7.67

(d, J= 7.2 Hz, 1H), 7.59 - 7.47 (m, 2H), 7.41 (t, J= 7.7 Hz, 1H), 6.77 (s, 1H), 6.59 (s,

1490 1H), 6.37 (d, J= 15.7 Hz, 1H), 5.88 (s, 1H), 5.86 (s, 1H), 5.79 (s, 1H), 5.60 (s, 1H),

4.35 (s, 1H), 4.18 (d, J= 14.1 Hz, 1H), 3.56 (d, J= 13.9 Hz, 1H), 3.44 - 3.31 (m, 1H),

2.99 (d, J= 10.4 Hz, 1H), 2.90 (d, J= 10.2 Hz, 1H), 2.67 (s, 2H), 2.51 - 2.36 (m, 1H);

13 C NMR (101 MHz, CDCl 3) 6 166.58, 146.57, 146.31, 144.07, 142.44, 133.64, 131.47,

131.36, 130.66, 129.38, 128.71, 127.20, 126.89, 126.22, 125.33, 125.05, 123.27, 120.16,

1495 117.45, 107.30, 105.09, 100.94, 73.12, 69.75, 61.78, 56.93, 53.79, 39.61, 28.70.

Experimental example: anti-tumor activity test of the compounds

Test cells: 5 different types of human tumor cells were used in the experiment, including lung cancer cell A549, hepatocellular carcinoma cell HepG2, glioma Hs683, gastric cancer cell HGC27 and colon cancer cell HCT 116.

1500 The test method comprises the following steps:

1. Primary screening: tumor cells were treated with compounds at a concentration

of 10 pM for 48 h, and compounds with stronger anti-tumor activity were screened by

the survival rate of the tumor cells for ICo detection.

2. ICso detection

1505 1) Reagent preparation: the compound to be tested was dissolved to the

concentration of 10 mM with DMSO, and then was diluted in 10-fold gradient to 1 mM,

100 p M, 10 p M, 1Ip M, 0.1 p M. The concentration of stock solutions and working

solutions were shown in the following table:

The concentration of stock The concentration of

solution working solution

10 mM 100 PM

1 mM 10 PM

100 PM 1 PM

10 PM 100 nM

1 PM 10 nM

0.1 PM 1 nM

2) Cell culture and plating: five kinds of tumor cells were cultured in DMEM

1510 medium containing 10% FBS. When the fusion degree reached 75-85%, the cells were

digested and counted and evenly spread into 96-well plates. The initial cell number is

shown in the following table:

Number of cells Cells per well A549 2000

Hs683 3000 HepG2 2000

HCT116 4000

HGC27 2000

3) Adding reagent: cells were plated for 24 h and dosed, DMSO solvent control

wells were set for each plate.

1515 4) MTT detection: after 48 h of dosing, MTT was added and after incubated for 4 h,

the supernatant was discarded, 100 p I1DMSO was added and shaked for 10 min for

detecting OD 5 7 0 and OD 72 0 values, wherein the cell viability is calculated as the

following formula:

Cell viability = (dosing groupOD57 0dosing group OD 720)/(DMSO group

1520 OD570-DMSOOD 72 0)

IC 50 of each compound was calculated by Graphpad software.

3. Test results:

(1) Preliminary screening results: cell viability at 10 pM (unit, %) is shown in the

following table.

Cell viability of tumor cells treated with lycorine and the derivatives thereof (10 M) for 48 h (0%)

Compound HCT116 HGC27 A549 HS683 HEPG2

Lycorine 17.6±1.7 14.8±1.3 18.8±3.7 67.0±11.2 66.3±6.1

Sl 74.1±6.7 54.6±0.9 45.8±27.9 105.7±9.4 83.4±5.3

S2 51.6±4.4 23.1±2.5 30.4±15.4 91.7±16.9 94.4±13.6 S3 65.9±6.8 40.6±2.9 74.9±8.8 105.4±18.6 103.7±13.8 S4 54.5±7.3 41.0±19.3 73.5±21.1 92.2±16.7 107.7±16.8

S5 43.9±5.9 22.3±3.5 38.6±4.4 73.8±12.0 93.0±7.0 S6 78.3±5.8 38.7±5.2 63.8±5.9 82.0±7.6 110.7±14.5 S7 54.4±8.3 19.2±2.8 52.5±5.3 82.4±11.9 93.8±18.2 S8 21.2±3.6 8.6±4.1 20.8±2.8 53.2±9.5 85.8±7.5 S9 50.9±6.1 3.7±0.6 21.9±2.5 74.0±4.5 74.8±14.6

S10 38.7±5.2 6.8±2.4 25.5±4.5 68.0±7.4 80.9±14.5 Sll 101.0±5.5 96.0±11.1 58.0±14.8 96.0±11.1 116.0±25.1 S12 95.0±6.5 63.0±11.2 35.2±6.8 63.2±11.5 95.0±13.8 S13 65.9±9.0 22.5±2.8 42.9±6.7 77.8±10.8 75.1±20.9

S14 60.6±8.7 21.2±3.3 33.1±5.1 96.7±17.9 86.0±14.6 S15 54.3±5.2 28.4±6.0 45.1±6.7 79.7±7.5 115.6±7.5 S16 92.2±10.5 49.2±10.5 43.2±8.8 49.3±10.5 85.2±5.3

S17 101.3±7.5 81.5±18.5 51.3±6.9 81.1±18.5 134.2±22.9 S18 90.0±8.5 72.2±22.6 43.3±9.8 72.5±22.6 109.3±6.7 S19 57.0±9.8 4.5±2.0 35.7±6.2 87.5±11.5 93.9±14.8

S20 95.1±11.5 66.5±17.3 42.4±8.3 66.5±17.3 149.6±20.7 S21 24.6±2.8 19.1±1.6 26.7±5.0 68.5±5.9 102.8±5.0 S22 24.6±3.4 11.9±1.7 27.1±5.7 71.5±6.1 96.3±5.4

S23 43.9±4.1 13.4±0.7 30.8±2.2 67.9±1.4 108.2±13.7 S24 27.3±9.5 8.0±0.4 26.3±6.2 8.6±0.4 32.6±4.3 S25 112.2±12.5 73.6±21.3 51.0±2.6 73.3±21.3 136.1±11.8

S26 107.1±12.8 104.9±6.9 108.0±2.2 111.1±11.5 101.3±28.1 S27 72.1±14.4 10.4±5.7 56.8±3.8 61.9±7.0 92.4±9.5 S28 85.6±8.1 59.6±9.1 103.2±14.4 92.3±10.5 118.3±22.9 S29 89.0±10.3 26.8±3.9 66.8±15.6 69.5±4.3 93.6±16.9 S30 94.3±13.6 32.7±3.4 62.8±7.3 67.8±5.1 100.1±21.2 S31 99.4±5.3 80.5±4.9 72.3±19.0 115.7±3.3 80.8±8.5

S32 100.3±7.4 63.4±10.2 94.0±4.4 100.3±9.4 102.3±11.7 S33 90.3±4.8 58.8±10.3 86.7±3.8 101.2±12.4 101.5±13.5 S34 61.5±5.8 46.4±5.2 38.8±9.5 89.6±4.0 72.6±4.7 S35 41.2±15.5 41.3±2.7 49.0±9.6 41.2±2.7 43.0±23.3 S36 117.0±13.5 71.0±22.9 73.1±8.3 71.6±22.9 128.2±18.1

S37 99.3±14.5 113.5±4.8 110.3±17.8 113.3±4.8 107.0±10.3

S38 47.0±16.5 50.1±1.5 45.6±4.2 50.3±1.5 60.0±6.7 S39 63.2±17.5 60.3±5.1 51.5±4.5 60.6±5.1 84.3±11.4

S40 108.1±18.5 96.3±14.4 70.6±6.3 96.4±14.4 99.3±12.1

1525 The results showed that most of the compounds of the present application showed

inhibitory activity to a different extent against tumor cells.

(2) IC 5o detection was carried out for the above compounds after preliminary

screening. For the tested five cell linesHs683, A549, HGC27, HCT116 and HepG2, the

IC 5 0of compounds S1-S40 were mainly concentrated in the range of 0.3-100 PM, which

1530 were generally superior to that of 5-FU.Among them, the compounds of this application

have generally better inhibitory activity against Hs683 than lycorine, and for other cell

lines, some of the compounds have the similar inhibitory activity as lycorine, and some

of the compounds have significantly better inhibitory activity than lycorine. As an

illustration, the IC 5o results for compounds having superior efficacy against all five cell

1535 lines are listed in the following table list.

IC 5 0test results (Unit, pM)

IC 50 ( mol/L) Compound Hs683 A549 HGC27 HCT116 HepG2

S8 5.03 2.21 1.63 0.99 7.49

S9 13.81 6.03 6.67 7.51 5.73 S1O 13.67 5.09 2.86 7.72 29.51 S21 11.65 2.50 1.33 1.64 30.83

S22 11.36 3.81 1.54 2.23 18.15 S23 10.72 4.75 1.62 6.99 23.27 S24 0.31 5.97 0.54 0.86 4.39 S35 6.44 5.55 8.12 1.80 27.66 S38 8.20 4.40 1.15 1.43 32.14

Lycorine 16.19 3.32 1.12 1.20 23.95

5-FU >100 40.07 36.28 16.81 68.71

From the data analysis in the above table, it can be seen that most of the

compounds showed good inhibitory activity against lung cancer cell A549,

hepatocellular carcinoma cell HepG2, glioma Hs683, gastric cancer cell HGC27 and

1540 colon cancer cell HCT116, and their tumor inhibitory activity were significantly better

than the positive control 5-fluorouracil. The inhibitory activity of some compounds on

tumor cells was equivalent to that of lycorine, and some were even better than that of

lycorine. The compound with the optimal activity is S24, which has more than 5 times

higher inhibitory activity on hepatocellular carcinoma cells HepG2 and 50 times higher

1545 inhibitory activity on glioma cells Hs683 than that of lycorine, which indicates that this

new structure of lycorine P-arylacrylate derivatives has a good prospect of anti-tumor

application.

The foregoing descriptions are only preferred embodiments of the application and

are not intended to limit the application. Although the application has been described in

1550 detail with reference to the foregoing embodiments, for those skilled in the art,

modifications to technical solutions recorded in the foregoing embodiments or

equivalent replacement of some of the technical features may still be made. Any

modification, equivalent replacement, or improvement made within the spirit and

principle of the present application shall fall within the protection scope of the present

1555 application.

Claims

CLAIMS What is claimed is:

1. A lycorine p-aryl acrylate derivative or a pharmaceutically acceptable salt or

solvate thereof, which has the structure shown in formula I:

0 OHH

0 N 0N

wherein, Ar is C6- 1 2 aromatic or C 3 -10 aromatic heterocycle, and the heteroatom in

the aromatic heterocycle is selected from N, 0 and S;

R is a substituent on Ar, which is monosubstituted or polysubstituted,R is

independently selected from hydrogen, halogen, halogenated C1.6 alkyl, halogenated

C 1 .6 alkoxy, nitro, hydroxyl, C 1 .6 alkyl, C1.6 alkoxy, C 2 .6 alkenyloxy, C2 -6 alkenyl, C 3-6

cycloalkyl and phenyl.

2. The lycorinefp-aryl acrylate derivative or the pharmaceutically acceptable salt or

solvate thereof according to claim 1, wherein Ar is selected from phenyl, naphthyl,

biphenyl, pyridyl, furanyl, thienyl, pyrrolyl, imidazolyl, benzofuranyl, benzothienyl,

benzodioxol;

preferably, R is monosubstituted or polysubstituted, R is independently selected

from hydrogen, halogen, halogenated C1-3 alkyl, halogenated C1-3 alkoxy, nitro,

hydroxyl, C 1 .4 alkyl, C 1.4 alkoxy, C 2 .6 alkenyloxy, C 2 .4 alkenyl and phenyl; preferably, R is monosubstituted or polysubstituted, the poly-substitution is disubstituted or trisubstituted; preferably, when R is monosubstituted, the substitution position is C-4 or C-3; when R is disubstituted, the substitution position is C-2 and C-4, C-3 and C-4, C-2 and

C-5, or C-2 and C-6 position; when R is trisubstituted, the substitution position is C-2,

C-4 and C-5, or C-3, C-4 and C-5.

3. The lycorinefp-aryl acrylate derivative or the pharmaceutically acceptable salt or

solvate thereof according to claim 1 or 2, wherein the compound has the structure

shown in formula II:

0 O OH R

O / N II

wherein X is C or N; R is as defined in claim 1 or 2;

preferably, R is monosubstituted or disubstituted, R is independently selected from

hydrogen, halogen, halogenated C1.6alkyl, halogenated C1.6alkoxy, nitro, hydroxyl,

C1-6alkyl, C1.6alkoxy, C2-6alkenyloxy, C2-6alkenyl, C3-6cycloalkyl and phenyl;

preferably, R is monosubstituted or disubstituted, wherein when R is

monosubstituted, R is selected from hydrogen, halogenated C16alkyl, halogenated

C1.6alkoxy, nitro, C1.6alkyl, C1.6alkoxy, C2.6alkenyloxy, phenyl; and when R is

disubstituted, R is independently selected from halogen and nitro; preferably, the compound has the structure of formula II':

0

R-- ~ ''s OH

o s O N II'.

R is as defined in claim 1 or 2;

halogen, halogenated C1.6 alkyl, halogenated C1.6 alkoxy, nitro, hydroxyl, C 1 .6 alkyl, C1 - 6

alkoxy, C2 -6 alkenyloxy and phenyl;

preferably, when R is monosubstituted, R is selected from halogenated C1.6 alkyl,

halogenated C1.6 alkoxy, nitro, C1.6 alkyl, C1.6 alkoxy, C 2 -6 alkenyloxy and phenyl; and

when R is disubstituted, R is independently selected from halogen and nitro;

preferably, when R is monosubstituted, the substitution position is C-4 or C-3;

when R is disubstituted, the substitution position is C-2 and C-5, or C-3 and C-4;

4. The lycorinefp-aryl acrylate derivative or the pharmaceutically acceptable salt or

solvate thereof according to claim 1 or 2, wherein the compound is selected from the

following structures:

compoundS1: 1-(2-fluorocinnamoyl)-lycorine;

compoundS2: 1-(3-fluorocinnamoyl)-lycorine;

compoundS3: 1-(4-fluorocinnamoyl)-lycorine;

compoundS4: 1-(2,4-difluorocinnamoyl)-lycorine; compoundS5: 1-(3,4-difluorocinnamoyl)-lycorine; compoundS6: 1-(2-trifluoromethylcinnamoyl)-lycorine; compoundS7: 1-(3-trifluoromethylcinnamoyl)-lycorine; compoundS8: 1-(4-trifluoromethylcinnamoyl)-lycorine; compoundS9: 1-(3-trifluoromethoxycinnamoyl)-lycorine; compoundS10: 1-(4-trifluoromethoxycinnamoyl)-lycorine; compoundS11: 1-(2-chlorocinnamyl)-lycorine; compoundS12: 1-(3-chlorocinnamyl)-lycorine; compoundS13: 1-(4-chlorocinnamyl)-lycorine; compoundS14: 1-(2,5-dichlorocinnamoyl)-lycorine; compoundS15: 1-(2,6-dichlorocinnamoyl)-lycorine; compoundS16: 1-(3,4-dichlorocinnamoyl)-lycorine; compoundS17: 1-4-fluoro-2-chlorocinnamyl)-lycorine; compoundS18: 1-(2-fluoro-4-chlorocinnamyl)-lycorine; compoundS19: 1-(4-bromocinnamoyl)-lycorine; compoundS20: 1-(2-nitrocinnamoyl)-lycorine; compoundS21: 1-(3-nitrocinnamoyl)-lycorine; compoundS22: 1-(4-nitrocinnamoyl)-lycorine; compoundS23: 1-(2-chloro-5-nitrocinnamoyl)-lycorine; compoundS24: 1-(4-chloro-3-nitrocinnamoyl)-lycorine; compoundS25: 1-(4,5-dimethoxy-2-nitrocinnamoyl)-lycorine; compoundS26: 1-cinnamoyl-lycorine; compoundS27: 1-(4-methylcinnamoyl)-lycorine; compoundS28: 1-(4-methoxycinnamoyl)-lycorine; compoundS29: 1-(4-propoxycainnamoyl)-lycorine; compoundS30: 1-(4-allyloxycinnamoyl)-lycorine; compoundS31: 1-(4-hydroxycinnamoyl)-lycorine; compoundS32: 1-(3-methoxy-4-hydroxycinnamoyl)-lycorine; compoundS33: 1-(3,4-methylenedioxycinnamoyl)-lycorine; compoundS34: 1-(3,4,5-trimethoxycinnamoyl)-lycorine; compoundS35: 1-[3-(1-biphenyl) acryloyl)]-lycorine; compoundS36: 1-[3-(2-furan) acryloyl)]-lycorine; compoundS37: 1-[3-(2-thiophene) acryloyl)]-lycorine; compoundS38: 1-[3-(3-pyridine) acryloyl)]-lycorine; compoundS39: 1-[3-(2-pyridine) acryloyl)]-lycorine; compoundS40: 1-[3-(1-naphthyl) acryloyl)]-lycorine.

5. The lycorinef-aryl acrylate derivative or the pharmaceutically acceptable salt or

solvate thereof according to any one of the claims 1 to 4, wherein the pharmaceutically

acceptable salt selected from the following: hydrochloride, hydrobromide, sulfate,

bisulfate, nitrate, phosphate, biphosphate, formate, acetate, propionate, benzoate, succinate, fumarate, maleate, lactate, citrate, tartrate, succinate, gluconate, methanesulfonate, ethanesulfonate,benzenesulfonate,p-toluenesulfonate.

6. The lycorinefp-aryl acrylate derivative or the pharmaceutically acceptable salt or

solvate thereof according to any one of the claims 1 to 4, wherein the solvate includes a

solvate formed by the compound of formula I with any one of water, ethanol,

100 isopropanol, acetone.

7. A processfor preparing the lycorine p-aryl acrylate derivative or the

pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 6,

wherein includes:

lycorine was taken as an initial compound, hydroxy at position 2 of lycorine was

105 selectively protected by adopting tert-butyldimethylchlorosilane to obtain an

intermediate INB; intermediate INB and p-aryl acrylic acid, i.e. R COOH

subjected to esterification reactionto obtain intermediate INC; the silane protecting

group at the position 2 of the intermediate INC is removed to obtain the lycorine8-aryl

acrylate derivative shown in the formula I;

110 wherein INB and INC have the following structures:

OTBS HO,, R OTBS

o0s

O - N <0 N

INB INC

Ar or R is as defined in any one of claims 1 to 6.

8. A pharmaceutical composition, wherein comprising the lycorine -aryl acrylate

derivative or the pharmaceutically acceptable salt or solvate thereof as claimed in any

115 one of the claims I to 6.

9. A pharmaceutical preparations, wherein comprising the lycorine -aryl acrylate

one of the claims 1 to 6, and at least one pharmaceutically acceptable adjuvant or

pharmaceutical carrier.

120 preferably, the pharmaceutical preparations selected from tablets, capsules, pills

and injections.

10. Application of the lycorinef-aryl acrylate derivative or the pharmaceutically

acceptable salt or solvate thereof as claimed in any one of the claims 1 to 6, or the

pharmaceutical composition as claimed in claim 8, or the pharmaceutical preparations

125 as claimed in claim 9 in the preparation of an anti-tumor medicine,

preferably, the tumor is selected from lung cancer, hepatic cancer, glioma, gastric

cancer, and colon cancer.