CN107235991A - Indolone spiral shell tetrahydrochysene thio-pyrylium class compound and its salt, preparation method and application - Google Patents
Indolone spiral shell tetrahydrochysene thio-pyrylium class compound and its salt, preparation method and application Download PDFInfo
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Abstract
The present invention provides a kind of indolone spiral shell tetrahydrochysene thio-pyrylium class compound and its salt, preparation method and application, belongs to pharmaceutical technology field.The indolone spiral shell tetrahydrochysene thio-pyrylium class compound that the present invention is provided has brand-new skeleton structure and stronger antitumor activity, more obvious inhibited proliferation is generated to lung carcinoma cell, human breast cancer cell and intestinal cancer HCT116, the antitumor activity of part of compounds is better than positive control drug Nutlin 3, can be applied in antineoplastic is prepared.
Description
Technical field
The invention belongs to pharmaceutical technology field, and in particular to indolone spiral shell tetrahydrochysene thio-pyrylium class compound and its salt, system
Preparation Method and application.
Background technology
Spiral shell indolone skeleton receives organic synthesis and pharmaceutical chemistry as natural products and the advantage skeleton of bioactive molecule
The extensive concern of researcher.At present, it has been reported that multifarious spiral shell indole ketone compound, and find have extensive medicine
Reason activity, such as progestogen receptor regulator (Jay E.Wrobel et al, Design, Synthesis, and SAR of New
Pyrrole-Oxindole Progesterone Receptor Modulators Leading to 5-(7-Fluoro-3,3-
dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile
(WAY-255348),J.Med.Chem.2008,51:1861-1873), anti-AIDS (Singh RK.et al, Rhodium
(II)acetate-catalyzed stereoselective synthesis,SAR and anti-HIV activity of
novel oxindoles bearing cyclopropane ring,Eur.J.Med.Chem.2011,46:1181-1188)、
Antitumor (WO2008055812A1), antituberculosis (Waldmann, H.et al, Identification of
thiazolidinones spiro-fused to indolin-2-ones as potent and selective
inhibitors of the Mycobacterium tuberculosis protein tyrosine phosphatase B,
Angew.Chem.Int.Ed.Engl.2010,49:5902-5905), anti-malarial (Diagana, T.T.et al,
Spiroindolones,a potent compound class for the treatment of malaria,Science
2010,329:1175-1180) with MDM2 inhibitor (Wang, S.et al, Structure-based design of potent
non-peptide MDM2inhibitors,J.Am.Chem.Soc.2005,127:10130-10131) etc..
Inventor constructs two class new indole ketone spiral shell tetrahydrochysene thio-pyrylium analog derivatives, and find in previous work
It has good anti tumor activity in vitro (publication No.：CN103992334A、CN106565742A).On this Research foundation,
In order to further do the research deeper entered to indolone spiral shell tetrahydrochysene thio-pyrylium analog derivative and find preferably antitumorization
Compound, inventor further constructs a class new indole ketone spiral shell tetrahydrochysene thio-pyrylium class compound.
The content of the invention
It is an object of the invention to provide a kind of indolone spiral shell tetrahydrochysene thio-pyrylium class compound and its salt, preparation method and
Using.Such compound has brand-new skeleton structure and stronger antitumor activity, can be answered in antineoplastic is prepared
With.
The present invention is to be achieved through the following technical solutions：
A kind of indolone spiral shell tetrahydrochysene thio-pyrylium class compound, including its raceme, d- types or l- type isomers, the chemical combination
The structure of thing is as shown in formula I：
Wherein R1The substituent on phenyl ring is represented, the wherein substituent on phenyl ring is monosubstituted or polysubstituted, replaces base table
Show hydrogen, halogen, low-grade halogenated alkyl, low alkyl group, hydroxyl, Lower hydroxy alkyl, lower alkoxy, amino, lower alkyl-ammonium
It is base, low-grade halogenated alkyl amino, low-grade cycloalkyl amino, alkynyl of low-grade chain amino, nitro, rudimentary 4-nitro alkyl, cyano group, rudimentary
Cyanoalkyl, amide groups, low-grade cycloalkyl amide groups, rudimentary amido alkyl；
R2Aromatic ring substituents group is represented, aromatic ring is phenyl ring, substituted benzene ring or hetero-aromatic ring；Substituent on substituted benzene ring is halogen
Element, low alkyl group, hydroxyl, lower alkoxy, amino, low-grade alkyl amino, low-grade cycloalkyl amino, nitro, amide groups or low
Grade naphthenic base amide groups；Hetero-aromatic ring is pyrroles, furans, thiophene or pyridine；
R3Aromatic ring substituents group or low alkyl group side chain are represented, aromatic ring is phenyl ring, substituted benzene ring or hetero-aromatic ring；Substituted benzene
Substituent on ring is halogen, low alkyl group, hydroxyl, lower alkoxy, amino, low-grade alkyl amino, low-grade cycloalkyl amino,
Nitro, amide groups or low-grade cycloalkyl amide groups；Hetero-aromatic ring is furans, thiophene, pyrroles or pyridine；
R4Represent hydrogen, low alkyl group or lower Oxo side chain；
X is represented：Sulphur atom, sulfoxide radicals or sulfone group；
Described " low-grade cycloalkyl " refers to the ring containing 3 to 7 carbon, and described " alkynyl of low-grade chain amino " refers to accordingly
The amount of carbon atom of alkynes chain is 3 to 6, and other described " rudimentary " substituents refer to that corresponding aliphatic group is straight or branched
, saturation and containing 1 to 6 carbon atom.
Preferably, in R1In the substituent of expression, the halogen is fluorine, chlorine or bromine, and the low alkyl group is methyl.
Preferably, in R2In the aromatic ring substituents group of expression, substituted benzene ring substituted radical is 4- bromophenyls, 4- methoxybenzenes
Base, 3,4- dichlorophenyls；Heteroaromatic substituted radical is the base of furans -2.
Preferably, in R3Substituted benzene ring substituted radical is in the aromatic ring substituents group of expression：4- chlorphenyls, 4- fluorophenyls,
4- bromophenyls, 4- nitrobenzophenones, 4- methoxyphenyls or 2- methoxyphenyls；R3The low alkyl group side chain of expression is n-propyl.
Preferably, the compound is any one in compound 1~21 as shown in table 1 below, and its structure such as formula I (is compiled
Numbers 1 to 21), wherein R1、R2、R3、R4, X combination it is as follows：
Table 1：R in preferred compound1、R2、R3、R4, X combination
A kind of preparation method of indolone spiral shell tetrahydrochysene thio-pyrylium class compound, it is characterised in that reaction process is as follows：
Concretely comprise the following steps：
A, target compound VIII preparation:
A) preparation of (E) -1- bromo- 2- (2- nitroethenyl groups) benzene of substitution：By nitromethane, substitution benzaldehyde I and
Ammonium acetate is added in acetic acid, and is reacted at 90~110 DEG C, after reaction completely, solvent evaporated, the purifying of residue column chromatography,
(E) -1- bromo- 2- (2- nitroethenyl groups) benzene replaced；Preferably, according to molar amount, nitromethane：Substituted benzene first
Aldehyde=1：(1.5~1.8)；
B) preparation of intermediate III：In dichloromethane, (E) -1- bromo- 2- (2- nitroethenyl groups) benzene of addition substitution,
Chloroacetic chloride and anhydrous ferric trichloride, are reacted at 20~30 DEG C, after reaction completely, solvent evaporated, and the purifying of residue column chromatography is obtained
Intermediate III；Preferably, according to molar amount, substituted (E) -1- bromo- 2- (2- nitroethenyl groups) benzene：Chloroacetic chloride：Anhydrous three
Iron chloride=1：(2~2.2)：(1.8~2.1)；
C) intermediate V preparation：Under nitrogen protection, intermediate III, intermediate compound IV, triethylamine are added to dichloromethane
In alkane, and 20~30 DEG C of stirring reactions, after reaction completely, solvent evaporated, column chromatography purifying obtains intermediate V；Preferably, press
According to molar amount, intermediate III：Intermediate compound IV=1：(1.1~1.5)；
D) target compound VIII preparation：In dichloromethane, catalyst VII, intermediate V, intermediate are sequentially added
VI, is stirred at 20~30 DEG C, and after reaction completely, solvent evaporated, residue is purified through column chromatography, obtains target compound VIII；
Described catalyst VII is L-PROLINE, consumption for intermediate V moles 10% preferably, according to molar amount, intermediate
V：Intermediate VI=1：(1.1~1.4)；
B, target compound IX preparation:
In dichloromethane, compound VIII, substitution reagent and 4- dimethylamino pyridines are added, after reaction completely, post layer
Analysis purifying, obtains target product IX；
Wherein, the substitution reagent is acid anhydrides or brominated alkanes；
C, target compound X preparation:
In dichloromethane, compound VIII, metachloroperbenzoic acid are added, after being reacted completely at 20~30 DEG C, post
Chromatographic purifying, obtains the target product X that oxidized sulfur atom is sulfoxide radicals；Wherein, calculated according to mole, compound VIII：
Metachloroperbenzoic acid=1：(1.3~1.8)；
In dichloromethane, compound VIII, metachloroperbenzoic acid are added, after being reacted completely at 20~30 DEG C, post
Chromatographic purifying, obtains the target product X that oxidized sulfur atom is sulfone group；Wherein, calculated according to mole, compound VIII：Between
Chloroperoxybenzoic acid=1：(4~6)；
D, target compound XI preparation:
In dichloromethane, compound IX, metachloroperbenzoic acid are added, after being reacted completely at 20~30 DEG C, post layer
Analysis purifying, obtains the target product X I that oxidized sulfur atom is sulfoxide radicals；Wherein, calculated according to mole, compound IX：M-chloro
Benzoyl hydroperoxide=1：(1.3~1.8)；
In dichloromethane, compound IX, metachloroperbenzoic acid are added, after being reacted completely at 20~30 DEG C, post layer
Analysis purifying, obtains the target product X I that oxidized sulfur atom is sulfone group；Wherein, calculated according to mole, compound IX：M-chloro mistake
Oxybenzoic acid=1：(4~6)；
The officinal salt of described indolone spiral shell tetrahydrochysene thio-pyrylium class compound.
Described indolone spiral shell tetrahydrochysene thio-pyrylium class compound or pharmaceutically acceptable salt thereof answering in antineoplastic is prepared
With.
Preferably, described tumour is lung cancer, intestinal cancer, breast cancer or liver cancer.
Compared with prior art, the present invention, which is provided, has following beneficial effect：
The indolone spiral shell tetrahydrochysene thio-pyrylium class compound that the present invention is provided, to A549 (human lung carcinoma cell), MCF-7 (people
Breast cancer cell) and intestinal cancer HCT116 generate more obvious inhibited proliferation, the antitumor activity of part of compounds
It is better than positive control drug Nutlin-3.Such as the IC of three kinds of cells of compound 13 pair50Respectively 2.3 μM, 11.3 μM and 7.4 μM, change
The IC of three kinds of cells of compound 23 pair50Respectively 1.5 μM, 8.8 μM and 5.9 μM, ICs of the Nutlin-3 to three kinds of cells50Respectively
10.9 μM, 21.9 μM and 17.7 μM.The compound that the present invention is provided has brand-new skeleton structure, contains the bases such as hydroxyl, amino
Group, is conducive to further quick derivatization；Compared compared with previous research, these compounds have brand-new skeleton structure；
And this kind of compound has stronger antitumor activity, can carry out the exploitation of antineoplastic.
The synthetic method that the present invention is provided, synthetic route is simple, and synthesis material is easy to get, synthetic method is easily realized.
The indolone spiral shell tetrahydrochysene thio-pyrylium class compound or pharmaceutically acceptable salt thereof that the present invention is provided is in the cancer therapy drug system of preparation
Application in agent, can provide more selections for clinical treatment.
Brief description of the drawings
Fig. 1：For the X single crystal diffraction data of compound 1.When monocrystalline is parsed, compound 1 is racemate form.
Fig. 2 is that the ee of compound 1 prepared by embodiment 1.2 determines analysis chart, wherein, measurement result is shown, its ee value is
30%.
The ee of compounds 1 of the Fig. 3 to be prepared in embodiment 1.1 using L-PROLINE determines analysis chart, wherein, measurement result
It has been shown that, its ee value is -7%.
Embodiment
In conjunction with embodiment and accompanying drawing, the present invention is described in detail, but the implementation of the present invention is not limited only to this.The present invention
Agents useful for same and raw material are commercially available or can be prepared by literature method.
The experimental method of unreceipted actual conditions in the following example, generally according to normal condition, or according to manufacturer
Proposed condition.
The chemical structural formula of the corresponding formula I of compound involved by following examples,1H-NMR、13C-NMR and HRMS data are referred to
Table 2, wherein the compound 1~21 in the difference corresponding table 1 of numbering 1~21, the compound 1~21 in table 3, embodiment 1~21.
The part preferred compound of the present invention of table 21H-NMR,13C-NMR and HRMS data
Embodiment 1：The synthesis of compound 1
The preparation (intermediate II) of A intermediates (E) -1- bromo- 2- (2- nitroethenyl groups) benzene
Method (the Advanced Synthesis＆Catalysis 2013,355 of reference literature report:829-835).Will
Nitromethane (7.2mL, 0.134mol), 2- bromobenzaldehydes (4.0g, 0.022mol) and ammonium acetate (0.20g, 2.6mmol) are added
10h is reacted into 80mL acetic acid, and at 100 DEG C.After reaction completely, solvent evaporated, residue column chromatography purifying (oil
Ether：Ethyl acetate=100:3) (E) -1- bromo- 2- (2- nitroethenyl groups) benzene, is obtained for yellow solid 4.21g, and yield is
85.4%.
The preparation (intermediate III) of the bromo- 3- chloro-indoles -2- ketone of B intermediates 4-
Method (the Advanced Synthesis＆Catalysis 2013,355 of reference literature report:829-835).
In 50mL dichloromethane, add (E) -1- bromo- 2- (2- nitroethenyl groups) benzene (3.2g, 14.0mmol), chloroacetic chloride (2.1mL,
29.6mmol) with anhydrous ferric trichloride (4.64g, 28.6mmol), 3h is reacted at room temperature.After reaction completely, solvent evaporated, residual
Thing column chromatography purifies (DCM:MeOH=100:1) the bromo- 3- chloro-indoles -2- ketone of 4-, is obtained for white-yellowish solid 2.25g, and yield is
65.6%.
The preparation (intermediate V) of the bromo- 3- of C intermediates 4- ((2- oxo -2- phenethyls) sulphur) indol-2-one
In 20mL dichloromethane, the bromo- 3- chloro-indoles -2- ketone (0.3g, 1.22mmol) of 4-, 2- sulfydryl -1- benzene are added
The triethylamine of ethyl ketone (0.24g, 1.59mmol) and 0.1mL, the lower room temperature reaction of nitrogen protection is stayed overnight.After reaction completely, it is evaporated molten
Agent, residue column chromatography purifying (DCM:MeOH=100:1) intermediate V, is obtained for white-yellowish solid 0.27g, and yield is 62%
。1H NMR(400MHz,CDCl3) δ 4.11 (d, J=15.5Hz, 1H), 4.34 (d, J=15.5Hz, 1H), 4.48 (s, 1H),
6.82 (d, J=7.4Hz, 1H), 7.10-7.17 (m, 2H), 7.46 (t, J=7.7Hz, 2H), 7.59 (t, J=7.4Hz, 1H),
7.93 (d, J=8.0Hz, 2H), 8.37 (s, 1H)13C NMR(100MHz,CDCl3)δ36.13,45.49,108.95,
120.63,124.97,126.57,128.60(2C),128.68(2C),130.84,133.52,135.55,142.76,
175.76,194.37.HRMS(ESI+)m/z calculated for C16H13BrNO2S(M+H):361.9850,found
361.9848.
The preparation of D target compounds 1
In 2mL DCM, catalyst VII (0.01mmol), intermediate V (0.10mmol) and VI are sequentially added
(0.12mmol), at room temperature stirring reaction 3d.After reaction completely, solvent evaporated.Residue purifies (DCM) through column chromatography and led
Product is the white solid of target compound 1 (32mg), and yield is 64%.Used catalyst VII is L-PROLINE.
The compound of the present invention can prepare target compound by using various configuration and different types of catalyst VII
VIII different isomer.The catalyst that can be selected is as follows：
For example：
Embodiment 1.1：Catalyst VII is L-PROLINE, and the ee values of obtained compound 1 are -7% (as shown in Figure 3).
Embodiment 1.2：Catalyst VII isThe ee values of obtained compound 1 are
30% (as shown in Figure 2).
When determining the ee values of compound 1, selected HPLC condition be Chiralpak OZ, 0.46cm I.D. ×
25cm L × 5 μm, 25 DEG C, isopropanol/n-hexane=15:85, flow velocity 0.8mL/min, λ=254nm.
The synthetic method of compound 2-18 synthesis reference compound 1.
Embodiment 2：The synthesis of compound 2
With reference to embodiment 1.The bromo- 3- of intermediate 4- ((2- oxo -2- phenethyls) sulphur) indol-2-ones (0.10mmol) and 4-
Chlorocinnamaldehyde (0.12mmol) reacts, and prepare compound 2 is white solid (31mg), yield 58%.
Embodiment 3：The synthesis of compound 3
With reference to embodiment 1.The bromo- 3- of intermediate 4- ((2- oxo -2- phenethyls) sulphur) indol-2-ones (0.10mmol) and 4-
Bromocinnamaldehyde (0.12mmol) reacts, and prepare compound 3 is white solid (31mg), yield 54%.
Embodiment 4：The synthesis of compound 4
With reference to embodiment 1.The bromo- 3- of intermediate 4- ((2- oxo -2- phenethyls) sulphur) indol-2-ones (0.10mmol) and 4-
Fluorine cinnamic acid (0.12mmol) reacts, and obtains compound 4 for white solid (29mg), yield 56%.
Embodiment 5：The synthesis of compound 5
With reference to embodiment 1.The bromo- 3- of intermediate 4- ((2- oxo -2- phenethyls) sulphur) indol-2-ones (0.10mmol) and 4-
Nitro cinnamaldehyde (0.12mmol) reacts, and obtains compound 5 for yellow solid (36mg), yield 66%.
Embodiment 6：The synthesis of compound 6
With reference to embodiment 1.The bromo- 3- of intermediate 4- ((2- oxo -2- phenethyls) sulphur) indol-2-ones (0.10mmol) and 4-
Methoxycinnamic aldehyde (0.12mmol) reacts, and prepare compound 6 is white solid (30mg), yield 57%.
Embodiment 7：The synthesis of compound 7
With reference to embodiment 1.The bromo- 3- of intermediate 4- ((2- oxo -2- phenethyls) sulphur) indol-2-ones (0.10mmol) and 2-
Methoxycinnamic aldehyde (0.12mmol) reacts, and prepare compound 7 is white solid (28mg), yield 53%.
Embodiment 8：The synthesis of compound 8
With reference to embodiment 1.The bromo- 3- of intermediate 4- ((2- oxo -2- phenethyls) sulphur) indol-2-ones (0.10mmol) and 2-
Furacrolein (0.12mmol) reacts, and prepare compound 8 is white solid (30mg), yield 62%.
Embodiment 9：The synthesis of compound 9
With reference to embodiment 1.The chloro- 3- of intermediate 4- ((2- oxo -2- phenethyls) sulphur) indol-2-ones (0.10mmol) and meat
Cinnamic aldehyde (0.12mmol) reacts, and prepare compound 9 is white solid (30mg), yield 66%.
Embodiment 10：The synthesis of compound 10
With reference to embodiment 1.The fluoro- 3- of intermediate 5- ((2- (4- methoxyphenyls) -2- oxoethyls) sulphur) indol-2-one
(0.10mmol) reacts with cinnamic acid (0.12mmol), and prepare compound 10 is white solid (27mg), yield 62%.
Embodiment 11：The synthesis of compound 11
With reference to embodiment 1.Intermediate 6- methyl -3- ((2- (4- methoxyphenyls) -2- oxoethyls) sulphur) indol-2-one
(0.10mmol) reacts with cinnamic acid (0.12mmol), obtains compound 11 for white solid (26mg), yield 60%.
Embodiment 12：The synthesis of compound 12
With reference to embodiment 1.Intermediate 3- ((2- (4- bromophenyls) -2- oxoethyls) sulphur) indol-2-one (0.10mmol)
Reacted with cinnamic acid (0.12mmol), obtain compound 12 for white solid (27mg), yield 64%.
Embodiment 13：The synthesis of compound 13
With reference to embodiment 1.The bromo- 3- of intermediate 4- ((2- (4- bromophenyls) -2- oxoethyls) sulphur) indol-2-one
(0.10mmol) reacts with cinnamic acid (0.12mmol), and prepare compound 13 is white solid (34mg), yield 59%.
Embodiment 14：The synthesis of compound 14
With reference to embodiment 1.The bromo- 3- of intermediate 4- ((2- (4- bromophenyls) -2- oxoethyls) sulphur) indol-2-one
(0.10mmol) reacts with 4- bromocinnamaldehydes (0.12mmol), obtains compound 14 for white solid (40mg), yield 61%.
Embodiment 15：The synthesis of compound 15
With reference to example 1.The bromo- 3- of intermediate 4- ((2- (4- methoxyphenyls) -2- oxoethyls) sulphur) indol-2-one
(0.10mmol) reacts with cinnamic acid (0.12mmol), obtains compound 15 for white solid (35mg), yield 66%.
Embodiment 16：The synthesis of compound 16
With reference to embodiment 1.The bromo- 3- of intermediate 4- ((2- (3,4- dichlorophenyls) -2- oxoethyls) sulphur) indol-2-one
(0.10mmol) reacts with cinnamic acid (0.12mmol), obtains compound 16 for white solid (34mg), yield 60%.
Embodiment 17：The synthesis of compound 17
With reference to example 1.The bromo- 3- of intermediate 4- ((2- (furans -2- bases) -2- oxoethyls) sulphur) indol-2-one
(0.10mmol) reacts with cinnamic acid (0.12mmol), obtains compound 17 for white solid (30mg), yield 62%.
Embodiment 18：The synthesis of compound 18
With reference to example 1.The bromo- 3- of intermediate 4- ((2- oxo -2- phenethyls) sulphur) indol-2-ones (0.10mmol) with it is anti-
Formula -2- hexenoic aldehydes (0.12mmol) react, and obtain compound 18 for white solid (32mg), yield 70%.
Embodiment 19：The synthesis of compound 19
In 5mL dichloromethane, compound 1 (30mg, 0.061mmol), acetic anhydride (15mg, 0.15mmol) and 4- are added
Dimethylamino pyridine (3mg), after reacting completely at normal temperatures, column chromatography purifying, eluant, eluent is PE:EtOAc=5:1, changed
Compound 19 is white solid (31mg), and yield is 95%.
Embodiment 20：The synthesis of compound 20
In 5mL dichloromethane, add compound 1 (30mg, 0.061mmol), metachloroperbenzoic acid (17mg,
0.10mmol), after reacting completely at normal temperatures, column chromatography purifying, eluant, eluent is dichloromethane:Methanol=100:1, obtain chemical combination
Thing 20 is white solid (28mg), and yield is 90%.
Embodiment 21：The synthesis of compound 21
In 5mL dichloromethane, add compound 1 (30mg, 0.061mmol), metachloroperbenzoic acid (57mg,
0.31mmol), after reacting completely at normal temperatures, column chromatography purifying, eluant, eluent is dichloromethane:Methanol=100:1, obtain chemical combination
Thing 20 is white solid (30mg), and yield is 93%.
Embodiment 22：Synthetic method is inquired into
In order to further inquire into differential responses condition to composite result, such as yield, ee values, the influence of product, inventor
Different catalyst and experiment condition are tested, Experimental results show is in table 3.
Wherein, the reaction used for：
The bromo- 3- of 4- ((2- oxo -2- phenethyls) sulphur) indol-2-one (0.10mmol), Chinese cassia tree in being added to 2.0mL solvents
Aldehyde (0.20mmol), catalyst (20mol%), room temperature reaction.Wherein, in partial reaction, also there is addition in reaction system
Agent.
Testing used catalyst is：
Experiment condition and experimental result are as follows：
Table 3：Experiment condition and result
Wherein, described yield, is the yield of the separation product after pillar layer separation.
Wherein, dr is to pass through1H NMR analyses are determined.
Wherein, ee is determined by chiral HPLC.
Wherein, N.R. represents not react.
Wherein, N.D. represents unmeasured.
Embodiment 23：The anti-tumor activity test of the compounds of this invention
Compound to the present invention has carried out Cytostatic to tumor cell experiment, and test method uses conventional mtt assay (such as
Lv Qiujun is edited《Developmental pharmacology research method》, 2007：242-243).
Cell line selects lung cancer A549, breast cancer MCF-7, and intestinal cancer HCT116 is purchased from Shanghai City medical industry research institute.
We test compound under the conditions of single 10 μM of concentration first, to the inhibiting rate of tumour cell, if inhibiting rate is more than 50%,
Carry out concentration gradient experiment, calculation of half inhibitory concentration IC50。
Nutrient solution is that DMEM+15%NBS+ is dual anti-.
Sample liquid is prepared：After being dissolved with DMSO (Merck), the solution or uniform mixed that PBS (-) is made into 100 μ g/mL is added
Suspension, then with DMSO PBS (-) dilution, ultimate density be respectively 10 μ g/mL, 1 μ g/mL, 0.1 μ g/mL, 0.01 μ g/mL,
0.001μg/mL、0.0001μg/mL。
Antitumoral compounds Nutlin-3 is made into reference substance solution with same condition.
It is 3 × 10 that 96 orifice plates, which add concentration per hole,4Individual/mL μ the L of cell suspension 100, i.e., 3000 cells/wells put 37
DEG C, 5%CO2In incubator.After 24 hours, sample liquid and reference substance liquid are separately added into, 10 μ L/ holes, 37 DEG C act on 72 hours.Often
Hole adds the 5mg/mL μ L of MTT (3- (4,5- dimethylthiazole -2- bases) -2,5- diphenyltetrazoliumbromide father-in-law bromide) solution 20, makees
With lysate DMSO is added after 4 hours, 100 μ L/ holes are put in incubator, and the secondary daily full-automatic ELIASAs of MK-2 survey 570nm OD
Value, calculation of half inhibitory concentration IC50。
The antitumor activity of part preferred compound refers to table 3, wherein, sample 1~21 refers to prepare in corresponding embodiment
Indolone spiral shell tetrahydrochysene thio-pyrylium class compound, such as compound 1 represent in embodiment 1 obtained by compound, similarly class
Push away.Wherein compound 22 is active optimal compound in patent CN201610924937.7, and compound 23 is patent
The optimal compound of activity in CN201410233972.5, structure is as shown in table 4.Wherein compound 21 does not carry out active testing.
Half-inhibition concentration IC of the part of compounds of the present invention of table 4 to tumour cell50(unit：μM)
It in compound concentration is the inhibiting rate under the conditions of 10 μM to tumour cell that 10 μM (%), which is, if more than 50%, entering
One step tests its IC by concentration gradient50；CPT is camptothecine.
As a result show, the compound aggregate performance of present patent application goes out wide spectrum, medium antitumor activity, part of compounds
Activity be better than control compound 22 and 23.Wherein half-inhibition concentration of the compound 7,9,11,13,16 to lung cancer A549
IC50Less than 5 μM, better than comparison medicine 22,23 and Nutlin-3.The aggregate performance wide spectrum of compound 13, stronger antitumor activity, it is right
The IC of three kinds of tumor cell lines50Below 12 μM, hence it is evident that better than comparison medicine Nutlin-3, it can enter as antineoplastic guide structure
Row more in-depth study.In addition, the compound of present patent application contains the group that hydroxyl, amino etc. are easy to derivatization, it is easy to
Quick derivatization, finds the antitumor lead compound of good activity.
Claims (9)
1. a kind of indolone spiral shell tetrahydrochysene thio-pyrylium class compound, including its raceme, d- types or l- type isomers, its feature exist
In the structure of the compound is as shown in formula I：
Wherein R1Represent the substituent on phenyl ring, wherein the substituent on phenyl ring be it is monosubstituted or polysubstituted, substitution basis representation hydrogen,
It is halogen, low-grade halogenated alkyl, low alkyl group, hydroxyl, Lower hydroxy alkyl, lower alkoxy, amino, low-grade alkyl amino, low
Level haloalkylamino, low-grade cycloalkyl amino, alkynyl of low-grade chain amino, nitro, rudimentary 4-nitro alkyl, cyano group, rudimentary cyano group
Alkyl, amide groups, low-grade cycloalkyl amide groups, rudimentary amido alkyl；
R2Aromatic ring substituents group is represented, the aromatic ring is phenyl ring, substituted benzene ring or hetero-aromatic ring；Substituent on substituted benzene ring is halogen
Element, low alkyl group, hydroxyl, lower alkoxy, amino, low-grade alkyl amino, low-grade cycloalkyl amino, nitro, amide groups or low
Grade naphthenic base amide groups；Hetero-aromatic ring is pyrroles, furans, thiophene or pyridine；
R3Aromatic ring substituents group or low alkyl group side chain are represented, the aromatic ring is phenyl ring, substituted benzene ring or hetero-aromatic ring；Substituted benzene
Substituent on ring is halogen, low alkyl group, hydroxyl, lower alkoxy, amino, low-grade alkyl amino, low-grade cycloalkyl amino,
Nitro, amide groups or low-grade cycloalkyl amide groups；Hetero-aromatic ring is furans, thiophene, pyrroles or pyridine；
R4Represent hydrogen, low alkyl group or lower Oxo side chain；
X is represented：Sulphur atom, sulfoxide radicals or sulfone group；
Described " low-grade cycloalkyl " refers to the ring containing 3 to 7 carbon, and described " alkynyl of low-grade chain amino " refers to corresponding alkynes chain
Amount of carbon atom be 3 to 6, other described " rudimentary " substituents refer to corresponding aliphatic group be straight or branched,
Saturation and containing 1 to 6 carbon atom.
2. a kind of indolone spiral shell tetrahydrochysene thio-pyrylium class compound according to claim 1, it is characterised in that in R1Represent
Substituent in, the halogen be fluorine, chlorine or bromine, the low alkyl group be methyl.
3. a kind of indolone spiral shell tetrahydrochysene thio-pyrylium class compound according to claim 1 or 2, it is characterised in that in R2Table
In the aromatic ring substituents group shown, substituted benzene ring substituted radical is 4- bromophenyls, 4- methoxyphenyls or 3,4- dichlorophenyl；Virtue is miscellaneous
Ring substitute group is the base of furans -2.
4. a kind of indolone spiral shell tetrahydrochysene thio-pyrylium class compound according to claim 1 or 2, it is characterised in that in R3Table
Substituted benzene ring substituted radical is in the aromatic ring substituents group shown：4- chlorphenyls, 4- fluorophenyls, 4- bromophenyls, 4- nitrobenzophenones, 4-
Methoxyphenyl or 2- methoxyphenyls；R4The low alkyl group side chain of expression is n-propyl.
5. a kind of indolone spiral shell tetrahydrochysene thio-pyrylium class compound according to claim 1, it is characterised in that the compound
R1、R2、R3、R4, the one kind of X in following combination：
6. a kind of preparation method of indolone spiral shell tetrahydrochysene thio-pyrylium class compound described in any one of Claims 1 to 5, it is special
Levy and be, reaction process is as follows：
Concretely comprise the following steps：
A, target compound VIII preparation:
In dichloromethane, the catalyst VII, intermediate V, intermediate VI of 10% mole are sequentially added, at 20~30 DEG C
Stirring, after reaction completely, isolates and purifies, obtains target compound VIII；Wherein, described catalyst VII is L-PROLINE；
B, target compound IX preparation:
In dichloromethane, compound VIII, substitution reagent and 4- dimethylamino pyridines are added, after reaction completely, is isolated and purified,
Obtain target product IX；
Wherein, the substitution reagent is acid anhydrides or brominated alkanes；
C, target compound X preparation:
In dichloromethane, compound VIII, metachloroperbenzoic acid are added, after being reacted completely at 20~30 DEG C, column chromatography
Purifying, obtains the target product X that oxidized sulfur atom is sulfoxide radicals；Wherein, calculated according to mole, compound VIII：M-chloro
Benzoyl hydroperoxide=1：(1.3~1.8)；
In dichloromethane, compound VIII, metachloroperbenzoic acid are added, after being reacted completely at 20~30 DEG C, column chromatography
Purifying, obtains the target product X that oxidized sulfur atom is sulfone group；Wherein, calculated according to mole, compound VIII：M-chloro mistake
Oxybenzoic acid=1：(4~6)；
D, target compound XI preparation:
In dichloromethane, compound IX, metachloroperbenzoic acid are added, after being reacted completely at 20~30 DEG C, column chromatography is pure
Change, obtain the target product X I that oxidized sulfur atom is sulfoxide radicals；Wherein, calculated according to mole, compound IX：M-chloro peroxide
Benzoic acid=1：(1.3~1.8)；
In dichloromethane, compound IX, metachloroperbenzoic acid are added, after being reacted completely at 20~30 DEG C, column chromatography is pure
Change, obtain the target product X I that oxidized sulfur atom is sulfone group；Wherein, calculated according to mole, compound IX：M-chloro peroxide benzene
Formic acid=1：(4~6).
7. the officinal salt of the indolone spiral shell tetrahydrochysene thio-pyrylium class compound described in any one of claim 1 to 5.
8. the Yin described in indolone spiral shell tetrahydrochysene thio-pyrylium class compound or claim 7 described in any one of claim 1 to 5
Application of the officinal salt of diindyl ketone spiral shell tetrahydrochysene thio-pyrylium class compound in antineoplastic is prepared.
9. application according to claim 8, it is characterised in that described tumour is lung cancer, intestinal cancer, breast cancer or liver cancer.
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| CN109796471A (en) * | 2019-02-25 | 2019-05-24 | 中国人民解放军第四军医大学 | Indolone spirocyclopropane spiral shell-thiazolone or spiral shell-terahydro thiazolone derivative and its preparation method and application |
| CN116253736A (en) * | 2023-01-06 | 2023-06-13 | 中山大学 | Pyrazole beta-lactam derivative and preparation method and application thereof |
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| CN103992334A (en) * | 2014-05-29 | 2014-08-20 | 中国人民解放军第二军医大学 | Indolone spiral tetrahydrothiopyran antitumour derivatives and preparation method thereof |
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| CN103992334A (en) * | 2014-05-29 | 2014-08-20 | 中国人民解放军第二军医大学 | Indolone spiral tetrahydrothiopyran antitumour derivatives and preparation method thereof |
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| SHENGZHENG WANG，等: "Meeting Organocatalysis with Drug Discovery: Asymmetric Synthesis of 3，3’-Spirooxindoles Fused with Tetrahydrothiopyrans as Novel p53-MDM2 Inhibitors", 《ORG. LETT.》 * |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109796471A (en) * | 2019-02-25 | 2019-05-24 | 中国人民解放军第四军医大学 | Indolone spirocyclopropane spiral shell-thiazolone or spiral shell-terahydro thiazolone derivative and its preparation method and application |
| CN109796471B (en) * | 2019-02-25 | 2021-07-16 | 中国人民解放军第四军医大学 | Indolone spiro-propane spiro-thiazolone or spiro-tetrahydrothiazolone derivative and preparation method and application thereof |
| CN116253736A (en) * | 2023-01-06 | 2023-06-13 | 中山大学 | Pyrazole beta-lactam derivative and preparation method and application thereof |
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