CN110305036A - A kind of nitrogen mustards anti-tumor predrug and preparation method thereof of hydrogen peroxide response - Google Patents
A kind of nitrogen mustards anti-tumor predrug and preparation method thereof of hydrogen peroxide response Download PDFInfo
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Abstract
The invention discloses a kind of nitrogen mustards anti-tumor predrugs and preparation method thereof of hydrogen peroxide response, belong to field of medicinal chemistry.The compounds of this invention contains alpha-keto amide structure and mustargen structure, is enable to respond quickly H2O2, can be used as nitrogen mustards anti-tumor predrug, to H2O2It is good to respond effect, cell selective with higher, toxic side effect are small, provide a kind of effective and safe, highly selective anti-tumor drug, enrich the type of mustargen series antineoplastic medicament, have good market prospects.
Description
Technical field
The present invention relates to a kind of nitrogen mustards anti-tumor predrugs and preparation method thereof of hydrogen peroxide response, belong to pharmaceutical chemistry
Field.
Background technique
Tumour is a kind of disease for seriously threatening human health, is so far still medical field a great problem.Traditional chemotherapy
Due to poor to tumor cells selectivity, it is also easy to produce biggish toxic side effect over the course for the treatment of.Mustargen is important alkylation
Anti-tumor drug, but due to its half-life short, toxic side effect is big, poor selectivity, therapeutic efficiency are low etc., seriously limit it and facing
Application on bed.
The prodrug activated under the distinctive microenvironment of tumour cell is the effective tool for reducing toxic and side.With
Normal cell is compared, and tumour cell is due to oxygen insufficient supply, and metabolic demand is big and protection mechanism lacks, and is in various oxidative stress
State, wherein active chalcogen (ROS) content significantly increases, it include hydroxyl radical free radical (HO), superoxide anion (O2 -), peroxide it is sub-
Nitrate (ONOO-), hydrogen peroxide (H2O2) etc..Research shows that the H of some human tumor cells2O2Generating rate reaches
0.5nmol/104Cell/h[1,2], at concentrations up to 5 μM~1.0mM.Therefore, the H of design high concentration in tumour cell2O2Condition
The prodrug of lower activation has good development prospect.
So far, H2O2Activated prodrugs are essentially all based on phenyl boric acid, borate ester, oxalate, thiazolinone knot
Structure, wherein phenyl boric acid, borate ester structural research are the most mature.2013, Peng seminar[3]Boron is introduced on aryl nitrogen mustard
Acid and boric acid ester structure have synthesized a series of H2O2The mustargen prodrug of activation.Cytotoxicity experiment shows these compounds (≤14 μ
M it is) 40~80% to human colon cancer cell inhibiting rate, and 25% is lower than to the inhibiting rate of normal lymphocytes.It can be seen that will
Mustargen is designed to that tumor cells selectivity can be improved in prodrug, reduces the secondary use of poison.
Summary of the invention
Research shows that being compared with normal cell, tumour cell H2O2At concentrations up to 5 μM~1.0mM.And so far, H2O2
Activated prodrugs are essentially all based on phenyl boric acid, borate ester structure, and structure type is more single.The present invention constructs a kind of containing ketone
The novel mustargen series antineoplastic medicament of amide structure, alpha-keto amide structure can be by H2O2It is broken (as shown in Figure 1), H first2O2
Then carbonyl carbon in anion nucleophilic attack alpha-keto amide structure occurs Baeyer-Villiger and resets, final hydrolysis generates
CO2, carboxylic acid and amine.Therefore, alpha-keto amide structure can be used for responding the H of high-content in tumour cell2O2.There is no related at present
The structure is used for H by reported in literature2O2Sensitive nitrogen mustards prodrug modification, nitrogen mustards prodrug of the invention enrich H2O2It is sensitive
Nitrogen mustards prodrug structure type, improve drug in tumour cell selectivity, reduce toxic side effect.
The first purpose of the invention is to provide a kind of nitrogen mustards compound containing alpha-keto amide, including Formulas I, II, III institute
Show that the compound of structure, the compound are the nitrogen mustards anti-tumor predrug compounds of hydrogen peroxide response,
Wherein X1And X2It is mutually independent to be selected from halogen or sulfonyl-SO2-Ra, wherein RaSelected from alkyl, halogenated alkyl, ring
Alkyl, halogenated cycloalkyl, alkenyl, halogenated alkenyl, aromatic radical；
R1For hydrogen, alkyl, halogen, nitro, cyano, trifluoroalkyl, amino, carboxyl, alkoxy, acylamino- Ra-CONH-、
RaOCO-, wherein RaSelected from alkyl, halogenated alkyl, naphthenic base, halogenated cycloalkyl, alkenyl, halogenated alkenyl, aromatic radical；
R2For hydrogen, alkyl, alkoxy, halogen, nitro, cyano, carboxyl, acylamino- Ra- CONH-, alkoxy carbonyl group RaOCO-,
Wherein RaSelected from alkyl, halogenated alkyl, naphthenic base, halogenated cycloalkyl, alkenyl, halogenated alkenyl, aromatic radical；
Y is halogen；
R3And R4It is mutually independent to be selected from alkyl, halogenated alkyl, naphthenic base, halogenated cycloalkyl, alkenyl, halogenated alkenyl.
Preferably X1And X2It is mutually independent to be selected from halogen or sulfonyl-SO2-Ra, wherein RaSelected from alkyl, halogenated alkyl,
Naphthenic base, halogenated cycloalkyl, aromatic radical；
R1And R2It is mutually independent to be selected from hydrogen, alkyl, halogen, nitro, cyano, alkoxy, carboxyl；
Y is halogen；
R3And R4It is mutually independent to be selected from alkyl, halogenated alkyl.
It is further preferred that R1、R2Hydrogen atom is indicated, shown in following general formula (IV, V and VI).X1And X2Mutually independent choosing
From halogen or benzenesulfonyl；Y is halogen；R3And R4It is mutually independent to be selected from alkyl.
It is further preferred that R3、R4Indicate methyl, it is characterised in that following general formula (VII, VIII and IX) is shown, wherein X1
And X2It is mutually independent to be selected from halogen or benzenesulfonyl；Y is halogen；
It is further preferred that general structure is wherein X shown in X, XI and XII1And X2It is mutually independent to be selected from halogen or benzene sulphur
Acyl group,
The structural formula of the compound of the present invention still more preferably is as follows:
In one embodiment of the invention, formula (I) compound is by -1 intermediate of Formulas I and N- (4- aminobenzene
Base) diethanol amine reacts to obtain -2 intermediate of Formulas I, then react with halide or sulfonyl compound；
Formula (II) compound is that -4 intermediate of Formula II and N- alkyldiethanolamine are obtained -5 intermediate of Formula II, then
It is reacted with halide or sulfonyl compound；
Formula (III) compound is to replace -6 intermediate of formula III or its halogen substituent by nitro reduction, then with
- 4 intermediate of Formula II obtains；Or formula III -6 and -4 intermediate of Formula II directly obtain；
In one embodiment of the invention, the preparation method of the compound includes:
(1) p-nitroacetophenone is dissolved in pyridine, selenium dioxide (SeO is added2), it is flowing back and is being stirred under nitrogen protection
It mixes, obtains intermediate 1, wherein p-nitroacetophenone and SeO2Molar ratio is 1:(1-2), wherein it is preferred that 1:1.5；
(2) using DMF as reaction dissolvent, intermediate 1 is added, p-aminophenyl methanol, EDCI and DIPEA are stirred at room temperature
Obtain intermediate 2, molar ratio 1:(0.8-1.5): (1-2): (1-2), preferably 1:1:1.5:1.5；
(3) using DCM as reaction dissolvent, intermediate 2, carbon tetrabromide (CBr is added4) and triphenylphosphine (PPh3), in room temperature and
Stirred under nitrogen atmosphere obtains intermediate 3, molar ratio 1:(1-2): (1-2), preferably 1:1.5:1.5；
(4) using DCM as reaction dissolvent, intermediate 4, SOCl is added2And pyridine, intermediate 6 is stirred to obtain under reflux conditions,
Its molar ratio is 1:(2-3): (1-2), preferably 1:2.2:1.7；
(5) using methanol (MeOH) and DCM, 1:1 is reaction dissolvent by volume, in hydrogen, palladium carbon (H2, Pd/C) reduction under
Obtain intermediate 7；
(6) using THF as reaction dissolvent, intermediate 7,37% formalin (37%HCHO), sodium borohydride is added
(NaBH4) and the concentrated sulfuric acid (conc.H2SO4) intermediate 8, molar ratio 1:(2-3 is stirred at room temperature to obtain): (2-3), preferably
1:2.5:2.5；
(7) using DMF as reaction dissolvent, intermediate 1, N- (4- aminophenyl) diethanol amine, 1- ethyl-(3- diformazan is added
Base aminopropyl) phosphinylidyne diimmonium salt hydrochlorate (EDCI) and n,N-diisopropylethylamine (DIPEA), it is stirred at room temperature intermediate
Body 9, molar ratio 1:(0.8-1.5): (1-2): (1-2), preferably 1:1:1.5:1.5；
(8) using anhydrous DCM as reaction dissolvent, intermediate 9, triethylamine (Et is added3N), 4-dimethylaminopyridine (DMAP)
Compound C, molar ratio 1:(3-5 are obtained in reflux and stirred under nitrogen atmosphere with mesyl chloride (MsCl)): (0.1-
0.5): (3-5), preferably 1:3.5:0.2:4；
(9) with chloroform (CHCl3) it is reaction dissolvent, intermediate 3 and N methyldiethanol amine is added, stirs under reflux conditions
Mix to obtain intermediate 10,1:(3-4), preferably 1:3.3；
(10) using DMF as reaction dissolvent, compound C, halide LiCl is added, compound A is stirred to get at 60 DEG C,
Middle compound C and LiCl molar ratio are 1:(4-6), preferably 1:5；
(11) using DMF as reaction dissolvent, compound C, halide NaBr is added, compound B is being stirred to get at 60 DEG C,
Wherein compound C and NaBr molar ratio are 1:(4-6), preferably 1:5；
(12) with CH3CN is reaction dissolvent, and compound C, halide LiCl is added, compound D is stirred to get at 60 DEG C,
Wherein compound C and LiCl molar ratio are 1:(0.8-1.5), preferably 1:1；
(13) with SOCl2For reaction dissolvent, intermediate 10 is added, is stirred overnight to obtain compound E at room temperature；
(14) with CH3CN is reaction dissolvent, and intermediate 3 and intermediate 8 is added, compound F is stirred at room temperature to obtain, rubs
You are than being 1:(0.8-1.5), preferably 1:1.
Second object of the present invention is that above compound is used for anti-tumor drug.
Third object of the present invention is to provide a kind of anti-tumor agent, the preparation contains above-mentioned compound.
In one embodiment of the invention, the preparation further includes pharmaceutical carrier and/or pharmaceutic adjuvant.
In one embodiment of the invention, the dosage form of the preparation includes injection, injection freeze-dried powder, controlled release
Injection, lipidosome injection, suspension, implant, suppository, capsule, tablet, pill and oral solution.
In one embodiment of the invention, the pharmaceutical carrier includes micro-capsule, microballoon, nanoparticle and liposome.
In one embodiment of the invention, the pharmaceutic adjuvant includes solvent, propellant, solubilizer, cosolvent, cream
Agent, binder, disintegrating agent, filler, lubricant, wetting agent, osmotic pressure regulator, stabilizer, glidant, is rectified colorant
Taste agent, preservative, suspending agent, coating material, aromatic, anti-binder, integrated agent, penetration enhancer, pH adjusting agent, buffering
Agent, plasticizer, surfactant, foaming agent, defoaming agent, thickener, inclusion agents, moisturizer, absorbent, diluent, flocculant
With deflocculant, filter aid and release retarding agent.
In one embodiment of the invention, the additives include microcrystalline cellulose, hydroxypropyl methyl cellulose with
And refined lecithin.
The invention has the advantages that:
The compound of the present invention is to H2O2It is good to respond effect, cell selective with higher, toxic side effect are small, provide one
Kind effective and safe, highly selective anti-tumor drug, enrich the type of mustargen series antineoplastic medicament.
Through cytotoxicity experiment, the result shows that, the part mustargen series antineoplastic medicament that the present invention synthesizes is white to acute myelogenous
Blood disease cell HL-60, human A549 cell lines, human colon cancer cell HCT-116, human liver cancer cell HepG2 have different journeys
The inhibiting effect of degree, wherein compound B inhibiting effect is most strong, and inhibiting rate is greater than 50% at 10 μM, and inhibiting rate is up at 20 μM
90%；Compound C and D take second place, and inhibiting rate is greater than 50% at 20 μM；Compound A, E and F inhibiting rate is minimum, inhibiting rate at 20 μM
Still less than 50%.
Prodrug is through H2O2Paranitrobenzoic acid is generated while activation release mustargen, thus we are detected by HPLC to nitre
Yl benzoic acid generates to study the degradation kinetics of prodrug.The result shows that compound B to be incubated in the PBS/ of different pH
CH3Different time in CN mixed solution still has about 80% to be stabilized in 12h；And in 10eq H2O2Middle incubation 2h, compound B
Almost all degradation.It can be seen that the mustargen anti-tumor compounds B synthesized in the present invention can preferably respond H2O2, and be in
H2O2Concentration dependent.
Confirm compound B in H by alkaline agarose gels electrophoresis and comet2O2Really mustargen can be discharged under effect
Damage dna.Flow cytomery discovery, compound B can be blocked by the G1 phase after acting on tumour cell and inducing cell
Apoptosis plays antiproliferative activity.
The above result shows that the mustargen series antineoplastic medicament that the present invention synthesizes has potential antitumor action.
Detailed description of the invention
Fig. 1 is alpha-keto amide in H2O2Reaction mechanism schematic diagram under effect；
Fig. 2 is compound A's1H NMR and13C NMR(CDCl3,400MHz)；
Fig. 3 is compound B's1H NMR and13C NMR(CDCl3,400MHz)；
Fig. 4 is compound C's1H NMR and13C NMR(DMSO,101MHz)；
Fig. 5 is compound D's1H NMR and13C NMR(DMSO,101MHz)；
Fig. 6 is compound E's1H NMR and13C NMR(DMSO,101MHz)；
Fig. 7 is compound F's1H NMR and13C NMR(DMSO,101MHz)；
Fig. 8 is MTT experiment interpretation of result chart；
Fig. 9 is 25 DEG C, and HPLC monitors the stability of compound B (100 μM) and to H2O2Responsiveness.A) compound B is incubated for
In the PBS/CH of different pH3Different time in CN mixed solution；B) compound B and H2O2(10eq) is incubated in PBS7.4/CH3CN
Different time in mixed solution；C) the H of compound B and various concentration2O2It is incubated for PBS7.4/CH31h in CN mixed solution；
Figure 10 is that alkaline agarose gels the results in electrophoresis analyzes chart: A) Lane1,1.0 μ g pBR322 (crosslinking rates
3.5%)；Lane2,1.0 μ g pBR322+100 μM B (1.8%)；Lane3,1.0 μ g pBR322+10mM H2O2(3.3%)；
Lane4,1.0 μ g pBR322+10 μM B+10mM H2O2(60.1%)；Lane5,1.0 μ g pBR322+50 μM B+10mM
H2O2(88.4%)；Lane6,1.0 μ g pBR322+100 μM B+10mM H2O2(94.8%)；Lane7,1.0 μ g pBR322+
40 μM of mustine hydrochlcrides (90.7%)；B) 50 μM of B and H2O2(10mM) is in 37 DEG C of incubation different times: Lane1,0.5h
(42.8%)；Lane2,1h (52.9%)；Lane3,1.5h (77.1%)；Lane4,2h (91.6%)；Lane5,3h
(86.1%)；
Figure 11 is compound B inducing cell cycle arrest result schematic diagram；
Figure 12 is that compound B induces cell apoptosis distribution results schematic diagram；
Figure 13 is compound B comet result schematic diagram.
Specific embodiment
Below with reference to embodiment, the present invention will be further described in detail, is only exemplary explanation, to being illustrated
The physical data of compound is consistent with structure specified by these compounds.But example is not limit the scope of the invention.
Embodiment 1: the synthesis of compound C
Step 1: the synthesis of p-nitrophenyl glyoxalic acid (intermediate 1)
Concrete operations: p-nitroacetophenone (1g) is dissolved in pyridine (10mL), and SeO is added2(1g), mixture is passed through
Nitrogen protection, in 90 DEG C of stirring 4h, wherein p-nitroacetophenone and SeO2Molar ratio is 1:1.5, after reaction cold filtration,
Filter cake is washed 3 times with ethyl acetate, is washed after collected organic layer with 2M HCl, is finally merged organic layer, is added anhydrous sodium sulfate drying, is subtracted
Solvent is distilled off in pressure, column chromatographic elution obtains yellow intermediate 1.
Step 2: the synthesis of N- (4- nitrobenzophenone) diethanol amine (intermediate 4)
Concrete operations: fluoronitrobenzene (1mL) is dissolved in dimethyl sulfoxide (DMSO), diethanol amine is added
(2.73mL) stirs 3.5h under reflux conditions, after reaction, successively uses water, saturated common salt washing merges organic layer, adds
Anhydrous sodium sulfate is dry, vacuum distillation removes solvent and obtains yellow intermediate 4, directly progress next step reaction.
Step 3: the synthesis of N- (4- aminophenyl) diethanol amine (intermediate 5)
Concrete operations: intermediate 4 (1.5g) is dissolved in CH3In OH/DCM (v:v, 1:2) mixed solution, stir under an atmosphere of hydrogen
It mixes, adds 10%Pd/C (0.5g).After reaction, it is filtered with diatomite, collects filtrate, vacuum distillation removes solvent
Dark brown intermediate 5 is obtained, directly progress next step reaction.
Step 4: N- (bis- (2- hydroxyethyl) amino of 4-) phenyl) -2- (4- nitrobenzophenone) -2- oxoaGetamide (centre
Body 9) synthesis
Concrete operations: intermediate 1 (0.78g) is dissolved in DMF (5mL), intermediate 5 (0.78g), EDCI (1.145g),
DIPEA (0.99mL) is sequentially added, and 1~2h is stirred at room temperature, and after reaction, successively uses water, saturated common salt washing merges
Organic layer adds dry anhydrous sodium sulfate, vacuum distillation removing solvent, column chromatographic elution to obtain dark brown intermediate 9.1H NMR
(400MHz,DMSO-d6)δ10.71(s,1H,NH),8.44–8.35(m,2H,Ar-H),8.33–8.26(m,2H,Ar-H),
7.60-7.49 (m, 2H, Ar-H), 6.75-6.64 (m, 2H, Ar-H), 4.76 (t, J=5.4Hz, 2H, OH), 3.55 (q, J=
6.0Hz,4H,NCH2),3.47–3.38(m,4H,CH2OH).13C NMR(101MHz,DMSO-d6)δ188.45,161.10,
150.87,145.86,138.38,131.96,126.38,124.33,122.23,111.67,58.64,53.79.Mass
spectrometry
(ESI-MS,m/z):Calcd for[M-H]+,327.14；found 327.32.m.p:95–96℃.
Step 5: N- (bis- (2- methylsulfonylethyl) amino of 4-) phenyl) -2- (4- nitrobenzophenone) -2- oxoaGetamide
The synthesis of (compound C)
Concrete operations: intermediate 9 (200mg) is dissolved in anhydrous DCM (5.0mL), Et3N(260μL)、MsCl(166μ
L), DMAP (13mg) is sequentially added, under nitrogen protection 1~2h of return stirring, after reaction, successively uses water, saturated common salt
Washing merges organic layer, and dry anhydrous sodium sulfate, vacuum distillation removing solvent, column chromatographic elution is added to obtain dark brown solid C.1H
NMR(400MHz,DMSO-d6)δ10.81(s,1H,NH),8.4–8.36(m,2H,Ar-H),8.34–8.27(m,2H,Ar-H),
7.64 (d, J=9.2Hz, 2H, Ar-H), 6.84 (d, J=9.2Hz, 2H, Ar-H), 4.32 (t, J=5.7Hz, NCH2),3.75
(t, J=5.8Hz, MsOCH2),3.17(s,6H,CH3).13CNMR(101MHz,DMSO-d6)δ187.94,160.82,150.44,
143.97,137.85,131.57,126.03,123.90,121.81,112.28,67.25,49.48,36.65.Mass
spectrometry(ESI-MS,m/z):Calcd for[M+H]+,485.10；found 485.17.m.p:96–98℃.
Embodiment 2: the synthesis of compound A
Concrete operations: compound C (100mg) is dissolved in DMF (3mL), is added halide LiCl (40.07mg), 60
3h is stirred at DEG C, after reaction, successively uses water, saturated common salt washing adds ethyl acetate to be extracted, collected organic layer adds
Anhydrous sodium sulfate is dry, vacuum distillation removes solvent, column chromatographic elution obtains dark brown solid A.1H NMR(400MHz,
Chloroform-d)δ8.83(s,1H,NH),8.64–8.56(m,2H,Ar-H),8.38–8.29(m,2H,Ar-H),7.63–
7.56(m,2H,Ar-H),6.78–6.68(m,2H,Ar-H),3.76(m,2H,NCH2),3.65(m,2H,ClCH2).13C NMR
(101MHz,Chloroform-d)δ186.27,157.38,150.84,144.06,137.87,132.57,126.70,
123.50,122.01,112.33,53.50,40.36.Mass spectrometry(ESI-MS,m/z):Calcd for[M+H]+,
409.06；found 410.061.m.p:141–143℃.
Embodiment 3: the synthesis of compound B
Concrete operations: compound C (100mg) is dissolved in DMF (3mL), is added halide NaBr (97mg), at 60 DEG C
3h is stirred, after reaction, successively uses water, saturated common salt washing adds ethyl acetate to be extracted, collected organic layer adds anhydrous
Sodium sulphate is dry, vacuum distillation removes solvent, column chromatographic elution obtains dark brown solid B.1H NMR(400MHz,Chloroform-
d)δ8.83(s,1H,NH),8.65–8.56(m,2H,Ar-H),8.40–8.29(m,2H,Ar-H),7.65–7.54(m,2H,Ar-
), H 6.77-6.65 (m, 2H, Ar-H), 3.80 (t, J=7.5Hz, 2H, NCH2), 3.48 (dd, J=8.1,6.9Hz, 2H,
BrCH2).13C NMR(101MHz,Chloroform-d)δ186.26,157.38,150.85,143.74,137.86,132.58,
126.81,123.50,122.06,112.32,53.30,28.16.Mass spectrometry(ESI-MS,m/z):Calcd
for[M+H]+,496.96；found 497.963.m.p:95–96℃.
Embodiment 4: the synthesis of compound D
Concrete operations: compound C (100mg) is dissolved in CH3In CN (3mL), it is added halide LiCl (9mg), at 60 DEG C
Lower stirring 10h, after reaction, vacuum distillation removes solvent, column chromatographic elution obtains dark brown solid D.1H NMR(400MHz,
Chloroform-d)δ8.84,8.64–8.56(m,2H,Ar-H),8.38–8.31(m,2H,Ar-H),7.64–7.56(m,2H,
), Ar-H 6.79-6.69 (m, 2H, Ar-H), 4.37 (t, J=5.9Hz, 2H, NCH2),3.85–3.71(m,4H),3.66(t,J
=6.5Hz, 2H)13C NMR(101MHz,Chloroform-d)δ186.25,157.47,150.90,144.18,137.88,
132.57,127.05,123.50,122.03,112.78,66.15,53.64,50.71,40.44,37.59.Mass
spectrometry(ESI-MS,m/z):Calcd for[M+H]+,470.07；found 470.09.m.p:83–85℃
Embodiment 5: the synthesis of compound E
Step 1: N- (4- methylol) phenyl) synthesis of -2- (4- nitrobenzophenone) -2- oxoaGetamide (intermediate 2)
Concrete operations: intermediate 1 (1g) is dissolved in THF (10mL), p-aminophenyl methanol (0.64mg), EDCI
(1.475g), DIPEA (1.28mL) are sequentially added, and 1~2h is stirred at room temperature, and after reaction, successively use water, saturated common salt
Washing merges organic layer, adds anhydrous sodium sulfate is dry, is evaporated under reduced pressure removing solvent to obtain dark brown intermediate 2, directly carries out next
Step reaction.
Step 2: N- (4- bromomethyl) phenyl) synthesis of -2- (4- nitrobenzophenone) -2- oxoaGetamide (intermediate 3)
Concrete operations: intermediate 2 (0.3g) is dissolved in anhydrous DCM, in 0 DEG C, stirred under nitrogen atmosphere, is sequentially added
PPh3(0.395g)、CBr4(0.5g) restores to room temperature to continue to stir 1h, and vacuum distillation removing solvent, column chromatographic elution obtain yellow
Color intermediate 3.1H NMR(400MHz,Chloroform-d)δ9.00(s,1H,NH),8.73–8.53(m,2H,Ar-H),
8.46–8.26(m,2H,Ar-H),7.78–7.65(m,2H,Ar-H),7.53–7.38(m,2H,Ar-H),4.53(s,2H,
ArCH2).13CNMR(101MHz,Chloroform-d)δ185.94,157.80,151.11,137.64,136.30,135.35,
132.76,130.29,123.71,120.33,32.98.Mass spectrometry(ESI-MS,m/z):Calcd for[M-
H]+,360.98；found 361.17.
Step 3: 2- hydroxy-n-(2- ethoxy)-N- methyl-N- (4- (2- (4- nitrobenzophenone) -2- oxo acetyl ammonia
Base) benzyl) second -1- ammonium bromide (intermediate 10) synthesis
Concrete operations: intermediate 3 (0.2g) is dissolved in CHCl3In, N methyldiethanol amine is added, under reflux conditions
1~2h is stirred, is directly filtered, filter cake is collected and obtains intermediate 10.1H NMR(400MHz,DMSO-d6)δ11.26(s,1H,NH),
8.42 (d, J=8.7Hz, 2H, Ar-H), 8.34-8.28 (m, 2H, Ar-H), 7.92 (d, J=8.3Hz, 2H, Ar-H), 7.64
(d, J=8.4Hz, 2H, Ar-H), 5.34 (t, J=4.9Hz, 2H, NH), 4.66 (s, 2H, OH), 4.02-3.85 (m, 4H,
NCH2),3.58–3.39(m,4H,CH2OH),3.00(s,3H,CH3).13C NMR(101MHz,DMSO-d6)δ187.75,
162.22,151.01,139.66,137.93,134.56,132.08,124.40,120.69,63.16,55.31,
48.45.m.p:185–186℃.
Step 4: the synthesis of compound E
Concrete operations: intermediate 10 (100mg) is dissolved in SOCl2It in (3mL), is stirred overnight at room temperature, vacuum distillation removes
Solvent is gone to obtain yellow compound E.1H NMR(400MHz,DMSO-d6) δ 11.35 (s, 1H, NH), 8.42 (d, J=8.5Hz, 2H,
), Ar-H 8.31 (d, J=8.6Hz, 2H, Ar-H), 7.95 (d, J=8.2Hz, 2H, Ar-H), 7.62 (d, J=8.3Hz, 2H,
Ar-H),4.73(s,2H,ArCH2),4.19(m,4H),3.83(m,2H),3.69(m,2H),3.09(s,3H,CH3).13C NMR
(101MHz,DMSO-d6)δ187.28,161.89,150.57,139.55,137.45,133.93,131.60,123.96,
123.17,120.43,65.24,60.81,47.26,36.08.Mass spectrometry(ESI-MS,m/z):Calcd for
[M-H]+,541.16；found 540.90.m.p:154–155℃.
Embodiment 6: the synthesis of compound F
Step 1: the synthesis of bis- (2- the chloroethyl) -4- nitroanilines (intermediate 6) of N, N-
Concrete operations: intermediate 4 (16g) is dissolved in DCM, and 0 DEG C of stirring is added pyridine (10mL), is slow added into
SOCl2(11.7mL) successively uses water after reaction, and saturated common salt washing merges organic layer, adds anhydrous sodium sulfate drying, subtracts
Pressure is distilled off solvent and obtains dark brown intermediate 6, directly progress next step reaction.
Step 2: the synthesis of bis- (2- the chloroethyl) -4- amino anilines (intermediate 7) of N, N-
Concrete operations: intermediate 6 (1.5g) is dissolved in CH3In OH/DCM (v:v, 1:2) mixed solution, stir under an atmosphere of hydrogen
It mixes, adds 10%Pd/C (0.5g) and be filtered after reaction with diatomite, collect filtrate, vacuum distillation removes solvent
Dark brown intermediate 7 is obtained, directly progress next step reaction.
Step 3: N1,N1Bis- (2- chloroethyl)-N4,N4Dimethyl benzene -1,4- diamines
Concrete operations: 37% formalin (3.7g) and the concentrated sulfuric acid (3mL) are dissolved in THF (10mL), intermediate 7
(2.5g) and sodium borohydride (1.4g) sequentially add in reaction solution, and 2h is stirred at room temperature, and use 1N hydroxide after reaction
Water is then successively used in sodium water solution quenching, and saturated common salt washing merges organic layer, and anhydrous sodium sulfate drying, vacuum distillation is added to remove
Solvent, column chromatographic elution is gone to obtain dark brown intermediate 8, directly progress next step reaction.
Step 4: the synthesis of compound F
Concrete operations: intermediate 3 (70mg) is dissolved in anhydrous CH3In CN (5mL), compound 8 is added at room temperature
(50mg), after being stirred overnight, vacuum distillation removes solvent, column chromatographic elution obtains compound F.1H NMR(400MHz,DMSO-d6)δ
11.16 (s, 1H, NH), 8.45-8.37 (m, 2H, Ar-H), 8.29 (d, J=8.8Hz, 2H, Ar-H), 7.75 (d, J=8.3Hz,
2H, Ar-H), 7.60 (d, J=9.1Hz, 2H, Ar-H), 7.11 (d, J=8.3Hz, 2H, Ar-H), 6.89 (d, J=9.3Hz,
2H,Ar-H),4.94(s,2H,ArCH2),3.90–3.66(m,8H),3.50(s,6H,CH3).13C NMR(101MHz,DMSO-
d6)δ187.20,161.66,150.54,147.22,139.19,137.44,133.53,133.28,131.63,124.44,
123.91,122.63,119.87,111.92,71.44,52.62,51.56,41.10.Mass spectrometry(ESI-MS,
m/z):Calcd for[M+H]+,542.16；found 543.155.m.p:82–84℃.
With1H NMR,13C NMR and ESI-MS characterization of compound molecular structure, and the product of acquisition is saved at 4 DEG C.
1H NMR,13C NMR result is as shown in Fig. 2-7, it was demonstrated that compound A, B, C, D, E and F are successfully synthesized.
Embodiment 7: anti tumor activity in vitro screening
Screen cell strain: acute myeloblastic leukemia cell HL-60, human A549 cell lines, human colon cancer cell
HCT-116, human liver cancer cell HepG2.
Experimental method:
It by cell dissociation, counts, prepares cell suspension, 100 μ L cell suspensions are added in every hole in 96 porocyte culture plates；96
Porocyte culture plates are placed in 37 DEG C, 5%CO2It is cultivated for 24 hours in incubator；Drug is diluted to required working solution concentration with culture medium,
The 100 corresponding pastille culture mediums of μ L are added in every hole, while setting up negative control group；96 porocyte culture plates are placed in 37 DEG C, 5%
CO2It is cultivated 72 hours in incubator；96 orifice plates are subjected to MTT dye, λ=490nm measures OD value；1) 20 μ L MTT are added in every hole
(5mg/mL) continues to cultivate 4h in incubator；2) supernatant is abandoned, 150 μ L DMSO are added in every hole, and shaking table 10min is lightly mixed；
3) λ=490nm, microplate reader read the OD value in every hole, calculate inhibiting rate.
As a result as shown in figure 8, the different mustargen analog derivatives that synthesize of the present invention are to tri- kinds of HCT-116, A549, HL-60
There is some difference for cell inhibitory effect.Wherein, compound B is to three kinds of cell inhibitory rate highests, and inhibiting rate is greater than at 10 μM
50%, inhibiting rate is up to 90% at 20 μM；Compound C and D take second place, and inhibiting rate is greater than 50% at 20 μM；Compound A, E and F suppression
Rate processed is minimum, and inhibiting rate is still less than 50% at 20 μM.The above results show that such compound has the latent of developing anti-tumor medicaments
It is being worth.
Embodiment 8: compound B external degradation dynamics research
Prodrug is through H2O2Paranitrobenzoic acid is generated while activation release mustargen, thus we are detected by HPLC to nitre
Prodrug degradation dynamics is studied in the generation of yl benzoic acid.The result shows that compound B to be incubated in the PBS/CH of different pH3CN
Different time in mixed solution still has about 80% to be stabilized (Fig. 9 A) in 12h；And by compound B and 10eq H2O2It is incubated for not
The same time, compound B gradually degrades as time went on, almost all degradation (Fig. 9 B) when 2h, it can be seen that compound B can be compared with
Good response H2O2It and is in H2O2Concentration dependent (Fig. 9 C).The above results show that compound B is with good stability and energy
Preferable response H2O2。
Embodiment 9: external DNA damage experiment (alkaline agarose gels electrophoresis experiment)
Experimental method:
(1) Plasmid DNA linearizes: 20 μ L digestion systems: in Plasmid DNA pBR322 (0.5 μ g/ μ L, 2 μ L), EcoRI enzyme
Aqua sterilisa is added in (1 μ L) and EcoRI Buffer (2 μ L) and complements to 20 μ L, is incubated for 1h at 37 DEG C.
(2) drug incubation: compound B is dissolved in DMSO and is configured to 1mM mother liquor.5 μ L linear DNAs are taken to be added to 1X TE/urea
(8M) buffer (10 μ L), 5 μ L compound B (0-100 μM), 5 μ L H2O2(10mM).3h is incubated at 37 DEG C.(40 μM) of mustargen works
For positive control.
(3) electrophoresis: preparing 1% alkaline agarose gels with 1X TAE/1M urea electrophoresis liquid, (0.2g agarose is dissolved in
20mL electrophoresis liquid, micro-wave oven dissolve by heating, are cooled to 60 DEG C, add 2 μ LGOLDVIEW I type nucleic acid dyes), each sample is added
6X loading buffer(5μL).It mixes, loading (6 μ L).Voltage 60V, electrophoresis 90min.Electrophoresis terminates, and 1X TAE washes glue three
Secondary, 100mM Nacl, which impregnates, neutralizes 30min.
(4) machine is taken pictures on, and Bio-Rad geldoc 2000 is analyzed
Experimental result is as shown in Figure 10, and the DNA crosslinking rate that the blank group 1 of any compound is not added is 3.5%, is individually added into
The control group 2 (1.8%) of compound B is individually added into 10mM H2O2Control group 3 (3.3%) DNA crosslinking rate be respectively less than sky
White group, it can be seen that compound B or H is used alone2O2Apparent DNA will not be caused to be crosslinked, when various concentration is added simultaneously
Compound B and 10mM H2O2When, as the concentration of compound B increases, DNA crosslinking rate is gradually risen (60.1-94.8%), and thin
There is similar result (90.7%) (Figure 10 A) after handling cell with 10 μM of mustine hydrochlcrides in born of the same parents；Then, discovery compound B crosslinking
DNA has time dependence, with the extension of time, the ability of compound B crosslinking DNA increases (42.8-91.6%), when 2h is handed over
Connection rate highest, but the time continues to extend, and crosslinking ability declines (86.1%) (Figure 10 B) instead, thus it is speculated that may be due to time mistake
It is long, cause DNA fragmentation excessive, is unfavorable for crosslinking.The above results show that compound B can actually preferably respond H2O2
Mustargen is discharged, in conjunction with DNA.
Embodiment 10: cell-cycle arrest experiment
By 5 × 105The HL-60 cell inoculation in the hole cells/ is to 9 orifice plates, every hole 1.5mL, culture for 24 hours, with final concentration of 0,
5,10 and 20 μM of compound B or 10 μM of mustine hydrochlcride effect 48h or cell first use 20mM NAC (N- acetylation cysteine)
After pre-processing 1h, add 10 μM of compound B effect 48h, with trypsin digestion and cell, 4 DEG C, 1000r/min be centrifuged 5min,
1mL phosphate buffer (PBS) is added to clean cell, supernatant is abandoned in centrifugation, and is repeated the above steps, and 400 μ L PI (iodate third are added
Pyridine) even dyeing, 4 DEG C are protected from light 30min, and upper machine testing records red fluorescence at excitation wavelength 488nm.
Experimental result is as shown in figure 11, and as the concentration of compound B increases, the cell percentages of G1 phase gradually increase (50-
70%), and after the cell percentages of G2 phase and S phase significantly reduce or even disappear and 10 μM of mustine hydrochlcrides processing cells of cell
There is similar result；And after cell first uses 20mM NAC (N- acetylation cysteine, ROS scavenger) to pre-process 1h, then
10 μM of compound B effect 48h are added, G1, S and G2 phase cell percentages (G1:52.43%, S:37.88%, G2:9.69%) are again
Restore to the percentage (G1:52.20%, S:37.99%, G2:9.8%) of blank group, it can be seen that compound B can be in tumour
Cell preferably responds H2O2, may be blocked by the inducing cell G1 phase to inhibit cell Proliferation.
Embodiment 11: Apoptosis detection
The Annexin V of FITC is marked as fluorescence probe, and matches use with PI, can be distinguished using flow cytometer
Detect viable apoptotic cell, non-viable apoptotic cell and dead cell.By 5 × 105The HL-60 cell inoculation in the hole cells/ is to 9
Orifice plate, every hole 1.5mL, culture act on 48h for 24 hours, with final concentration of 0,5,10 and 20 μM of compound B or 10 μM of mustine hydrochlcrides,
Or after cell first uses 20mM NAC (N- acetylation cysteine) to pre-process 1h, 10 μM of compound B effect 48h are added；Use pancreas
Protease digestion cell, 4 DEG C, 1000rpm centrifugation 5min, abandons supernatant, 1mL phosphate buffer (PBS) is added to clean cell, centrifugation
Supernatant is abandoned, and is repeated the above steps, then plus 5 μ L AnnexinV-FITC mix and be protected from light 15min, thin using streaming
Born of the same parents' instrument detects.
Experimental result is as shown in figure 12, as the concentration of compound B increases, the cell in apoptosis early stage and apoptosis advanced stage
Percentage gradually increases (23.74-45.38%), and normal cell percentage significantly reduces (73.04-49.49%) and cell
There is similar result after handling cell with 10 μM of mustine hydrochlcrides；And when cell first use 20mM NAC (N- acetylation cysteine,
ROS scavenger) after pretreatment 1h, add 10 μM of compound B effect 48h, normal cell and apoptotic cell percentage
(80.63%, 19.28%) raises and reduces respectively, it can be seen that compound B can be activated in tumour cell, may be passed through
It is apoptosis-induced to inhibit cell Proliferation.
Embodiment 12: internal DNA damage experiment (comet)
Experimental method:
(1) separation prepares single cell suspension: the HL-60 cell strain of in vitro culture: being digested with pancreatin, is finally suspended with PBS
Blow and beat into single cell suspension, cell count.
(2) prepared by offset plate: a) 0.5%NMA for taking 100 μ L to keep the temperature in 45 DEG C of water-baths is laid on frosted glass slide, is formed
Primer.Coverslip pushes away even, cannot there is bubble, 4 DEG C of 5-8min of solidification；B) level removes cover plate, and 100 μ L is taken to protect in 37 DEG C of water-baths
The 1%LMA and 100 μ L cell suspensions (about 400 cells) of temperature are mixed, immediately tile, in addition coverslip, 4 DEG C of 5-8min of solidification.
(3) cell cracking and electrophoresis: a) offset plate prepared is removed into coverslip after, be dipped in 4 DEG C pre-cooling cell crackings
In liquid, 1-3h is cracked at 4 DEG C；B) offset plate is taken out, with being put into electrophoresis tank after distilled water submergence rinsing, is immersed in 4 DEG C of pre-coolings
Electrophoresis liquid in untwist 0.5-1h；C) slide is horizontally arranged near anode tap, 4 DEG C of 20-25min of electrophoresis (25V, 300mA).It can be
Electrophoresis tank body icing block is to keep low temperature.
(4) neutralize and dye: a) electrophoresis terminates, offset plate is soaked in neutralizer, each 10min, altogether neutralization 3 times, often
Secondary replacement neutralizer, finally dries；B) offset plate is taken out, PI dyeing, 5-8min are dyed in dark place；C) distilled water rinsing 2 times, every time
5min.It slightly dries, filter paper sucks excessive moisture, as early as possible in fluorescence microscopy microscopic observation.
Experimental result is as shown in figure 13 to be compared with blank group, and when cell handles 48h with 20 μM of compound B, cell occurs
Apparent trailing phenomenon, cell tail portion DNA content increase to 45% by 20%, and cell migration distance increases to 26 and cell by 6
There is similar result (45%, 24) with 10 μM of mustine hydrochlcride processing, and when cell first uses 20mM NAC (half Guang ammonia of N- acetylation
Acid, ROS scavenger) after pretreatment 1h, 10 μM of compound B effect 48h are added, tail portion DNA content and migration distance are again obvious
(26%, 10) are reduced to blank class value.The above result shows that compound B can activate release mustargen damage dna in the cell.
Claims (10)
1. a kind of nitrogen mustards compound containing alpha-keto amide, including formula (I), (II) or formula (III) compound represented:
Wherein X1And X2It is mutually independent to be selected from halogen or sulfonyl-SO2-Ra, wherein RaSelected from alkyl, halogenated alkyl, naphthenic base,
Halogenated cycloalkyl, alkenyl, halogenated alkenyl, aromatic radical；
R1For hydrogen, alkyl, halogen, nitro, cyano, trifluoroalkyl, amino, carboxyl, alkoxy, acylamino- Ra-CONH-、
RaOCO-, wherein RaSelected from alkyl, halogenated alkyl, naphthenic base, halogenated cycloalkyl, alkenyl, halogenated alkenyl, aromatic radical；
R2For hydrogen, alkyl, alkoxy, halogen, nitro, cyano, carboxyl, acylamino- Ra- CONH-, alkoxy carbonyl group RaOCO-, wherein Ra
Selected from alkyl, halogenated alkyl, naphthenic base, halogenated cycloalkyl, alkenyl, halogenated alkenyl, aromatic radical；
Y is halogen；
R3And R4It is mutually independent to be selected from alkyl, halogenated alkyl, naphthenic base, halogenated cycloalkyl, alkenyl, halogenated alkenyl.
2. compound according to claim 1, which is characterized in that the nitrogen mustards that the compound comprises the following structure are derivative
Object:
3. compound according to claim 1, which is characterized in that formula (I) compound is by -1 intermediate of Formulas I and N-
(4- aminophenyl) diethanol amine reacts to obtain -2 intermediate of Formulas I, then reacts with halide or sulfonyl compound；
Formula (II) compound is that -4 intermediate of Formula II and N- alkyldiethanolamine are obtained -5 intermediate of Formula II, then with halogen
What compound or sulfonyl compound reacted；
Formula (III) compound is to replace -6 intermediate of formula III or its halogen substituent by nitro reduction, then with formula
II-4 intermediate obtains；Or formula III -6 and -4 intermediate of Formula II directly obtain；
4. purposes of any compound of claim 1-3 as anti-tumor drug.
5. a kind of anti-tumor agent, which is characterized in that the preparation contains any compound of claim 1-3.
6. preparation according to claim 5, which is characterized in that the preparation further includes pharmaceutical carrier and/or pharmaceutic adjuvant.
7. preparation according to claim 5 or 6, which is characterized in that the dosage form of the preparation includes injection, injection jelly
Dry powder needle, controlled release injection, lipidosome injection, suspension, implant, suppository, capsule, tablet, pill and oral solution.
8. preparation according to claim 6, which is characterized in that the pharmaceutical carrier includes micro-capsule, microballoon, nanoparticle and rouge
Plastid.
9. preparation according to claim 6, which is characterized in that the pharmaceutic adjuvant include solvent, propellant, solubilizer,
Cosolvent, emulsifier, colorant, binder, disintegrating agent, filler, lubricant, wetting agent, osmotic pressure regulator, stabilizer,
Glidant, corrigent, preservative, suspending agent, coating material, aromatic, anti-binder, integrated agent, penetration enhancer, pH value tune
Save agent, buffer, plasticizer, surfactant, foaming agent, defoaming agent, thickener, inclusion agents, moisturizer, absorbent, dilution
Agent, flocculant and deflocculant, filter aid and release retarding agent.
10. preparation according to claim 9, which is characterized in that the additives include microcrystalline cellulose, hydroxypropyl methyl
Cellulose and refined lecithin.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112341406A (en) * | 2020-11-18 | 2021-02-09 | 韶远科技（上海)有限公司 | Synthesis method of trans-4- [4- (3-methoxy-4-nitrophenyl) -1-piperazinyl ] adamantane-1-ol |
| US11452785B1 (en) * | 2020-06-05 | 2022-09-27 | Zachiry Charles Crouch | Viral radiopharmaceuticals for the treatment/cure of COVID-19 and other viruses |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002085322A1 (en) * | 2001-04-25 | 2002-10-31 | State Of Israel Prime Minister's Office Israel Institute For Biological Research | Skin-protective compositions effective against vesicants and percutaneous chemical agents |
| CN1878769A (en) * | 2003-09-11 | 2006-12-13 | 凯米亚公司 | Cytokine inhibitors |
| WO2007109080A2 (en) * | 2006-03-16 | 2007-09-27 | Vertex Pharmaceuticals Incorporated | Deuterated hepatitis c protease inhibitors |
| CN104292167A (en) * | 2014-09-18 | 2015-01-21 | 成都大学 | Nitric oxide donor derivatives of bendamustine hydrochloride and preparation method of nitric oxide donor derivatives |
| CN107266483A (en) * | 2017-06-08 | 2017-10-20 | 浙江工业大学 | A kind of hydrogen peroxide that responds kills photaesthesia targeting anti-tumor prodrug of tumour cell and preparation method and application |
-
2019
- 2019-01-15 CN CN201910033808.2A patent/CN110305036B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002085322A1 (en) * | 2001-04-25 | 2002-10-31 | State Of Israel Prime Minister's Office Israel Institute For Biological Research | Skin-protective compositions effective against vesicants and percutaneous chemical agents |
| CN1878769A (en) * | 2003-09-11 | 2006-12-13 | 凯米亚公司 | Cytokine inhibitors |
| WO2007109080A2 (en) * | 2006-03-16 | 2007-09-27 | Vertex Pharmaceuticals Incorporated | Deuterated hepatitis c protease inhibitors |
| CN104292167A (en) * | 2014-09-18 | 2015-01-21 | 成都大学 | Nitric oxide donor derivatives of bendamustine hydrochloride and preparation method of nitric oxide donor derivatives |
| CN107266483A (en) * | 2017-06-08 | 2017-10-20 | 浙江工业大学 | A kind of hydrogen peroxide that responds kills photaesthesia targeting anti-tumor prodrug of tumour cell and preparation method and application |
Non-Patent Citations (4)
| Title |
|---|
| W. C. J. ROSS，等: "Aryl-2-halogenoalkylamines. Part XIV. Some compounds possessing latent cytotoxic activity", 《JOURNAL OF THE CHEMICAL SOCIETY (RESUMED)》 * |
| 唐波，等: "Rational Design of an a-Ketoamide-Based Near-Infrared Fluorescent Probe Specific for Hydrogen Peroxide in Living Systems", 《ANALYTICAL CHEMISTRY》 * |
| 庄雅云，等: "氮芥类抗肿瘤药物研究进展", 《中国药学杂志》 * |
| 徐寒梅: "《抗肿瘤药物药理学实验指南》", 31 October 2015, 中国医药科技出版社 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11452785B1 (en) * | 2020-06-05 | 2022-09-27 | Zachiry Charles Crouch | Viral radiopharmaceuticals for the treatment/cure of COVID-19 and other viruses |
| CN112341406A (en) * | 2020-11-18 | 2021-02-09 | 韶远科技（上海)有限公司 | Synthesis method of trans-4- [4- (3-methoxy-4-nitrophenyl) -1-piperazinyl ] adamantane-1-ol |
| CN112341406B (en) * | 2020-11-18 | 2023-02-10 | 韶远科技（上海)有限公司 | Synthesis method of trans-4- [4- (3-methoxy-4-nitrophenyl) -1-piperazinyl ] adamantane-1-ol |
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