CN104876992B - AZT quinoline conjugate derivative and synthetic method for light power antineoplaston - Google Patents
AZT quinoline conjugate derivative and synthetic method for light power antineoplaston Download PDFInfo
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- CN104876992B CN104876992B CN201510249608.2A CN201510249608A CN104876992B CN 104876992 B CN104876992 B CN 104876992B CN 201510249608 A CN201510249608 A CN 201510249608A CN 104876992 B CN104876992 B CN 104876992B
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- antineoplaston
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- 238000010189 synthetic method Methods 0.000 title claims abstract description 7
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 10
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- 125000001153 fluoro group Chemical group F* 0.000 claims description 9
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 claims description 6
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
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Abstract
The invention discloses the AZT quinoline conjugate derivative for light power antineoplaston, the derivative is with formulaRepresent, wherein n is 1,3,5 or 7, R1And R2It is each independent, represent hydrogen atom or halogen atom；The invention also discloses the synthetic method of the new derivatives and its application.The derivative has antitumor action, has photodynamic effect, the enhancing of its antitumous effect especially under ultraviolet light.
Description
Technical field
The invention belongs to field of photodynamic, more particularly, to the AZT for light power antineoplaston-
Quinoline conjugate derivative and synthetic method.
Background technology
Chemotherapeutics is one of Main Means of oncotherapy, but many chemotherapeutics lack the selection to tumour cell
Property killing, its kill or suppress cancer cell while, normal tissue organ causes damage, especially to myeloid element
With gastrointestinal tract mucosa epithelial cell, the major obstacle played as limitation chemotherapeutics consumption, obstruction curative effect.Chemotherapy can also be produced
Delay or the side reaction in long term.Chemotherapeutics adverse reaction it is serious cause patient death, its adverse reaction mainly has digestion
Road reaction, oral mucosa reaction after underwent, alopecia, bone marrow suppression, cardiopulmonary adverse reaction and skin adverse reaction etc..
Tumor photodynamic therapy utilizes sensitising agent and laser, expeditiously eliminates cancer cell, is a kind of noninvasive therapy.It with
Surgical operation, radiotherapy, chemotherapy are compared, with efficient, low toxicity, selectively killing tumour, resistance to without intersecting with Radiotherapy chemotherapy
The advantage of medicine.Its treat principle be sensitising agent in target tissue under the light source activation of specific wavelength, with the molecule in target tissue
Oxygen interacts, and produces necrosis and apoptosis that the reactive oxygen species with cytotoxic effect are induced, and indirect stimulation production
Inflammatory mediator, cause the damage of cell or tissue.It is different from using the localized hyperthermia produced by high energy laser beam, to lesion
Organize the laser surgey cut, vaporized or solidified.
The pharmaceutical properties of oxygen concentration and sensitising agent have decision to make to the curative effect of photodynamic therapy in excitation source, tissue
With.Using intravenous injection sensitising agent, cancerous tissue largely absorbs sensitising agent, and normal structure very absorbs less；Irradiated with special laser
Cancerous swelling, under luminous energy effect, sensitising agent produces active oxygen (ROS), produces lethal effect to cancer cell, plays antineoplastic treatment
Effect.Active oxygen is the focus that preclinical medicine and life science are studied in recent years.Many researchs show active oxygen and its spread out
It is biological closely related with Apoptosis.Therefore, can be with indirect detection to tumour by detecting the generation of activity of tumor cells oxygen
The process of Apoptosis.
The content of the invention
In view of the above-mentioned deficiencies in the prior art, it is an object of the present invention to there is provided be used for the antineoplastic AZT of light power-
Quinoline conjugate derivative.The ultraviolet that this analog derivative is subjected to UVA wave bands excites and produces photodynamic effect, is combining UVA
After irradiation, the effect for killing tumour cell exceedes some commercially available antineoplastics, is answered with potentially widely antitumor
Use prospect.
To achieve the above object, according to one aspect of the present invention there is provided for the antineoplastic AZT of light power-
Quinoline conjugate derivative, it is characterised in that the derivative is represented by formula I：
In formula, n is 1,3,5 or 7, R1And R2It is simultaneously hydrogen atom；
Or n is 5, R1For fluorine atom, R2For hydrogen atom；
Or n is 5, R1For hydrogen atom, R2For fluorine atom；
Or n is 5, R1And R2It is simultaneously chlorine atom；
Or n is 5, R1And R2It is simultaneously fluorine atom；
Or n is 5, R1And R2It is simultaneously bromine atoms.
It is another aspect of this invention to provide that there is provided the synthetic method for preparing derivative of the present invention, its synthetic route
It is as follows：
It is another aspect of this invention to provide that there is provided the synthetic method for preparing derivative of the present invention, this method includes
Following steps：
(1) with propine amine hydrochlorate condensation reaction occurs in anhydrous methylene chloride for the compound of formula II, obtains the chemical combination of formula III
Thing.
(2) compound of formula III and 4b, 5,6,7,8,8a- it is cis-hexahydro -2- hydroxyls -4b, 8,8a- trimethyl phenanthrene -9,10-
The compound of substitution reaction production IV occurs in anhydrous DMF, under alkalescence condition for diketone.
(3) compound of formula IV is dehydrated aromatization with o-phenylenediamine or halo o-phenylenediamine under conditions of backflow, by poly-
Close reaction and obtain the compound of formula V.
(4) mixed solvent of the compound of formula V and Zidovudine in water, N,N-dimethylformamide and dichloromethane
In, click-reaction occurs under the catalysis of univalent copper ion, derivative of the present invention is generated.
It is another aspect of this invention to provide that there is provided a kind of cancer therapy drug, using derivative of the present invention as active component.
It is another aspect of this invention to provide that there is provided a kind of medicine for light power antineoplaston, with institute of the present invention
Derivative is stated for active component.
It is another aspect of this invention to provide that being main using derivative of the present invention there is provided a kind of anti-cancer drug preparation
Composition, and contain pharmaceutically other acceptable carrier, excipient or/and additives.
It is another aspect of this invention to provide that a kind of medicines resistant to liver cancer preparation or anti-pancreatic cancer medicament preparation are provided, with
Derivative of the present invention is main component, and contains pharmaceutically other acceptable carrier, excipient or/and additives.
The derivative that the present invention is provided can promote tumour cell to produce active oxygen after UVA irradiations are combined, and induced tumor is thin
The apoptosis of born of the same parents, and the effect of kill tumour cell exceedes some commercially available antineoplastics, with potential extensive antitumor
Application prospect.
Brief description of the drawings
Chemical structural formulas of the Fig. 1 for the present invention for AZT-quinoline conjugate derivative of light power antineoplaston.
Fig. 2 a and Fig. 2 b are respectively in 0.85mW/cm2Under UVA irradiations, compound 3, compound 9 and compound B are to liver cancer
Cell (Bel7402) and pancreatic cancer cell (Panc-1) produce the influence of the speed of active oxygen.
Embodiment
In order to make the purpose , technical scheme and advantage of the present invention be clearer, it is right below in conjunction with drawings and Examples
The present invention is further elaborated.It should be appreciated that the specific embodiments described herein are merely illustrative of the present invention, and
It is not used in the restriction present invention.As long as in addition, technical characteristic involved in each embodiment of invention described below
Not constituting conflict each other can just be mutually combined.
Embodiment 1
N-((1- (2- (methylol) -5- ((the 2H)-yl of 5- methyl -2,4- dioxo -3,4- dihydro-pyrimidins -1) tetrahydrochysene furans
Mutter -3- bases) -1H-1,2,3- triazole-4-yls) methyl) -2- (4b, 8,8- trimethyl -4b, 5,6,7,8,8a, 9,10- hexahydros two
Benzo [a, c] phenazinyl -2- oxos) acetamide (compound 1)
Step one：Bromoacetic acid 846mg is dissolved in the solution that 20ml is made in dichloromethane, by propargylamine 500mg, triethylamine
555mg and 1- ethyls -3 (3- dimethyl propylamines) carbodiimide 2.1g is added thereto carry out amidation process, reacts close in room temperature
Carried out under conditions of closing 16 hours, then with dichloromethane extractive reaction solution three times, the purifying of concentrated and silica,
Obtain 2- bromo- N- (2-propynyl) acetamides 270mg.
Step 2：2- bromo- N- (2-propynyl) the acetamides 356mg that step one is obtained is dissolved in anhydrous dimethyl formamide
In 20ml, 4b is added in the solution formed, 5,6,7,8,8a- cis-hexahydro -2- hydroxyls -4b, 8,8a- trimethyls phenanthrene -9,
10- diketone 590mg and potassium carbonate carry out substitution reaction, and reaction is carried out 16 hours under conditions of room temperature is closed, then uses dichloro
Methane extract three times, merge organic phase, after concentration cross silicagel column, obtain N- (2-propynyl) -2- (4b, 8,8- trimethyl -9,
Epoxide -4b, 5,6,7,8,8a, the 9,10- octahydro phenanthryl -2- oxos of 10- bis-) acetamide 378mg.
Step 3：Step 2 is obtained N- (2-propynyl) -2- (4b, 8,8- trimethyl -9,10- two epoxide -4b, 5,
6,7,8,8a, 9,10- octahydro phenanthryl -2- oxos) acetamide 184mg is dissolved in toluene 25ml, added in the solution formed
O-phenylenediamine 59mg and silica white 200mg, is reacted, and reaction flows back 16 hours under conditions of logical nitrogen, directly does removing
Toluene, dry method loading is dissolved in quick eluting silica gel post with 10% methanol dichloromethane, be spin-dried for solvent obtain N- (2-propynyl)-
The thick production of n- (4b, 8,8- trimethyl -4b, 5,6,7,8,8a, 9,10- hexahydro dibenzo [a, c] phenazinyl -2- oxos) acetamide
Thing.
Step 4：Step 3 is obtained N- (2-propynyl)-n- (4b, 8,8- trimethyl -4b, 5,6,7,8,8a, 9,
10- hexahydros dibenzo [a, c] phenazinyl -2- oxos) acetamide and Zidovudine 54mg be dissolved in dimethylformamide 5ml and dichloro
In methane 10ml solution, 40mM ascorbic acid sodium water solution 15ml are added in the solution formed, reaction solution leads to nitrogen 5
After minute deoxygenation, 0.03mmol Salzburg vitriol 8mg, confined reaction 18 hours are added.Reaction solution is extracted with dichloromethane
Three times, merge organic phase, silicagel column is crossed after concentration, obtain title compound 1.
1H NMR (hydrogen spectrum) (MeOH-d4,400MHz):δ=8.14 (d,3J (H, H)=2.7Hz, 1H；CH),8.12-8.09
(m,1H；CH),8.05-8.03(m,1H；CH),8.01(d,3J (H, H)=3.7Hz, 1H；CH),7.83(d,3J (H, H)=
4.9Hz,1H；CH),7.80-7.74(m,2H；2CH),7.44(d,3J (H, H)=8.6Hz, 1H；CH),7.2(dd,3J (H, H)=
8.5Hz,4J (H, H)=2.5Hz, 1H；CH),6.39(t,3J (H, H)=6.6Hz, 1H；CH),5.33-5.25(m,1H；CH),
4.71(s,2H；CH2),4.6(s,2H；CH2),4.30-4.29(m,1H；CH),3.84-3.66(m,2H；CH2),2.87(s,1H；
CH),2.82-2.51(m,3H；CH,CH2),1.89(s,3H；CH3),1.68-1.45(m,5H；3CH2),0.99(d,3J(H,H)
=3.0Hz, 3H；CH3),0.95(s,3H；CH3),0.13ppm(s,3H；CH3)；13C NMR (carbon spectrum) (MeOH-d4,
100.6MHz):δ=171.3,166.4,158.4,156.0,152.2,149.7,146.6,143.2,142.4,14 0.2,
138.2,136.2,130.9,129.4,130.2,129.2,126.8,124.0,119.7,112.8,111.7,86.7,86.3,
68.5,62.2,61.0,60.9,43.0,39.1,38.6,37.2,36.8,35.5,35.2,32.2,22.6,20.1,
12.5ppm；High resolution mass spectrum, calculated value C38H42N8O6Na[M+Na]+729.3125, measured value 729.3129.
Embodiment 2
N-((1- (2- (methylol) -5- ((the 2H)-yl of 5- methyl -2,4- dioxo -3,4- dihydro-pyrimidins -1) tetrahydrochysene furans
Mutter -3- bases) -1H-1,2,3- triazole-4-yls) methyl) -4- (4b, 8,8- trimethyl -4b, 5,6,7,8,8a, 9,10- hexahydros two
Benzo [a, c] phenazinyl -2- oxos) butyramide (compound 2)
Using 4- bromo-butyric acids 1g as raw material, be the same as Example 1 is operated, title compound 2 is obtained.
1H NMR (hydrogen spectrum) (MeOH-d4,400MHz):δ=8.14-8.11 (m,3J (H, H)=7.8Hz,4J (H, H)=
2.2Hz,1H；CH),8.05-8.03(m,2H；2CH),8.01(d,3J (H, H)=4.2Hz, 1H；CH),7.85(d,3J(H,H)
=1.1Hz, 1H；CH),7.81-7.75(m,2H；2CH),7.40(d,3J (H, H)=8.5Hz, 1H；CH),7.09-7.06(m,
1H；CH),6.46-6.42(m,3J (H, H)=6.5Hz,4J (H, H)=2.7Hz, 1H；CH),5.40-5.34(m,1H；CH),
4.48(s,2H；CH2),4.33-4.30(m,1H；CH),4.15-4.11(m,2H；CH2),3.86-3.68(m,2H；CH2),
2.87-2.79(m,2H；CH2),2.67-2.60(m,2H；CH2),2.49(t,3J (H, H)=7.3Hz, 2H；CH2),2.17(q,3J (H, H)=6.3Hz, 2H；CH2),1.88(s,3H；CH3),1.62-1.48(m,5H；CH,2CH2),0.99(d,3J (H, H)=
1.2Hz,3H；CH3),0.95(s,3H；CH3),0.14ppm(s,3H；CH3)；13C NMR (carbon spectrum) (MeOH-d4,100.6MHz):
δ=175.6,166.4,159.5,156.1,152.3,150.0,146.7,143.2,142.3,13 9.0,138.2,136.0,
130.9,130.8,130.2,129.1,126.6,124.1,119.5,112.5,111.7,86.7,86.4,68.4,62.1,
61.1,60.9,43.1,39.1,38.5,37.2,36.9,35.7,35.3,33.5,32.2,26.6,22.6,20.1,
12.5ppm；High resolution mass spectrum, calculated value C40H46N8O6Na[M+Na]+757.3438, measured value 757.3439.
Embodiment 3
N-((1- (2- (methylol) -5- ((the 2H)-yl of 5- methyl -2,4- dioxo -3,4- dihydro-pyrimidins -1) tetrahydrochysene furans
Mutter -3- bases) -1H-1,2,3- triazole-4-yls) methyl) -6- ((4b, 8a- are cis) -4b, 8,8- trimethyl -4b, 5,6,7,8,
8a, 9,10- hexahydro dibenzo [a, c] phenazinyl -2- oxos) caproamide (compound 3)
N- ((1- (2- (methylol) -5- ((the 2H)-yl of 5- methyl -2,4- dioxo -3,4- dihydro-pyrimidins -1) tetrahydrochysene furans
Mutter -3- bases) -1H-1,2,3- triazole-4-yls) methyl) -6- ((4b, 8a- are trans) -4b, 8,8- trimethyl -4b, 5,6,7,8,
8a, 9,10- hexahydro dibenzo [a, c] phenazinyl -2- oxos) caproamide (compound 4)
Step one：Acid 1.2g is dissolved in the solution that 20ml is made in dichloromethane to 6- bromines, by propargylamine 500mg, triethylamine
555mg and 1- ethyls -3 (3- dimethyl propylamines) carbodiimide 2.1g is added thereto carry out amidation process, reacts close in room temperature
Carried out under conditions of closing 16 hours, then with dichloromethane extractive reaction solution three times, the purifying of concentrated and silica,
Obtain bromo N- (2-propynyl) amide.
Step 2：Bromo N- (2-propynyl) the amides 2mmol that step one is obtained is dissolved in anhydrous dimethyl formamide
In 20ml, 4b is added in the solution formed, 5,6,7,8,8a- cis-hexahydro -2- hydroxyls -4b, 8,8a- trimethyls phenanthrene -9,
10- diketone 590mg and potassium carbonate carry out substitution reaction, and reaction is carried out 16 hours under conditions of room temperature is closed, then uses dichloro
Methane extract three times, merge organic phase, after concentration cross silicagel column, obtain N- (2-propynyl) -2- (4b, 8,8- trimethyl -9,
Epoxide -4b, 5,6,7,8,8a, the 9,10- octahydro phenanthryl -2- oxos of 10- bis-) amide.
Step 3：Step 2 is obtained N- (2-propynyl) -2- (4b, 8,8- trimethyl -9,10- two epoxide -4b, 5,
6,7,8,8a, 9,10- octahydro phenanthryl -2- oxos) amide 184mg is dissolved in toluene 25ml, added in the solution formed
O-phenylenediamine 59mg and silica white 200mg, is reacted, and reaction flows back 16 hours under conditions of logical nitrogen, directly does removing
Toluene, dry method loading is dissolved in quick eluting silica gel post with 10% methanol dichloromethane, be spin-dried for solvent obtain N- (2-propynyl)-
The thick production of n- (4b, 8,8- trimethyl -4b, 5,6,7,8,8a, 9,10- hexahydro dibenzo [a, c] phenazinyl -2- oxos) amide
Thing.
Step 4：Step 3 is obtained N- (2-propynyl) -2- (4b, 8,8- trimethyl -4b, 5,6,7,8,8a, 9,
10- hexahydros dibenzo [a, c] phenazinyl -2- oxos) caproamide and Zidovudine 54mg be dissolved in dimethylformamide 5ml and dichloromethane
In alkane 10ml solution, 40mM ascorbic acid sodium water solution 15ml are added in the solution formed, reaction solution leads to 5 points of nitrogen
After clock deoxygenation, 0.03mmol Salzburg vitriol 8mg, confined reaction 18 hours are added.Reaction solution extracts three with dichloromethane
It is secondary, merge organic phase, silicagel column is crossed after concentration, title compound 3 and title compound 4 is obtained, both can pass through efficient liquid phase
Chromatographic isolation.
Compound 3
1H NMR (hydrogen spectrum) (MeOH-d4,400MHz):δ=11.35 (s, 1H；OH), 8.34 (t, 3J (H, H)=5.5Hz,
1H；CH),8.14-8.11(m,2H；2CH),8.06-8.04(m,1H；), CH 7.96 (d, 4J (H, H)=2.8Hz, 1H；CH),
7.79(m,3H；2CH, NH), 7.39 (d, 3J (H, H)=8.7Hz, 1H；CH), 7.11 (dd, 3J (H, H)=8.5Hz, 4J (H,
H)=2.8Hz, 1H；), CH 6.40 (t, 3J (H, H)=6.6Hz, 1H；CH),5.36-5.33(m,1H；CH),5.28(t,3J(H,
H)=5.2Hz, 1H；), NH 4.31 (d, 3J (H, H)=5.5Hz, 2H；CH2),4.18(m,1H；CH), 4.06 (t, 3J (H, H)=
6.4Hz,2H；CH2),3.67-3.60(m,2H；CH2),2.85(s,1H；CH),2.67-2.57(m,2H；CH2),2.16(t,3J
(H, H)=7.4Hz, 2H；CH2),1.79-1.62(m,5H；CH3,CH2),1.56-1.43(m,10H；5CH2),0.93(s,3H；
CH3),0.91(s,3H；CH3),0.07ppm(s,3H；CH3)；13C NMR (carbon spectrum) (DMSO-d6,100.6MHz):δ=
172.0,163.6,157.4,154.2,150.4,147.5,145.2,141.1,140.9,137.1,136.1,134.1,
129.5,129.4,128.9,128.4,125.3,122.4,117.7,110.8,109.5,84.4,83.8,67.4,60.6,
59.0,58.5,41.2,37.0,36.8,35.5,35.1,34.9,34.4,34.0,31.3,28.5,25.2,24.9,21.6,
18.5,12.2ppm；High resolution mass spectrum, calculated value C42H51N8O6[M+H]+763.3932, measured value 763.3959.
Compound 4
1H NMR (hydrogen spectrum) (MeOH-d4,400MHz):δ=8.09-8.01 (m, 2H；2CH),7.97(s,1H；CH),7.94
(d,3J (H, H)=2.8Hz, 1H；CH),7.83(t,3J (H, H)=1.3Hz, 1H；CH),7.75-7.72(m,2H；2CH),7.36
(d,3J (H, H)=8.7Hz, 1H；CH),7.05-7.02(m,1H；CH),6.44-6.40(m,1H；CH),5.40-5.34(m,
1H；CH),4.45(s,2H；CH2),4.32-4.28(m,1H；CH),4.14-4.04(m,2H；CH2),3.85-3.69(m,2H；
CH2),2.94(s,1H；CH),2.88-2.62(m,2H；CH2),2.38(d,3J (H, H)=11.4Hz, 1H；CH),2.29(t,3J
(H, H)=7.3Hz, 2H；CH2),1.96-1.87(m,2H；CH2),1.86(s,3H；CH3),1.84-1.70(m,6H；3CH2),
1.61(s,3H；CH3),1.58-1.52(m,3H；CH,CH2),1.49(s,3H；CH3),1.47-1.29(m,2H；CH2),
0.99ppm(s,3H；CH3)；13C NMR (carbon spectrum) (MeOH-d4,100.6MHz):δ=157.9,155.2,152.4,150.8,
148.4,146.9,145.9,145.3,144.8,144.6,140.7,140.4,136.7,132.3,129.1,128.9,
128.6, 128.5,124.3,122.6,118.2,110.5,110.2,85.2,85.0,85.0,67.7,60.8,59.7,
56.0,44.1,37.5,35.5,34.3,33.7,32.6,28.8,25.4,25.3,23.4,20.4,18.3,11.2ppm；High score
Distinguish mass spectrum, calculated value C42H50N8O6Na[M+Na]+785.3751, measured value 785.3750.
Embodiment 4
N- ((1- (2- (methylol) -5- ((the 2H)-yl of 5- methyl -2,4- dioxo -3,4- dihydro-pyrimidins -1) tetrahydrochysene furans
Mutter -3- bases) -1H-1,2,3- triazole-4-yls) methyl) -8- ((4b, 8a- are cis)-(and 4b, 8,8- trimethyl -4b, 5,6,7,8,
8a, 9,10- hexahydro dibenzo [a, c] phenazinyl -2- oxos) caprylamide (compound 5)
N- ((1- (2- (methylol) -5- ((the 2H)-yl of 5- methyl -2,4- dioxo -3,4- dihydro-pyrimidins -1) tetrahydrochysene furans
Mutter -3- bases) -1H-1,2,3- triazole-4-yls) methyl) -8- ((4b, 8a- are trans) -4b, 8,8- trimethyl -4b, 5,6,7,8,
8a- hexahydros benzo [a, c] phenazinyl -2- oxos) caprylamide (compound 6)
Using 8- bromines octanoic acid 1.34g as raw material, be the same as Example 3 is operated, title compound 5 and title compound 6 is obtained.
Compound 5
1H NMR (hydrogen spectrum) (MeOH-d4,400MHz):δ=8.13-8.10 (m, 1H；CH),8.05-8.01(m,2H；
2CH),7.99(s,1H；), CH 7.88 (d, 3J (H, H)=1.1Hz, 1H；CH),7.78-7.72(m,2H；2CH),7.35(d,3J
(H, H)=8.7Hz, 1H；), CH 7.06 (dd, 3J (H, H)=8.6Hz, 4J (H, H)=2.8Hz, 1H；CH),6.46(t,3J(H,
H)=6.4Hz, 1H；CH),5.42-5.37(m,1H；CH),4.44(s,2H；CH2),4.34-4.32(m,1H；CH),4.09-
4.04(m,2H；CH2),3.89-3.72(m,2H；CH2),2.90-2.83(m,2H；CH2),2.73-2.57(m,2H；CH2),
2.23(t,3J (H, H)=7.4Hz, 2H；CH2),1.87(s,3H；CH3),1.83-1.76(m,2H；CH2),1.68-1.26(m,
14H；7CH2),0.96(s,3H；CH3),0.92(s,3H；CH3),0.12ppm(s,3H；CH3)；13C NMR (carbon spectrum) (MeOH-
d4,100.6MHz):δ=176.2,166.4,159.6,156.1,152.3,150.0,146.6,143.2,142.3,13 8.7,
138.2,135.9,130.8,130.7, 130.2,129.1,126.5,124.0,119.4,112.4,111.7,86.7,86.4,
69.2,62.2,61.0,60.9,43.0,39.1,38.4,37.1,36.9,36.9,35.6,35.3,32.2,30.4,30.2,
30.2,27.1,26.8,22.6,20.1,12.6ppm；High resolution mass spectrum, calculated value C44H54N8O6Na[M+Na]+813.4064,
Measured value 813.4061.
Compound 6
1H NMR (hydrogen spectrum) (MeOH-d4,400MHz):δ=8.17-8.14 (m, 1H；CH),8.11-8.09(m,1H；CH),
8.06(s,1H；CH),8.01(d,3J (H, H)=2.8Hz, 1H；CH),7.90(d,3J (H, H)=1.0Hz, 1H；CH),7.84-
7.81(m,2H；2CH),7.45(d,3J (H, H)=8.7Hz, 1H；CH),7.13(dd,3J (H, H)=8.6Hz,4J (H, H)=
2.8Hz,1H；CH),6.53(t,3J (H, H)=6.6Hz, 1H；CH),5.46-5.42(m,1H；CH),4.46(s,2H；CH2),
4.17-4.12(m,2H；CH2),3.89-3.74(m,2H；CH2),3.02(s,1H；CH),2.89-2.69(m,2H；CH2),2.45
(d,3J (H, H)=10.9Hz, 2H；CH2),2.26(t,3J (H, H)=7.4Hz, 2H；CH2),1.99-1.78(m,8H；CH,
2CH2,CH3),1.72-1.33(m,18H；6CH2,2CH3),1.04ppm(s,3H；CH3)；13C NMR (carbon spectrum) (MeOH-d4,
100.6MHz):δ=174.1,164.5,158.0,155.3,150.9,148.4,145.5,144.6,140.8,14 0.5,
136.6,132.4,129.4,129.2,128.8,128.8,124.6,122.8,122.7,118.4,110.6,110.2,85.1,
85.0,68.0,61.0,59.8,56.0,44.2,37.7,37.5,35.6,34.4,33.8,32.9,29.1,29.0,28.9,
25.9,25.6,23.8,20.8,18.5,11.7ppm；High resolution mass spectrum, calculated value C44H54N8O6Na[M+Na]+813.4064,
Measured value 813.4060.
Embodiment 5
6- ((the fluoro- 4b of (4bR, 8aS) -12-, 8- dimethyl -4b, 5,6,7,8,8a- hexahydro dibenzo [a, c] phenazinyl -
2- yls) oxo)-N- ((1- (2- (methylol) -5- ((the 2H)-yl of 5- methyl -2,4- dioxo -3,4- dihydro-pyrimidins -1) tetrahydrochysenes
Furans -3- bases) -1H-1,2,3- triazole-4-yls) methyl) caproamide (compound 7)
6- ((the fluoro- 4b of (4bR, 8aS) -11-, 8- dimethyl -4b, 5,6,7,8,8a- hexahydro dibenzo [a, c] phenazinyl -
2- yls) oxo)-N- ((1- (2- (methylol) -5- ((the 2H)-yl of 5- methyl -2,4- dioxo -3,4- dihydro-pyrimidins -1) tetrahydrochysenes
Furans -3- bases) -1H-1,2,3- triazole-4-yls) methyl) caproamide (compound 8)
Be the same as Example 3 is operated, difference is, with the fluoro- o-phenylenediamine 69.4mg substituted o-phenylenediamine 59mg of 4- in step 3,
Obtain title compound 7 and title compound 8.
Compound 7
1H NMR (hydrogen spectrum) (MeOH-d4,400MHz):δ=8.08 (dd,3J (H, H)=9.2Hz,4J (H, H)=5.7Hz,
1H；CH),8.04(d,3J (H, H)=2.8Hz, 1H；CH),7.99(s,1H；CH),7.86(d,3J (H, H)=1.0Hz, 1H；
CH),7.81-7.77(m,1H；CH),7.62-7.57(m,3J (H, H)=8.5Hz,4J (H, H)=2.8Hz, 1H；CH),7.40
(d,3J (H, H)=8.6Hz, 1H；CH),7.10(dd,3J (H, H)=8.6Hz,4J (H, H)=2.8Hz, 1H；CH),6.45(t,3J (H, H)=6.4Hz, 1H；CH),5.42-5.36(m,1H；CH),4.46(s,2H；CH2),4.35-4.32(m,1H；CH),
4.10(t,3J (H, H)=6.3Hz, 2H；CH2),3.88-3.71(m,2H；CH2),2.91-2.84(m,2H；CH2),2.72-
2.61(m,2H；CH2),2.29(t,3J (H, H)=7.3Hz, 2H；CH2),1.90-1.82(m,5H；CH2,CH3),1.78-1.45
(m,10H；5CH2),0.99(s,3H；CH3),0.94(s,3H；CH3),0.14ppm(s,3H；CH3)；13C NMR (carbon spectrum)
(MeOH-d4,100.6MHz):δ=176.2,166.4,159.7,152.3,150.7,146.7,139.6,139.1,138.2,
135.6,131.6,131.5,126.6,124.1,120.6,120.4,119.8,113.6,113.4,112.5,111.7,86.7,
86.4,69.1,62.2,61.1,60.8,43.0,39.1,38.5,37.1,36.9,36.8,35.6,35.3,32.2,30.2,
26.8,26.7,22.6,20.1,12.5ppm；High resolution mass spectrum, calculated value C42H49FN8O6Na[M+Na]+803.3657, actual measurement
Value 803.3660.
Compound 8
1H NMR (hydrogen spectrum) (MeOH-d4,400MHz):δ=8.19-8.15 (m, 1H；CH),8.02(d,3J (H, H)=
2.8Hz,1H；CH),7.99(s,1H；CH),7.86(d,3J (H, H)=1.1Hz, 1H；CH),7.68(dd,3J (H, H)=
9.4Hz,4J (H, H)=2.8Hz, 1H；CH),7.63-7.58(m,3J (H, H)=8.6Hz,4J (H, H)=2.8Hz, 1H；CH),
7.38(d,3J (H, H)=8.6Hz, 1H；CH),7.07(dd,3J (H, H)=8.6Hz,4J (H, H)=2.7Hz, 1H；CH),6.45
(t,3J (H, H)=6.5Hz, 1H；CH),5.42-5.36(m,1H；CH),4.46(s,2H；CH2),4.34-4.31(m,1H；CH),
4.09(t,3J (H, H)=6.3Hz, 2H；CH2),3.88-3.71(m,2H；CH2),2.90-2.83(m,2H；CH2),2.71-
2.60(m,2H；CH2),2.29(t,3J (H, H)=7.3Hz, 2H；CH2),1.89-1.81(m,5H；CH2,CH3),1.78-1.44
(m,10H；5CH2),0.98(s,3H；CH3),0.94(s,3H；CH3),0.14ppm(s,3H；CH3)；13C NMR (carbon spectrum)
(MeOH-d4,100.6MHz):δ=176.2,166.4,159.7,157.2,152.3,146.7,143.1,140.4,138.7,
138.2,135.7,132.6,126.5,124.0,120.8,120.5,119.5,112.9,112.7,112.3,111.7,86.7,
86.4,69.1,62.2,61.1,61.0,43.1,39.1,38.4,37.2,36.9,36.8,35.6,35.3,32.3,30.2,
26.9,26.7,22.6,20.1,12.5ppm；High resolution mass spectrum, calculated value C42H49FN8O6Na[M+Na]+803.3657, actual measurement
Value 803.3660.
Embodiment 6
6- ((the chloro- 4b of (4bR, 8aS) -11,12- two, 8- dimethyl -4b, 5,6,7,8,8a- hexahydro dibenzo [a, c] fen
Piperazine base -2- bases) oxo)-N- ((1- (2- (methylol) -5- ((the 2H)-yl of 5- methyl -2,4- dioxo -3,4- dihydro-pyrimidins -1)
Tetrahydrofuran -3- bases) -1H-1,2,3- triazole-4-yls) methyl) methyl) caproamide (compound 9)
Be the same as Example 3 is operated, difference is, with the chloro- o-phenylenediamine 97.4mg substituted o-phenylenediamines of 4,5- bis- in step 3
59mg, obtains title compound 9.
1H NMR (hydrogen spectrum) (DMSO-d6,400MHz):δ=11.34 (s, 1H；OH),8.43(s,1H；CH),8.35-8.32
(m,2H；2CH),8.11(s,1H；CH),7.92(d,3J (H, H)=2.8Hz, 1H；CH),7.79(s,1H；CH),7.41(d,3J
(H, H)=8.7Hz, 1H；CH),7.14(dd,3J (H, H)=8.5Hz,4J (H, H)=2.8Hz, 1H；CH), 6.40(t,3J(H,
H)=6.7Hz, 1H；CH),5.36-5.32(m,1H；CH),5.28(t,3J (H, H)=5.1Hz, 1H；CH),4.31(d,3J(H,
H)=5.5Hz, 2H；CH2),4.20-4.17(m,1H；CH),4.05(t,3J (H, H)=6.3Hz, 2H；CH2),3.70-3.57
(m,2H；CH2),2.86(s,1H；CH),2.71-2.57(m,3H；CH,CH2),2.16(t, 3J (H, H)=7.3Hz, 2H；
CH2),1.79-1.69(m,5H；CH2,CH3),1.65-1.39(m,10H；5CH2),0.93(s,3H；CH3),0.89(s,3H；
CH3),0.07ppm(s,3H；CH3)；13C NMR (carbon spectrum) (DMSO-d6,100.6MHz):δ=172.0,163.6,157.5,
156.0,150.3,148.7,145.2,140.2,139.9,137.4,136.1,133.4,132.2,132.0,129.8,
129.3,125.4,122.5,118.4,111.0,109.5,84.4,83.8,67.4,60.6,59.0,58.6,41.1,37.0,
36.8,35.6,35.1,34.8,34.5,34.0,31.1,28.5,25.2,24.9,21.7,18.5,12.2ppm；High-resolution matter
Spectrum, calculated value C42H48Cl2N8O6Na[M+Na]+853.2972, measured value 853.2969.
Embodiment 7
Be the same as Example 3 is operated, difference is, with the fluoro- o-phenylenediamine 78.6mg substituted o-phenylenediamines of 4,5- bis- in step 3
59mg, obtains title compound 10.
1H NMR (hydrogen spectrum) (MeOH-d4,400MHz):δ=8.09-8.01 (m, 2H；2CH),7.97(s,1H；CH),7.94
(d,3J (H, H)=2.8Hz, 1H；CH),7.83(t,3J (H, H)=1.3Hz, 1H；CH),7.75-7.72(m,2H；2CH),7.36
(d,3J (H, H)=8.7Hz, 1H；CH),7.05-7.02(m,1H；CH),6.44-6.40(m,1H；CH),5.40-5.34(m,
1H；CH),4.45(s,2H；CH2),4.32-4.28(m,1H；CH),4.14-4.04(m,2H；CH2),3.85-3.69(m,2H；
CH2),2.94(s,1H；CH),2.88-2.62(m,2H；CH2),2.38(d,3J (H, H)=11.4Hz, 1H；CH),2.29(t,3J
(H, H)=7.3Hz, 2H；CH2),1.96-1.87(m,2H；CH2),1.86(s,3H；CH3),1.84-1.70(m,6H；3CH2),
1.61(s,3H；CH3),1.58-1.52(m,3H；CH,CH2),1.49(s,3H；CH3),1.47-1.29(m,2H；CH2),
0.99ppm(s,3H；CH3)；13C NMR (carbon spectrum) (MeOH-d4,100.6MHz):δ=157.9,155.2,152.4,150.8,
148.4,146.9,145.9, 145.3,144.8,144.6,140.7,140.4,136.7,132.3,129.1,128.9,
128.6,128.5,124.3,122.6,118.2,110.5,110.2,85.2,85.0,85.0,67.7,60.8,59.7,56.0,
44.1,37.5,35.5,34.3,33.7,32.6,28.8,25.4,25.3,23.4,20.4,18.3,11.2ppm；High-resolution matter
Spectrum, calculated value C42H50N8O6Na[M+Na]+785.3751, measured value 785.3750.
Embodiment 8
Be the same as Example 3 is operated, difference is, with the bromo- o-phenylenediamine 145mg substituted o-phenylenediamines of 4,5- bis- in step 3
59mg, obtains title compound 11.
(MeOH-d4,400MHz):δ=8.17-8.14 (m, 1H；CH),8.11-8.09(m,1H；CH),8.06(s,1H；
CH),8.01(d,3J (H, H)=2.8Hz, 1H；CH),7.90(d,3J (H, H)=1.0Hz, 1H；CH),7.84-7.81(m,2H；
2CH),7.45(d,3J (H, H)=8.7Hz, 1H；CH),7.13(dd,3J (H, H)=8.6Hz,4J (H, H)=2.8Hz, 1H；
CH),6.53(t,3J (H, H)=6.6Hz, 1H；CH),5.46-5.42(m,1H；CH),4.46(s,2H；CH2),4.17-4.12
(m,2H；CH2),3.89-3.74(m,2H；CH2),3.02(s,1H；CH),2.89-2.69(m,2H；CH2),2.45(d,3J(H,
H)=10.9Hz, 2H；CH2),2.26(t,3J (H, H)=7.4Hz, 2H；CH2),1.99-1.78(m,8H；CH,2CH2,CH3),
1.72-1.33(m,18H；6CH2,2CH3),1.04ppm(s,3H；CH3)；13C NMR (carbon spectrum) (MeOH-d4,100.6MHz):δ
=174.1,164.5,158.0,155.3,150.9,148.4,145.5,144.6,140.8,14 0.5,136.6,132.4,
129.4,129.2,128.8,128.8,124.6,122.8,122.7,118.4,110.6,110.2,85.1,85.0,68.0,
61.0,59.8,56.0,44.2,37.7,37.5,35.6,34.4,33.8,32.9,29.1,29.0,28.9,25.9,25.6,
23.8,20.8,18.5,11.7ppm；High resolution mass spectrum, calculated value C44H54N8O6Na[M+Na]+813.4064, measured value
813.4060。
Comparative example A
N- ((1- (2- (methylol) -5- ((the 2H)-yl of 5- methyl -2,4- dioxo -3,4- dihydro-pyrimidins -1) tetrahydrochysene furans
Mutter -3- bases) -1H-1,2,3- triazole-4-yls) methyl) -6- (((4bS, 8aR) -4b, 8,8- trimethyl -9,10- dioxos -
4b, 5,6,7,8,8a, 9,10- octahydro phenanthryl -2- bases) oxo) caproamide (compound A)
The step of step one and step 2 are with embodiment 3 one and step 2 are identical.
Step 3：Weigh N- (2-propynyl) -2- (4b, 8,8- trimethyl -9,10- two epoxide -4b, 5,6,7,8,8a, 9,
10- octahydro phenanthryl -2- oxos) amide 184mg is dissolved in N,N-dimethylformamide 5mL and dichloromethane 10mL mixed solvent
In, Zidovudine 54mg and 40mmol ascorbic acid sodium water solution 15ml is added, the mixed solution excludes air with nitrogen, then adds
Enter 0.03mmol Salzburg vitriol 8mg, confined reaction 18 hours.Reaction solution is extracted three times with dichloromethane, merges organic phase,
Silicagel column is crossed after concentration, compound A is obtained.
1H NMR (hydrogen spectrum) (MeOH-d4,400MHz):δ=8.00 (s, 1H；CH),7.90(d,3J (H, H)=1.1Hz,
1H；CH),7.53(d,3J (H, H)=6.2Hz, 1H；CH),7.52(s,1H；CH),7.33(dd,3J (H, H)=8.7Hz,4J(H,
H)=2.9Hz, 1H；CH),6.47(t,3J (H, H)=6.5Hz, 1H；CH),5.43-5.38(m,1H；CH),4.44(s,2H；
CH2),4.35-4.33(m,1H；CH),4.05(t,3J (H, H)=6.3Hz, 2H；CH2),3.90-3.73(m,2H；CH2),
2.91-2.85(m,1H；CH),2.75-2.62(m,3H；CH,CH2),2.27(t,3J (H, H)=7.4Hz, 2H；CH2),1.90
(d,3J (H, H)=1.0Hz, 3H；CH3),1.85-1.35(m,13H；CH,6CH2),1.19(s,3H；CH3),0.93(s,3H；
CH3),0.39ppm(s,3H；CH3)；13C NMR (carbon spectrum) (MeOH-d4,100.6MHz):δ=200.7,182.9,176.1,
166.4,159.8,152.3,144.2,138.3,135.8,127.9,125.2,124.0,113.8,111.7,101.4,86.8,
86.4,70.0,69.3,62.2,61.1,42.9,40.3,39.2,39.1,37.0,36.8,36.4,35.6,31.8,29.9,
26.7,26.6,24.6,20.0,12.5ppm；High resolution mass spectrum, calculated value C36H47N6O8[M+H]+691.3455, measured value
691.3460。
Comparative example B
N- ((1- ((3R, 4S, 5S, 6R) -3,4,5- trihydroxies -6- (methylol) tetrahydrochysene -2H- pyrans -2- bases) -1H-1,
2,3- triazole-4-yls) methyl) -6- (((4b, 8a- are cis) -4b, 8,8- trimethyl -4b, 5,6,7,8,8a- hexahydro benzo [a,
C] phenazinyl -2- bases) oxo) caproamide (compound B)
N- ((1- ((3R, 4S, 5S, 6R) -3,4,5- trihydroxies -6- (methylol) tetrahydrochysene -2H- pyrans -2- bases) -1H-1,
2,3- triazole-4-yls) methyl) -6- (((4b, 8a- are trans) -4b, 8,8- trimethyl -4b, 5,6,7,8,8a- hexahydro benzo [a,
C] phenazinyl -2- bases) oxo) caproamide (compound C)
Embodiment 5 is repeated by described same steps, difference is, with 1- nitrine -1- deoxidation-β-D- pyrans in step 3
Galactoside 41mg replaces Zidovudine, obtains compound B and compound C.
Compound B
1H NMR (hydrogen spectrum) (MeOH-d4,400MHz):δ=8.16-8.13 (m, 1H；CH),8.09(s,1H；CH),8.07-
8.03(m,2H；2CH),7.81-7.74(m,2H；2CH),7.39(d,3J (H, H)=8.7Hz, 1H；CH),7.09(dd,3J(H,
H)=8.6Hz,4J (H, H)=2.8Hz, 1H；CH),5.54(q,3J (H, H)=9.2Hz,4J (H, H)=1.2Hz, 1H；CH),
4.47(d,3J (H, H)=2.3Hz, 2H；CH2),4.15-4.09(m,3H；CH,CH2),3.97(d,3J (H, H)=3.1Hz, 1H；
CH),3.83-3.66(m,4H；2CH,CH2),2.86(s,1H；CH),2.64(d,3J (H, H)=14.2Hz, 1H；CH),2.30
(t,3J (H, H)=7.4Hz, 2H；CH2),1.90-1.83(m,2H；CH2),1.78-1.44(m,10H；5CH2),0.99(s,3H；
CH3),0.95(s,3H；CH3),0.15ppm(s,3H；CH3)；13C NMR (carbon spectrum) (MeOH-d4,100.6MHz):δ=176.2,
159.7,156.1,150.1,150.0,146.6,143.2,142.3,138.8,135.9,130.8,130.7,130.2,
129.1,126.5,123.0,119.5,112.4,90.3,80.0,75.3,71.5,70.4,69.0,62.4,60.9,43.1,
38.5,37.2,36.9,36.9,35.7,35.3,32.2,30.2,26.9,26.7,22.6,20.1ppm；High resolution mass spectrum, meter
Calculation value C44H54N8O6Na[M+Na]+723.3482, measured value 723.3480.
Comparative example C
4- (1- (2- (methylol) -5- ((the 2H)-yl of 5- methyl -2,4- dioxo -3,4- dihydro-pyrimidins -1) tetrahydrofuran -
3- yls) -1H-1,2,3- triazole-4-yls)-N- (pyrene -2- bases) acetamide (compound D)
Weigh 0.92mmol 2- amino pyrene 200mg and 1.01mmol hexynic acids 113.5mg and be dissolved in dry dichloromethane
In 10mL, 0.92mmol DIPEA 200mg and 2mmol1- ethyl-(3- dimethylaminopropyls) phosphinylidyne are added
Diimmonium salt hydrochlorate 383mg, closed stirring reaction 18 hours.Reaction solution is extracted three times with dichloromethane, merges organic phase, concentration
Silicagel column is crossed afterwards, obtains -5- alkynyl the caproamides of the higher N- of purity (pyrene -2- bases) six.
Weigh -5- alkynyl caproamides the 62mg of N- (pyrene -2- bases) six and be dissolved in N,N-dimethylformamide 5mL and dichloromethane
10mL in the mixed solvent, adds 0.2mmol Zidovudine 54mg and 40mM ascorbic acid sodium water solution 15ml, the mixed solution
Air is excluded with nitrogen, 0.03mmol Salzburg vitriol 8mg, confined reaction 18 hours is added.Reaction solution dichloromethane
Extraction three times, merges organic phase, and silicagel column is crossed after concentration, the higher compound D of purity is obtained.
1H NMR (hydrogen spectrum) (MeOH-d4,400MHz):δ=11.37 (s, 1H；NH),10.31(s,1H；NH),8.32-
8.20(m,6H；6CH),8.17-8.12(m,3H；3CH),8.07(t,3J (H, H)=7.6Hz, 1H；CH),7.83(s,1H；
CH),6.44(t,3J (H, H)=6.5Hz, 1H；CH),5.37-5.32(m,2H；2CH),4.23-4.22(m,1H；OH),3.72-
3.62(m,2H；CH2),2.83-2.60(m,6H；3CH2),2.08(qui,2H；CH2),1.82ppm(s,3H；CH3)；13C NMR
(carbon spectrum) (MeOH-d4,100.6MHz):δ=171.7,163.6,150.3,146.7,136.1,131.8,130.7,130.4,
128.0,127.1,126.9,126.4,126.2,125.1,124.8,124.7,124.3,123.8,123.7,123.3,
122.3, 121.5,109.5,84.4,83.8,60.7,58.9,37.0,35.3,25.0,24.7,12.1ppm；High-resolution matter
Spectrum, calculated value C32H30N6O5Na[M+Na]+601.2175, measured value 601.2170.
Particular compound structure is as shown in table 1 in embodiment and comparative example.
Table 1
Test example 1
Key instrument：Bruker Avance-400 and 600 magnetic resonance spectroscopy instrument, Thermo Fisher TSQ Quantum
Max Triple Stage Quadrupole mass spectrographs (MA, USA) etc..
Cell culture：Bel7402 (Bel7402), human pancreatic cancer cell (Panc-1) is from Chinese Academy of Sciences Shanghai
Life science Cell Culture Center (Chinese Shanghai) research institute buys.All cell culture are in 37 DEG C, 5%CO2And DMEM in high glucose
In culture medium (Invitrogen companies, California, USA), it is aided with 10% heat inactivation calf serum, 25mmol/ rises 4-
Hydroxyethyl piperazineethanesulfonic acid cushioning liquid, 2mmol/L Glus, 0.1mmol/L nonessential amino acid, 1.0mmol/L third
Ketone acid sodium, 50U/mL penicillin, 50 μ g/mL streptomysins.
Cytoactive experimental procedure：By cancer cell culture in 96 porocyte culture plates, several title compounds are separately added into
Thing and control compound, after cultivating 48 hours, the activity of cell is determined with mtt assay【Method referring to：Zhou,et
al.Chem.Res.Toxicol.2008,21,732-738】, the results are shown in Table 2.
Each compound of table 2 is in 0.85mW/cm2To two kinds of cell lines (Bel7402 and Panc-1) under UVA and no light
IC50 (uM) value influence
Upper table result shows that the antitumous effect of 9 kinds of derivatives of the invention is better than control compound, is preferably anti-
Cancer drug.
Test example 2
With test example 1 under the same conditions, it is and commercially available antitumor by taking compound 9, compound 10 and compound 11 as an example
Medicine Sutent and gemcitabine have done the control experiment of different light intensity, and experiment is from UVA 5.4mW/cm2、UVA 3mW/cm2
With three conditions of no light, its IC50 is shown in Table 3：
The compound 9 of table 3, Buddhist nun of relaxing replace the IC50 (uM) of you and gemcitabine under different light intensity to Bel7402 and Panc-1
The influence of value
Upper table result shows, under UVA irradiations, and the antitumous effect of the derivative synthesized according to the present invention is better than commercially available
Antineoplastic, with good light power antineoplaston effect.Wherein compound 9 is in 5.4mW/cm2UVA irradiation bar
Under part, compared with conditions of no light, its antitumor activity improves nearly 100 times.
Test example 3
Fig. 2 is under the same conditions, compound 3, compound 9 and control compound B are in 0.85mW/ with test example 1
cm2Under UVA irradiations, detect that Bel7402 (Fig. 2 a) and Panc-1 (Fig. 2 b) produces the speed of active oxygen by H2DCFDA fluorescence probes
Rate figure.
As can be seen from Figure 2, it can promote to swell under UVA irradiations according to AZT-quinoline conjugate derivative of the present invention
Oncocyte produces substantial amounts of active oxygen, and green fluorescence is sent with reference to H2DCFDA fluorescence probes.The wherein activity of compound 9 is slightly better than
Compound 3, better than control compound B.After UVA irradiations, with the raising of AZT-quinoline conjugate derivative activity,
A large amount of generations of cell activity itself oxygen are excited, so that inducing cell active oxygen Apoptosis mechanism, and then make tumour cell dead
Die.
Above description of test, the AZT-quinoline conjugate derivative synthesized according to the present invention has antitumor action, and
And after UVA irradiations are combined, it kills the active stronger of tumour cell, more than some commercially available antineoplastics, with latent
Extensive antitumor application thereof prospect.
Test example 4
42g compounds 9 are dissolved in dimethyl sulfoxide solvent, 1L is settled to, 50mmol/L solution is configured to.The solution
Again with 1:1000 are diluted in physiological saline, are made into 50 μm of ol/L solution, and filtering sterilization is intravenous injection.It is recommended that injection
Measure as daily 0.1mg/kg~0.5mg/kg.
As it will be easily appreciated by one skilled in the art that the foregoing is merely illustrative of the preferred embodiments of the present invention, it is not used to
The limitation present invention, any modifications, equivalent substitutions and improvements made within the spirit and principles of the invention etc., it all should include
Within protection scope of the present invention.
Claims (8)
1. AZT-quinoline conjugate derivative for light power antineoplaston, it is characterised in that the derivative is by formula I
To represent：
In formula, n is 1,3 or 7, R1And R2It is simultaneously hydrogen atom；
Or n is 5, R1For fluorine atom, R2For hydrogen atom；
Or n is 5, R1For hydrogen atom, R2For fluorine atom；
Or n is 5, R1And R2It is simultaneously chlorine atom；
Or n is 5, R1And R2It is simultaneously fluorine atom；
Or n is 5, R1And R2It is simultaneously bromine atoms.
2. a kind of synthetic method for being used to prepare derivative as claimed in claim 1, its synthetic route is as follows：
3. a kind of synthetic method for being used to prepare derivative as claimed in claim 1, it is characterised in that this method includes following step
Suddenly：
(1) with propine amine hydrochlorate condensation reaction occurs in anhydrous methylene chloride for the compound of formula II, obtains the compound of formula III；
(2) compound of formula III and 4b, 5,6,7,8,8a- it is cis-hexahydro -2- hydroxyls -4b, 8,8a- trimethyl phenanthrene -9,10- diketone
The compound of substitution reaction production IV occurs in anhydrous DMF, under alkalescence condition；
(3) compound of formula IV is dehydrated aromatization with o-phenylenediamine or halo o-phenylenediamine under conditions of backflow, anti-by polymerization
The compound of formula V should be obtained；
(4) compound of formula V and Zidovudine water, DMF and dichloromethane in the mixed solvent, one
Click-reaction, derivative described in generation claim 1 occur under the catalysis of valency copper ion；
Wherein, the structure of II compound, the compound of the formula III, the compound of the formula IV and the compound of the formula V
Formula difference is as follows：
4. a kind of cancer therapy drug, using derivative described in claim 1 as active component.
5. a kind of medicine for light power antineoplaston, using derivative described in claim 1 as active component.
6. a kind of anti-cancer drug preparation, using derivative described in claim 1 as main component, and containing pharmaceutically other be subjected to
Carrier, excipient or/and additive.
7. a kind of medicines resistant to liver cancer preparation or anti-pancreatic cancer medicament preparation, using derivative described in claim 1 as main component,
And contain pharmaceutically other acceptable carrier, excipient or/and additives.
8. a kind of AZT-quinoline conjugate derivative is in medicine or pharmaceutical preparation for light power antineoplaston is prepared
Purposes, the wherein derivative represents by formula I：
In formula, n is 1,3 or 7, R1And R2It is simultaneously hydrogen atom；
Or n is 5, R1For fluorine atom, R2For hydrogen atom；
Or n is 5, R1For hydrogen atom, R2For fluorine atom；
Or n is 5, R1And R2It is simultaneously chlorine atom；
Or n is 5, R1And R2It is simultaneously fluorine atom；
Or n is 5, R1And R2It is simultaneously bromine atoms；
In addition, the photodynamic effect of the medicine or pharmaceutical preparation is excited under the ultraviolet irradiation of UVA wave bands.
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Non-Patent Citations (2)
| Title |
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| "Anticancer activity of a thymidine quinoxaline conjugate is modulated by cytosolic thymidine pathways";Qiong Wei等;《BMC Cancer》;20150321;第15卷(第1期);第1-11页 * |
| "Design, Synthesis, and In Vitro and In Vivo Biological Studies of a 39-Deoxythymidine Conjugate that Potentially Kills Cancer Cells Selectively";Qiong Wei等;《PLOS ONE》;20121226;第7卷(第12期);第1-8页 * |
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