CN108948029A - Phenanthridines ketone derivatives and its synthetic method and antitumor application thereof - Google Patents

Phenanthridines ketone derivatives and its synthetic method and antitumor application thereof Download PDF

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CN108948029A
CN108948029A CN201710392955.XA CN201710392955A CN108948029A CN 108948029 A CN108948029 A CN 108948029A CN 201710392955 A CN201710392955 A CN 201710392955A CN 108948029 A CN108948029 A CN 108948029A
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represent
ketone derivatives
zyh005
phenanthridone
methyl
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张勇慧
童擎
童擎一
罗增伟
袁明
王空潮
朱虎成
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Huazhong University of Science and Technology
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    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P35/02—Antineoplastic agents specific for leukemia
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/06—Ring systems of three rings
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Abstract

The present invention provides new phenanthridines ketone derivatives and its synthetic methods and antitumor application thereof, belong to pharmaceutical technology field, the present invention has carried out antitumor activity evaluation to provided compound, prove that phenanthridines ketone derivatives provided by the invention have antitumor action, it can be used for preparing anti-tumor drug, phenanthridines ketone derivatives ZYH005 therein can be used for the progranulocyte leukemia of anti-progranulocyte leukemia and anti-reflective formula retinoic acid resistance, and there is stable structure, high-efficiency low-toxicity, activity is nanomole rank, the advantages that onset time is fast, it can overcome the shortcomings of current clinic APL treatment medication retinotic acid and arsenic trioxide.Phenanthridines ketone derivatives ZYH005 APL drug resistant to retinotic acid has inhibiting effect in vivo and in vitro, can solve the resistance problems in clinically APL treatment.Synthetic method of the present invention does not need transition metal-catalyzed, avoids heavy metal pollution.

Description

Phenanthridines ketone derivatives and its synthetic method and antitumor application thereof
Technical field
The invention belongs to pharmaceutical technology fields, are related to synthesis, antitumor pharmacology activity rating and the use of phenanthridines ketone derivatives On the way.
Background technique
Leukaemia is common one of malignant tumour, and disease incidence occupies first in pediatric malignancies, and leads to 35 Year old or less the lethal major malignant tumor of crowd.Study most thorough in leukaemia is the M3 phase of acute myelocytic leukemia -- Acute promyelocytic leukemia (APL), pathogenesis are No. 15 and No. 17 chromosome translocations, form PML-RAR α and merge base Cause, the gene can play dual dominant negative regulation to its Parent Protease and act on, and inadequately inhibit or activate related target gene, into And obstacle leukocyte differentiation leads to APL.Currently, utilizing retinotic acid (ATRA) and arsenic trioxide (ATO) or joint Other chemotherapeutics can make APL reach good therapeutic effect.But there are still many insufficient: first is that ATRA's and ATO makes With some side effects can be generated, for example have a headache, pseudotumor cerebri, leukocytosis, conjunctivitis, electrolyte disturbance, the lethal rhythm of the heart It is not normal, differentiation syndrome etc.；Second is that disease morbidity is dangerous, caused Infant Mortality is high slowly for state of an illness Diagnosis delay and drug effect Up to 30%；Third is that some patients can generate ATRA and ATO drug resistance, wherein ATRA drug resistance is clinically more high-incidence at present shows As there is no good remedy measures at present.It is rapid-action and the drug resistant drug of ATRA can be blocked so it is low to develop a kind of side effect It is current APL research field urgent problem.
Natural products (including its secondary metabolite) always is the most important source of drug.This seminar early period is to more Active constituent in year raw herbaceous plant green onion lotus has carried out system research, isolated 40 kinds of compounds, including 24 kinds of newization Close object.Further pharmaceutical research shows that have antitumor action in these compounds is a kind of phenanthridines ketone derivatives, and And they are much stronger than other cancerous cell lines to the lethal effect of Leukemia Cell Lines HL60 and K562.Wherein noval chemical compound N- Methylhemeanthidine chloride shows the killing cancer cell effect better than positive drug cis-platinum, to HL60 and The IC of K56250Value is respectively 0.91 and 1 μM, and weaker to the cytotoxicity of normal cell Beas-2B, shows that such phenanthridone spreads out Biology has the antileukemie effect of specificity, has the potentiality further developed.
However, the natural content of phenanthridines ketone derivatives is considerably less, the further research to them is limited.Therefore, it develops A kind of completely new synthetic method prepares this kind of compound out, and passes through screening active ingredients, Structure-activity analysis and deep effect It has very important significance with Mechanism Study to find lead compound.
Summary of the invention
The task of the present invention is provide new phenanthridines ketone derivatives.
Another task of the invention is to provide the synthetic method of the phenanthridines ketone derivatives.
Another task of the invention is to provide the phenanthridines ketone derivatives in the application of anti-tumor aspect.
Realize the technical scheme is that
Phenanthridines ketone derivatives provided by the invention have structure shown in following formula (1) or formula (2):
In formula (1): R is methoxyl group, benzyl, phenethyl, phenylpropyl or to anisylethyl；
In formula (2):
R1Representation methoxy, R2=R3=R4=R5=R6=R7=H；Or
R4Representation methoxy, R1=R2=R3=R5=R6=R7=H；Or
R4Represent trifluoromethyl, R1=R2=R3=R5=R6=R7=H；Or
R4Represent acetyl group, R1=R2=R3=R5=R6=R7=H；Or
R4Represent chlorine, R1=R2=R3=R5=R6=R7=H；Or
R1Represent trifluoromethyl, R2=R3=R4=R5=R6=R7=H；Or
R7Represent methyl, R1=R2=R3=R4=R5=R6=H；Or
R1Represent methyl, R2=R3=R4=R5=R6=R7=H；Or
R2Represent methyl, R1=R3=R4=R5=R6=R7=H；Or
R4Represent methyl, R1=R2=R3=R5=R6=R7=H；Or
R4Represent itrile group, R2=R3=R4=R5=R6=R7=H；Or
R1Represent chlorine, R2=R3=R4=R5=R6=R7=H；Or
R1Represent fluorine, R2=R3=R4=R5=R6=R7=H；Or
R7Represent fluorine, R1=R2=R3=R4=R5=R6=H；Or
R5Represent methyl, R1=R2=R3=R4=R6=R7=H.
The preparation method of the phenanthridines ketone derivatives of structure shown in previously described formula (1), comprising the following steps:
Step 1: 2- (4 ', 5 '-two methene base) phenyl-N- oxalic acid list formyl is passed through again by free radical decarboxylation attack phenyl ring The ring that reaches a standard forms substrate phenanthridone ZYH0001, and reaction equation is as follows:
Step 2: choosing one of following five kinds of bromo-hydrocarbons according to target product to be prepared,
Nucleophilic substitution, which is carried out, with the substrate phenanthridone ZYH0001 that step 1 obtains obtains corresponding target product One of ZYH001-ZYH005, reaction equation are as follows:
In target product phenanthridines ketone derivatives ZYH001-ZYH005, the substituent R in each product is respectively as follows:
The corresponding R representation methoxy of ZYH001；
The corresponding R of ZYH002 represents benzyl；
The corresponding R of ZYH003 represents phenethyl；
The corresponding R of ZYH004 represents phenylpropyl；
The corresponding R of ZYH005 is represented to anisylethyl.
The preparation method of the phenanthridines ketone derivatives of structure shown in previously described formula (2), comprising the following steps:
Step (1): corresponding carboxylic acid substrate is chosen according to target product to be prepared, passes through free radical decarboxylation attack benzene Ring obtains one of corresponding substrate phenanthridone ZYH0002-ZYH0016 using cyclization, and reaction equation is as follows:
In substrate phenanthridone ZYH0002-ZYH0016, the substituent group in each substrate phenanthridone is respectively as follows:
The R of ZYH00021Representation methoxy, R2=R3=R4=R5=R6=R7=H；
The R of ZYH00034Representation methoxy, R1=R2=R3=R5=R6=R7=H；
The R of ZYH00044Represent trifluoromethyl, R1=R2=R3=R5=R6=R7=H；
The R of ZYH00054Represent acetyl group, R1=R2=R3=R5=R6=R7=H；
The R of ZYH00064Represent chlorine, R1=R2=R3=R5=R6=R7=H；
The R of ZYH00071Represent trifluoromethyl, R2=R3=R4=R5=R6=R7=H；
The R of ZYH00087Represent methyl, R1=R2=R3=R4=R5=R6=H；
The R of ZYH00091Represent methyl, R2=R3=R4=R5=R6=R7=H；
The R of ZYH00102Represent methyl, R1=R3=R4=R5=R6=R7=H；
The R of ZYH00114Represent methyl, R1=R2=R3=R5=R6=R7=H；
The R of ZYH00124Represent itrile group, R2=R3=R4=R5=R6=R7=H；
The R of ZYH00131Represent chlorine, R2=R3=R4=R5=R6=R7=H；
The R of ZYH00141Represent fluorine, R2=R3=R4=R5=R6=R7=H；
The R of ZYH00157Represent fluorine, R1=R2=R3=R4=R5=R6=H；
The R of ZYH00165Represent methyl, R1=R2=R3=R4=R6=R7=H；
Step (2): one of ZYH0002-ZYH0016 obtained with methoxy-benzyl (1) above-mentioned to step substrate is luxuriant and rich with fragrance The phenanthridone female ring hydrogen bound to nitrogen of pyridine ketone is replaced, and one of corresponding target product ZYH006-ZYH020, reaction equation are obtained It is as follows:
In target product ZYH006-ZYH020, the substituent group in each target product is respectively as follows:
The R of ZYH0061Representation methoxy, R2=R3=R4=R5=R6=R7=H；
The R of ZYH0074Representation methoxy, R1=R2=R3=R5=R6=R7=H；
The R of ZYH0084Represent trifluoromethyl, R1=R2=R3=R5=R6=R7=H；
The R of ZYH0094Represent acetyl group, R1=R2=R3=R5=R6=R7=H；
The R of ZYH0104Represent chlorine, R1=R2=R3=R5=R6=R7=H；
The R of ZYH0111Represent trifluoromethyl, R2=R3=R4=R5=R6=R7=H；
The R of ZYH0127Represent methyl, R1=R2=R3=R4=R5=R6=H；
The R of ZYH0131Represent methyl, R2=R3=R4=R5=R6=R7=H；
The R of ZYH0142Represent methyl, R1=R3=R4=R5=R6=R7=H；
The R of ZYH0154Represent methyl, R1=R2=R3=R5=R6=R7=H；
The R of ZYH0164Represent itrile group, R2=R3=R4=R5=R6=R7=H；
The R of ZYH0171Represent chlorine, R2=R3=R4=R5=R6=R7=H；
The R of ZYH0181Represent fluorine, R2=R3=R4=R5=R6=R7=H；
The R of ZYH0197Represent fluorine, R1=R2=R3=R4=R5=R6=H；
The R of ZYH0205Represent methyl, R1=R2=R3=R4=R6=R7=H.
The present invention utilizes high resolution mass spectrum, ultraviolet spectra, infrared spectroscopy, optically-active, core to synthesized phenanthridines ketone derivatives Magnetic resonance, circular dichroism spectra and X-ray single crystal diffraction carry out comprehensive analysis, it is determined that their structure, and it is ordered Name.Phenanthridone derivant structure synthesized by the present invention is as follows:
The name of above-mentioned each compound is successively are as follows:
ZYH001 (N- methoxyl group -4,5- dimethoxy pitches base-phenanthridone)；
ZYH002 (N- benzyl -4,5- dimethoxy pitches base-phenanthridone)；
ZYH003 (N- phenethyl -4,5- dimethoxy pitches base-phenanthridone)；
ZYH004 (N- phenylpropyl -4,5- dimethoxy pitches base-phenanthridone)；
ZYH005 (N- (4- methoxy benzene) ethyl -4,5- dimethoxy pitches base-phenanthridone)；
ZYH006 (N- (4- methoxy benzene) ethyl -9- methoxyl group phenanthridone)；
ZYH007 (N- (4- methoxy benzene) ethyl -4- methoxyl group phenanthridone)；
ZYH008 (N- (4- methoxy benzene) ethyl -4- trifluoromethyl phenanthridone)；
ZYH009 (N- (4- methoxy benzene) ethyl -4- acetyl group phenanthridone)；
ZYH010 (N- (4- methoxy benzene) ethyl -4- chlorine phenanthridone)；
ZYH011 (N- (4- methoxy benzene) ethyl -9- trifluoromethyl phenanthridone)
ZYH012 (N- (4- methoxy benzene) ethyl -8- methyl phenanthridone)；
ZYH013 (N- (4- methoxy benzene) ethyl -9- methyl phenanthridone)；
ZYH014 (N- (4- methoxy benzene) ethyl -7- methyl phenanthridone)；
ZYH015 (N- (4- methoxy benzene) ethyl -4- methyl phenanthridone)；
ZYH016 (N- (4- methoxy benzene) ethyl -4- itrile group phenanthridone)；
ZYH017 (N- (4- methoxy benzene) ethyl -9- chlorine phenanthridone)；
ZYH018 (N- (4- methoxy benzene) ethyl -9- fluorine phenanthridone)；
ZYH019 (N- (4- methoxy benzene) ethyl -8- fluorine phenanthridone)；
ZYH020 (N- (4- methoxy benzene) ethyl -3- methyl phenanthridone).
The present invention has carried out antitumor activity evaluation to above compound, experiments have shown that above compound provided by the invention It with antitumor action, can be used for preparing anti-tumor drug, be particularly used in preparation treatment leukaemia, lung cancer, liver cancer, breast cancer With the drug of colon cancer.Experiments have shown that phenanthridines ketone derivatives ZYH005 provided by the invention can be used for the white blood of anti-progranulocyte Disease, phenanthridines ketone derivatives ZYH005 provided by the invention can be used for the progranulocyte leukemia of anti-reflective formula retinoic acid resistance.
An embodiment provides the preparation methods of above-mentioned phenanthridines ketone derivatives ZYH001-ZYH020, go forward side by side It has gone Structural Identification, has been confirmed as required target product.
An embodiment provides phenanthridines ketone derivatives ZYH001-ZYH005 to human leukemia cell line HL- 60, Bel7402 SMMC-7721, human lung cancer cell line A-549, human breast carcinoma cell lines MCF-7 and human colon cancer cell It is the experimental data of SW480 proliferation inhibition activity, shows strongest effect relative to other compounds ZYH005, especially To HL-60 cell line.On this basis, it is model with HL-60, compares the growth of ZYH005 and ZYH006-ZYH020 to it Inhibiting effect.
One embodiment of the present of invention carries out the purposes of the anti-progranulocyte leukemia of phenanthridines ketone derivatives ZYH005 Evaluation.Progranulocyte white blood of the another embodiment of the invention to phenanthridines ketone derivatives ZYH005 anti-reflective formula retinoic acid resistance The purposes of disease is evaluated.
Compared with the prior art, the advantages of the present invention are as follows avoid first, synthetic method does not need transition metal-catalyzed Heavy metal pollution.Second, phenanthridines ketone derivatives ZYH005 stable structure, high-efficiency low-toxicity, and the medication of clinic APL treatment at present is anti- Formula vitamin A acid and arsenic trioxide are without this advantage；Third, phenanthridines ketone derivatives ZYH005 has inhibition to APL in vivo and in vitro Effect, activity is nanomole rank, and onset time is fast.Fourth, phenanthridines ketone derivatives ZYH005 is to retinotic acid drug resistance APL have inhibiting effect in vivo and in vitro, the resistance problems in clinically APL treatment can be solved.
Figure of description
Fig. 1: compound ZYH001-ZYH005 to 48 hours half-inhibitory concentration (IC of five kinds of tumour cells50)；
Fig. 2: the compound ZYH005-ZYH020 comparison to Leukemia Cell Lines HL60 growth inhibition effect；
Fig. 3 compound ZYH005 has proliferated specifically inhibiting effect to APL cell line.Data are at least 3 times in figure Average value ± standard deviation,**, P < 0.01；
The internal anti-APL effect of Fig. 4 compound ZYH005, a, the bush of peripheral blood, marrow Wright's staining and spleen, liver Plain eosin stains H&E dyeing；B, spleen picture；The weight of c, spleen and liver compares；D, life cycle curve.Data are extremely in figure Few 3 average value ± standard deviations,***, P < 0.001；
Fig. 5: compound ZYH005 to the growth inhibition effect of retinotic acid drug resistance APL cell line.Data are extremely in figure Few 3 average value ± standard deviations, ATRA is positive control,**, P < 0.01；
Fig. 6: compound ZYH005 resists the resistance to retinotic acid drug resistance APL to act in vivo.A, life cycle curve；B, spleen figure Piece；The weight of c, spleen and liver compares；D, the haematoxylin eosin stains H&E of peripheral blood, marrow Wright's staining and spleen, liver Dyeing.Average value ± the standard deviation that data are at least 3 times in figure,**, P < 0.01；***, P < 0.001.
Specific embodiment
Embodiment 1: the preparation of phenanthridines ketone derivatives ZYH001-ZYH020 and Structural Identification
(1) the preparation example of phenanthridines ketone derivatives ZYH005
Substrate phenanthridone ZYH0001 is first prepared, process is as follows: in 10ml Schlenk reaction flask, weighing addition (2- (4 ', 5 '-two methene bases) phenyl-N- oxalic acid list formyl) aniline (50mg, 0.175mmol), sodium sulphate (Na2SO4) (82.9mg, 0.35mmol), dimethyl sulfoxide (DMSO) 3ml, reacts 36h at 110 DEG C, after completion of the reaction, 10 times of DMSO volumes is added Water and the extraction of appropriate ethyl acetate three times, obtain organic phase ethyl acetate, filter after anhydrous sodium sulfate is dry, mix after solvent evaporated Sample carries out column chromatography for separation (petroleum ether: ethyl acetate=2:1) and obtains substrate ZYH0001.
Phenanthridines ketone derivatives ZYH005 is prepared again, process is as follows: in three mouthfuls of reaction flasks of 25ml dried and clean, weighing and be added Phenanthridone (100mg, 0.42mmol), 5ml dimethylformamide (DMF), nitrogen displacement, are placed in 0 DEG C of cold well, are added dropwise The sodium hydride (NaH) (21mg, 0.84mmol) of 5ml dimethylformamide (DMF) dissolution, is stirred to react 0.5h postposition at room temperature 1h is reacted again.Then reaction is placed in 0 DEG C of cold well again, be slowly added into reaction mixture to methylbenzene second bromine (180mg, 0.84mmol), it is stirred to react 0.5h postposition and reacts 1h again at room temperature.After completion of the reaction, 10 times of dimethylformamides are added (DMF) water of volume and appropriate ethyl acetate, extraction obtain organic phase ethyl acetate, sodium sulphate (Na three times2SO4) dry, it is evaporated Ethyl acetate mixes sample, carries out column chromatography for separation (petroleum ether: ethyl acetate=4:1) and obtains target compound ZYH005 (118.6mg, yield:76%).
(2) Structural Identification of phenanthridines ketone derivatives ZYH005
To the high resolution mass spectrum of phenanthridines ketone derivatives ZYH005, ultraviolet spectra, infrared spectroscopy, optically-active, nuclear magnetic resonance, circle two The data such as chromatography and X-ray single crystal diffraction carry out comprehensive analysis, so that it is determined that the structure of the compound.
ZYH005:1H NMR(400MHz,CDCl3)δ8.13–8.09(m,1H),7.91(s,1H),7.62(s,1H), 7.56–7.50(m,1H),7.48–7.44(m,1H),7.33–7.28(m,3H),6.92–6.88(m,2H),6.13(s,2H), 4.61–4.47(m,2H),3.81(s,3H),3.08–2.96(m,2H).13C NMR(100MHz,CDCl3):δ160.7,158.5, 152.4,148.5,136.5,130.7,130.6,129.9,129.1,123.4,122.4,121.4,119.6,114.9, 114.2,106.9,102.1,100.5,55.4,44.7,32.9.HRMS m/z(ESI)calcd for C23H20NO4(M+H)+ 374.1387,found 374.1378.
(3) preparation of the another 19 phenanthridines ketone derivatives of the present invention in addition to ZYH005
According to target product to be prepared choose corresponding carboxylic acid substrate by free radical decarboxylation attack phenyl ring using Cyclization obtains corresponding substrate phenanthridone ZYH0006-ZYH0020.
ZYH001-ZYH005 is shared same substrate phenanthridone ZYH0001 and is obtained using different bromo-hydrocarbons through nucleophilic displacement of fluorine To target product.What ZYH006-ZYH020 was utilized is different substrate phenanthridone ZYH0006-ZYH0020, then to first Oxy-benzyl replaces phenanthridone female ring hydrogen bound to nitrogen, obtains corresponding target product.Shown in table specific as follows:
Target compound:
(4) in addition to phenanthridines ketone derivatives ZYH005 another 19 compounds of the present invention Structural Identification data
ZYH001 (72.3mg, yield:64%)
Compound ZYH001:1H NMR(400MHz,CDCl3) δ 8.05 (d, J=8.05Hz, 1H), 7.88 (s, 1H), 7.63 (d, J=8.36Hz, 1H), 7.59 (s, 1H), 7.53 (t, J=8.36Hz, 1H), 7.30 (t, J=8.36Hz, 1H), 6.12(s,2H),4.11(s,3H)；13C NMR(100MHz,CDCl3)δ156.9,152.6,148.7,135.3,130.1, 129.5,123.3,123.1,122.1,118.5,112.8,106.8,102.4,100.9,62.9.HRMS m/z(ESI)calcd for C15H12NO4(M+H)+270.0761,found 270.0753.
ZYH002 (111.9mg, yield:81%)
Compound ZYH002:1H NMR(400MHz,CDCl3):δ8.14–8.05(m,1H),7.97(s,1H),7.65 (s,1H),7.38–7.33(m,1H),7.32–7.29(m,2H),7.29–7.22(m,5H),6.14(s,2H),5.65(s,2H) .13C NMR(100MHz,CDCl3):δ161.4,152.6,148.6,136.9,136.8,130.9,129.0,128.9,127.3, 126.6,123.1,122.5,121.2,119.6,116.1,107.3,102.1,100.6,46.6.HRMS m/z(ESI)calcd for C21H16NO3(M+H)+330.1125,found 330.1117
ZYH003 (113.8mg, yield:79%)
Compound ZYH003:1H NMR(400MHz,CDCl3)δ8.15–8.10(m,1H),7.92(s,1H),7.63 (s, 1H), 7.55-7.49 (m, 1H), 7.46 (d, J=7.9Hz, 1H), 7.46 (d, J=7.9Hz, 1H), 7.43-7.36 (m, 3H),7.36(s,1H),7.35–7.27(m,2H),6.13(s,2H),4.67–4.48(m,2H),3.20–2.96(m,2H).13C NMR(100MHz,CDCl3):δ160.7,152.4,148.6,138.7,136.5,130.6,129.1,128.9,128.8, 126.8,123.4,122.4,121.4,119.6,114.9,106.9,102.1,100.5,44.5,33.8.HRMS m/z(ESI) calcd for C22H18NO3(M+H)+344.1281,found 344.1275.
ZYH004 (106.4mg, yield:71%)
Compound ZYH004:1H NMR(400MHz,CDCl3) δ 8.08 (dd, J=8.1,1.3Hz, 1H), 7.91 (s, 1H), 7.61 (s, 1H), 7.46-7.39 (m, 1H), 7.31-7.27 (m, 4H), 7.20 (d, J=7.2Hz, 3H), 4.45-4.35 (m, 2H), 2.83 (t, J=7.7Hz, 2H), 2.19-2.09 (m, 2H)13C NMR(100MHz,CDCl3):δ160.6,152.3, 148.5,138.6,136.4,130.5,129.0,128.8,128.7,126.7,123.3,122.3,121.3,119.5, 114.8,106.8,102.0,100.4,44.4,33.7,28.6.HRMS m/z(ESI)calcd for C23H20NO3(M+H)+ 358.1438,found 344.1431.
ZYH006 (104.0mg, yield:69%)
Compound ZYH006:1H NMR(400MHz,CDCl3) δ 8.43 (d, J=8.9Hz, 1H), 8.18 (dd, J= 8.1,1.2Hz, 1H), 7.59 (d, J=2.4Hz, 1H), 7.54-7.47 (m, 1H), 7.40 (d, J=8.1Hz, 1H), 7.25 (dt, J=7.0,2.7Hz, 3H), 7.10 (dd, J=8.9,2.4Hz, 1H), 6.86-6.79 (m, 2H), 4.46 (dd, J=9.9, 6.9Hz,2H),3.93(s,3H),3.75(s,3H),3.04–2.85(m,2H).
ZYH007 (102.5mg, yield:68%)
Compound ZYH007:1H NMR(400MHz,CDCl3) δ 8.23-8.09 (m, 2H), 7.92 (d, J=2.8Hz, 1H), 7.48-7.43 (m, 1H), 7.41 (d, J=7.3Hz, 1H), 7.32-7.25 (m, 3H), 7.19 (s, 1H), 6.83 (d, J= 8.6Hz,2H),4.55–4.44(m,2H),3.90(s,3H),3.74(s,3H),3.07–2.87(m,2H).
ZYH008 (140.1mg, yield:84%)
Compound ZYH008:1H NMR(400MHz,CDCl3) δ 8.79 (s, 1H), 8.34 (d, J=8.6Hz, 1H), 8.27 (d, J=7.1Hz, 1H), 7.91 (d, J=8.5Hz, 1H), 7.57 (t, J=7.8Hz, 1H), 7.44 (d, J=8.4Hz, 1H), 7.31 (t, J=7.6Hz, 1H), 7.24 (d, J=8.5Hz, 2H), 6.83 (d, J=8.6Hz, 2H), 4.63-4.34 (m, 2H),3.75(s,3H),3.18–2.81(m,2H).
ZYH009 (116.8mg, yield:75%)
Compound ZYH009:1H NMR(400MHz,CDCl3) δ 8.21 (d, J=8.0Hz, 1H), 7.83 (d, J= 8.2Hz, 1H), 7.61 (t, J=8.2Hz, 1H), 7.48 (t, J=7.6Hz, 1H), 7.35 (d, J=8.5Hz, 1H), 7.28 (d, J=8.4Hz, 2H), 7.22 (d, J=7.7Hz, 1H), 7.00 (d, J=8.2Hz, 1H), 6.83 (d, J=8.4Hz, 2H), 4.48–4.34(m,2H),3.99(s,3H),3.74(s,3H),3.05–2.91(m,2H).
ZYH010 (121.9mg, yield:80%)
Compound ZYH010:1H NMR(400MHz,CDCl3) δ 8.20 (d, J=7.9Hz, 1H), 8.16 (d, J= 8.7Hz, 1H), 7.65 (dd, J=8.7,2.4Hz, 1H), 7.52 (t, J=8.5Hz, 1H), 7.42 (d, J=8.2Hz, 1H), 7.31-7.25 (m, 2H), 7.23 (d, J=8.6Hz, 2H), 6.83 (d, J=8.6Hz, 2H), 4.53-4.45 (m, 2H), 3.75 (s,3H),3.01–2.91(m,2H).
ZYH011 (101.7mg, yield:61%)
Compound ZYH011:1H NMR(400MHz,CDCl3) δ 8.62 (d, J=7.9Hz, 1H), 8.43 (d, J= 8.4Hz, 1H), 8.34 (d, J=8.1Hz, 1H), 7.86 (t, J=7.6Hz, 1H), 7.71 (t, J=7.6Hz, 1H), 7.65 (s, 1H), 7.57 (d, J=8.3Hz, 1H), 7.35-7.25 (m, 3H), 6.91 (d, J=8.5Hz, 2H), 4.71-4.48 (m, 2H), 3.83(s,3H),3.25–2.98(m,2H).13C NMR(101MHz,CDCl3)δ161.13,158.54,137.10,132.90, 132.45,131.35,130.11,129.80,129.20,129.01,126.08,124.26,122.11,118.73,118.70, 114.26,112.13,112.09,55.30,44.83,32.86.
ZYH012 (110.9mg, yield:77%)
Compound ZYH012:1H NMR(400MHz,CDCl3) δ 8.59 (d, J=7.8Hz, 1H), 8.32 (d, J= 8.2Hz, 1H), 8.15 (s, 1H), 7.79 (t, J=7.3Hz, 1H), 7.62 (t, J=7.5Hz, 1H), 7.41 (s, 2H), 7.35 (d, J=8.4Hz, 2H), 6.93 (d, J=8.5Hz, 2H), 4.61-4.53 (m, 2H), 3.84 (s, 3H), 3.09-3.01 (m, 2H),2.53(s,3H).13C NMR(101MHz,CDCl3)δ161.17,158.38,134.88,133.53,132.37, 131.83,130.69,130.66,129.81,128.78,127.88,125.62,123.71,121.59,119.41,114.81, 114.12,55.32,44.53,32.78,20.99.
ZYH013 (122.4mg, yield:85%)
Compound ZYH013:1H NMR(400MHz,CDCl3) δ 8.57 (d, J=7.9Hz, 1H), 8.28 (d, J= 8.2Hz, 1H), 8.22 (d, J=8.2Hz, 1H), 7.78 (t, J=7.6Hz, 1H), 7.60 (t, J=7.5Hz, 1H), 7.35 (d, J=8.4Hz, 2H), 7.29 (d, J=3.0Hz, 1H), 7.18 (d, J=8.1Hz, 1H), 6.93 (d, J=8.5Hz, 2H), 4.65–4.52(m,2H),3.85(s,3H),3.11–3.01(m,2H),2.55(s,3H).13C NMR(101MHz,CDCl3)δ 161.44,158.42,139.89,137.00,133.70,132.44,130.77,129.81,128.74,127.53,125.18, 123.57,123.45,121.40,117.15,115.31,114.13,55.33,44.46,32.80,22.11.
ZYH014 (108.0mg, yield:75%)
Compound ZYH014:1H NMR(400MHz,CDCl3) δ 8.67 (d, J=6.7Hz, 1H), 8.49 (d, J= 8.4Hz, 1H), 7.79 (t, J=7.0Hz, 1H), 7.64 (t, J=7.5Hz, 1H), 7.52-7.43 (m, 2H), 7.36 (d, J= 8.4Hz, 2H), 7.23 (d, J=6.5Hz, 1H), 6.93 (d, J=8.5Hz, 2H), 4.67-4.52 (m, 2H), 3.85 (s, 3H), 3.13–3.04(m,2H),3.01(s,3H).13C NMR(101MHz,CDCl3)δ160.71,157.46,137.43,134.51, 132.59,132.04,131.71,131.59,129.65,129.09,128.01,127.55,125.13,121.24,114.19, 112.41,55.74,53.81,34.06,18.75.
ZYH015 (110.9mg, yield:77%)
Compound ZYH015:1H NMR(400MHz,CDCl3) δ 8.39 (s, 1H), 8.32 (d, J=7.7Hz, 1H), 8.22 (d, J=8.3Hz, 1H), 7.62 (d, J=8.3Hz, 1H), 7.57 (t, J=7.3Hz, 1H), 7.50 (d, J=8.3Hz, 1H), 7.35 (t, J=6.5Hz, 3H), 6.93 (d, J=8.5Hz, 2H), 4.68-4.44 (m, 2H), 3.85 (s, 3H), 3.14- 2.94(m,2H),2.56(s,3H).13C NMR(101MHz,CDCl3)δ161.41,158.35,138.18,136.74, 133.85,131.05,130.66,129.82,129.16,128.52,125.35,123.34,122.35,121.66,119.64, 114.84,114.12,55.32,44.51,32.78,21.41.
ZYH016 (121.9mg, yield:82%)
Compound ZYH016:1H NMR(400MHz,CDCl3) δ 8.33 (d, J=8.0Hz, 1H), 8.22 (d, J= 8.2Hz, 1H), 7.64 (t, J=7.8Hz, 1H), 7.57 (t, J=8.0Hz, 1H), 7.45 (d, J=8.4Hz, 1H), 7.40 (d, J=7.3Hz, 1H), 7.36 (d, J=8.4Hz, 2H), 7.33 (d, J=7.9Hz, 1H), 6.93 (d, J=8.5Hz, 2H), 4.57–4.48(m,2H),3.85(s,3H),3.09–3.02(m,2H).
ZYH017 (115.8mg, yield:76%)
Compound ZYH017:1H NMR(400MHz,CDCl3) δ 8.57 (d, J=8.0Hz, 1H), 8.25 (d, J= 8.5Hz, 2H), 7.81 (t, J=7.6Hz, 1H), 7.64 (t, J=7.5Hz, 1H), 7.44 (d, J=1.4Hz, 1H), 7.36- 7.30 (m, 3H), 6.93 (d, J=8.5Hz, 2H), 4.68-4.41 (m, 2H), 3.84 (s, 3H), 3.21-2.92 (m, 2H)13C NMR(101MHz,CDCl3)δ161.22,158.46,138.05,135.44,132.97,132.76,130.26,129.83, 128.91,128.31,125.31,124.76,122.59,121.60,118.01,115.06,114.21,55.34,44.74, 32.71.
ZYH018 (99.1mg, yield:68%)
Compound ZYH018:1H NMR(400MHz,CDCl3) δ 8.57 (d, J=7.9Hz, 1H), 8.31 (dd, J= 8.9,6.2Hz, 1H), 8.23 (d, J=8.1Hz, 1H), 7.81 (t, J=7.7Hz, 1H), 7.62 (t, J=7.6Hz, 1H), 7.34 (d, J=8.5Hz, 2H), 7.18 (dd, J=11.2,2.2Hz, 1H), 7.12-7.05 (m, 1H), 6.93 (d, J= 8.5Hz,2H),4.57–4.47(m,2H),3.84(s,3H),3.11–3.00(m,2H).13C NMR(101MHz,CDCl3)δ 161.43,158.46,133.20,132.69,130.19,129.74,128.81,127.86,125.45,125.36,124.84, 121.47,114.14,110.13,109.84,102.13,101.93,55.33,44.98,32.61.
ZYH019 (93.2mg, yield:64%)
Compound ZYH019:1H NMR(400MHz,CDCl3) δ 8.60 (d, J=7.9Hz, 1H), 8.22 (d, J= 8.1Hz, 1H), 8.00 (dd, J=9.7,2.7Hz, 1H), 7.82 (t, J=7.6Hz, 1H), 7.67 (t, J=7.6Hz, 1H), 7.44 (dd, J=9.2,4.7Hz, 1H), 7.33 (d, J=8.4Hz, 3H), 6.92 (d, J=8.5Hz, 2H), 4.64-4.51 (m, 2H),3.84(s,3H),3.12–2.97(m,2H).13C NMR(101MHz,CDCl3)δ160.87,158.59,157.00, 133.49,132.69,130.34,129.79,128.97,128.75,125.85,121.80,117.02,116.77,116.47, 116.34,114.10,109.69,55.33,44.96,32.77.
ZYH020 (92.1mg, yield:64%)
Compound ZYH020:1H NMR(400MHz,CDCl3) δ 8.47 (d, J=8.1Hz, 1H), 8.35 (d, J= 7.6Hz, 1H), 8.12 (s, 1H), 7.59 (t, J=7.9Hz, 1H), 7.50 (d, J=8.2Hz, 1H), 7.45 (d, J=7.9Hz, 1H), 7.36 (dd, J=7.7,3.9Hz, 3H), 6.93 (d, J=8.5Hz, 2H), 4.66-4.53 (m, 2H), 3.84 (s, 3H), 3.11–3.00(m,2H),2.61(s,3H)
Embodiment 2: the antitumor activity evaluation of compound ZYH001-ZYH020.Utilize cell viability determination techniques (MTS Method), the anti-tumor activity of ZYH001-ZYH005 is evaluated first, find compound ZYH002, ZYH003, ZYH005 pairs Leukemia Cell Lines HL-60 has very strong growth inhibition effect, and wherein ZYH005 is also to Bel7402 SMMC-7721, The inhibiting effect of human lung cancer cell line A-549, human breast carcinoma cell lines MCF-7 and human colon cancer cell line SW480 are better than the positive Control drug cis-platinum (DDP) (Fig. 1).On the basis of this, the present inventor speculates N-4- methoxyphenethyl to this kind of compound Activity have an impact, and then have detected ZYH006-ZYH020 to the growth inhibition effect of Leukemia Cell Lines HL-60, and with ZYH005 is compared, the results show that compound ZYH006-ZYH020 is to the growth inhibition effect of HL-60 without ZYH005 By force, see Fig. 2, the structure for disclosing dioxolane is the key that drug effect.
Embodiment 3: compound ZYH005 acts on the in vitro and in vivo of APL
Using cell viability determination techniques (MTS method), detection compound ZYH005 is to 10 plants of Leukemia Cell Lines (acute marrows Cell leukemia cell line Kg1a, THP-1, Kasumi, HL60 and NB4；Acute lymphoblastic leukemia cell strain DND41, KOPTK-1, CUTLL-1, MOLT4；Chronic myelocytic leukemia cell cycling inhibiting) and 2 plants of normal cell strains (people's Pancreatic ductal epithelium is thin Born of the same parents system HPDE6-C7, people's colon epithelial cell system NCM460) growth inhibition effect.As a result as shown in figure 3, compound ZYH005 The specific inhibiting effect having to acute promyelocytic leukemia cell line HL60 and NB4.
APL mouse model is constructed using the splenocyte in hMRP8-PML-RAR α transgenic mice source, verifying ZYH005 exists In vivo to the effect of APL, the results show that can to reduce (BM) leukaemia in APL mouse peripheral blood (PB) and marrow thin by ZYH005 The number of born of the same parents mitigates the infiltration of leukaemia cell in liver and spleen, and effect and positive control ATO are suitable.APL can also be alleviated The enlargement of mouse liver and spleen extends the life cycle of APL mouse, sees Fig. 4.
Embodiment 4: compound ZYH005 acts on the in vitro and in vivo of retinotic acid drug resistance APL
Using the vitality test technology (MTS method) of cell, detection compound ZYH005 is drug resistant to 2 plants of retinotic acids The growth inhibition effect of APL cell line NB4-LR2 and NB4-MR2, the results show that compound ZYH005 is to retinoic acid resistance APL cell line has significant growth inhibition effect, sees Fig. 5.
The APL mouse model for further constructing resistance to retinotic acid, verifies the effect of ZYH005, the results show that ZYH005 The life cycle that the APL of resistance to retinotic acid mouse can be extended, mitigates liver and spleen enlargement and the infiltration of leukaemia cell, subtract The number of leukaemia cell, is shown in Fig. 6 in the few APL of resistance to retinotic acid mouse peripheral blood and marrow.
Experiment conclusion: phenanthridines ketone derivatives ZYH005 has APL and the drug resistant APL of retinotic acid in vitro and in vivo There is remarkable inhibiting activity, having exploitation is the potentiality of related drugs.

Claims (7)

1. the phenanthridines ketone derivatives with structure shown in following formula (1) or formula (2):
In formula (1): R is methoxyl group, benzyl, phenethyl, phenylpropyl or to anisylethyl；
In formula (2):
R1Representation methoxy, R2=R3=R4=R5=R6=R7=H；Or
R4Representation methoxy, R1=R2=R3=R5=R6=R7=H；Or
R4Represent trifluoromethyl, R1=R2=R3=R5=R6=R7=H；Or
R4Represent acetyl group, R1=R2=R3=R5=R6=R7=H；Or
R4Represent chlorine, R1=R2=R3=R5=R6=R7=H；Or
R1Represent trifluoromethyl, R2=R3=R4=R5=R6=R7=H；Or
R7Represent methyl, R1=R2=R3=R4=R5=R6=H；Or
R1Represent methyl, R2=R3=R4=R5=R6=R7=H；Or
R2Represent methyl, R1=R3=R4=R5=R6=R7=H；Or
R4Represent methyl, R1=R2=R3=R5=R6=R7=H；Or
R4Represent itrile group, R2=R3=R4=R5=R6=R7=H；Or
R1Represent chlorine, R2=R3=R4=R5=R6=R7=H；Or
R1Represent fluorine, R2=R3=R4=R5=R6=R7=H；Or
R7Represent fluorine, R1=R2=R3=R4=R5=R6=H；Or
R5Represent methyl, R1=R2=R3=R4=R6=R7=H.
2. the preparation method of the phenanthridines ketone derivatives with structure shown in formula (1) described in claim 1, including following step It is rapid:
Step 1: 2- (4 ', 5 '-two methene base) phenyl-N- oxalic acid list formyl is by free radical decarboxylation attack phenyl ring using pass Ring forms substrate phenanthridone ZYH0001, and reaction equation is as follows:
Step 2: one of following five kinds of bromo-hydrocarbons are chosen according to target product to be prepared
Nucleophilic substitution, which is carried out, with the substrate phenanthridone ZYH0001 that step 1 obtains obtains corresponding target product One of ZYH001-ZYH005, reaction equation are as follows:
In target product phenanthridines ketone derivatives ZYH001-ZYH005, the substituent R in each product is respectively as follows:
The corresponding R representation methoxy of ZYH001；
The corresponding R of ZYH002 represents benzyl；
The corresponding R of ZYH003 represents phenethyl；
The corresponding R of ZYH004 represents phenylpropyl；
The corresponding R of ZYH005 is represented to anisylethyl.
3. the preparation method of the phenanthridines ketone derivatives with structure shown in formula (2) described in claim 1, including following step It is rapid:
Step (1): corresponding carboxylic acid substrate is chosen according to target product to be prepared, again by free radical decarboxylation attack phenyl ring One of corresponding substrate phenanthridone ZYH0002-ZYH0016 is obtained by cyclization, reaction equation is as follows:
Substituent group in each substrate phenanthridone is respectively as follows:
The R of ZYH00021Representation methoxy, R2=R3=R4=R5=R6=R7=H；
The R of ZYH00034Representation methoxy, R1=R2=R3=R5=R6=R7=H；
The R of ZYH00044Represent trifluoromethyl, R1=R2=R3=R5=R6=R7=H；
The R of ZYH00054Represent acetyl group, R1=R2=R3=R5=R6=R7=H；
The R of ZYH00064Represent chlorine, R1=R2=R3=R5=R6=R7=H；
The R of ZYH00071Represent trifluoromethyl, R2=R3=R4=R5=R6=R7=H；
The R of ZYH00087Represent methyl, R1=R2=R3=R4=R5=R6=H；
The R of ZYH00091Represent methyl, R2=R3=R4=R5=R6=R7=H；
The R of ZYH00102Represent methyl, R1=R3=R4=R5=R6=R7=H；
The R of ZYH00114Represent methyl, R1=R2=R3=R5=R6=R7=H；
The R of ZYH00124Represent itrile group, R2=R3=R4=R5=R6=R7=H；
The R of ZYH00131Represent chlorine, R2=R3=R4=R5=R6=R7=H；
The R of ZYH00141Represent fluorine, R2=R3=R4=R5=R6=R7=H；
The R of ZYH00157Represent fluorine, R1=R2=R3=R4=R5=R6=H；
The R of ZYH00165Represent methyl, R1=R2=R3=R4=R6=R7=H；
Step 2: one of ZYH0002-ZYH0016 obtained with methoxy-benzyl (1) above-mentioned to step substrate phenanthridone Phenanthridone female ring hydrogen bound to nitrogen is replaced, and obtains one of corresponding target product ZYH006-ZYH020, reaction equation is as follows:
In target product ZYH006-ZYH020, the substituent group in each target product is respectively as follows:
The R of ZYH0061Representation methoxy, R2=R3=R4=R5=R6=R7=H；
The R of ZYH0074Representation methoxy, R1=R2=R3=R5=R6=R7=H；
The R of ZYH0084Represent trifluoromethyl, R1=R2=R3=R5=R6=R7=H；
The R of ZYH0094Represent acetyl group, R1=R2=R3=R5=R6=R7=H；
The R of ZYH0104Represent chlorine, R1=R2=R3=R5=R6=R7=H；
The R of ZYH0111Represent trifluoromethyl, R2=R3=R4=R5=R6=R7=H；
The R of ZYH0127Represent methyl, R1=R2=R3=R4=R5=R6=H；
The R of ZYH0131Represent methyl, R2=R3=R4=R5=R6=R7=H；
The R of ZYH0142Represent methyl, R1=R3=R4=R5=R6=R7=H；
The R of ZYH0154Represent methyl, R1=R2=R3=R5=R6=R7=H；
The R of ZYH0164Represent itrile group, R2=R3=R4=R5=R6=R7=H；
The R of ZYH0171Represent chlorine, R2=R3=R4=R5=R6=R7=H；
The R of ZYH0181Represent fluorine, R2=R3=R4=R5=R6=R7=H；
The R of ZYH0197Represent fluorine, R1=R2=R3=R4=R5=R6=H；
The R of ZYH0205Represent methyl, R1=R2=R3=R4=R6=R7=H.
4. the application of phenanthridines ketone derivatives described in claim 1 in the preparation of medicament for cancer treatment.
5. application according to claim 4, which is characterized in that the cancer is leukaemia, lung cancer, liver cancer, breast cancer Or colon cancer.
6. phenanthridines ketone derivatives shown in structural formula ZYH005 below are preparing the application in anti-progranulocyte leukemia drug,
7. phenanthridines ketone derivatives shown in structural formula ZYH005 below are in the preparation white blood of anti-reflective formula retinoic acid resistance progranulocyte Application in medicine.
。
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Citations (2)

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WO1992021660A1 (en) * 1991-05-29 1992-12-10 Pfizer, Inc. Tricyclic polyhydroxylic tyrosine kinase inhibitors
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Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103588776B (en) * 2011-12-22 2016-03-02 华中科技大学 There is in green onion lotus the compound of antitumor action and method for separating and preparing thereof and application

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992021660A1 (en) * 1991-05-29 1992-12-10 Pfizer, Inc. Tricyclic polyhydroxylic tyrosine kinase inhibitors
CN101068810A (en) * 2004-09-28 2007-11-07 大塚制药株式会社 Carbostyril compound

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
DONGDONG LIANG，等: "Iodobenzene-Catalyzed Synthesis of Phenanthridinones via Oxidative C−H Amidation", 《THE JOURNAL OF ORGANIC CHEMISTRY》 *
MING YUAN，等: "Transition-Metal-Free Synthesis of Phenanthridinones from Biaryl-2-oxamic Acid under Radical Conditions", 《ORGANIC LETTERS》 *
MINGHAO FENG，等: "Ligand Controlled Regiodivergent C1 Insertion on Arynes for Construction of Phenanthridinone and Acridone Alkaloids", 《ANGEW. CHEM.》 *
ZENGWEI LUO，等: "Cytotoxic alkaloids from the whole plants of Zephyranthes candida", 《JOURNAL OF NATURAL PRODUCTS》 *

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