CN114591189B - Anthracene and nitrogen mustard substituted alpha, beta unsaturated ketone compound and preparation and application thereof - Google Patents
Anthracene and nitrogen mustard substituted alpha, beta unsaturated ketone compound and preparation and application thereof Download PDFInfo
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- CN114591189B CN114591189B CN202210356190.5A CN202210356190A CN114591189B CN 114591189 B CN114591189 B CN 114591189B CN 202210356190 A CN202210356190 A CN 202210356190A CN 114591189 B CN114591189 B CN 114591189B
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- anthracene
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- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical group C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 title claims abstract description 49
- 238000002360 preparation method Methods 0.000 title claims abstract description 35
- -1 ketone compound Chemical class 0.000 title claims abstract description 33
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical group ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 title claims abstract description 25
- 229960004961 mechlorethamine Drugs 0.000 title claims abstract description 25
- 238000000034 method Methods 0.000 claims abstract description 9
- 230000008569 process Effects 0.000 claims abstract description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 35
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 29
- 239000003054 catalyst Substances 0.000 claims description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- 206010028980 Neoplasm Diseases 0.000 claims description 7
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 7
- DQFWGPPCMONVDS-UHFFFAOYSA-N 1-anthracen-2-ylethanone Chemical compound C1=CC=CC2=CC3=CC(C(=O)C)=CC=C3C=C21 DQFWGPPCMONVDS-UHFFFAOYSA-N 0.000 claims description 6
- PXUFHXLGUJLBMI-UHFFFAOYSA-N 4-[bis(2-chloroethyl)amino]benzaldehyde Chemical compound ClCCN(CCCl)C1=CC=C(C=O)C=C1 PXUFHXLGUJLBMI-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- 206010006187 Breast cancer Diseases 0.000 claims description 3
- 208000026310 Breast neoplasm Diseases 0.000 claims description 3
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 3
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 3
- 206010038389 Renal cancer Diseases 0.000 claims description 3
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 3
- 239000002246 antineoplastic agent Substances 0.000 claims description 3
- 229940041181 antineoplastic drug Drugs 0.000 claims description 3
- 201000010881 cervical cancer Diseases 0.000 claims description 3
- 201000010982 kidney cancer Diseases 0.000 claims description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- 201000005202 lung cancer Diseases 0.000 claims description 2
- 208000020816 lung neoplasm Diseases 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 210000004881 tumor cell Anatomy 0.000 abstract description 12
- 230000000259 anti-tumor effect Effects 0.000 abstract description 8
- 239000003814 drug Substances 0.000 abstract description 8
- 230000018199 S phase Effects 0.000 abstract description 7
- 206010027476 Metastases Diseases 0.000 abstract description 3
- 125000005577 anthracene group Chemical group 0.000 abstract description 3
- 230000022131 cell cycle Effects 0.000 abstract description 3
- 230000009401 metastasis Effects 0.000 abstract description 3
- 210000004027 cell Anatomy 0.000 description 45
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 30
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 22
- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 description 17
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 230000000694 effects Effects 0.000 description 11
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 11
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 7
- 229940125904 compound 1 Drugs 0.000 description 7
- 239000003480 eluent Substances 0.000 description 7
- 150000002576 ketones Chemical class 0.000 description 7
- 125000003277 amino group Chemical group 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 230000009193 crawling Effects 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- NXXNVJDXUHMAHU-UHFFFAOYSA-N 1-anthracen-9-ylethanone Chemical compound C1=CC=C2C(C(=O)C)=C(C=CC=C3)C3=CC2=C1 NXXNVJDXUHMAHU-UHFFFAOYSA-N 0.000 description 5
- 238000012512 characterization method Methods 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 238000013508 migration Methods 0.000 description 4
- 230000005012 migration Effects 0.000 description 4
- 231100000820 toxicity test Toxicity 0.000 description 4
- 150000001454 anthracenes Chemical class 0.000 description 3
- 230000001028 anti-proliverative effect Effects 0.000 description 3
- 238000006555 catalytic reaction Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- MUVQKFGNPGZBII-UHFFFAOYSA-N 1-anthrol Chemical compound C1=CC=C2C=C3C(O)=CC=CC3=CC2=C1 MUVQKFGNPGZBII-UHFFFAOYSA-N 0.000 description 2
- OJPDDQSCZGTACX-UHFFFAOYSA-N 2-[n-(2-hydroxyethyl)anilino]ethanol Chemical compound OCCN(CCO)C1=CC=CC=C1 OJPDDQSCZGTACX-UHFFFAOYSA-N 0.000 description 2
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 description 2
- 241000806990 Hala Species 0.000 description 2
- 235000005311 Pandanus odoratissimus Nutrition 0.000 description 2
- 230000003698 anagen phase Effects 0.000 description 2
- PYKYMHQGRFAEBM-UHFFFAOYSA-N anthraquinone Natural products CCC(=O)c1c(O)c2C(=O)C3C(C=CC=C3O)C(=O)c2cc1CC(=O)OC PYKYMHQGRFAEBM-UHFFFAOYSA-N 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000004896 high resolution mass spectrometry Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- XJMOSONTPMZWPB-UHFFFAOYSA-M propidium iodide Chemical compound [I-].[I-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CCC[N+](C)(CC)CC)=C1C1=CC=CC=C1 XJMOSONTPMZWPB-UHFFFAOYSA-M 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 150000004350 1,4-dihydroxyanthraquinones Chemical class 0.000 description 1
- MRVNKBNZHOHVER-UHFFFAOYSA-N 2h-anthracen-1-one Chemical compound C1=CC=C2C=C3C(=O)CC=CC3=CC2=C1 MRVNKBNZHOHVER-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000220485 Fabaceae Species 0.000 description 1
- 230000010190 G1 phase Effects 0.000 description 1
- 241000234280 Liliaceae Species 0.000 description 1
- 239000004677 Nylon Substances 0.000 description 1
- 241000013557 Plantaginaceae Species 0.000 description 1
- 241000219050 Polygonaceae Species 0.000 description 1
- 241000219100 Rhamnaceae Species 0.000 description 1
- 241001107098 Rubiaceae Species 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 208000009956 adenocarcinoma Diseases 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000025084 cell cycle arrest Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 238000000684 flow cytometry Methods 0.000 description 1
- 230000005918 in vitro anti-tumor Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 230000031700 light absorption Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229920001778 nylon Polymers 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
- C07C225/22—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention belongs to the technical field of biological medicine, and in particular relates to an alpha, beta unsaturated ketone compound substituted by anthracene and nitrogen mustard, and preparation and application thereof. The anthracene and nitrogen mustard substituted alpha, beta unsaturated ketone compounds prepared by the invention can inhibit the metastasis of various tumor cells, so that the tumor cell cycle is blocked in the S phase, thereby achieving excellent anti-tumor effect. The preparation method is simple and convenient, the process route is short, and the preparation can be carried out by one step.
Description
Technical Field
The invention belongs to the technical field of biological medicine. More particularly, it relates to an anthracene and nitrogen mustard substituted alpha, beta unsaturated ketone compound, and preparation and application thereof.
Background
Malignant tumor seriously threatens human life, and the third national resident death factor investigation result shows that the death rate caused by tumor in China is the second most in all etiologies, accounts for 17.9%, and the incidence rate is in a trend of rising year by year. In recent 20 years, the tumor death rate of China rises 29.42 percent. In the middle-aged and elderly population, tumors have been the first cause of various death. Finding effective anticancer medicine and method to thoroughly overcome cancer is an important subject in the world medical field.
The anthracene compound has certain antitumor activity and can be used as a lead compound of a tumor drug. It is distributed in more than thirty higher plants of Polygonaceae, rhamnaceae, rubiaceae, leguminosae, liliaceae and Scrophulariaceae, and its existence forms are various, including oxidized anthracenol, anthracenol and anthracenone. However, anthracene compounds are various, and are often separated and purified by raw materials, so that the application and development of the anthracene compounds are greatly limited. Therefore, the anthracene compound is subjected to structural modification through chemical synthesis to obtain a medicament with ideal activity, and the method has important significance, for example, chinese patent application discloses a 1, 4-dihydroxyanthraquinone derivative, a preparation method and application thereof, and has a certain anti-tumor effect, but the report of the existing anthraquinone compound is less, and the report of the anthraquinone compound with the anti-tumor effect is more limited.
Disclosure of Invention
The invention aims to overcome the defect of less anthracene compounds with anti-tumor effect, and provides an alpha, beta unsaturated ketone compound substituted by anthracene and nitrogen mustard with excellent anti-tumor effect.
The invention aims to provide a preparation method of an alpha, beta unsaturated ketone compound substituted by anthracene and nitrogen mustard.
The invention also aims to provide an application of the anthracene and nitrogen mustard substituted alpha, beta unsaturated ketone compounds in preparing antitumor drugs.
The above object of the present invention is achieved by the following technical scheme is realized:
an anthracene and nitrogen mustard substituted alpha, beta unsaturated ketone compound, the structure of which is shown as a formula (I) or a formula (II):
the anthracene and nitrogen mustard substituted alpha, beta unsaturated ketone compound can effectively inhibit the metastasis of various tumor cells, the proportion of the S phase of the tumor cells is gradually increased along with the increase of the concentration of the compound of the invention, and G 1 And G 2 There is no obvious increase in the phase/M, so that the effect of resisting the proliferation of tumor cells is achieved.
The invention further provides a preparation method of the anthracene and nitrogen mustard substituted alpha, beta unsaturated ketone compounds, which comprises the following steps:
dissolving 4- [ bis- (2-chloroethyl) amino ] benzaldehyde and an acetyl anthracene compound in an organic solvent to react completely, and performing post-treatment to obtain the catalyst;
the acetyl anthracene compound is 9-acetyl anthracene or 2-acetyl anthracene.
Preferably, the molar ratio of the 4- [ bis- (2-chloroethyl) amino ] benzaldehyde, the acetyl anthracene compound and the basic catalyst is 1: (0.5-1.5): (1-2).
More preferably, the molar ratio of the 4- [ bis- (2-chloroethyl) amino ] benzaldehyde, the acetyl anthracene compound and the basic catalyst is 1: (1-1.5): (1 to 1.5).
Preferably, the alkaline catalyst comprises sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide.
More preferably, the basic catalyst is sodium hydroxide, sodium ethoxide or potassium hydroxide.
Preferably, the organic solvent is one or more of methanol, ethanol, toluene, xylene, chlorobenzene, o-dichlorobenzene or acetonitrile.
Preferably, the temperature of the reaction is 25 to 35 ℃.
Preferably, the reaction time is 20 to 30 hours.
Preferably, the post-treatment step comprises concentrating under reduced pressure to remove organic solvent, eluting with column chromatography, eluting with CH as eluent 2 Cl 2 /CH 3 OH＝(40～50):1(V：V)。
Preferably, the 4- [ bis- (2-chloroethyl) amino group]The preparation method of benzaldehyde comprises the steps of adding POCl 3 And N, N-dihydroxyethyl anilineDissolving in organic solvent, heating to react completely, and post-treating.
More preferably, the temperature of the heating reaction is 80-100 ℃, and the time of the heating reaction is 2-4 hours.
Preferably, the post-treatment comprises pouring into ice water to adjust the pH to neutral, filtering, washing and drying.
The invention further protects application of an anthracene and nitrogen mustard substituted alpha, beta unsaturated ketone compound or pharmaceutically acceptable salt thereof in preparing antitumor drugs.
Preferably, the tumor comprises cervical cancer, lung cancer, breast cancer, kidney cancer.
The invention has the following beneficial effects:
the anthracene and nitrogen mustard substituted alpha, beta unsaturated ketone compounds prepared by the invention can inhibit the metastasis of various tumor cells, so that the tumor cell cycle is blocked in the S phase, thereby achieving excellent anti-tumor effect. The preparation method is simple and convenient, the process route is short, and the preparation can be carried out by one step.
Drawings
FIG. 1 is a graph showing the results of toxicity experiments on A549 cells of the compound 1a prepared in example 1 and the compound 1b prepared in example 2 according to the present invention.
FIG. 2 shows the compound 1a prepared in example 1 and example 2 of the present invention the toxicity test result diagram of the prepared compound 1b on 786-O cells.
FIG. 3 is a graph showing the results of toxicity test of compound 1a prepared in example 1 and compound 1b prepared in example 2 of the present invention on Hela cells.
FIG. 4 is a graph showing the toxicity test results of the compound 1a prepared in example 1 and the compound 1b prepared in example 2 of the present invention on MDA-MB-231 cells.
FIG. 5 is a graph showing the migration inhibition effect of Compound 1a prepared in example 1 of the present invention on Hala cells.
FIG. 6 is a graph showing the effect of compound 1a prepared in example 1 of the present invention on inhibiting migration of Hala cells.
FIG. 7 shows the effect of compound 1a prepared in example 1 of the present invention on the Hela cell cycle.
Detailed Description
The invention is further illustrated in the following drawings and specific examples, which are not intended to limit the invention in any way. Unless specifically stated otherwise, the reagents, methods and apparatus employed in the present invention are those conventional in the art.
Reagents and materials used in the following examples are commercially available unless otherwise specified.
EXAMPLE 1 preparation of Anthracene and Nitrogen mustard substituted alpha, beta unsaturated Ketone Compound 1a
S1.4- [ bis- (2-chloroethyl) amino group]Preparation of benzaldehyde: DMF (9 mmol), POCl 3 (5 mmol) and N, N-dihydroxyethylaniline (2 mmol) were added to a round-bottomed flask, heated to 90℃for 3 hours, the reacted liquid was poured into ice water, pH was adjusted to neutral with NaOH, then filtered, the obtained solid was washed twice with pure water, and once with cold ethanol, and dried to give the intermediate 4- [ bis- (2-chloroethyl) amino]And (3) benzaldehyde. The yield was 85%.
Characterization data: 1 H NMR(300MHz,DMSO-d 6 )δ:9.72(s,1H,CHO),7.72(d,J＝8.89Hz,2H,ArH),6.90(d,J＝8.83Hz,2H,ArH),3.85(t,J＝5.78Hz,4H,CH 2 CH 2 Cl),3.79(t,J＝5.60Hz,4H,CH 2 CH 2 Cl)；
HRMS(ESI)calcd for C 11 H 14 C l2 NO[M+H] + 246.0452,found 246.0468。
s2, preparation of a compound 1 a: 4- [ bis (. Beta. -chloroethyl) amino group]Benzaldehyde (1 mmol), 9-acetyl anthracene (1 mmol), naOH (1 mmol) are reacted in ethanol (13 mL) for 24h, then ethanol is removed by decompression concentration, and the compound 1a is obtained by eluting and separating by column chromatography, the eluent is CH 2 Cl 2 /CH 3 Oh=45:1 (V: V), yield 82%.
Characterization data: 1 H NMR(600MHz,DMSO-d 6 )δ:8.73(s,1H,ArH),8.18(d,J＝8.51Hz,2H,ArH),7.81(d,J＝8.49Hz,2H,ArH),7.57～7.52(m,4H,ArH),7.46(d,J＝8.96Hz,2H,ArH),7.22(d,J＝16.07Hz,1H,CH),7.05(d,J＝16.07Hz,1H,CH),6.73(d,J＝8.96Hz,2H,ArH),3.78(t,J＝6.20Hz,4H,CH 2 ).3.72(t,J＝6.20Hz,4H,CH 2 )；
13 C NMR(150MHz,DMSO-d 6 )δ:198.96,149.61,148.52,135.68,131.58,131.15,129.15,128.24,128.06,127.15,126.09,125.40,124.88,122.62 122.42,52.12,41.44；
HR-MS(ESI)m/z:Calcd for C 27 H 24 Cl 2 NO{[M+H] + }448.1235,found 448.1234。
EXAMPLE 2 preparation of Anthracene and Nitrogen mustard substituted alpha, beta unsaturated Ketone Compound 1b
S1.4- [ bis- (2-chloroethyl) amino group]Preparation of benzaldehyde: DMF (9 mmol), POCl 3 (5 mmol) and N, N-dihydroxyethylaniline (2 mmol) were added to a round-bottomed flask, heated to 90℃for 3 hours, the reacted liquid was poured into ice water, pH was adjusted to neutral with NaOH, then filtered, the obtained solid was washed twice with pure water, and once with cold ethanol, and dried to give the intermediate 4- [ bis- (2-chloroethyl) amino]And (3) benzaldehyde. Yield: 85%.
Characterization data: 1 H NMR(300MHz,DMSO-d 6 )δ:9.72(s,1H,CHO),7.72(d,J＝8.89Hz,2H,ArH),6.90(d,J＝8.83Hz,2H,ArH),3.85(t,J＝5.78Hz,4H,CH 2 CH 2 Cl),3.79(t,J＝5.60Hz,4H,CH 2 CH 2 Cl)；
HRMS(ESI)calcd for C 11 H 14 C l2 NO[M+H] + 246.0452,found 246.0468。
s2, preparation of a compound 1 b: 4- [ bis (. Beta. -chloroethyl) amino group]Benzaldehyde (1 mmol), 2-acetyl anthracene (1 mmol), naOH (1 mmol) are reacted in ethanol (13 mL) for 24h, then ethanol is removed by decompression concentration, and the compound 1b is obtained by eluting and separating by column chromatography, the eluent is CH 2 Cl 2 /CH 3 Oh=45:1 (V: V), 76% yield.
Characterization data: 1 H NMR(600MHz,DMSO-d 6 )δ:8.96(s,1H,ArH),8.72(s,1H,ArH),8.31(d,J＝8.70Hz,1H,ArH),8.13(dd,J＝8.17Hz,13.19H,2H,ArH),7.94(d,J＝6.80,1H,ArH),7.67(d,J＝8.93Hz,2H,ArH),7.64(dd,J＝6.90,8.62Hz,1H,ArH),7.62～7.56(m,3H,ArH,CH),7.39(d,J＝15.61Hz,1H,CH),6.94(d,J＝8.97Hz,2H,ArH),3.84(t,J＝6.81Hz,4H,CH 2 ).3.78(t,J＝6.11Hz,4H,CH 2 )；
13 C NMR(150MHz,DMSO-d 6 )δ:194.49,149.31,146.34,137.41,132.22,132.15,131.89,131.57,131.46,129.02,128.33,128.25,127.81,127.38,126.65,126.63,124.91,124.81,123.26,122.37,112.44,52.21,41.51；
HR-MS(ESI)m/z:Calcd for C 27 H 24 Cl 2 NO{[M+H] + }448.1235,found 448.1233。
the difference from example 1 is that 9-acetylanthracene of example 1 is changed to 2-acetylanthracene, and the remaining raw materials, reagents and conditions are the same as those of example 1.
EXAMPLE 3 preparation of Anthracene and Nitrogen mustard substituted alpha, beta unsaturated Ketone Compound 1a
S1.4 preparation of- [ bis- (2-chloroethyl) amino ] benzaldehyde: as in example 1.
S2, preparation of a compound 1 a: 4- [ bis (. Beta. -chloroethyl) amino group]Benzaldehyde (1 mmol), 9-acetyl anthracene (1 mmol), sodium ethoxide (1 mmol) reacted in ethanol (13 mL) for 24h, then ethanol was removed by vacuum concentration, and further eluted and separated by column chromatography to obtain compound 1a, eluent is CH 2 Cl 2 /CH 3 OH＝45:1(V：V)。
The difference from example 1 is that in step S2, the base used for the catalysis of example 1 is changed from original NaOH to sodium ethoxide, and the rest of raw materials, reagents and conditions are the same as those of example 1.
EXAMPLE 4 preparation of Anthracene and Nitrogen mustard substituted alpha, beta unsaturated Ketone Compound 1b
S1.4 preparation of- [ bis- (2-chloroethyl) amino ] benzaldehyde: as in example 2.
S2, preparation of a compound 1 b: 4- [ bis (. Beta. -chloroethyl) amino group]Benzaldehyde (1 mmol), 2-acetyl anthracene (1 mmol), sodium ethoxide (1 mmol) reacted in ethanol (13 mL) for 24h, then ethanol was removed by vacuum concentration, and further eluted and separated by column chromatography to obtain compound 1b, eluent is CH 2 Cl 2 /CH 3 OH＝45:1(V：V)。
The difference from example 2 is that in step S2, the base used for the catalysis of example 2 is changed from original NaOH to sodium ethoxide, and the rest of raw materials, reagents and conditions are the same as those of example 2.
Comparative example 1 preparation of Anthracene and Nitrogen mustard substituted alpha, beta unsaturated Ketone Compound 1a
S1.4 preparation of- [ bis- (2-chloroethyl) amino ] benzaldehyde: as in example 1.
S2, preparation of a compound 1 a: 4- [ bis (. Beta. -chloroethyl) amino group]Benzaldehyde (1 mmol), 9-acetyl anthracene (1 mmol), triethylamine (1 mmol) reacted in ethanol (13 mL) for 24h, then ethanol was removed by vacuum concentration, and further eluted and separated by column chromatography to obtain compound 1a as eluent CH 2 Cl 2 /CH 3 Oh=45:1 (V: V). The yield was 2%.
The difference from example 1 is that in step S2, the base used for the catalyst in example 1 is changed from original NaOH to triethylamine, and the remaining raw materials, reagents and conditions are the same as those in example 1.
Comparative example 2 preparation of Anthracene and Nitrogen mustard substituted alpha, beta unsaturated Ketone Compound 1b
S1.4 preparation of- [ bis- (2-chloroethyl) amino ] benzaldehyde: as in example 2.
S2, preparation of a compound 1 b: 4- [ bis (. Beta. -chloroethyl) amino group]Benzaldehyde (1 mmol), 2-acetyl anthracene (1 mmol), triethylamine (1 mmol) reacted in ethanol (13 mL) for 24h, then ethanol was removed by vacuum concentration, and further eluted and separated by column chromatography to obtain compound 1b as eluent CH 2 Cl 2 /CH 3 Oh=45:1 (V: V). The yield was 3%.
The difference from example 2 is that in step S2, the base used for the catalysis of example 2 is changed from original NaOH to triethylamine, and the rest of raw materials, reagents and conditions are the same as those of example 2.
Experimental example 1 in vitro antitumor Activity study of Anthracene and Nitrogen mustard substituted alpha, beta unsaturated Ketone Compounds
Tumor cells in logarithmic growth phase (cervical cancer cells Hela, adenocarcinoma)Human alveolar basal epithelial cells A549, human breast cancer cells MDA-MB-231, and human renal cancer cells 786-O) were seeded in 96-well dishes (density: 2X 10 3 Cells/well) cells were attached, compound 1a or 1b was added at different concentrations (0. Mu.M, 1. Mu.M, 2. Mu.M, 4. Mu.M, 8. Mu.M, 16. Mu.M, 32. Mu.M, 64. Mu.M) per well, incubated at 37℃for 72 hours, the medium in 96-well plates was discarded, 25. Mu.L of thiazole blue (MTT) reagent per well was added, and incubation in an incubator was continued for 3 hours. Then the enzyme label instrument is used for reading the light absorption value OD of each hole 570 The change in activity of cells after treatment with different concentrations of drug was calculated.
As shown in fig. 1 to 4, the compounds 1a and 1b showed concentration-dependent effects on the proliferation inhibition ability of a549 (fig. 1), 786-O (fig. 2), hela (fig. 3) and MDA-MB-231 (fig. 4) tumor cells, and the higher the concentration of the compound 1a or 1b, the stronger the inhibition activity on four cells. In general, the effect of compounds 1a and 1b on Hela cells was more pronounced than the other three cells. According to the data of figures 1 to 4, IC of Compounds 1a and 1b on four cells 50 The values are summarized in table 1.
As shown in table 1: compound 1a (IC) on a549 cells 50 ) 28.8. Mu.M, for 786-O cells (IC 50 ) 23.5. Mu.M, for Hela cells (IC 50 ) 18.3. Mu.M, for MDA-MB-231 cells (IC 50 ) 27.1. Mu.M. It can be seen that compound 1a has the best inhibitory effect on Hela proliferation.
Compound 1b (IC) on a549 cells 50 ) 33.4. Mu.M, for 786-O cells (IC 50 ) 27.1. Mu.M, for Hela cells (IC 50 ) 24.9. Mu.M, for MDA-MB-231 cells (IC 50 ) 27.5. Mu.M. It can be seen that compound 1b also has the best inhibitory effect on Hela cell proliferation.
In contrast, the activity of compound 1a was slightly better than that of compound 1b, as compared with that of compound 1a and compound 1b. The results prove that the antiproliferative activity of the two compounds 1a and 1b of the invention on tumor cells is obvious; in addition, the antiproliferative activity of compound 1a on each tumor cell was slightly more prominent than that of compound 1b.
TABLE 1 half-Inhibitory Concentrations (IC) of Compounds 1a and 1b on various cells 50 ，μM)
Experimental example 2 cell scratch test of Anthracene and Nitrogen mustard substituted alpha, beta unsaturated Ketone Compounds
HeLa cells in logarithmic growth phase were seeded in 6-well plates (4X 10) 5 cell/well), after adherence, the cells were streaked vertically in the central area of cell growth with a gun head, the debris was washed with PBS and aspirated, then medium was added, compound 1a was added at different concentrations (0. Mu.M, 20. Mu.M, 40. Mu.M) and incubated for 24h; after removal of the medium, hoechst dye was added and the incubation was performed for 30min at 37℃and after 2 washes with PBS, the image was taken under an inverted fluorescence microscope, the results of which are shown in FIG. 5.
As can be seen from fig. 5, only after 24 hours of crawling, hela cells of the non-dosing group show very strong migration ability, while the dosing group obviously inhibits migration and crawling of cells, and the inhibition effect is more obvious along with the increase of concentration, and the concentration dependency relationship is shown.
The corresponding statistical graph is shown in FIG. 6, the relative crawling distance of the cells of the non-dosing group is 49.5% after 24 hours crawling, and the relative crawling distances are 74.6% and 83.2% when the dosing concentration is 20 mu M and 40 mu M respectively, which shows that the compound 1a effectively inhibits crawling of Hela cells, and the result shows that the compound 1a can play an anti-tumor role by reducing the metastatic capacity of tumor cells.
Experimental example 3 cell cycle arrest Studies of Anthracene and Nitrogen mustard substituted alpha, beta unsaturated ketones
HeLa cells were seeded in 10 cm cell culture dishes (1X 10) 6 cells/well), after adherence, drug (compound 1 a) was added, after 48h of drug action, cells were collected by digestion in centrifuge tubes, dried by buckling, re-suspended with PBS, re-buckled by buckling after 12h of fixation with 72% alcohol, centrifuged to buckling, stained with 300 μl of Propidium Iodide (PI), and incubated for 30min in the dark. Then filtering with nylon net on sample tube for machine, and finally analyzing and detecting with flow cytometry to obtain the cell at G 1 Stage, S stage and G 2 Proportion of phase/M. The results are shown in FIG. 7.
As can be seen from fig. 7, the proportion of Hela cells in S phase increases with increasing concentration of compound 1a, and the area of the hatched portion in fig. 7 represents the proportion of cells, wherein the dark-colored hatched portion on the left side is the proportion of cells in G1 phase; the middle light shaded portion indicates the proportion of cells in S phase; the dark shaded portion on the right indicates that the cell is at G 2 Ratio of phase/M. Specifically, G of Compound 1a is not added 1 S and G 2 The ratio of phase/M was 54.1%,30.8% and 15.1%, respectively; g when the concentration of Compound 1a was 20. Mu.M 1 The proportion of the period was reduced to 20.9%. And S and G 2 phase/M increased to 49.9% and 29.2%, respectively; when the concentration of Compound 1a was up-regulated to 40. Mu.M, G 1 The proportion of the phase was further reduced to 12.3%, the proportion of the S phase was significantly increased to 67.7%, and the proportion of G 2 The ratio of phase/M was reduced to 20.0%. It was found that the increase in the S phase ratio of Hela cells was generally concentration-dependent, and G was the same time 1 And G 2 There was no significant increase in phase/M, indicating that compound 1a was effective in blocking Hela cells in phase S and exerting an anti-proliferation effect on Hela cells.
The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.
Claims (9)
1. An anthracene and nitrogen mustard substituted alpha, beta unsaturated ketone compound, which is characterized in that the structure is shown as a formula (II)
The following is shown:
2. the process for the preparation of anthracene and nitrogen mustard substituted alpha, beta unsaturated ketone compounds according to claim 1, comprising the steps of:
dissolving 4- [ bis- (2-chloroethyl) amino ] benzaldehyde and an acetyl anthracene compound in an organic solvent to react completely, and performing post-treatment to obtain the catalyst;
the acetyl anthracene compound is 2-acetyl anthracene.
3. The method according to claim 2, wherein the molar ratio of the 4- [ bis- (2-chloroethyl) amino ] benzaldehyde, the acetyl anthracene compound and the basic catalyst is 1:0.5 to 1.5:1 to 2.
4. The method according to claim 2, wherein the molar ratio of the 4- [ bis- (2-chloroethyl) amino ] benzaldehyde, the acetyl anthracene compound and the basic catalyst is 1:1 to 1.5:1 to 1.5.
5. The preparation method according to claim 2, wherein the alkaline catalyst comprises sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide.
6. The preparation method according to claim 2, wherein the organic solvent is one or more of methanol, ethanol, toluene, xylene, chlorobenzene, o-dichlorobenzene or acetonitrile.
7. The process according to claim 2, wherein the temperature of the reaction is 25 to 35 ℃.
8. The preparation method according to claim 2, wherein the reaction time is 20 to 30 hours.
9. The use of an anthracene and nitrogen mustard substituted alpha, beta unsaturated ketone compound or a pharmaceutically acceptable salt thereof according to claim 1 in the preparation of an antitumor drug; wherein the tumor comprises cervical cancer, lung cancer, breast cancer and renal cancer.
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