CN109824618A - 1- oxygen/sulphur/nitrogen -4- azaspiro quinones and application thereof - Google Patents
1- oxygen/sulphur/nitrogen -4- azaspiro quinones and application thereof Download PDFInfo
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- glucose
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- 239000001301 oxygen Substances 0.000 title claims abstract description 26
- 229910052760 oxygen Inorganic materials 0.000 title claims abstract description 26
- 150000004053 quinones Chemical class 0.000 title claims abstract description 14
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 title claims abstract description 11
- 239000005864 Sulphur Substances 0.000 title claims abstract description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 title description 12
- 229910052757 nitrogen Inorganic materials 0.000 title description 6
- -1 oxyl Chemical group 0.000 claims abstract description 34
- 239000001257 hydrogen Substances 0.000 claims abstract description 32
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 32
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 27
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 24
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims abstract description 20
- 229930195735 unsaturated hydrocarbon Natural products 0.000 claims abstract description 20
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 19
- 150000002367 halogens Chemical class 0.000 claims abstract description 19
- 229930091371 Fructose Chemical group 0.000 claims abstract description 18
- 239000005715 Fructose Chemical group 0.000 claims abstract description 18
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims abstract description 18
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical group OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 claims abstract description 17
- 125000004185 ester group Chemical group 0.000 claims abstract description 17
- 239000008103 glucose Substances 0.000 claims abstract description 17
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical group OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 claims abstract description 16
- 150000002337 glycosamines Chemical group 0.000 claims abstract description 16
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims abstract description 13
- 125000003118 aryl group Chemical group 0.000 claims abstract description 11
- 229910021529 ammonia Inorganic materials 0.000 claims abstract description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 10
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 9
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 9
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 claims abstract description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 3
- 239000002246 antineoplastic agent Substances 0.000 claims abstract 2
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- BJHIKXHVCXFQLS-UYFOZJQFSA-N fructose group Chemical group OCC(=O)[C@@H](O)[C@H](O)[C@H](O)CO BJHIKXHVCXFQLS-UYFOZJQFSA-N 0.000 claims description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 11
- 230000000694 effects Effects 0.000 abstract description 6
- 206010006187 Breast cancer Diseases 0.000 abstract description 4
- 208000026310 Breast neoplasm Diseases 0.000 abstract description 4
- 238000002474 experimental method Methods 0.000 abstract description 4
- 125000004151 quinonyl group Chemical group 0.000 abstract description 3
- 208000019065 cervical carcinoma Diseases 0.000 abstract description 2
- 125000000524 functional group Chemical group 0.000 abstract description 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 abstract description 2
- 201000008275 breast carcinoma Diseases 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 30
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 18
- 210000004027 cell Anatomy 0.000 description 11
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 230000000259 anti-tumor effect Effects 0.000 description 8
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- PLIKAWJENQZMHA-UHFFFAOYSA-N 4-aminophenol Chemical compound NC1=CC=C(O)C=C1 PLIKAWJENQZMHA-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene chloride Substances ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- 238000012216 screening Methods 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- 238000002835 absorbance Methods 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000001212 derivatisation Methods 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 2
- 206010008342 Cervix carcinoma Diseases 0.000 description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 2
- ZBIKORITPGTTGI-UHFFFAOYSA-N [acetyloxy(phenyl)-$l^{3}-iodanyl] acetate Chemical compound CC(=O)OI(OC(C)=O)C1=CC=CC=C1 ZBIKORITPGTTGI-UHFFFAOYSA-N 0.000 description 2
- 150000003869 acetamides Chemical class 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 229940061720 alpha hydroxy acid Drugs 0.000 description 2
- 150000001280 alpha hydroxy acids Chemical class 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 201000010881 cervical cancer Diseases 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 150000008282 halocarbons Chemical class 0.000 description 2
- 201000005202 lung cancer Diseases 0.000 description 2
- 208000020816 lung neoplasm Diseases 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- DAEPDZWVDSPTHF-UHFFFAOYSA-M sodium pyruvate Chemical compound [Na+].CC(=O)C([O-])=O DAEPDZWVDSPTHF-UHFFFAOYSA-M 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- WIGIZIANZCJQQY-UHFFFAOYSA-N 4-ethyl-3-methyl-N-[2-[4-[[[(4-methylcyclohexyl)amino]-oxomethyl]sulfamoyl]phenyl]ethyl]-5-oxo-2H-pyrrole-1-carboxamide Chemical compound O=C1C(CC)=C(C)CN1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCC(C)CC2)C=C1 WIGIZIANZCJQQY-UHFFFAOYSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 229930192627 Naphthoquinone Natural products 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 150000001336 alkenes Chemical group 0.000 description 1
- 150000001345 alkine derivatives Chemical group 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- YTKUWDBFDASYHO-UHFFFAOYSA-N bendamustine Chemical compound ClCCN(CCCl)C1=CC=C2N(C)C(CCCC(O)=O)=NC2=C1 YTKUWDBFDASYHO-UHFFFAOYSA-N 0.000 description 1
- 229960002707 bendamustine Drugs 0.000 description 1
- 230000005907 cancer growth Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- 229910000366 copper(II) sulfate Inorganic materials 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 125000001967 indiganyl group Chemical group [H][In]([H])[*] 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 150000002791 naphthoquinones Chemical class 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 1
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229940054269 sodium pyruvate Drugs 0.000 description 1
- IVGPGQSSDLDOLH-UHFFFAOYSA-M sodium;10-oxido-7-oxophenoxazin-10-ium-3-olate Chemical compound [Na+].C1=CC(=O)C=C2OC3=CC([O-])=CC=C3[N+]([O-])=C21 IVGPGQSSDLDOLH-UHFFFAOYSA-M 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- WAEXFXRVDQXREF-UHFFFAOYSA-N vorinostat Chemical compound ONC(=O)CCCCCCC(=O)NC1=CC=CC=C1 WAEXFXRVDQXREF-UHFFFAOYSA-N 0.000 description 1
- 229960000237 vorinostat Drugs 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Quinone ring and oxygen/sulphur/ammonia-azacyclo- composition 1- oxygen/sulphur/ammonia -4- azaspiro quinones, structure is as shown in logical formula (I), and each R base can indicate identical or different group, R in formula1、R2、R3、R4、R7It can simultaneously or separately be hydrogen, the alkyl of linear chain or branched chain or unsaturated hydrocarbons, halogen, oxyl, ester group, carboxyl, amino, nitro, hydroxyl, aromatic ring or heterocycle etc.；R5、R7Can be hydrogen, linear chain or branched chain alkyl or be the functional groups such as glucose, mannose, amino sugar, fructose, unsaturated hydrocarbons, oxyl etc.；R6Can for hydrogen, the alkyl of linear chain or branched chain or unsaturated hydrocarbons, oxyl, halogen, Glucose, mannose, amino sugar, fructose etc..Y is-O- ,-S-, NH-.Experiment display, such compound significantly inhibit Non-small cell lung carcinoma, human breast carcinoma and human cervical carcinoma cell activity, have the application value as anti-tumor drug.
Description
[technical field]
It is a kind of with inhibition human non-small cell lung cancer (A549), breast cancer (MD- the present invention relates to pharmaceutical technology field
BMA-231) and the active 1- oxygen/sulphur/ammonia -4- azaspiro quinones of growth of cancer cells such as cervical carcinoma (Hela) and such
The purposes of compound.
[background technique]
New cases of cancer and cancer mortality increase year by year in recent years.It is many antitumor due to the extensive use along with chemotherapy
Drug all generates drug resistance, this makes the worker for being engaged in medicine research and development face more stern challenge.In addition, small-molecule drug has
Have using advantages such as extensive, theoretical maturations.And loop coil quinones improves quinones anti-tumor activity because having, and it is dynamic to improve medicine generation
The advantages that mechanical property, raising quinones stability；Meanwhile many natural products containing loop coil and naphthoquinone derivatives are all
Show good anti-tumor activity.Therefore, pass through chemical structure design and screening active ingredients loop coil quinones small molecule guide's chemical combination
Object is of great significance to the discovery better anti-tumor medicine object of novel active high toxicity low selectivity.This patent passes through synthesis
A series of 1- oxygen/sulphur/ammonia -4- azaspiro quinones noval chemical compound, and the screening of extracorporeal anti-tumor cell activity has been carried out to it, it was demonstrated that
Such 1- oxygen/sulphur/ammonia -4- azaspiro quinone structure compound on tumor cell has inhibition increment active function.
[summary of the invention]
From above said content as can be seen that the present invention provides a kind of new 1- oxygen/sulphur/ammonia -4- azaspiro quinone structures, and
Further derivatization in this structure, including synthesis substituent group are alkyl, aromatic ring, heteroaromatic class compound and its a corresponding system
Column salt.The drug for having good tumors inhibition activity is provided by experiment screening gradually, can be applied to antitumor
Treatment.The present invention provides a kind of 1- oxygen/sulphur/ammonia -4- azaspiro naphtoquinone compounds that can replace for alkyl, aromatic ring, heteroaromatic class,
Shown in its structure such as formula (I):
R in formula (I)1、R2、R3、R4Can simultaneously or separately be hydrogen, the alkyl of linear chain or branched chain or unsaturated hydrocarbons, halogen element,
Oxyl, ester group, carboxyl, amino, nitro, hydroxyl, aromatic ring or heterocycle etc.；R5It can be hydrogen, the alkyl or function of linear chain or branched chain
It can property (such as TMS group) group, unsaturated hydrocarbons, oxyl；R6Can for hydrogen, the alkyl of linear chain or branched chain or unsaturated hydrocarbons,
Oxyl, halogen, Portugal
Grape sugar, mannose, amino sugar, fructose etc..Wherein R7For hydrogen atom, the alkyl of linear chain or branched chain, unsaturated hydro carbons, halogen, ester
The groups such as base, oxyl, carboxyl, amino, nitro, hydroxyl, aromatic ring or heterocycle, glucose, mannose, amino sugar, fructose.Y be-
O-,-S-,NH-.When Y is oxygen, R5For hydrogen, R6For hydrogen, linear chain or branched chain hydrocarbyl group,It is glucose, sweet
When revealing a series of groups such as sugar, amino sugar, fructose, R1, R2, R3, R4It can simultaneously or separately be hydrogen, methyl, halogen, ester group.Wherein
R7For hydrogen, the alkyl of linear chain or branched chain, unsaturated hydro carbons, halogen, ester group, oxyl, carboxyl, amino, nitro, hydroxyl, aromatic ring,
The groups such as heterocycle, glucose, mannose, amino sugar, fructose.Shown in structure such as formula (II):
Work as R6For hydrogen, R1, R2, R3, R4When being simultaneously or separately hydrogen, methyl, halogen, ester group, R5It can be hydrogen or alkyl.Structure such as formula
(III) shown in:
Work as R1, R2、R3、R4For hydrogen, R5When for hydrogen or methyl, R6Can indicate the alkyl group of linear chain or branched chain, unsaturated hydro carbons,Glucose, mannose,
A series of groups such as amino sugar, fructose, wherein R7For hydrogen, the alkyl of linear chain or branched chain, unsaturated hydro carbons, oxyl, ester group, carboxylic
The groups such as base, halogen, amino, nitro, hydroxyl, glucose, mannose, amino sugar, fructose.Shown in structure such as formula (IV):
Work as R5For methyl, R6For the alkyl group of linear chain or branched chain, unsaturated hydro carbons, A series of substituent groups such as glucose, mannose, amino sugar, fructose
When, R1, R2, R3, R4It can simultaneously or separately be a series of substituent groups such as methyl, halogen, ester group.Wherein R7For hydrogen, linear chain or branched chain
Alkyl, unsaturated hydro carbons, alkoxy, ester group, carboxyl, halogen, amino, nitro, hydroxyl, glucose, mannose, amino sugar,
The groups such as fructose.Shown in structure such as formula (V):
Through preliminary extracorporeal anti-tumor cell activity experiment screening, all compounds in the compound of above-mentioned general formula (I) are found
There is different degrees of inhibiting effect to tumour cell.Work as R1, R2, R3, R4It is simultaneously or separately H, CH3, Cl or other groups,
Such as ester group, pentamethylene base, ethyl or chain alkyl, aromatic ring or heterocycle；R5For H, CH3, ethyl, phenyl ring, aromatic ring or other heterocycles take
Generation；R6For alkyl substitution or aryl, heterocyclic substituted, show to inhibit tumor cell growth activity (such as formula (II, III, IV, V)
It is shown), this patent is using it as specific example compound:
It, which is synthesized, can be used with dicyclohexylurea (DCU) (DCC) as condensing agent, obtain golden in iodobenzene diacetate (DIB) and transition after amide
Under category effect, dearomatization obtains 1- oxygen -4- azaspiro quinone structure parent nucleus, then on this basis, further derivatization.Wherein,
Hydrocarbylation substrate is terminal alkyne, terminal olefin or when other functional groups, can further derivatization, synthetic route such as following formula:
Specific operation process is as follows:
1,4-aminophenol, alpha-hydroxy acid are solvent in acetonitrile, and DCC is dehydrating condensation under conditions of condensing agent into amide；
2, under nitrogen protection, raw material amide, DIB, catalyst are added in reaction flask, add anhydrous CH2Cl2Room temperature is anti-
It answers, thin-layer chromatography (TLC) detection reaction generates -4 azaspiro quinone of 1- oxygen to get corresponding formula (III) structured product is arrived；
3, under nitrogen protection, -4 azaspiro quinone of 1- oxygen is dissolved in dry THF, 15min is stirred after alkali is added, adds halogenated
Hydrocarbon reacts half an hour under ice bath, generates 4- substitution -1- oxygen -4- azaspiro quinone, obtains corresponding formula (IV) structured product；
4, the 4- containing active group is replaced into -1- oxygen -4- azaspiro quinone and azido compound or other groups, according to related text
It offers, generates the 4- heterocyclic substituted -1- oxygen -4- azaspiro quinone of such as triazole, tetrazole, oxazole, oxazole woods, imidazoles heterocycle, obtain
To corresponding formula (V) structured product.
Above content of the invention is described in further detail again below by way of the example of specific embodiment.But no
The range that this should be interpreted as to the above-mentioned theme of the present invention is only limitted to example below.The above-mentioned technical idea feelings of the present invention are not being departed from
Under condition, the various replacements or change made according to ordinary skill knowledge and customary means are included in model of the invention
In enclosing.
[specific embodiment]
The synthesis of -4 azaspiro quinones of embodiment 1:1- oxygen
(1) 4-aminophenol derivative, alpha-hydroxy acid are solvent in acetonitrile, DCC be under conditions of condensing agent dehydrating condensation at amide,
By being filtered to remove extra DCC, after reduced pressure, unreacted 4-aminophenol derivative is removed with dilute hydrochloric acid, after concentration
Silica gel column chromatography separating purification obtains 2- hydroxy-n-(4- hydroxy phenyl) acetamides；
(2) under nitrogen protection, 2- hydroxy-n-(4- hydroxy phenyl) acetamides are dissolved in DIB, catalyst anhydrous
It in methylene chloride, reacts, TLC detection reaction, after fully reacting, through silica gel column chromatography separating purification, obtains corresponding at room temperature
Formula (II or III) structured product；
7-methyl-1-oxa-4-azaspiro[4.5]deca-6,9-diene-3,8-dione
1H NMR(400MHz,CDCl3) δ 7.82 (d, J=6.8Hz, 1H), 6.69 (d, J=9.6Hz, 1H), 6.49 (s, 1H),
6.20 (d, J=9.8Hz, 1H), 4.35 (s, 2H), 1.89 (s, 3H)13C NMR(150MHz,CDCl3)δ184.8,173.4,
143.9,139.3,136.9,129.6,84.8,66.4,15.5.HRMS(ESI)Calcd C9H9NO3{[M+H]+}:
180.0661,Found 166.0658
7,9-dichloro-1-oxa-4-azaspiro[4.5]deca-6,9-diene-3,8-dione
1H NMR(400MHz,DMSO-d6) (s, the 2H) of δ 9.33 (s, 1H), 7.59 (d, J=3.1Hz, 2H), 4.3613C NMR
(100MHz,DMSO-d6)δ176.9,176.9,148.7,135.6,91.0,71.3.HR-MS(ESI)Calcd C8H5Cl2NO3
{[M+H]+}:233.9725,Found 233.9721
1H NMR(400MHz,CDCl3) δ 6.73-6.59 (m, 1H), 6.54-6.39 (m, 1H), 6.21 (dd, J=16.0,
9.9Hz, 1H), 4.51 (qd, J=6.7,3.9Hz, 1H), 1.89 (dd, J=6.4,1.2Hz, 3H), 1.48 (dd, J=6.7,
2.7Hz,3H).13C NMR(100MHz,CDCl3)δ184.9,175.5(175.49),175.5(175.46),145.3,144.1,
140.6,139.6,137.6,136.2,130.2,129.0,82.9,82.9,73.3,73.2,18.5,18.4,15.6,
15.5.HRMS(ESI)Calcd C10H11NO3{[M+H]+}:194.0817,Found194.0815。
The synthesis of embodiment 2:4- substitution -1- oxygen -4- azaspiro quinones
Under nitrogen protection, -4 azaspiro quinone of 1- oxygen is dissolved in dry THF, 15min is stirred after alkali is added, adds halogenated hydrocarbons,
It is reacted half an hour under ice bath, generates 4- substitution -1- oxygen -4- azaspiro quinone, obtain corresponding formula (IV) structured product
4-ethyl-2-methyl-1-oxa-4-azaspiro[4.5]deca-6,9-diene-3,8-dione(4f)
1H NMR(400MHz,CDCl3) δ 6.60 (ddd, J=32.7,10.0,2.8Hz, 2H), 6.37-6.25 (m, 2H), 4.52
(q, J=6.6Hz, 1H), 3.23-3.15 (m, 2H), 1.49 (d, J=6.7Hz, 3H), 1.14 (d, J=7.2Hz, 3H)13C
NMR(100MHz,CDCl3)δ184.00,171.77,145.61,144.4,131.3,130.3,85.9,73.3,35.2,18.7,
14.6.HRMS(ESI)Calcd C11H14NO3{[M+H]+}:208.0974,Found 209.0969
4-(but-2-yn-1-yl)-2-methyl-1-oxa-4-azaspiro[4.5]deca-6,9-diene-3,8-dione
1H NMR (400MHz, CDCl3) δ 6.67 (dd, J=10.0,3.1Hz, 1H), 6.59 (dd, J=10.0,3.1Hz, 1H),
6.33 (ddd, J=15.9,10.1,2.0Hz, 2H), 4.54 (q, J=6.7Hz, 1H), 3.94 (d, J=2.4Hz, 2H), 1.72
(t, J=2.4Hz, 3H), 1.50 (d, J=6.7Hz, 3H) .13C NMR (100MHz, CDCl3) δ 184.2,171.3,145.0,
143.9,131.6,130.4,85.6,81.2,73.2,73.0,29.5,18.6,3.4.HRMS(ESI)Calcd C13H14NO3{[M
+H]+}:232.0974,Found 232.0968
4-((2'-(1-trityl-1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-1-oxa-4-
azaspiro[4.5]deca-6,9-diene-3,8-dione
1H NMR(400MHz,CDCl3) δ 7.90 (d, J=7.5Hz, 1H), 7.47 (dq, J=15.4,6.9,6.3Hz, 2H),
7.34 (dd, J=12.5,6.6Hz, 5H), 7.28 (s, 2H), 7.25 (d, J=4.1Hz, 3H), 7.04 (d, J=7.9Hz, 2H),
6.94 (t, J=8.7Hz, 8H), 6.34 (d, J=10.0Hz, 2H), 6.10 (d, J=10.0Hz, 2H), 4.43 (s, 2H), 4.27
(s,2H).HRMS(ESI)Calcd C41H31N5O3{[M+H]+}:642.2505,Found 642.2498
7-chloro-4-methyl-1-oxa-4-azaspiro[4.5]deca-6,9-diene-3,8-dione
1H NMR(400MHz,CDCl3) δ 6.79 (d, J=2.9Hz, 1H), 6.63 (dd, J=10.0,2.9Hz, 1H), 6.45
(d, J=10.0Hz, 1H), 4.42 (s, 2H), 2.77 (s, 3H)13C NMR(100MHz,CDCl3)δ176.8,169.2,
144.2,139.6,135.5,130.4,89.1,66.6,25.0.HRMS(ESI)Calcd C9H9ClNO3{[M+H]+}:
214.0271,Found 232.0265
1H NMR(400MHz,CDCl3) δ 7.09 (d, J=7.6Hz, 2H), 7.04 (d, J=7.8Hz, 2H), 6.50-6.46 (m,
2H), 6.25 (d, J=9.8Hz, 1H), 4.51 (d, J=15.0Hz, 1H), 4.46 (s, 2H), 4.27 (d, J=14.9Hz, 1H),
2.31(s,3H).HRMS(ESI)Calcd C16H14ClNO3{[M+H]+}:304.0740,Found 304.0732。
The synthesis of embodiment 3:4- heterocyclic substituted -1- oxygen -4- azaspiro quinones
By 4- propargyl -1- oxygen -4- azaspiro quinone and azido compound in mixed solvent DMSO:H2In O=2:1, addition is added
Agent cupric sulfate pentahydrate, vitamine C sodium react 3h at room temperature, and 4- (1-R can be obtained7- 1H-1,2,3- triazole-4-yl-methyl)-
1- oxygen -4- azaspiro quinone, obtains corresponding formula (V) structured product
4-((1-(2-oxo-2-phenylethyl)-1H-1,2,3-triazol-4-yl)methyl)-1-oxa-4-
azaspiro[4.5]deca-6,9-diene-3,8-dione
1H NMR(400MHz,CDCl3) δ 7.98 (d, J=7.6Hz, 2H), 7.67 (d, J=8.3Hz, 2H), 7.55 (t, J=
7.6Hz, 2H), 6.56 (d, J=10.0Hz, 2H), 6.27 (d, J=10.0Hz, 2H), 5.83 (s, 2H), 4.53 (s, 2H),
4.44(s,2H).13C NMR(150MHz,CDCl3)δ189.9,183.9,169.7,143.3,142.7,134.7,133.7,
131.2,129.2,128.08,125.2,87.4,66.3,55.5,35.1.HRMS(ESI)Calcd C19H16N4O4{[M+H]+}:
365.1250,Found 365.1244
4-((1-((2'-(1-trityl-1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-1H-1,
2,3-triazol-4-yl)methyl)-1-oxa-4-azaspiro[4.5]deca-6,9-diene-3,8-dione
1H NMR(400MHz,CDCl3) δ 7.97 (d, J=7.5Hz, 1H), 7.53-7.44 (m, 3H), 7.38-7.31 (m, 6H),
7.24 (d, J=7.4Hz, 6H), 7.13 (d, J=7.7Hz, 2H), 6.98 (d, J=7.8Hz, 2H), 6.89 (d, J=8.0Hz,
4H), 6.53 (d, J=9.7Hz, 2H), 6.23 (d, J=9.7Hz, 2H), 5.33 (s, 2H), 4.38 (s, 2H), 4.32 (s, 2H)
.HRMS(ESI)Calcd C44H34N8O3{[M+H]+}:723.2832,Found 723.2822。
The inhibitory activity of embodiment 4:MTT method measurement compound on tumor cell
Experimental method:
Inhibiting rate of the mtt assay Preliminary Determination compound to screened cancer cell line: logarithmic growth phase lung cancer cell line A549, people
Breast cancer cell MDA-BM-231 and cervical cancer tumer line Hela, with complete culture solution diluting cells concentration to 2*104/ml,
It is inoculated in 96 orifice plates (100 μ L cell liquid are added in every orifice plate), is put into after being cultivated for 24 hours in incubator, replaces various concentration 1- oxygen -4-
The complete medium of azaspiro quinones (1 μm of ol/Ml, 10 μm of ol/Ml), blank control is 0.1%DMSO solution, in perseverance
Continue after cultivating 72h in warm incubator, be added 10 μ L of MTT (5 μ g/mL), after being incubated for 4 well, removes culture medium, DMSO is added
(150 μ L) shakes 15min, and absorbance is measured at 570nm with microplate reader, calculates versus cell and inhibits growth rate, inhibiting rate
(%)=(feminine gender group absorbance-dosing group absorbance)/(feminine gender group absorbance-blank group absorbance) × 100%, lung cancer is thin
Born of the same parents system A549, human breast cancer cell MDA-BM-231 and cervical cancer tumer line Hela have routinely replenished 10%FBS, 4mM paddy
Glutamine, 1mM Sodium Pyruvate, 100IU/mL penicillin, the culture medium of 100 μ g/mL streptomysins and 0.25 μ g/mL anphotericin
In, 37 DEG C are placed in, 5%CO2Incubator in culture, with cell per well 5 × 103Density be seeded in 96 orifice plates and cultivate for 24 hours,
Positive control drug bendamustine, Vorinostat and the target compound of synthesis is added by various dose concentration respectively, is incubated for 72h
20mL resazurin sodium is added afterwards and handles 2h, (is swashed using Victor microtiter fluorescence meter (Perkin-Elmer, USA) in 560nm
Hair), 590nm (transmitting) records fluorescence, measures IC50It is worth as follows:
The anti tumor activity in vitro of compound
Claims (6)
1.1- oxygen/sulphur/ammonia -4- azaspiro quinones, shown in structure such as formula (I), each R base can indicate identical or different base in formula
Group, R1、R2、R3、R4It can simultaneously or separately be hydrogen, methyl, halogen, ester group；R5For hydrogen or methyl；R6For hydrogen, the alkyl of linear chain or branched chain
Group or unsaturated hydro carbons,
A series of groups such as glucose, mannose, amino sugar, fructose etc., wherein R7For hydrogen, the alkyl of linear chain or branched chain, unsaturated hydrocarbons
Class, halogen, ester group, oxyl, carboxyl, amino, nitro, hydroxyl, aromatic ring, heterocycle, glucose, mannose, amino sugar, fructose etc.
Group；Y is-O- ,-S- ,-NH-；(I) it is
2. working as R5For hydrogen, R6For hydrogen, the alkyl group of linear chain or branched chain or unsaturated hydro carbons, One system such as glucose, mannose, amino sugar, fructose
When column group, R1, R2, R3, R4It can simultaneously or separately be hydrogen, methyl, halogen, ester group, wherein R7For hydrogen, the alkane of linear chain or branched chain
Base, unsaturated hydro carbons, halogen, ester group, oxyl, carboxyl, amino, nitro, hydroxyl, aromatic ring, heterocycle, glucose, mannose, ammonia
The groups such as base sugar, fructose, shown in structure such as formula (II),
3. working as R6For hydrogen, R1, R2, R3, R4When being simultaneously or separately hydrogen, methyl, halogen, ester group, R5It can be hydrogen or methyl, structure is such as
Shown in formula (III),
4. working as R1, R2、R3、R4For hydrogen, R5When for hydrogen or methyl, R6Can indicate the alkyl group of linear chain or branched chain, unsaturated hydro carbons,Glucose, mannose, ammonia
A series of groups such as base sugar, fructose, wherein R7For hydrogen, the alkyl of linear chain or branched chain, unsaturated hydro carbons, oxyl, ester group, carboxyl, halogen
The groups such as element, amino, nitro, hydroxyl, glucose, mannose, amino sugar, fructose, shown in structure such as formula (IV),
5. working as R5For methyl, R6For the alkyl group of linear chain or branched chain, unsaturated hydro carbons, Glucose, mannose, amino sugar, fructose etc. are a series of
When substituent group, R1, R2, R3, R4It can simultaneously or separately be the substituent groups such as methyl, halogen, ester group, wherein R7For hydrogen, linear chain or branched chain
Alkyl, unsaturated hydro carbons, alkoxy, ester group, carboxyl, halogen, amino, nitro, hydroxyl, glucose, mannose, amino sugar,
The groups such as fructose, shown in structure such as formula (V),
6. the oxygen of 1- described in claim 1/sulphur/ammonia -4- azaspiro quinones is used to prepare anti-tumor drug.
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