CN116375698A - Novel urushiol-based hydroxamic acid type HDAC inhibitor with targeted antitumor activity and preparation method and application thereof - Google Patents
Novel urushiol-based hydroxamic acid type HDAC inhibitor with targeted antitumor activity and preparation method and application thereof Download PDFInfo
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- CN116375698A CN116375698A CN202310656470.2A CN202310656470A CN116375698A CN 116375698 A CN116375698 A CN 116375698A CN 202310656470 A CN202310656470 A CN 202310656470A CN 116375698 A CN116375698 A CN 116375698A
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- QARRXYBJLBIVAK-UEMSJJPVSA-N 3-[(8e,11e)-pentadeca-8,11-dienyl]benzene-1,2-diol;3-[(8e,11e)-pentadeca-8,11,14-trienyl]benzene-1,2-diol;3-[(8e,11e,13e)-pentadeca-8,11,13-trienyl]benzene-1,2-diol;3-[(e)-pentadec-8-enyl]benzene-1,2-diol;3-pentadecylbenzene-1,2-diol Chemical compound CCCCCCCCCCCCCCCC1=CC=CC(O)=C1O.CCCCCC\C=C\CCCCCCCC1=CC=CC(O)=C1O.CCC\C=C\C\C=C\CCCCCCCC1=CC=CC(O)=C1O.C\C=C\C=C\C\C=C\CCCCCCCC1=CC=CC(O)=C1O.OC1=CC=CC(CCCCCCC\C=C\C\C=C\CC=C)=C1O QARRXYBJLBIVAK-UEMSJJPVSA-N 0.000 title claims abstract description 48
- RMTXUPIIESNLPW-UHFFFAOYSA-N 1,2-dihydroxy-3-(pentadeca-8,11-dienyl)benzene Natural products CCCC=CCC=CCCCCCCCC1=CC=CC(O)=C1O RMTXUPIIESNLPW-UHFFFAOYSA-N 0.000 title claims abstract description 47
- IYROWZYPEIMDDN-UHFFFAOYSA-N 3-n-pentadec-8,11,13-trienyl catechol Natural products CC=CC=CCC=CCCCCCCCC1=CC=CC(O)=C1O IYROWZYPEIMDDN-UHFFFAOYSA-N 0.000 title claims abstract description 47
- DQTMTQZSOJMZSF-UHFFFAOYSA-N urushiol Natural products CCCCCCCCCCCCCCCC1=CC=CC(O)=C1O DQTMTQZSOJMZSF-UHFFFAOYSA-N 0.000 title claims abstract description 47
- 239000003276 histone deacetylase inhibitor Substances 0.000 title claims abstract description 38
- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical compound C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 title claims abstract description 35
- 239000002253 acid Substances 0.000 title claims abstract description 34
- 230000000259 anti-tumor effect Effects 0.000 title claims abstract description 25
- 229940121372 histone deacetylase inhibitor Drugs 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 115
- 238000006243 chemical reaction Methods 0.000 claims abstract description 42
- 102100039996 Histone deacetylase 1 Human genes 0.000 claims abstract description 25
- 101001035024 Homo sapiens Histone deacetylase 1 Proteins 0.000 claims abstract description 25
- 210000004881 tumor cell Anatomy 0.000 claims abstract description 22
- 239000002994 raw material Substances 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 10
- KENNKQXJFVDKAB-UHFFFAOYSA-N formohydrazide;thiophene Chemical compound NNC=O.C=1C=CSC=1 KENNKQXJFVDKAB-UHFFFAOYSA-N 0.000 claims abstract description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 81
- 239000002904 solvent Substances 0.000 claims description 65
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 42
- 210000004027 cell Anatomy 0.000 claims description 42
- 238000001704 evaporation Methods 0.000 claims description 40
- 239000000243 solution Substances 0.000 claims description 37
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 33
- 238000003756 stirring Methods 0.000 claims description 26
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 22
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- 102000003964 Histone deacetylase Human genes 0.000 claims description 19
- 108090000353 Histone deacetylase Proteins 0.000 claims description 19
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 18
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 18
- 239000011259 mixed solution Substances 0.000 claims description 14
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 13
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- 238000010992 reflux Methods 0.000 claims description 11
- 238000010898 silica gel chromatography Methods 0.000 claims description 11
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 9
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- 102100022537 Histone deacetylase 6 Human genes 0.000 claims description 7
- 101000899330 Homo sapiens Histone deacetylase 6 Proteins 0.000 claims description 7
- WWGBHDIHIVGYLZ-UHFFFAOYSA-N N-[4-[3-[[[7-(hydroxyamino)-7-oxoheptyl]amino]-oxomethyl]-5-isoxazolyl]phenyl]carbamic acid tert-butyl ester Chemical compound C1=CC(NC(=O)OC(C)(C)C)=CC=C1C1=CC(C(=O)NCCCCCCC(=O)NO)=NO1 WWGBHDIHIVGYLZ-UHFFFAOYSA-N 0.000 claims description 7
- 206010006187 Breast cancer Diseases 0.000 claims description 6
- 208000026310 Breast neoplasm Diseases 0.000 claims description 6
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- 102100039999 Histone deacetylase 2 Human genes 0.000 claims description 6
- 101001035011 Homo sapiens Histone deacetylase 2 Proteins 0.000 claims description 6
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 6
- 206010033128 Ovarian cancer Diseases 0.000 claims description 6
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 6
- 208000029742 colonic neoplasm Diseases 0.000 claims description 6
- 201000007270 liver cancer Diseases 0.000 claims description 6
- 208000014018 liver neoplasm Diseases 0.000 claims description 6
- 201000005202 lung cancer Diseases 0.000 claims description 6
- 208000020816 lung neoplasm Diseases 0.000 claims description 6
- 201000001441 melanoma Diseases 0.000 claims description 6
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- 229920006395 saturated elastomer Polymers 0.000 claims description 4
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- 230000002401 inhibitory effect Effects 0.000 abstract description 39
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 13
- 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 abstract description 8
- 239000002246 antineoplastic agent Substances 0.000 abstract description 8
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 8
- 239000008103 glucose Substances 0.000 abstract description 8
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 8
- 238000009833 condensation Methods 0.000 abstract description 7
- 230000005494 condensation Effects 0.000 abstract description 7
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- 238000007254 oxidation reaction Methods 0.000 abstract description 7
- 230000003647 oxidation Effects 0.000 abstract description 6
- 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 abstract description 5
- 125000005997 bromomethyl group Chemical group 0.000 abstract description 5
- 238000005698 Diels-Alder reaction Methods 0.000 abstract description 4
- 238000006467 substitution reaction Methods 0.000 abstract description 4
- 238000006266 etherification reaction Methods 0.000 abstract description 3
- 238000006116 polymerization reaction Methods 0.000 abstract description 3
- IBBMAWULFFBRKK-UHFFFAOYSA-N picolinamide Chemical compound NC(=O)C1=CC=CC=N1 IBBMAWULFFBRKK-UHFFFAOYSA-N 0.000 abstract description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 abstract 1
- 230000005764 inhibitory process Effects 0.000 description 29
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 16
- 230000000694 effects Effects 0.000 description 12
- 229940079593 drug Drugs 0.000 description 10
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 9
- 238000005481 NMR spectroscopy Methods 0.000 description 8
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical group O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 8
- 239000012071 phase Substances 0.000 description 8
- -1 [1,3] dioxolan-4-yl Chemical group 0.000 description 7
- 230000001028 anti-proliverative effect Effects 0.000 description 7
- 230000004663 cell proliferation Effects 0.000 description 7
- 238000001514 detection method Methods 0.000 description 7
- 206010028980 Neoplasm Diseases 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
- 230000027455 binding Effects 0.000 description 5
- 238000001308 synthesis method Methods 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- PTFCDOFLOPIGGS-UHFFFAOYSA-N Zinc dication Chemical compound [Zn+2] PTFCDOFLOPIGGS-UHFFFAOYSA-N 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- 125000005605 benzo group Chemical group 0.000 description 3
- FJBFPHVGVWTDIP-UHFFFAOYSA-N dibromomethane Chemical compound BrCBr FJBFPHVGVWTDIP-UHFFFAOYSA-N 0.000 description 3
- 239000004922 lacquer Substances 0.000 description 3
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 3
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 3
- USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical compound [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- 239000012980 RPMI-1640 medium Substances 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
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- YVUBWJOBCFNMES-UHFFFAOYSA-N formamide;pyridine Chemical compound NC=O.C1=CC=NC=C1 YVUBWJOBCFNMES-UHFFFAOYSA-N 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- VFQXVTODMYMSMJ-UHFFFAOYSA-N isonicotinamide Chemical compound NC(=O)C1=CC=NC=C1 VFQXVTODMYMSMJ-UHFFFAOYSA-N 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
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- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 238000000134 MTT assay Methods 0.000 description 1
- 231100000002 MTT assay Toxicity 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000159241 Toxicodendron Species 0.000 description 1
- 244000044283 Toxicodendron succedaneum Species 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 150000001263 acyl chlorides Chemical group 0.000 description 1
- 238000009098 adjuvant therapy Methods 0.000 description 1
- 238000005882 aldol condensation reaction Methods 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 230000001174 ascending effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229940054066 benzamide antipsychotics Drugs 0.000 description 1
- 150000003936 benzamides Chemical class 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000009702 cancer cell proliferation Effects 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical group OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
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- 230000004069 differentiation Effects 0.000 description 1
- 239000012039 electrophile Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000006195 histone acetylation Effects 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
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- 239000013641 positive control Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
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- 238000013519 translation Methods 0.000 description 1
- 230000005747 tumor angiogenesis Effects 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
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses a novel urushiol-based hydroxamic acid HDAC inhibitor with targeted anti-tumor activity, and a preparation method and application thereof, belonging to the technical field of pharmaceutical synthetic chemistry. The method is characterized in that urushiol is taken as a raw material, oxidation polymerization of urushiol is blocked through etherification reaction, hydroxamic acid groups are introduced into the tail part of a side chain of the urushiol alkyl through Diels-Alder, hydrolysis, condensation and other reactions, different pharmacophores such as bromomethyl, pyridine carboxamide, thiophene formylhydrazine, glucose and the like are introduced into a benzene ring of the urushiol through oxidation, chloracyl, substitution and other reactions, and a novel urushiol hydroxamic acid HDAC inhibitor is synthesized, and the compound inhibits the IC of HDAC1/2/6/8 50 IC for inhibiting 6 kinds of tumor cells 50 IC's with values below the FDA approved HDAC inhibitor SAHA 50 Value, can develop novel paintThe phenol-based HDAC inhibitor is used in antitumor drugs, and has extremely high added value.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical synthetic chemistry, and in particular relates to a novel urushiol-based hydroxamic acid HDAC inhibitor with targeted antitumor activity, and a preparation method and application thereof.
Background
Urushiol is a natural active ingredient in raw lacquer secreted by lacquer tree (Toxicodendron verniciflum (Stokes) F.A. bark), is an important forest product in China, and 85% of raw lacquer in the world is produced in China. Urushiol is an alkylphenol compound with catechol structure, and its side chain is C with different saturation 15 Is an alkane of (a). Urushiol has good anti-tumor biological activity, and has inhibition effect on 29 tumor cells of 9 organs of human body, and the action mechanisms comprise induction of tumor cell apoptosis, inhibition of tumor cell proliferation, inhibition of tumor angiogenesis, inhibition of nuclear transcription factor, poisoning of tumor cells and the like. The lacquer is used as a traditional Chinese medicine for adjuvant treatment of tumors in China for thousands of years. Therefore, the urushiol is hopefully developed into an anticancer drug, however, the chemical structure of the urushiol is unstable and is easy to oxidize and polymerize, the anti-tumor curative effect of the urushiol is seriously reduced, and the development and application of the unsaturated urushiol as an anti-tumor drug are limited.
Histone Deacetylase (HDAC) is an important target for treating cancers accepted at home and abroad. The imbalance in histone acetylation status caused by HDAC abnormalities has been closely related to the occurrence and progression of tumors, and over-expression of HDAC has been found in most tumor cells. HDAC inhibitors produce antitumor activity in regulating the translation process of genes, inhibiting cell growth, inducing apoptosis or differentiation, inhibiting tumor cell angiogenesis, etc., by altering intracellular acetylation levels. The design and development of low-toxicity and high-efficiency HDAC inhibitor analogues have become hot spots for research on antitumor targeted drugs at home and abroad. HDAC inhibitors can be divided into four general classes, according to structural features: hydroxamic acids, benzamides, electrophiles and cyclic peptides. The hydroxamic acid compound has the advantages of strong specificity, good anti-tumor activity, small toxic and side effects and the like, is the most widely studied and deepest HDAC inhibitor at present, and the structure of a typical hydroxamic acid HDAC inhibitor can be divided into 3 parts according to functions: a surface recognition region, a linker arm region, and a zinc ion binding region; the surface recognition region is mainly composed of hydrophobic segments, typically benzene ring derivatives; the connecting arm region is a fatty chain; the functional group of the zinc ion binding region is hydroxamic acid. Studies have shown that hydroxamic acid groups are key pharmacophores of HDAC inhibitors, which can be directly linked to Zn of HDAC enzymes 2+ The structure binds, thereby effectively inhibiting the activity of HDAC. Currently, the hydroxamic acid HDAC inhibitor Vorinostat (SAHA) of Merck corporation has been approved by the us FDA for the treatment of lymphoma, and in addition, a number of hydroxamic acid HDAC inhibitors are in the clinical stage of research.
Studies have shown that unsaturated urushiol has a certain HDAC inhibitory activity, and its structure is similar to that of the HDAC inhibitor SAHA approved by the FDA, but it also lacks the zinc ion binding region of the key structural unit for inhibiting HDAC. The invention takes unsaturated urushiol as raw material, blocks oxidation polymerization of urushiol through etherification reaction, introduces hydroxamic acid group at the tail of the side chain of the urushiol alkyl through Diels-Alder, hydrolysis, condensation and other reactions, introduces different pharmacophores such as bromomethyl, pyridine formamide, thiophene formylhydrazine, glucose and the like into the benzene ring of the urushiol through oxidation, chloracyl, substitution and other reactions, synthesizes 4 novel urushiol hydroxamic acid HDAC inhibitors, has good HDAC1/2/6/8 inhibition activity, and half Inhibition Concentration (IC) of 4 compounds to HDAC1 50 ) Half Inhibition Concentration (IC) of HDAC2 in the range 40.21-50.05 nM 50 ) Half Inhibition Concentration (IC) of HDAC6 in the 74.16-82.05nM range 50 ) Half Inhibition Concentration (IC) of HDAC8 in the 61.52-98.47nM range 50 ) IC's in the 12.54-16.08nM range, all lower than FDA approved HDAC inhibitor SAHA 50 The value shows better proliferation inhibition activity on 6 tumor cells (A2780 human ovarian cancer cells, NCI-H1975 human lung cancer cells, HT-29 human colon cancer cells, MDA-MB-231 human breast cancer cells, hepG2 human liver cancer cells and HT-144 human melanoma cells) in vitro than that of positive control SAHA, so that the synthesized series of urushiol hydroxamic acid HDAC inhibitors are expected to be applied to clinical antitumor drugs, have extremely high added value, and can become a new technology for clinically developing novel urushiol HDAC inhibitors. And no studies of urushiol hydroxamic acid HDAC inhibitors on HDAC1 and HDAC6 have been reported so far.
Disclosure of Invention
The first technical problem to be solved by the present invention is to provide a novel urushiol-based hydroxamic acid type HDAC inhibitor with targeted antitumor activity, which has good HDAC1/2/6/8 inhibitory activity and antitumor activity. The second technical problem to be solved by the invention is to provide a synthesis method of a novel urushiol-based hydroxamic acid type HDAC inhibitor with targeted anti-tumor activity, which is used for inhibiting HDAC1/2/6/8 and anti-tumor drugs. The third technical problem to be solved by the invention is to provide an application of a novel urushiol-based hydroxamic acid type HDAC inhibitor with targeted antitumor activity in inhibiting HDAC1/2/6/8 and antitumor drugs.
In order to solve the problems, the technical scheme adopted by the invention is as follows:
novel urushiol-based hydroxamic acid HDAC inhibitors with targeted antitumor activity, including UHA1-4, have the following structural formulas:
the compounds UHA1-4 are respectively 5- (10- (7-bromomethylbenzo [ d ] [1,3] dioxolan-4-yl) decane-2-en-1-yl) -N-hydroxy-2-methylcyclohexane-3-ene-1-carboxamide, 5- (10- (7- (pyridine-4-carboxamide methanone) benzo [ d ] [1,3] dioxolan-4-yl) decane-2-en-1-yl) -N-hydroxy-2-methylcyclohexane-3-ene-1-carboxamide, 5- (10- (7- (thiophene-2-formylhydrazono) benzo [ d ] [1,3] dioxolan-4-yl) decane-2-en-1-yl) -N-hydroxy-2-methylcyclohexane-3-ene-1-carboxamide, and 5- (10- (7-gluco-methylester) benzo [ d ] [1,3] dioxolan-2-en-1-yl) -N-hydroxy-2-methylcyclohexane-3-carboxamide.
The synthesis method of the compound UHA1 comprises the following steps:
taking a certain amount of S1 as a raw material, dissolving the S1 in DMF, adding a certain amount of sodium hydride, mixing and stirring for 2 hours at room temperature, dropwise adding a DMF solution of dibromomethane into the mixed solution, stirring and reacting the mixed solution at 60 ℃ for 2 hours, evaporating the solvent from the reaction solution, adding a certain amount of water, extracting for 3 times by using ethyl acetate, concentrating an organic layer under reduced pressure, performing flash column chromatography, eluting by using PE-EA, and evaporating the solvent under reduced pressure to obtain a compound S2; dissolving a certain amount of S2 in methanol, adding a certain amount of water and potassium hydroxide, heating and refluxing for 6 hours, then evaporating the solvent under reduced pressure, adding a certain amount of water and saturated ammonium chloride solution, extracting for 3 times by using ethyl acetate, and evaporating the solvent under reduced pressure on an organic layer to obtain a compound S3; s3 is dissolved in a certain amount of dichloromethane,sequentially adding a certain amount of NH 2 After OTHP, EDC.Cl and DMAP, a certain amount of DIPEA is added dropwise, stirring is carried out at room temperature for reaction for 8 hours, the solvent is evaporated under reduced pressure, silica gel column chromatography is carried out, PE-EA is used for eluting, and the solvent is evaporated under reduced pressure to obtain a compound S4; dissolving a certain amount of S4 in methanol, adding a certain amount of 1M hydrochloric acid solution, stirring at room temperature for 10 hours, evaporating the solvent under reduced pressure, dissolving the obtained compound in chromatographic methanol, filtering with a microporous filter membrane, and purifying with HPLC to obtain the target compound UHA-1.
The UHA-1 reaction process is as follows:
wherein, the compound S1 is prepared by taking urushiol as a raw material, firstly carrying out aldol condensation reaction to obtain methylene ether urushiol, and then carrying out Diels-Alder and hydrolysis reaction to obtain the compound S1, wherein the purity of the compound S1 is more than or equal to 90%.
HPLC purification method, wherein the chromatographic column is C18 preparation column, the mobile phase is methanol-water, the ratio is 65:35, and the detection wavelength is 210nm.
The synthesis method of the compound UHA2 comprises the following steps:
taking S1 as a raw material, dissolving a certain amount of S1 into HAc, introducing CO gas at normal temperature, adding a certain amount of trifluoroacetic acid, potassium persulfate and palladium acetate, stirring at normal temperature for reaction for 10 hours, adding a certain amount of water after evaporating the reaction solution to dryness, adjusting the pH value to 13 by using NaOH aqueous solution, extracting the aqueous phase for 2 times by using methyl tertiary butyl ether, adjusting the pH value of the aqueous phase to 1 by using hydrochloric acid solution, extracting for 3 times by using EA, evaporating the solvent by using an organic phase to obtain a compound S5, mixing a certain amount of S5 with thionyl chloride, carrying out reflux reaction for 1.5 hours under the protection of argon, cooling the reaction solution to the room temperature, evaporating the solvent by decompression, carrying out column chromatography, eluting by using PE-EA, and evaporating the solvent by decompression to obtain a compound S6; dissolving a certain amount of S6 in DMF, then dropwise adding into a mixed solution of triethylamine and pyridine-4-formamide, stirring at 0 ℃ for reaction for 12 hours, evaporating the solvent under reduced pressure, recrystallizing with a mixed solution of DMSO and water, drying in vacuum at 80 ℃ for 12 hours to obtain a compound S7, dissolving the S7 in methanol completely, adding a certain amount of water and potassium hydroxideHeating and refluxing for 6 hours, then decompressing and evaporating the solvent, adding a certain amount of water and saturated NH4Cl solution, extracting for 3 times by using ethyl acetate, decompressing and evaporating the solvent from the organic layer to obtain a compound S8; dissolving S8 in a certain amount of DCM, sequentially adding a certain amount of NH 2 After OTHP, EDC.Cl and DMAP, a certain amount of DIPEA is added dropwise, stirring is carried out at room temperature for reaction for 8 hours, the solvent is evaporated under reduced pressure, silica gel column chromatography is carried out, PE-EA is used for eluting, and the solvent is evaporated under reduced pressure to obtain a compound S9; dissolving a certain amount of S9 in methanol, adding a certain amount of 1M hydrochloric acid solution, stirring at room temperature for 10 hours, evaporating the solvent under reduced pressure, dissolving the obtained compound in chromatographic methanol, filtering with a microporous filter membrane, and purifying with HPLC to obtain the target compound UHA-2.
The UHA-2 reaction process is as follows:
wherein, the HPLC purification method comprises the steps of preparing a chromatographic column with C18, preparing a mobile phase with methanol-water at a ratio of 68:32, and detecting the wavelength of 210nm.
The synthesis method of the compound UHA3 comprises the following steps:
taking S6 as a raw material, dissolving a certain amount of S6 in DMF, then dropwise adding the DMF into a mixed solution of triethylamine and thiophene-2-formylhydrazine, stirring the mixture at 20 ℃ for reaction for 24 hours, evaporating the solvent under reduced pressure, recrystallizing the mixture of DMSO and water, drying the mixture under vacuum at 80 ℃ for 12 hours to obtain a compound S10, dissolving the S10 in methanol, adding a certain amount of water and potassium hydroxide, heating and refluxing the mixture for 6 hours, evaporating the solvent under reduced pressure, adding a certain amount of water and saturated NH4Cl solution, extracting the mixture with ethyl acetate for 3 times, and evaporating the solvent under reduced pressure to obtain a compound S11; s11 is dissolved in a certain amount of DCM, and a certain amount of NH is added in sequence 2 After OTHP, EDC.Cl and DMAP, a certain amount of DIPEA is added dropwise, stirring is carried out at room temperature for reaction for 8 hours, the solvent is evaporated under reduced pressure, silica gel column chromatography is carried out, PE-EA is used for eluting, and the solvent is evaporated under reduced pressure to obtain a compound S12; dissolving a certain amount of S12 in methanol, adding a certain amount of 1M hydrochloric acid solution, stirring at room temperature for 10 hr, evaporating solvent under reduced pressure, dissolving the obtained compound in chromatographic methanol, and microporous membraneFiltering and purifying by HPLC to obtain the target compound UHA-3.
The UHA-3 reaction process is as follows:
according to the HPLC purification method, the chromatographic column is a C18 preparation column, the mobile phase is methanol-water, the ratio is 65:35, and the detection wavelength is 210nm.
The synthesis method of the compound UHA4 comprises the following steps:
taking S6 as a raw material, dissolving a certain amount of S6 in DMF, then dropwise adding the DMF into a mixed solution of triethylamine and glucose, stirring and reacting for 5 hours at 20 ℃, decompressing and evaporating the reaction solution to dryness, adding a certain amount of water, extracting for 3 times by using ethyl acetate, decompressing and evaporating the organic layer to dryness to obtain a compound S13, dissolving all the S13 in methanol, adding a certain amount of water and potassium hydroxide, decompressing and evaporating the solvent after heating and refluxing for 6 hours, adding a certain amount of water and saturated NH4Cl solution, extracting for 3 times by using ethyl acetate, decompressing and evaporating the solvent by using an organic layer to obtain a compound S14; dissolving S14 in a certain amount of DCM, sequentially adding a certain amount of NH 2 After OTHP, EDC.Cl and DMAP, a certain amount of DIPEA is added dropwise, stirring is carried out at room temperature for reaction for 8 hours, the solvent is evaporated under reduced pressure, silica gel column chromatography is carried out, PE-EA is used for eluting, and the solvent is evaporated under reduced pressure to obtain a compound S15; dissolving a certain amount of S15 in methanol, adding a certain amount of 1M hydrochloric acid solution, stirring at room temperature for 10 hours, evaporating the solvent under reduced pressure, dissolving the obtained compound in chromatographic methanol, filtering with a microporous filter membrane, and purifying with HPLC to obtain the target compound UHA-4.
The UHA-4 reaction process is as follows:
wherein, the HPLC purification method comprises the steps of preparing a C18 chromatographic column, preparing methanol-water as a mobile phase, and detecting the wavelength of 210nm at a ratio of 62:38.
The novel urushiol-based hydroxamic acid HDAC inhibitor with the targeted anti-tumor activity is applied to the novel urushiol-based HDAC inhibitor.
The HDAC includes HDAC1, HDAC2, HDAC6 and HDAC8.
The novel urushiol-based hydroxamic acid type HDAC inhibitor with targeted anti-tumor activity is applied to anti-tumor drugs.
The tumors are A2780 human ovarian cancer cells, NCI-H1975 human lung cancer cells, HT-29 human colon cancer cells, MDA-MB-231 human breast cancer cells, hepG2 human liver cancer cells and HT-144 human melanoma cells.
The invention takes an intermediate compound S1 as a raw material, sodium hydride and dibromomethane are added for substitution reaction, a bromomethyl group can be introduced on a benzene ring, and KOH and NH are added 2 OTHP and other reagents, and performing hydrolysis, condensation and other reactions to finally obtain a target compound UHA1 with bromomethyl groups on benzene rings and hydroxamic acid groups on the tail parts of alkyl side chains; taking S1 as a raw material, adding reagents such as trifluoroacetic acid, potassium persulfate and palladium acetate to perform oxidation reaction, introducing carboxylic acid groups into a benzene ring, then adding thionyl chloride reagent to perform chloracylation reaction to introduce acyl chloride groups into the benzene ring to obtain an intermediate S6, then performing nucleophilic substitution reaction with pyridine carboxamide to introduce pyridine-4-carboxamide ketone groups into the benzene ring, and then adding KOH and NH 2 Carrying out hydrolysis, condensation and other reactions on the reagent such as OTHP and the like to finally obtain a target compound UHA2 with pyridine-4-formamide ketone groups on benzene ring and hydroxamic acid groups on the tail part of an alkyl side chain; s6 is taken as a raw material, thiophene-2-formylhydrazine ketone groups can be introduced into a benzene ring through nucleophilic substitution reaction with thiophene formylhydrazine, and KOH and NH are added 2 The target compound UHA3 with thiophene-2-formylhydrazone ketone group in the benzene ring and hydroxamic acid group in the tail of the alkyl side chain can be finally obtained by carrying out hydrolysis, condensation and other reactions on the OTHP and other reagents; s6 is taken as a raw material, glucose methyl ester groups can be introduced into a benzene ring through nucleophilic substitution reaction with glucose, and KOH and NH are added 2 The reagent such as OTHP carries out hydrolysis, condensation and other reactions to finally obtain the product with glucose methyl ester group in the benzene ring and hydroxamic acid group in the tail part of the alkyl side chainIs a target compound UHA4; the invention is realized by 1 H-NMR、 13 The structures of 4 target compounds are confirmed by technical means such as C-NMR, ESI-MS, IR and the like.
The invention adopts an HDAC inhibition activity detection kit to respectively determine the inhibition activity of the compound UHA1-4 on HDAC1/2/6/8 under different concentration conditions; the compounds UHA1-4 have good inhibition effect on HDAC1/2/6/8, the inhibition rate is in an ascending trend along with the increase of the concentration of the compounds, and the half inhibition concentration (IC 50 ) Half Inhibition Concentration (IC) of HDAC2 in the range 40.21-50.05 nM 50 ) Half Inhibition Concentration (IC) of HDAC6 in the 74.16-82.05nM range 50 ) Half Inhibition Concentration (IC) of HDAC8 in the 61.52-98.47nM range 50 ) IC with 4 compounds inhibiting HDAC1/2/6/8 in the 12.54-16.08nM range 50 IC with values lower than that of SAHA positive drug 50 The values indicated that 4 compounds UHA1-4 have better HDAC1/2/6/8 inhibitory activity than the positive drug SAHA.
The invention adopts MTT method to respectively determine the antiproliferative activity of the compound UHA1-4 on 6 tumor cells (A2780 human ovarian cancer cells, NCI-H1975 human lung cancer cells, HT-29 human colon cancer cells, MDA-MB-231 human breast cancer cells, hepG2 human liver cancer cells and HT-144 human melanoma cells) under different concentration conditions, and the result shows that the compound UHA1-4 has good antiproliferative capacity on 6 tumor cells, and the antiproliferative capacity of the compound gradually increases along with the increase of the concentration, so that the larger the concentration of the compound is, the stronger the inhibition capacity on the proliferation of cancer cells is; half maximal Inhibitory Concentration (IC) of compound UHA1-4 on A2780 cells 50 ) In the range of 3.15-4.08. Mu.M, the median inhibitory concentration (IC 50 ) In the range of 2.73-3.56. Mu.M, the half maximal inhibitory concentration (IC 50 ) Half Inhibition Concentration (IC) for MDA-MB-231 in the range of 2.58-3.49. Mu.M 50 ) In the range 1.68-2.29. Mu.M, the median inhibitory concentration (IC 50 ) In the range of 2.05-2.82. Mu.M, the half maximal inhibitory concentration (IC 50 ) IC of 4 compounds to 6 tumor cells in the range of 5.87-7.69 [ mu ] M 50 All values areIC showing lower than the positive drug SAHA 50 Values. The compound UHA1-4 has better antiproliferative effect on the 6 tumor cells than the positive drug SAHA.
The beneficial effects are that: compared with the prior art, the invention has the advantages that:
(1) According to the invention, urushiol is taken as a raw material, oxidation polymerization of urushiol is blocked through etherification reaction, so that the chemical structure of urushiol is stable, and HDAC inhibition key pharmacophore hydroxamic acid is introduced into the tail part of a side chain of urushiol through Diels-Alder, hydrolysis, condensation and other reactions, so that the urushiol can act on the pocket part of HDAC enzyme in a targeted manner, and is effectively chelated with zinc ions in the HDAC enzyme, thereby achieving the effect of selectively inhibiting the HDAC enzyme, and improving the biocompatibility of unsaturated urushiol; different pharmacophores such as bromomethyl, pyridine formamide, thiophene formylhydrazine, glucose and the like are introduced into a urushiol benzene ring through reactions such as oxidation, chloracylation, substitution and the like, so that the HDAC inhibition activity of the urushiol can be enhanced, and the recognition and binding force of the urushiol to HDAC enzyme are improved.
(2) The 4 novel urushiol-based hydroxamic acid HDAC inhibitors synthesized by the invention have good HDAC binding and inhibiting activity and good anti-tumor cell proliferation capacity for 6 tumor cells in vitro; half-maximal Inhibitory Concentrations (IC) of 4 compounds on HDAC1/2/6/8 enzyme and 6 tumor cells 50 ) IC's lower than the FDA approved HDAC inhibitor SAHA 50 Therefore, the series of novel urushiol-based hydroxamic acid HDAC inhibitors synthesized by the invention are very expected to be developed into novel natural HDAC inhibitors, are applied to targeted antitumor drugs, and effectively improve the added value of natural urushiol.
(3) The 4 novel urushiol hydroxamic acid HDAC inhibitors synthesized by the invention have good inhibition rate on HDAC1/2/6/8, and have good anti-tumor cell proliferation capability on A2780 human ovarian cancer cells, NCI-H1975 human lung cancer cells, HT-29 human colon cancer cells, MDA-MB-231 human breast cancer cells, hepG2 human liver cancer cells and HT-144 human melanoma cells.
Detailed Description
The invention is further described below in connection with specific embodiments.
Example 1
1. Synthesis of target Compound UHA1
Dissolving 6.0g of a compound S1 in 60mLDMF, adding 0.70g of sodium hydride, mixing and stirring for 2 hours at room temperature, dropwise adding a 20mLDMF solution containing 2.6g of dibromomethane into the mixed solution, stirring and reacting for 2 hours at the temperature of 60 ℃, evaporating the solvent from the reaction solution, adding 60mL of water, extracting for 3 times by using ethyl acetate, using 50mL each time, concentrating under reduced pressure, performing silica gel column chromatography, eluting by using PE-EA, wherein PE is equal to EA=7:3, and evaporating the solvent from the eluent under reduced pressure to obtain 2.5g of the compound S2; dissolving 1.0g of S2 in 30mL of methanol, adding 1.5mL of water and 0.30g of potassium hydroxide, heating and refluxing for 6 hours, then evaporating the solvent under reduced pressure, adding 15mL of water and 15mL of saturated ammonium chloride solution, extracting 3 times with ethyl acetate, each time with the dosage of 30mL, and evaporating the solvent under reduced pressure to obtain 0.72g of compound S3; s3 was dissolved in 10mL of dichloromethane, followed by the addition of 276mg of NH 2 After OTHP,414mg of EDC.Cl and 69mg of DMAP, 0.4mL of DIPEA is added dropwise, stirring is carried out at room temperature for reaction for 8 hours, the solvent is evaporated under reduced pressure to obtain a product, silica gel column chromatography is carried out, PE is eluted by PE-EA, EA=4:3, and the solvent is evaporated under reduced pressure to obtain 0.45g of S4 of a compound; 100mg of S4 is dissolved in 6mL of methanol, 2mL of 1M hydrochloric acid solution is added, stirring is carried out at room temperature for 10 hours, the solvent is evaporated to dryness under reduced pressure, the obtained compound is dissolved in 5mL of chromatographic methanol, the solution is filtered by a microporous filter membrane and is further purified by HPLC, the chromatographic column is a C18 preparation column, the mobile phase is methanol-water, the ratio is 65:35, the detection wavelength is 210nm, and the target component is collected and the solvent is evaporated to dryness under reduced pressure, thus obtaining 62.4mg of target compound UHA-1.
By using 1 H-NMR、 13 The chemical structure of the synthesized target compound UHA-1 is identified and confirmed by means of C-NMR, ESI-MS, IR and the like, and the physicochemical properties and spectrum data of the compound UHA-1 are as follows:
a light brown oil. IR (KBr) v/cm -1 :3210(-OH), 3016(NH),1625（O=C-）, 1452(Ar ,C=C),1054(C-O-C); 1 H NMR(500 MHz,CDCl 3 ): δ 9.35(d, J = 3.5 Hz,1H,-OH), 8.71(d, J = 3.3 Hz ,1H,O=C-NH-),6.85 (d, J =1.9 Hz ,1H,Ar-H), 6.68 (d, J =2.1 Hz ,1H,Ar-H), 5.88 (s ,2H, O-CH 2 -O), 5.71~5.65 (m ,2H, -CH=CH- ), 5.48~5.43 (m, 2H, -CH=CH-),4.47 (t , J = 0.8 Hz, 2H, -CH 2 -Br ), 2.74 (t, J = 8.1Hz, 2H , Ar-CH 2 ), 2.68 (m ,1H,-CH-), 2.60 (d , J = 7.6 Hz, 1H, O=C-CH-), 2.46~1.87 (m, 5H,-CH 2 -CH-CH 2 -), 1.99~1.27 (m, 12H,-CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -) ,1.05(s, 3H,-CH 3 ). 13 C NMR(151 MHz,CDCl 3 ) :δ 173.19, 147.79, 145.81,132.94, 132.35, 131.56, 131.16,130.82, 125.56, 123.06, 108.57,101.12, 43.48, 37.63,35.60,33.08, 33.03,30.02, 29.96, 29.81, 29.77, 29.65, 29.60, 29.51, 28.57, 18.51. ESI-MS（m/z）: [M+H] + = 507.4812。
2. Synthesis of target Compound UHA-2
Dissolving 3g of a compound S1 in 40mL of HAc, introducing CO gas at normal temperature, adding 1.0mL of trifluoroacetic acid, 2.9g of potassium persulfate and 2.5g of palladium acetate, stirring at normal temperature for reaction for 10 hours, evaporating the reaction solution to dryness, adding 40mL of water, adjusting the pH to 13 by using a 20% NaOH aqueous solution, extracting the aqueous phase with methyl tertiary butyl ether for 2 times, each time with 30mL of water, adjusting the pH of the aqueous phase to 1 by using a hydrochloric acid solution, extracting with EA for 3 times, each time with 30mL of water, evaporating the solvent from the organic phase to obtain 2.2g of a compound S5, mixing 1.0g of S5 with 0.37g of thionyl chloride, refluxing under the protection of argon for reaction for 1.5 hours, evaporating the solvent under reduced pressure after cooling the reaction solution to room temperature, performing silica gel column chromatography, eluting by using PE-EA=2:1, evaporating the solvent under reduced pressure to obtain 0.68g of a compound S6; 0.5g of S6 is dissolved in 20mL of DMF and then added dropwise to a mixed solution containing 30mL of DMF, 0.2mL of triethylamine and 0.18g of pyridine-4-carboxamide, the reaction is stirred at 0 ℃ for 12 hours, the solvent is evaporated under reduced pressure, the mixed solution of DMSO and water is used for recrystallization, DMSO: water=100:50, 0.32g of compound S7 is obtained after 12 hours of vacuum drying at 80 ℃, all of S7 is dissolved in 30mL of methanol, 3mL of water and 0.42g of potassium hydroxide are added, the solvent is evaporated under reduced pressure after heating and refluxing for 6 hours, 10mL of water and 10mL of saturated NH are added 4 Extracting the Cl solution with ethyl acetate for 3 times, wherein the dosage of the Cl solution is 15mL each time, and evaporating the solvent from the organic layer under reduced pressure to obtain 0.22g of compound S8; s8 was dissolved in 15mL DCMSequentially adding a certain amount of 98mg of NH 2 After OTHP,175mg of EDC.Cl and 15mg of DMAP, 350uL of DIPEA is added dropwise, stirred at room temperature for reaction for 8 hours, after the solvent is evaporated under reduced pressure, the product is subjected to silica gel column chromatography and eluted by PE-EA, PE is EA=1:1, and the eluent is evaporated under reduced pressure to obtain 95mg of compound S9; s9 is dissolved in 10mL of methanol, a 1M hydrochloric acid solution of 2mL is added, stirring is carried out for 10 hours at room temperature, the solvent is evaporated to dryness under reduced pressure, the obtained compound is dissolved in 5mL of chromatographic methanol, the solution is filtered by a microporous filter membrane and is further purified by HPLC, the chromatographic column is a C18 preparation column, the mobile phase is methanol-water, the ratio is 68:32, the detection wavelength is 210nm, and the target component is collected and the solvent is evaporated to dryness under reduced pressure, thus obtaining 57.3mg of target compound UHA-2.
By using 1 H-NMR、 13 The chemical structure of the synthesized target compound UHA-2 is identified and confirmed by means of C-NMR, ESI-MS, IR and the like, and the physicochemical properties and spectrum data of the compound UHA-2 are as follows:
yellow oil. IR (KBr) v/cm -1 :3260(-OH),3020(-NH),1629（O=C-NH）, 1638（O=C-）, 1562(C-C=N),1470(Ar ,C=C),1048(C-O-C); 1 H NMR(500 MHz,CDCl 3 ): δ 9.35(d, J = 3.8 Hz,1H,-OH), 8.73 (d, J =15.6Hz ,2H,CH=N-CH), 8.70 (s, 1H,O=C-NH-C=O),7.82 (d, J =4.8Hz ,2H,CH= C,C-CH) , 7.81 (s, 1H,O=C-NH-),7.52 (d, J =10.6 Hz ,1H,Ar-H), 7.26 (d, J =11.4 Hz ,1H,Ar-H), 5.87 (s ,2H, O-CH 2 -O), 5.68~5.65 (m ,2H, -CH=CH- ), 5.46~5.43 (m, 2H, -CH=CH-), 2.77 (m ,2H , Ar-CH 2 ), 2.67 (m ,1H,-CH-),2.59(d, J =7.5Hz ,1H,O=C-CH-), 2.46~2.01 (m, 5H,-CH 2 -CH-CH 2 -), 1.98~1.27 (m, 12H,-CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -) ,1.06(s, 3H,-CH 3 ). 13 C NMR(151 MHz,CDCl 3 ) : δ 173.19, 167.41, 167.30, 150.97, 150.96,149.12, 148.57, 141.06, 132.35, 131.56, 131.16, 130.82, 129.30, 125.27, 123.34, 122.25, 122.21, 106.24, 101.12, 43.48, 37.63, 35.60, 33.03, 31.16, 30.02, 29.82, 29.77, 29.65, 29.60, 29.51, 28.57, 18.51. ESI-MS（m/z）: [M+H] + = 577.7102。
3. Synthesis of target Compound UHA-3
0.5g of compound S6 is dissolved in 20mL of DMF, then dropwise added into a mixed solution containing 20mL of DMF, 0.15mL of triethylamine and 0.2g of thiophene-2-formylhydrazine, the reaction is stirred at 20 ℃ for 24 hours, the solvent is evaporated under reduced pressure, the mixed solution of DMSO and water is used for recrystallization, DMSO: water=120:60, 0.36g of compound S10 is obtained after vacuum drying at 80 ℃ for 12 hours, all S10 is dissolved in 30mL of methanol, 4mL of water and 0.51g of potassium hydroxide are added, the solvent is evaporated under reduced pressure after heating and refluxing for 6 hours, 10mL of water and 10mL of saturated NH are added 4 Extracting the Cl solution with ethyl acetate for 3 times, wherein the dosage of the Cl solution is 15mL each time, and evaporating the solvent from the organic layer under reduced pressure to obtain 0.25g of compound S11; s11 was dissolved in 20mL of DCM and 110mg of NH was added sequentially 2 After OTHP,195mg of EDC.Cl and 17mg of DMAP, 390uL of DIPEA is added dropwise, stirred at room temperature for reaction for 8 hours, the solvent is evaporated under reduced pressure, the product is subjected to silica gel column chromatography, PE is eluted by PE-EA, EA=2:1, and the solvent is evaporated under reduced pressure to obtain 190mg of compound S12; s12 is taken and dissolved in 15mL of methanol, 4mL of 1M hydrochloric acid solution is added, stirring is carried out for 10 hours at room temperature, the solvent is evaporated to dryness under reduced pressure, the obtained compound is dissolved in 5mL of chromatographic methanol, the solution is filtered by a microporous filter membrane and is further purified by HPLC, the chromatographic column is a C18 preparation column, the mobile phase is methanol-water, the ratio is 65:35, the detection wavelength is 210nm, the target component is collected, and the solvent is evaporated to dryness under reduced pressure, thus obtaining 89.5mg of target compound UHA-3.
By using 1 H-NMR、 13 The chemical structure of the synthesized target compound UHA-3 is identified and confirmed by means of C-NMR, ESI-MS, IR and the like, and the physicochemical properties and spectrum data of the compound UHA-3 are as follows:
yellow oil. IR (KBr) v/cm -1 :3282(OH), 3074（CH-S-CH）,3018(NH),1641（O=C-）, 1482(Ar ,C=C),1050(C-O-C); 1 H NMR(500 MHz,CDCl 3 ): δ 9.45 (d, J =12.5 Hz ,2H,O=C-NH-NH-), 9.35(d, J = 3.8 Hz,1H,-OH), 8.71 (s, 1H,O=C-NH-),7.78 (s,1H,CH=CH),7.73 (s ,1H,C=CH), 7.21 (d, J =12.5 Hz ,1H,CH=CH),7.38 (d, J =10.3 Hz ,1H,Ar-H), 7.19 (d, J =11.5 Hz ,1H,Ar-H), 5.87 (s ,2H, O-CH 2 -O), 5.70~5.67 (m ,2H, -CH=CH- ), 5.47~5.45 (m, 2H, -CH=CH-), 2.76 (m ,2H , Ar-CH 2 ), 2.69 (m ,1H,-CH-), 2.59 (s ,1H,O=C-CH-), 2.46~1.90 (m, 5H,-CH 2 -CH-CH 2 -), 2.02~1.28 (m, 12H,-CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -) , 1.06(s, 3H,-CH 3 ). 13 C NMR(151 MHz,CDCl 3 ) : δ 173.19, 165.85, 160.59, 149.13, 148.63, 137.53, 132.91, 132.35, 131.56, 131.16, 130.82, 128.71, 128.12, 126.38, 125.48, 121.16, 105.07, 101.12, 43.48, 37.63, 35.60, 33.03, 30.02, 29.82, 29.77, 29.65, 29.60, 29.58, 29.51, 28.57, 18.51. ESI-MS（m/z）: [M+H] + = 597.7624。
4. Synthesis of target Compound UHA-4
Dissolving 0.4g of compound S6 in 20mL of DMF, dropwise adding into a mixed solution containing 20mL of DMF, 0.12mL of triethylamine and 0.22g of glucose, stirring at 20 ℃ for reaction for 5 hours, evaporating the solvent under reduced pressure, adding 30mL of water, extracting 3 times with ethyl acetate, each time with 30mL of ethyl acetate, evaporating the solvent under reduced pressure to obtain 0.31g of compound S13, dissolving all S13 in 20mL of methanol, adding 4mL of water and 0.44g of potassium hydroxide, heating and refluxing for 6 hours, evaporating the solvent under reduced pressure, adding 10mL of water and 10mL of saturated NH 4 Extracting the Cl solution with ethyl acetate for 3 times, wherein the dosage of the Cl solution is 15mL each time, and evaporating the solvent from the organic layer under reduced pressure to obtain 0.28g of compound S14; s14 was dissolved in 20mL of DCM and 123mg of NH was added sequentially 2 After OTHP,208mg of EDC.Cl and 19mg of DMAP, 435uL of DIPEA is added dropwise, stirred at room temperature for reaction for 8 hours, the solvent is evaporated under reduced pressure, the product is subjected to silica gel column chromatography, PE is eluted by PE-EA, EA=1:1, and the solvent is evaporated under reduced pressure to obtain 210mg of compound S15; s15 is taken and dissolved in 15mL of methanol, 4mL of 1M hydrochloric acid solution is added, stirring is carried out for 10 hours at room temperature, the solvent is evaporated to dryness under reduced pressure, the obtained compound is dissolved in 5mL of chromatographic methanol, the solution is filtered by a microporous filter membrane and is further purified by HPLC, a chromatographic column is a C18 preparation column, the mobile phase is methanol-water, the ratio is 62:38, the detection wavelength is 210nm, and the target component is collected and the solvent is evaporated to dryness under reduced pressure, thus obtaining 97.5mg of target compound UHA-4.
By using 1 H-NMR、 13 C-NMR、ESI-MS、The chemical structure of the synthesized target compound UHA-4 is identified and confirmed by means of IR and the like, and the physicochemical properties and spectrum data of the compound UHA-4 are as follows:
a pale yellow oil. IR (KBr) v/cm -1 :3323(OH),3017(NH),1760（O=C-O）,(1647（O=C-）, 1471(Ar ,C=C),1059(C-O-C); 1 H NMR(500 MHz,CDCl 3 ): δ 9.35(d, J = 3.9Hz,1H,-OH), 8.71 (s, 1H,O=C-NH-),7.55 (d, J =12.3 Hz ,1H,Ar-H), 7.30 (d, J =15.2 Hz ,1H,Ar-H), 5.87(s ,2H, O-CH 2 -O), 5.70~5.65 (m ,2H, -CH=CH- ), 5.48~5.45 (m, 2H, -CH=CH-), 5.69~4.74 (m , 4H, -OH ), 4.96(d, J =11.7 Hz ,1H, -CH-O- ), 4.57(d, J =15.4 Hz ,2H, -CH 2 -O- C-), 3.89~3.43 (m ,4H, -CH-CH-CH- CH-), 2.77 (m ,2H , Ar-CH 2 ), 2.60 (s ,1H,O=C-CH-), 2.69 (m ,1H,-CH-), 2.46~1.87 (m, 5H,-CH 2 -CH-CH 2 -), 1.97~1.29 (m, 12H,-CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -) ,1.05(s, 3H,-CH 3 ). 13 C NMR(151 MHz,CDCl 3 ) : δ 173.19, 165.86, 150.41, 148.58, 132.35, 131.56, 131.16, 130.82, 125.38, 124.31, 124.18, 106.88, 101.12, 95.77, 76.27, 74.53, 74.00, 71.88, 65.11, 43.48, 37.63, 35.60, 33.03, 30.02, 29.82, 29.77, 29.65, 29.60, 29.51, 29.43, 28.57, 18.51.ESI-MS（m/z）: [M+H] + = 635.7439。
Example 2
1. Evaluation of the inhibitory Activity of target Compound UHA1-4 on HDAC1/2/6/8
In this example, the inhibitory activity of the compound UHA1-4 (SAHA as a control) against HDAC1/2/6 and HDAC8 in the concentration range of 0.174-44uM and 0.043-11uM were measured using an HDAC inhibitory activity test kit, respectively, according to the instructions of the kit, and IC was calculated using spss13.0 software 50 （nM）。
Table 1 results of inhibitory Activity of Compounds UHA1-4 on HDAC1/2/6/8
Note that: all experiments were performed 3 times and the test values are expressed as mean ± SD.
As a result, as shown in Table 1, the compounds UHA1-4 showed good inhibitory activity against HDAC1/2/6/8, the inhibitory activity against HDAC8 was superior to that of HDAC1/2/6, and the inhibitory activity against HDAC1/2/6/8 of the compounds was gradually increased with the increase of the concentration. Half maximal Inhibitory Concentration (IC) of compound UHA1-4 on HDAC1 50 ) Half Inhibition Concentration (IC) of HDAC2 in the range 40.21-50.05 nM 50 ) Half Inhibition Concentration (IC) of HDAC6 in the 74.16-82.05nM range 50 ) Half Inhibition Concentration (IC) of HDAC8 in the 61.52-98.47nM range 50 ) In the range of 12.54-16.08 nM; whereas the half-Inhibitory Concentration (IC) of the positive drug SAHA on HDAC1 50 ) Half maximal Inhibitory Concentration (IC) of HDAC2 at 105.93nM 50 ) Half maximal Inhibitory Concentration (IC) of HDAC6 at 160.07nM 50 ) Half maximal Inhibitory Concentration (IC) of HDAC8 at 132.09nM 50 ) 28.98nM; thus, the 4 compounds synthesized according to the present invention inhibit HDAC1/2/6/8 IC 50 IC with values lower than that of SAHA positive drug 50 Values, 4 compounds UHA1-4 have better HDAC1/2/6/8 inhibitory activity than the positive drug SAHA.
2. Evaluation of tumor cell proliferation inhibitory Activity of target Compound UHA1-4
In this example, the antiproliferative activity of compounds UHA1-4 (with SAHA as control) on 6 tumor cells (A2780 human ovarian cancer cells, NCI-H1975 human lung cancer cells, HT-29 human colon cancer cells, MDA-MB-231 human breast cancer cells, hepG2 human liver cancer cells and HT-144 human melanoma cells) was measured by MTT method in the concentration range of 100-0.032 [ mu ] M, respectively.
The main steps of the MTT method are as follows: tumor cells were cultured in a 5% carbon dioxide humidified incubator at 37 ℃ using RPMI1640 medium containing 10% fetal bovine serum. Anti-proliferative activity of compounds UHA1-4 in 6 human cancer cell lines was determined using MTT assay, cells (5×10 4 Individual cells/well) were inoculated into 96-well plates (RPMI 1640 medium with 10% fetal bovine serum) and incubated for 24 hours in humidified incubator with 5% carbon dioxide. mu.L of each of the different concentrations of compound was added to the wells, followed by incubation for 48 hours, followed by 20. Mu.L of MTT (5 mg/mL) and after incubation for 2 hours, 150. Mu.L of DMSO solution was added to each well. Absorbance was recorded using a microplate reader (SpectraMax M5) at 490 nm wavelength. Calculation of the half maximal inhibitory concentration value (IC) using spss13.0 software 50 Units [ mu ] M).
Table 2 inhibitory Activity of compounds UHA1-4 against proliferation of 6 tumor cells IC 50 Value of
The results are shown in Table 2, and indicate that 4 compounds have good anti-tumor cell proliferation capacity on all 6 tumor cells, and the inhibition effect on MDA-MB-231 cell proliferation is the best. The anti-tumor cell proliferation ability of the compound gradually increases with the increase of the concentration, which means that the larger the concentration of the compound is, the stronger the inhibition ability of cancer cell proliferation is. Half maximal Inhibitory Concentration (IC) of compound UHA1-4 on A2780 cells 50 ) In the range of 3.15-4.08. Mu.M, the median inhibitory concentration (IC 50 ) In the range of 2.73-3.56. Mu.M, the half maximal inhibitory concentration (IC 50 ) Half Inhibition Concentration (IC) for MDA-MB-231 in the range of 2.58-3.49. Mu.M 50 ) In the range 1.68-2.29. Mu.M, the median inhibitory concentration (IC 50 ) In the range of 2.05-2.82. Mu.M, the half maximal inhibitory concentration (IC 50 ) In the range of 5.87-7.69 mu M. IC of 4 Compounds against 6 tumor cells 50 IC with values lower than that of SAHA positive drug 50 The values indicate that the compound UHA1-4 has better antiproliferative effect on the 6 tumor cells than the positive drug SAHA.
Claims (6)
1. Novel urushiol-based hydroxamic acid HDAC inhibitors with targeted antitumor activity characterized by the following structural formula:
2. a method of preparing a novel urushiol-based hydroxamic acid HDAC inhibitor having targeted anti-tumor activity according to claim 1, comprising the steps of:
taking S6 as a raw material, dissolving a certain amount of S6 in DMF, then dropwise adding the DMF into a mixed solution of triethylamine and thiophene-2-formylhydrazine, stirring the mixture at 20 ℃ for reaction for 24 hours, evaporating the solvent under reduced pressure, recrystallizing the solvent by using a mixed solution of DMSO and water, drying the mixture under vacuum at 80 ℃ for 12 hours to obtain a compound S10, dissolving the S10 in methanol completely, adding a certain amount of water and potassium hydroxide, heating and refluxing the mixture for 6 hours, evaporating the solvent under reduced pressure, and adding a certain amount of water and saturated NH 4 Extracting the Cl solution with ethyl acetate for 3 times, and evaporating the organic layer under reduced pressure to dryness to obtain a compound S11; s11 is dissolved in a certain amount of DCM, and a certain amount of NH is added in sequence 2 After OTHP, EDC.Cl and DMAP, a certain amount of DIPEA is added dropwise, stirring is carried out at room temperature for reaction for 8 hours, the solvent is evaporated under reduced pressure, silica gel column chromatography is carried out, PE-EA is used for eluting, and the solvent is evaporated under reduced pressure to obtain a compound S12; dissolving a certain amount of S12 in methanol, addingAdding a certain amount of 1M hydrochloric acid solution, stirring at room temperature for 10 hours, evaporating the solvent under reduced pressure, dissolving the obtained compound in chromatographic methanol, filtering with a microporous filter membrane, and purifying with HPLC to obtain a target compound UHA-3;
the specific reaction formula is as follows:
3. use of a novel urushiol-based hydroxamic acid HDAC inhibitor with targeted anti-tumor activity according to claim 1 for the preparation of an HDAC inhibitor.
4. The use of claim 3, wherein the HDAC comprises HDAC1, HDAC2, HDAC6 and HDAC8.
5. Use of the novel urushiol-based hydroxamic acid HDAC inhibitor with targeted anti-tumor activity according to claim 1 for the preparation of an anti-tumor medicament.
6. The use according to claim 5, wherein the tumor cells are A2780 human ovarian cancer cells, NCI-H1975 human lung cancer cells, HT-29 human colon cancer cells, MDA-MB-231 human breast cancer cells, hepG2 human liver cancer cells and HT-144 human melanoma cells.
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