CN115381815A - 独脚金内酯衍生物在制备线粒体自噬抑制剂中的应用 - Google Patents
独脚金内酯衍生物在制备线粒体自噬抑制剂中的应用 Download PDFInfo
- Publication number
- CN115381815A CN115381815A CN202210909296.3A CN202210909296A CN115381815A CN 115381815 A CN115381815 A CN 115381815A CN 202210909296 A CN202210909296 A CN 202210909296A CN 115381815 A CN115381815 A CN 115381815A
- Authority
- CN
- China
- Prior art keywords
- acid
- strigolactone
- compound
- mitophagy
- cells
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- XHSDUVBUZOUAOQ-WJQMYRPNSA-N (3e,3ar,8bs)-3-[[(2r)-4-methyl-5-oxo-2h-furan-2-yl]oxymethylidene]-4,8b-dihydro-3ah-indeno[1,2-b]furan-2-one Chemical class O1C(=O)C(C)=C[C@@H]1O\C=C/1C(=O)O[C@@H]2C3=CC=CC=C3C[C@@H]2\1 XHSDUVBUZOUAOQ-WJQMYRPNSA-N 0.000 title claims abstract description 74
- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 210000003470 mitochondria Anatomy 0.000 title abstract description 9
- 239000012822 autophagy inhibitor Substances 0.000 title abstract description 8
- 230000021125 mitochondrion degradation Effects 0.000 claims abstract description 40
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 32
- 239000003112 inhibitor Substances 0.000 claims abstract description 29
- 239000003814 drug Substances 0.000 claims abstract description 22
- 230000004900 autophagic degradation Effects 0.000 claims abstract description 11
- 230000004770 neurodegeneration Effects 0.000 claims abstract description 7
- 208000015122 neurodegenerative disease Diseases 0.000 claims abstract description 7
- 208000027866 inflammatory disease Diseases 0.000 claims abstract description 6
- 230000007246 mechanism Effects 0.000 claims abstract description 6
- 229930012538 Paclitaxel Natural products 0.000 claims abstract description 5
- 230000000259 anti-tumor effect Effects 0.000 claims abstract description 5
- 229960001592 paclitaxel Drugs 0.000 claims abstract description 5
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 claims abstract description 5
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 claims abstract description 4
- 229960004316 cisplatin Drugs 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 24
- 206010009944 Colon cancer Diseases 0.000 claims description 21
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 19
- 229940079593 drug Drugs 0.000 claims description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 10
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
- 229960002949 fluorouracil Drugs 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- 230000002401 inhibitory effect Effects 0.000 claims description 8
- 239000002246 antineoplastic agent Substances 0.000 claims description 7
- 229940044683 chemotherapy drug Drugs 0.000 claims description 7
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 230000002265 prevention Effects 0.000 claims description 6
- 239000011734 sodium Substances 0.000 claims description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 6
- -1 amino, substituted amino, fluorine atom Chemical group 0.000 claims description 5
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- 208000018737 Parkinson disease Diseases 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 claims description 4
- 229910052783 alkali metal Inorganic materials 0.000 claims description 4
- 150000001340 alkali metals Chemical class 0.000 claims description 4
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 4
- 150000001342 alkaline earth metals Chemical class 0.000 claims description 4
- 150000001413 amino acids Chemical class 0.000 claims description 4
- 125000005587 carbonate group Chemical group 0.000 claims description 4
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- 150000007522 mineralic acids Chemical class 0.000 claims description 4
- 230000002438 mitochondrial effect Effects 0.000 claims description 4
- 150000007524 organic acids Chemical class 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 3
- 206010033128 Ovarian cancer Diseases 0.000 claims description 3
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 3
- 235000011054 acetic acid Nutrition 0.000 claims description 3
- 201000005202 lung cancer Diseases 0.000 claims description 3
- 208000020816 lung neoplasm Diseases 0.000 claims description 3
- TUSDEZXZIZRFGC-UHFFFAOYSA-N 1-O-galloyl-3,6-(R)-HHDP-beta-D-glucose Natural products OC1C(O2)COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC1C(O)C2OC(=O)C1=CC(O)=C(O)C(O)=C1 TUSDEZXZIZRFGC-UHFFFAOYSA-N 0.000 claims description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 2
- 208000024827 Alzheimer disease Diseases 0.000 claims description 2
- 206010002329 Aneurysm Diseases 0.000 claims description 2
- 201000006474 Brain Ischemia Diseases 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 2
- 206010008120 Cerebral ischaemia Diseases 0.000 claims description 2
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- 239000001263 FEMA 3042 Substances 0.000 claims description 2
- 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 claims description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 2
- 239000004472 Lysine Substances 0.000 claims description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 2
- 208000001826 Marfan syndrome Diseases 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- 235000021314 Palmitic acid Nutrition 0.000 claims description 2
- LRBQNJMCXXYXIU-PPKXGCFTSA-N Penta-digallate-beta-D-glucose Natural products OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@@H]2[C@H]([C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-PPKXGCFTSA-N 0.000 claims description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- 206010069351 acute lung injury Diseases 0.000 claims description 2
- 239000001361 adipic acid Substances 0.000 claims description 2
- 235000011037 adipic acid Nutrition 0.000 claims description 2
- 239000002671 adjuvant Substances 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims description 2
- 208000029028 brain injury Diseases 0.000 claims description 2
- 239000011575 calcium Substances 0.000 claims description 2
- 229910052791 calcium Inorganic materials 0.000 claims description 2
- 206010008118 cerebral infarction Diseases 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 235000015165 citric acid Nutrition 0.000 claims description 2
- 239000001530 fumaric acid Substances 0.000 claims description 2
- 235000011087 fumaric acid Nutrition 0.000 claims description 2
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 claims description 2
- 239000004310 lactic acid Substances 0.000 claims description 2
- 235000014655 lactic acid Nutrition 0.000 claims description 2
- 229910052744 lithium Inorganic materials 0.000 claims description 2
- 201000007270 liver cancer Diseases 0.000 claims description 2
- 208000014018 liver neoplasm Diseases 0.000 claims description 2
- 239000011777 magnesium Substances 0.000 claims description 2
- 229910052749 magnesium Inorganic materials 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 239000011976 maleic acid Substances 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 125000005245 nitryl group Chemical group [N+](=O)([O-])* 0.000 claims description 2
- 208000002815 pulmonary hypertension Diseases 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- LRBQNJMCXXYXIU-NRMVVENXSA-N tannic acid Chemical compound OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@@H]2[C@H]([C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-NRMVVENXSA-N 0.000 claims description 2
- 229940033123 tannic acid Drugs 0.000 claims description 2
- 235000015523 tannic acid Nutrition 0.000 claims description 2
- 229920002258 tannic acid Polymers 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- 230000002708 enhancing effect Effects 0.000 claims 1
- 210000004027 cell Anatomy 0.000 abstract description 77
- 210000004881 tumor cell Anatomy 0.000 abstract description 31
- 230000006907 apoptotic process Effects 0.000 abstract description 16
- 230000005012 migration Effects 0.000 abstract description 7
- 238000013508 migration Methods 0.000 abstract description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 57
- 230000000694 effects Effects 0.000 description 40
- 239000007787 solid Substances 0.000 description 40
- WCDLCPLAAKUJNY-UHFFFAOYSA-N 4-[4-[3-(1h-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-6-yl]phenyl]morpholine Chemical compound C1COCCN1C1=CC=C(C2=CN3N=CC(=C3N=C2)C2=CNN=C2)C=C1 WCDLCPLAAKUJNY-UHFFFAOYSA-N 0.000 description 39
- 238000012360 testing method Methods 0.000 description 25
- 238000006243 chemical reaction Methods 0.000 description 21
- 108090000623 proteins and genes Proteins 0.000 description 18
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 16
- RHDGNLCLDBVESU-UHFFFAOYSA-N but-3-en-4-olide Chemical compound O=C1CC=CO1 RHDGNLCLDBVESU-UHFFFAOYSA-N 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- 102000004169 proteins and genes Human genes 0.000 description 14
- 239000000243 solution Substances 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 238000002474 experimental method Methods 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
- 239000012043 crude product Substances 0.000 description 11
- 239000011541 reaction mixture Substances 0.000 description 10
- 230000002829 reductive effect Effects 0.000 description 10
- 238000005406 washing Methods 0.000 description 10
- 241000699670 Mus sp. Species 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 230000012010 growth Effects 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 8
- 101800001821 Precursor of protein E3/E2 Proteins 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 101800002664 p62 Proteins 0.000 description 8
- 239000003208 petroleum Substances 0.000 description 8
- 239000007858 starting material Substances 0.000 description 8
- 241000699666 Mus <mouse, genus> Species 0.000 description 7
- 102100020814 Sequestosome-1 Human genes 0.000 description 7
- 238000003119 immunoblot Methods 0.000 description 7
- WHTVZRBIWZFKQO-AWEZNQCLSA-N (S)-chloroquine Chemical compound ClC1=CC=C2C(N[C@@H](C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-AWEZNQCLSA-N 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 230000022131 cell cycle Effects 0.000 description 6
- 229960003677 chloroquine Drugs 0.000 description 6
- WHTVZRBIWZFKQO-UHFFFAOYSA-N chloroquine Natural products ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000011729 BALB/c nude mouse Methods 0.000 description 5
- 108090000397 Caspase 3 Proteins 0.000 description 5
- 102100029855 Caspase-3 Human genes 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 238000011580 nude mouse model Methods 0.000 description 5
- 230000035755 proliferation Effects 0.000 description 5
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 5
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 5
- 229960002930 sirolimus Drugs 0.000 description 5
- UOHPEWIBMAQKCN-UHFFFAOYSA-N 1,3,5,5,6-pentafluoro-1,3-diazinane-2,4-dione Chemical compound FC1C(C(N(C(N1F)=O)F)=O)(F)F UOHPEWIBMAQKCN-UHFFFAOYSA-N 0.000 description 4
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 4
- 102100037919 Insulin-like growth factor 2 mRNA-binding protein 2 Human genes 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 230000004663 cell proliferation Effects 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 230000001419 dependent effect Effects 0.000 description 4
- 239000003937 drug carrier Substances 0.000 description 4
- 210000002919 epithelial cell Anatomy 0.000 description 4
- 239000012091 fetal bovine serum Substances 0.000 description 4
- 238000003818 flash chromatography Methods 0.000 description 4
- 238000000684 flow cytometry Methods 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 230000001965 increasing effect Effects 0.000 description 4
- QNXSIUBBGPHDDE-UHFFFAOYSA-N indan-1-one Chemical compound C1=CC=C2C(=O)CCC2=C1 QNXSIUBBGPHDDE-UHFFFAOYSA-N 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 230000001404 mediated effect Effects 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 238000012544 monitoring process Methods 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- 230000002588 toxic effect Effects 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- MITGKKFYIJJQGL-UHFFFAOYSA-N 9-(4-chlorobenzoyl)-6-methylsulfonyl-2,3-dihydro-1H-carbazol-4-one Chemical compound ClC1=CC=C(C(=O)N2C3=CC=C(C=C3C=3C(CCCC2=3)=O)S(=O)(=O)C)C=C1 MITGKKFYIJJQGL-UHFFFAOYSA-N 0.000 description 3
- 101000619542 Homo sapiens E3 ubiquitin-protein ligase parkin Proteins 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- HPKJGHVHQWJOOT-ZJOUEHCJSA-N N-[(2S)-3-cyclohexyl-1-oxo-1-({(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}amino)propan-2-yl]-1H-indole-2-carboxamide Chemical compound C1C(CCCC1)C[C@H](NC(=O)C=1NC2=CC=CC=C2C=1)C(=O)N[C@@H](C[C@H]1C(=O)NCC1)C=O HPKJGHVHQWJOOT-ZJOUEHCJSA-N 0.000 description 3
- 229920002556 Polyethylene Glycol 300 Polymers 0.000 description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 230000001464 adherent effect Effects 0.000 description 3
- 230000003698 anagen phase Effects 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 230000001472 cytotoxic effect Effects 0.000 description 3
- 230000029087 digestion Effects 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000009396 hybridization Methods 0.000 description 3
- 239000000411 inducer Substances 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 239000007928 intraperitoneal injection Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 102000045222 parkin Human genes 0.000 description 3
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 3
- 229920000053 polysorbate 80 Polymers 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 230000003595 spectral effect Effects 0.000 description 3
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 2
- VUDZSIYXZUYWSC-DBRKOABJSA-N (4r)-1-[(2r,4r,5r)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-4-hydroxy-1,3-diazinan-2-one Chemical compound FC1(F)[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N[C@H](O)CC1 VUDZSIYXZUYWSC-DBRKOABJSA-N 0.000 description 2
- VIMMECPCYZXUCI-MIMFYIINSA-N (4s,6r)-6-[(1e)-4,4-bis(4-fluorophenyl)-3-(1-methyltetrazol-5-yl)buta-1,3-dienyl]-4-hydroxyoxan-2-one Chemical compound CN1N=NN=C1C(\C=C\[C@@H]1OC(=O)C[C@@H](O)C1)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 VIMMECPCYZXUCI-MIMFYIINSA-N 0.000 description 2
- WXYYACUWOMKZQC-UHFFFAOYSA-N 1-benzyl-4-(4-propan-2-ylphenyl)-6-prop-2-ynoxyquinazolin-2-one Chemical compound C1=CC(C(C)C)=CC=C1C(C1=CC(OCC#C)=CC=C11)=NC(=O)N1CC1=CC=CC=C1 WXYYACUWOMKZQC-UHFFFAOYSA-N 0.000 description 2
- AZKSAVLVSZKNRD-UHFFFAOYSA-M 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide Chemical compound [Br-].S1C(C)=C(C)N=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 AZKSAVLVSZKNRD-UHFFFAOYSA-M 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 238000011740 C57BL/6 mouse Methods 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 102100026548 Caspase-8 Human genes 0.000 description 2
- 108090000538 Caspase-8 Proteins 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 101710088172 HTH-type transcriptional regulator RipA Proteins 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 108010009254 Lysosomal-Associated Membrane Protein 1 Proteins 0.000 description 2
- 231100000002 MTT assay Toxicity 0.000 description 2
- 238000000134 MTT assay Methods 0.000 description 2
- 241001529936 Murinae Species 0.000 description 2
- 241000699660 Mus musculus Species 0.000 description 2
- 108010019160 Pancreatin Proteins 0.000 description 2
- 229930040373 Paraformaldehyde Natural products 0.000 description 2
- 108010064218 Poly (ADP-Ribose) Polymerase-1 Proteins 0.000 description 2
- 102000015087 Poly (ADP-Ribose) Polymerase-1 Human genes 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 description 2
- 230000025084 cell cycle arrest Effects 0.000 description 2
- 230000012292 cell migration Effects 0.000 description 2
- 230000003833 cell viability Effects 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 210000001072 colon Anatomy 0.000 description 2
- 208000029742 colonic neoplasm Diseases 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 230000000857 drug effect Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000003623 enhancer Substances 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 230000017188 evasion or tolerance of host immune response Effects 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 210000003194 forelimb Anatomy 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 2
- LEQAOMBKQFMDFZ-UHFFFAOYSA-N glyoxal Chemical compound O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 210000003712 lysosome Anatomy 0.000 description 2
- 230000001868 lysosomic effect Effects 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 2
- 229940055695 pancreatin Drugs 0.000 description 2
- 229920002866 paraformaldehyde Polymers 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- XIPFMBOWZXULIA-UHFFFAOYSA-N pivalamide Chemical compound CC(C)(C)C(N)=O XIPFMBOWZXULIA-UHFFFAOYSA-N 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000010814 radioimmunoprecipitation assay Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000012192 staining solution Substances 0.000 description 2
- 239000010902 straw Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- 230000029663 wound healing Effects 0.000 description 2
- 239000002759 woven fabric Substances 0.000 description 2
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 description 1
- KAFZOLYKKCWUBI-HPMAGDRPSA-N (2s)-2-[[(2s)-2-[[(2s)-1-[(2s)-3-amino-2-[[(2s)-2-[[(2s)-2-(3-cyclohexylpropanoylamino)-4-methylpentanoyl]amino]-5-methylhexanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]butanediamide Chemical compound N([C@@H](CC(C)C)C(=O)N[C@@H](CCC(C)C)C(=O)N[C@@H](CN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC(N)=O)C(N)=O)C(=O)CCC1CCCCC1 KAFZOLYKKCWUBI-HPMAGDRPSA-N 0.000 description 1
- FOLCUFKJHSQMEL-BIXPGCQOSA-N (4-butylcyclohexyl) N-[(2S)-4-methyl-1-oxo-1-[[(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]amino]pentan-2-yl]carbamate Chemical compound CCCCC1CCC(CC1)OC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C[C@@H]2CCNC2=O)C=O FOLCUFKJHSQMEL-BIXPGCQOSA-N 0.000 description 1
- QBTROWHSMGZXCV-RQURQNPSSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-4,7-dihydroxy-6-(11-phenoxyundecoxy)-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@@H]([C@@H](OCCCCCCCCCCCOC=3C=CC=CC=3)C(O1)(C(O)=O)C(O)(C(O2)C(O)=O)C(O)=O)O)C1=CC=CC=C1 QBTROWHSMGZXCV-RQURQNPSSA-N 0.000 description 1
- UXKLQDCALAWFIU-VKNDCNMPSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-4,7-dihydroxy-6-tetradecoxy-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@H](O)[C@H](C(O2)(C(O)=O)C(O)(C(O1)C(O)=O)C(O)=O)OCCCCCCCCCCCCCC)C1=CC=CC=C1 UXKLQDCALAWFIU-VKNDCNMPSA-N 0.000 description 1
- VGNCBRNRHXEODV-XXVHXNRLSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-6-dodecoxy-4,7-dihydroxy-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@H](O)[C@H](C(O2)(C(O)=O)C(O)(C(O1)C(O)=O)C(O)=O)OCCCCCCCCCCCC)C1=CC=CC=C1 VGNCBRNRHXEODV-XXVHXNRLSA-N 0.000 description 1
- APJSHECCIRQQDV-ZRDIBKRKSA-N (e)-3-[4-hydroxy-3-(5,5,8,8-tetramethyl-3-pentoxy-6,7-dihydronaphthalen-2-yl)phenyl]prop-2-enoic acid Chemical compound CCCCCOC1=CC(C(CCC2(C)C)(C)C)=C2C=C1C1=CC(\C=C\C(O)=O)=CC=C1O APJSHECCIRQQDV-ZRDIBKRKSA-N 0.000 description 1
- DPRJPRMZJGWLHY-HNGSOEQISA-N (e,3r,5s)-7-[5-(4-fluorophenyl)-3-propan-2-yl-1-pyrazin-2-ylpyrazol-4-yl]-3,5-dihydroxyhept-6-enoic acid Chemical compound OC(=O)C[C@H](O)C[C@H](O)/C=C/C=1C(C(C)C)=NN(C=2N=CC=NC=2)C=1C1=CC=C(F)C=C1 DPRJPRMZJGWLHY-HNGSOEQISA-N 0.000 description 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
- IOOWNWLVCOUUEX-WPRPVWTQSA-N 2-[(3r,6s)-2-hydroxy-3-[(2-thiophen-2-ylacetyl)amino]oxaborinan-6-yl]acetic acid Chemical compound OB1O[C@H](CC(O)=O)CC[C@@H]1NC(=O)CC1=CC=CS1 IOOWNWLVCOUUEX-WPRPVWTQSA-N 0.000 description 1
- PPSMYAUEJRADFE-HXUWFJFHSA-N 2-[(5r)-4-[2-[3-(6-methylpyridin-3-yl)oxyphenyl]acetyl]-8-(trifluoromethyl)-1,2,3,5-tetrahydropyrido[2,3-e][1,4]diazepin-5-yl]acetic acid Chemical compound C1=NC(C)=CC=C1OC1=CC=CC(CC(=O)N2[C@@H](C3=CC=C(N=C3NCC2)C(F)(F)F)CC(O)=O)=C1 PPSMYAUEJRADFE-HXUWFJFHSA-N 0.000 description 1
- JGMXNNSYEFOBHQ-OWOJBTEDSA-N 2-[(e)-4-morpholin-4-ylbut-2-enyl]-1,1-dioxothieno[3,2-e]thiazine-6-sulfonamide Chemical compound O=S1(=O)C=2SC(S(=O)(=O)N)=CC=2C=CN1C\C=C\CN1CCOCC1 JGMXNNSYEFOBHQ-OWOJBTEDSA-N 0.000 description 1
- WNFAQVLTRONMFD-UHFFFAOYSA-N 3-[4-carbamoyl-1-[5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-1,3-thiazol-2-yl]piperidin-4-yl]benzoic acid Chemical compound C1CC(C(=O)N)(C=2C=C(C=CC=2)C(O)=O)CCN1C1=NC=C(C(O)(C(F)(F)F)C(F)(F)F)S1 WNFAQVLTRONMFD-UHFFFAOYSA-N 0.000 description 1
- OVDGUTHABMXVMI-UHFFFAOYSA-N 3-nitro-4-(propylamino)benzoic acid Chemical compound CCCNC1=CC=C(C(O)=O)C=C1[N+]([O-])=O OVDGUTHABMXVMI-UHFFFAOYSA-N 0.000 description 1
- LTUZPODERZUPRD-UHFFFAOYSA-N 6-chloro-2-(1h-indol-3-yl)-4-phenylquinoline Chemical compound C12=CC(Cl)=CC=C2N=C(C=2C3=CC=CC=C3NC=2)C=C1C1=CC=CC=C1 LTUZPODERZUPRD-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- 102000007469 Actins Human genes 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 102100021569 Apoptosis regulator Bcl-2 Human genes 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- QUMCIHKVKQYNPA-RUZDIDTESA-N C1(CCCCC1)CN1[C@@H](C=2N(C=3C=NC(=NC1=3)NC1=C(C=C(C(=O)NC3CCN(CC3)C)C=C1)OC)C(=NN=2)C)CC Chemical compound C1(CCCCC1)CN1[C@@H](C=2N(C=3C=NC(=NC1=3)NC1=C(C=C(C(=O)NC3CCN(CC3)C)C=C1)OC)C(=NN=2)C)CC QUMCIHKVKQYNPA-RUZDIDTESA-N 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 235000009025 Carya illinoensis Nutrition 0.000 description 1
- 241001453450 Carya illinoinensis Species 0.000 description 1
- 229940125761 Compound 6g Drugs 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 230000005971 DNA damage repair Effects 0.000 description 1
- 241000252212 Danio rerio Species 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 102100030478 FUN14 domain-containing protein 1 Human genes 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 101000971171 Homo sapiens Apoptosis regulator Bcl-2 Proteins 0.000 description 1
- 101001062715 Homo sapiens FUN14 domain-containing protein 1 Proteins 0.000 description 1
- 101000605835 Homo sapiens Serine/threonine-protein kinase PINK1, mitochondrial Proteins 0.000 description 1
- 101000851007 Homo sapiens Vascular endothelial growth factor receptor 2 Proteins 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 102100035133 Lysosome-associated membrane glycoprotein 1 Human genes 0.000 description 1
- 208000002720 Malnutrition Diseases 0.000 description 1
- TZYWCYJVHRLUCT-VABKMULXSA-N N-benzyloxycarbonyl-L-leucyl-L-leucyl-L-leucinal Chemical compound CC(C)C[C@@H](C=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OCC1=CC=CC=C1 TZYWCYJVHRLUCT-VABKMULXSA-N 0.000 description 1
- TZCCKCLHNUSAMQ-DUGSHLAESA-N NC(=O)C[C@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](Cc2ccc(F)cc2)NC(=O)[C@H](Cc3c[nH]c4ccccc34)NC(=O)Cc5cccs5)C(=O)N Chemical compound NC(=O)C[C@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](Cc2ccc(F)cc2)NC(=O)[C@H](Cc3c[nH]c4ccccc34)NC(=O)Cc5cccs5)C(=O)N TZCCKCLHNUSAMQ-DUGSHLAESA-N 0.000 description 1
- AKQOBHZKBDHWQI-BZEFIUHZSA-N O[C@H]1C[C@@H](CCC1)N1C(C2(C3=C1N=C(N=C3)NC1=CC=C(C=C1)S(=O)(=O)NC([2H])([2H])[2H])CC2)=O Chemical compound O[C@H]1C[C@@H](CCC1)N1C(C2(C3=C1N=C(N=C3)NC1=CC=C(C=C1)S(=O)(=O)NC([2H])([2H])[2H])CC2)=O AKQOBHZKBDHWQI-BZEFIUHZSA-N 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 230000018199 S phase Effects 0.000 description 1
- 102100038376 Serine/threonine-protein kinase PINK1, mitochondrial Human genes 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- HATRDXDCPOXQJX-UHFFFAOYSA-N Thapsigargin Natural products CCCCCCCC(=O)OC1C(OC(O)C(=C/C)C)C(=C2C3OC(=O)C(C)(O)C3(O)C(CC(C)(OC(=O)C)C12)OC(=O)CCC)C HATRDXDCPOXQJX-UHFFFAOYSA-N 0.000 description 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000003044 adaptive effect Effects 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 230000000274 adsorptive effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000005809 anti-tumor immunity Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000002238 attenuated effect Effects 0.000 description 1
- 210000004957 autophagosome Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- 150000001555 benzenes Chemical group 0.000 description 1
- 239000012148 binding buffer Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- UDSAIICHUKSCKT-UHFFFAOYSA-N bromophenol blue Chemical compound C1=C(Br)C(O)=C(Br)C=C1C1(C=2C=C(Br)C(O)=C(Br)C=2)C2=CC=CC=C2S(=O)(=O)O1 UDSAIICHUKSCKT-UHFFFAOYSA-N 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 239000012830 cancer therapeutic Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000032677 cell aging Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000007910 cell fusion Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000004637 cellular stress Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 210000004922 colonic epithelial cell Anatomy 0.000 description 1
- 238000010293 colony formation assay Methods 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940127108 compound 5g Drugs 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 238000003235 crystal violet staining Methods 0.000 description 1
- 230000001351 cycling effect Effects 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000003412 degenerative effect Effects 0.000 description 1
- UQLDLKMNUJERMK-UHFFFAOYSA-L di(octadecanoyloxy)lead Chemical compound [Pb+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O UQLDLKMNUJERMK-UHFFFAOYSA-L 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 229940015043 glyoxal Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 210000004013 groin Anatomy 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 230000037451 immune surveillance Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000000266 injurious effect Effects 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 239000012160 loading buffer Substances 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 230000004142 macroautophagy Effects 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- ZIYVHBGGAOATLY-UHFFFAOYSA-N methylmalonic acid Chemical compound OC(=O)C(C)C(O)=O ZIYVHBGGAOATLY-UHFFFAOYSA-N 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- JBLLRCOZJMVOAE-HSQYWUDLSA-N n-[(2s)-1-[[(2s)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3s)-2-oxopyrrolidin-3-yl]propan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]-4-methoxy-1h-indole-2-carboxamide Chemical compound C([C@H](NC(=O)[C@H](CC(C)C)NC(=O)C=1NC=2C=CC=C(C=2C=1)OC)C(=O)C=1SC2=CC=CC=C2N=1)[C@@H]1CCNC1=O JBLLRCOZJMVOAE-HSQYWUDLSA-N 0.000 description 1
- MUJNAWXXOJRNGK-UHFFFAOYSA-N n-[3-(6-methyl-1,2,3,4-tetrahydrocarbazol-9-yl)propyl]cyclohexanamine Chemical compound C1=2CCCCC=2C2=CC(C)=CC=C2N1CCCNC1CCCCC1 MUJNAWXXOJRNGK-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 235000018343 nutrient deficiency Nutrition 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- PFGVNLZDWRZPJW-OPAMFIHVSA-N otamixaban Chemical compound C([C@@H](C(=O)OC)[C@@H](C)NC(=O)C=1C=CC(=CC=1)C=1C=C[N+]([O-])=CC=1)C1=CC=CC(C(N)=N)=C1 PFGVNLZDWRZPJW-OPAMFIHVSA-N 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- MOOYVEVEDVVKGD-UHFFFAOYSA-N oxaldehydic acid;hydrate Chemical compound O.OC(=O)C=O MOOYVEVEDVVKGD-UHFFFAOYSA-N 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 230000008823 permeabilization Effects 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 229930195732 phytohormone Natural products 0.000 description 1
- 239000003375 plant hormone Substances 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 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
- 238000005086 pumping Methods 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 229930009674 sesquiterpene lactone Natural products 0.000 description 1
- 150000002107 sesquiterpene lactone derivatives Chemical class 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 239000001119 stannous chloride Substances 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 230000023895 stem cell maintenance Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- FWQHRZXEQNUCSY-UHFFFAOYSA-N tert-butyl N-[2-(ethoxycarbonylamino)-5-[(4-fluorophenyl)methyl-prop-2-ynylamino]phenyl]carbamate Chemical compound CCOC(=O)NC1=C(C=C(C=C1)N(CC#C)CC2=CC=C(C=C2)F)NC(=O)OC(C)(C)C FWQHRZXEQNUCSY-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000002723 toxicity assay Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- JQSHBVHOMNKWFT-DTORHVGOSA-N varenicline Chemical compound C12=CC3=NC=CN=C3C=C2[C@H]2C[C@@H]1CNC2 JQSHBVHOMNKWFT-DTORHVGOSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 239000012224 working solution Substances 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
Landscapes
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Cardiology (AREA)
- Vascular Medicine (AREA)
- Heart & Thoracic Surgery (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Psychology (AREA)
- Epidemiology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Urology & Nephrology (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了独脚金内酯衍生物在制备线粒体自噬抑制剂中的应用。本发明方案将独脚金内酯衍生物作为线粒体自噬抑制剂,可以选择性诱导肿瘤细胞凋亡,抑制肿瘤细胞的迁移,可用于制备预防或治疗肿瘤的药物,也可作为化疗药物增敏剂,与化疗药物紫杉醇或顺铂联合用药,或用于研究细胞自噬或凋亡的机制,此外,独脚金内酯衍生物作为线粒体自噬抑制剂还可用于制备神经退行性疾病和炎症性疾病的治疗药物。本发明进一步扩大了独脚金内酯衍生物的应用范围,也抗肿瘤治疗提供了新方案。
Description
技术领域
本发明属于生物医药技术领域,具体涉及独脚金内酯衍生物在制备线粒体自噬抑制剂中的应用。
背景技术
在ROS、营养缺乏、细胞衰老等刺激下,细胞内的线粒体发生去极化损伤,进而被特异性的包裹进自噬体中,并与溶酶体融合,从而降解功能失调和受损的线粒体,这一过程称之为线粒体自噬。线粒体自噬是一种选择性的巨自噬,在生理条件下,线粒体自噬对于维持整个线粒体网络和细胞功能的完整性,防止细胞应激反应和基因组损伤方面至关重要。目前已知调控哺乳动物线粒体自噬的机制包括两种,一种是parkin依赖的,剂PINK1-parkin介导的线粒体自噬;另一种是parkin非依赖的,包括FUNDC1参与的缺氧介导的线粒体自噬及Bnip3/Nix介导的线粒体自噬。
研究表明,线粒体自噬与多种疾病的发生发展密切相关。例如线粒体自噬被证明有助于致癌、细胞迁移、铁死亡抑制、肿瘤干细胞维持、肿瘤免疫逃逸、耐药性。此外,前述的PINK1和parkin 是帕金森病的主要致病蛋白,线粒体自噬异常与帕金森病等神经退行性疾病的发生密切相关。
天然的独脚金内酯是一种倍半萜内酯的植物激素,在调控植物生长发育以及对干旱、低磷、低氮等逆境适应能力等方面起关键作用,对农作物改良增产具有重要价值。相关技术合成独脚金内酯类似物(±)-GR-24,发现其具有与天然独脚金内酯相当或更好的植物激素活性。相关技术发现独脚金内酯类似物可抑制乳腺癌、前列腺癌、肺癌、黑色素瘤、骨肉瘤等多种实体瘤细胞和白血病细胞的增殖,并诱导其凋亡,活性最好的衍生物IC50为12.9μΜ,其中MEB55与紫杉醇联合使用对 MDA-MB-231移植瘤裸鼠模型也有显著的抑制作用。机制研究表明,其可能通过抑制DNA损伤修复,从而诱导细胞凋亡。Hasan等人也报道了独脚金内酯衍生物可抑制肝癌细胞系HepG2的增殖,并对正常细胞没有明显的影响。相关技术报道了(±)-GR-24在斑马鱼模型上对血管生成表现出显著的抑制作用,其机制可能是通过抑制VEGFR2的磷酸化和降低下游蛋白FAK的活化有关。相关研究报道GR-24类似物也可以诱导G2/M细胞周期阻滞和凋亡,并对几种细胞系表现出较强的抗癌活性。
目前,关于独脚金内酯衍生物尚无作为线粒体自噬抑制剂、诱导肿瘤细胞凋亡,用于抗肿瘤治疗的报道,并且目前报道的独脚金内酯衍生物均为消旋化合物或无手性中心,尚未考察手性中心对活性的影响。
发明内容
本发明旨在至少解决上述现有技术中存在的技术问题之一。为此,本发明提出一种独脚金内酯衍生物在制备线粒体自噬抑制剂中的应用。
本发明还提出一种具有上述独脚金内酯衍生物的线粒体自噬抑制剂。
本发明还提出一种具有上述组合物的应用。
根据本发明的一个方面,提出了独脚金内酯衍生物在制备线粒体自噬抑制剂中的应用,所述独脚金内酯衍生物包括如式(I)所述的化合物或其药学上可接受的盐:
其中,R1、R2独立选自氢、甲基、硝基、氨基、取代胺基、氟原子、氯原子、溴原子、取代脲基和取代碳酸酯基中的一种;
R3、R4、R5选自氢、含1-10个碳的直链烷基或苯基;
n为1或2;
X、Y选自-O-、-S-、-NH-和-CH2-中的一种;
根据本发明的一些实施方式,将R1、R2取代的苯环定义为A环,从结构式(I)中从左至右依次定义为B环、C环和D环;其中,B环、C环与D环C1位手性中心的相对构型为syn或anti。
根据本发明的一些实施方式,所述取代胺基包括NHBoc、NHCbz、NHPiv或NHBz中的一种。
根据本发明的一些实施方式,所述取代脲基是指带有取代基的脲基。
根据本发明的一些实施方式,所述取代碳酸酯基是指带有取代基的碳酸酯基。
根据本发明的一些实施方式,所述药学上可接受的盐为无机酸、有机酸、碱金属、碱土金属和碱性氨基酸形成的盐。
根据本发明的一些实施方式,所述无机酸包括盐酸、硝酸、硫酸、磷酸、氢溴酸中的至少一种。
根据本发明的一些实施方式,有机酸包括马来酸、富马酸、酒石酸、乳酸、柠檬酸、乙酸、甲磺酸、对甲苯磺酸,己二酸,棕榈酸和单宁酸中的至少一种。
根据本发明的一些实施方式,所述碱金属包括锂、钠和钾中至少一种。
根据本发明的一些实施方式,所述碱土金属包括钙和镁中至少一种。
根据本发明的一些实施方式,所述碱性氨基酸包括赖氨酸。
根据本发明的一些实施方式,所述独脚金内酯衍生物包括消旋独脚金内酯衍生物和光学活性独脚金内酯衍生物。
根据本发明的一些实施方式,所述独脚金内酯衍生物包括消旋独脚金内酯衍生物和所述消旋独脚金内酯衍生物包括下述结构式所示的化合物5a-5h,6a-6h,7a-7h,8a-8h及其衍生物或其药理上容许的盐中的至少一种:
根据本发明的一些实施方式,所述光学活性独脚金内酯衍生物包括下述结构式所示的化合物13a、13b、14a和14b及其衍生物或其药理上容许的盐中的至少一种:
根据本发明的再一个方面,提出了一种具有上述独脚金内酯衍生物的线粒体自噬抑制剂,所述线粒体自噬抑制剂包括上述独脚金内酯衍生物或其药学上可接受的盐。
根据本发明的再一个方面,提出了一种具有上述独脚金内酯衍生物的线粒体自噬抑制剂的应用。
根据本发明的一些实施方式,所述线粒体自噬抑制剂在制备抑制肿瘤细胞凋亡的试剂中的应用。
根据本发明的一些实施方式,所述线粒体自噬抑制剂在制备预防或治疗神经退行性疾病的药物及其组合物中的应用。
根据本发明的一些实施方式,所述神经退行性疾病为脑缺血、脑损伤、帕金森病、阿尔兹海默症。
根据本发明的一些实施方式,所述线粒体自噬抑制剂在制备预防或治疗炎症性疾病的药物及其组合物中的应用。
根据本发明的一些实施方式,所述炎症性疾病为急性肺损伤、慢阻肺、肺动脉高压、动脉瘤、马凡综合症。
根据本发明的一些实施方式,所述线粒体自噬抑制剂在制备化疗药物增敏剂中的应用。
根据本发明的一些实施方式,所述化疗药物增敏剂为增强紫杉醇、顺铂或5-氟尿嘧啶抗肿瘤作用的药物。
根据本发明的一些实施方式,上述线粒体自噬抑制剂在制备预防或治疗肿瘤的药物或辅助药物中的用途。
根据本发明的一些实施方式,所述癌症包括结直肠癌、胰腺癌、卵巢癌、肺癌、肝癌。
根据本发明的一些实施方式,所述线粒体自噬抑制剂在制备抑制线粒体自噬机制研究试剂中的应用。
根据本发明的一些实施方式,所述线粒体为肿瘤细胞线粒体。
根据本发明的一些实施方式,所述线粒体自噬抑制剂在制备Caspase-3蛋白表达促进剂中的应用。
根据本发明的一些实施方式,所述线粒体自噬抑制剂在制备P62蛋白表达促进剂中的应用。根据本发明的一些实施方式,所述线粒体自噬抑制剂在制备LC3B II的蛋白表达抑制剂中的应用。
根据本发明的一些实施方式,所述线粒体自噬抑制剂包括所述独脚金内酯衍生物。
根据本发明的一些实施方式,所述线粒体自噬抑制剂的制备原料还包括药用载体。
根据本发明的一些实施方式,所述药用载体为药学领域常规的药物载体。
根据本发明的一些实施方式,所述药用载体包括稀释剂、赋形剂、填充剂、黏合剂、崩解剂、吸收促进剂、表面活性剂、吸附载体、润滑剂、甜味剂和香味剂中的至少一种。
根据本发明的一些实施方式,所述赋形剂包括水。
根据本发明的一些实施方式,所述填充剂包括淀粉和蔗糖中的至少一种。
根据本发明的一些实施方式,所述黏合剂包括纤维素衍生物、藻酸盐、明胶和聚乙烯吡咯烷酮中的至少一种。
根据本发明的一些实施方式,所述湿润剂包括甘油。
根据本发明的一些实施方式,所述崩解剂包括琼脂、碳酸钙和碳酸氢钠中的至少一种。
根据本发明的一些实施方式,所述吸收促进剂包括季铵化合物。
根据本发明的一些实施方式,所述表面活性剂包括十六烷醇。
根据本发明的一些实施方式,所述吸附载体包括高岭土和皂黏土中的至少一种。
根据本发明的一些实施方式,所述润滑剂包括滑石粉、硬脂酸钙、硬脂酸镁和聚乙二醇中的至少一种。
根据本发明的一些实施方式,所述消旋或光活独脚金内酯衍生物在药物中的质量分数为0.1%~ 99%。
根据本发明的一些优选实施方式,所述消旋或光活独脚金内酯衍生物在药物中的质量分数为 0.5%~95%。
根据本发明的一些优选实施方式,所述消旋或光活独脚金内酯衍生物在药物中的质量分数为 10%~20%。
根据本发明的一些实施方式,所述癌症治疗药物的给药量标准为:消旋或光活独脚金内酯衍生物0.1mg/天~1000mg/天。
根据本发明的一些实施方式,所述药物的剂型为本领域常规的各种剂型,优选地为固体、半固体或液体的形式,可以为水溶液、非水溶液或混悬液,更优选地为片剂、胶囊剂、软胶囊剂、颗粒剂、丸剂、口服液、干混悬剂、滴丸剂、干浸膏剂、注射剂或输注剂。
根据本发明的一些实施方式,所述药物的给药方式可以为本领域常规的给药方式,包括但不限于注射给药或口服给药。所述注射给药可以为静脉注射、肌肉注射、腹腔注射、皮内注射或皮下注射等途径。
本文所述的术语“给药剂量”为能够缓解或延迟疾病、退化性或损伤性病症进展的量。可以随被治疗的具体疾病以及其它因素而定,其它因素包括年龄、体重、健康状况、症状的严重程度、给药途径、治疗的频率和在治疗期间是否伴随其它的药物。
本文所述的术语“治疗”是指减轻癌症及其并发症的程度,或者治愈癌症及其并发症使之正常化,或者减缓癌症及其并发症的进程。
根据本发明实施方式的所述的应用,至少具备如下有益效果:本发明方案提供了独脚金内酯衍生物作为线粒体自噬抑制剂,可以选择性诱导肿瘤细胞凋亡,抑制肿瘤细胞的迁移,促进肿瘤微环境的抗肿瘤免疫,抑制肿瘤细胞免疫逃避,增强免疫监视,加强CD8+T细胞介导的细胞毒性作用。也可作为化疗药物增敏剂,与化疗药物紫杉醇或顺铂联合用药,还可以有效的用于预防或治疗神经退行性疾病和炎症性疾病。本发明进一步扩大了独脚金内酯衍生物的应用范围,也抗肿瘤治疗提供了新方案。
附图说明
下面结合附图和实施例对本发明做进一步的说明,其中:
图1为本发明测试例中的不同浓度的化合物13a对结直肠癌细胞HCT116、MC38以及正常结肠上皮细胞细胞增殖能力的影响的结果图;
图2为本发明测试例中的不同浓度的化合物13a对结直肠癌细胞HCT116、MC38以及正常结肠上皮细胞细胞增殖能力的影响的结果图,其中,*、**、***和****分别是与对照组比较p<0.05,p<0.01, p<0.001,p<0.0001,NS表示无显著性差异;
图3为本发明测试例中的不同浓度的化合物13a对结直肠癌细胞SW620细胞细胞增殖能力的影响的结果图;
图4为本发明测试例中的不同浓度的化合物13a对结直肠癌细胞SW620细胞细胞增殖能力的影响的结果图,其中,***表示为p<0.001;
图5为本发明测试例中的不同浓度的化合物13a对结直肠癌细胞HCT116迁移的影响结果图;
图6为本发明测试例中的不同浓度的化合物13a对结直肠癌细胞HCT116迁移的影响结果图,其中,*、***和****分别是与对照组比较p<0.05,p<0.001,p<0.0001,NS表示无显著性差异;
图7为本发明测试例中的不同浓度的化合物13a对结直肠细胞HCT116凋亡的影响结果图;
图8为本发明测试例中的不同浓度的化合物13a对结直肠细胞HCT116凋亡的影响结果图,其中,*和**分别是与对照组比较p<0.05,p<0.01,NS表示无显著性差异;
图9为本发明测试例中的不同浓度的化合物13a对结直肠细胞HCT116细胞周期的影响结果图;
图10为本发明测试例中的不同浓度的化合物13a对结直肠细胞HCT116细胞周期的影响结果图,其中,***和****分别表示为p<0.001,p<0.0001;
图11为本发明测试例中的不同浓度的化合物13a对HCT116、NCM460、A2780、Hosepic、H358 细胞LC3B、p62、caspase3蛋白表达的影响结果图,其中,A为肿瘤细胞系HCT116的免疫杂交印记结果图;B为正常细胞系NCM 460的免疫杂交印记结果图;C为肿瘤细胞系A2780的免疫杂交印记结果图;D为正常细胞系Hosepic的免疫杂交印记结果图;E为自噬抑制剂氯喹和化合物13a联用和自噬诱导剂雷帕霉素和化合物13a联用,对p62蛋白表达影响结果图;F为肿瘤细胞系H358的免疫杂交印记结果图;
图12为本发明测试例中的不同浓度的化合物13a对SW620细胞LC3B、p62、caspase3、caspase8、 PARP1、LAMP1蛋白表达的影响结果图;
图13为本发明测试例中的不同浓度的化合物13a对HCT116细胞线粒体自噬相关蛋白 p-PINK1(S228)和p-Parkin(S65)蛋白表达的影响结果图;
图14为本发明测试例中的13a在裸鼠移植瘤模型的活性评价结果图,其中A为不同浓度的化合物13a对小鼠肿瘤质量的影响结果图;B为不同浓度的化合物13a对小鼠肿瘤质量的影响结果图,C 为服用化合物13a后小鼠的体重变化图,*和**分别是与对照组比较p<0.05,p<0.01,NS表示无显著性差异;
图15为本发明测试例中的不同浓度的化合物13a抑制HCT116异种移植瘤的生长影响的结果图;
图16为本发明测试例中的不同浓度的化合物13a对小鼠肿瘤质量的影响结果图,其中,*、** 和***分别是与对照组比较p<0.05,p<0.01,p<0.001,NS表示无显著性差异;
图17为本发明测试例中的服用不同浓度化合物13a后小鼠的体重变化图;
图18为本发明测试例中的为不同浓度的化合物13a处理后C-Casepase 3和p62在肿瘤细胞中表达结果图;
图19为本发明测试例中的不同浓度的化合物13a处理后肿瘤细胞中p62和LC3B的蛋白表达水平结果图;
图20为本发明测试例中的不同浓度的化合物13a处理后肿瘤细胞中p62和LC3B的表达水平结果图,其中,A为不同浓度的化合物13a对肿瘤细胞中p62基因的表达水平影响结果图,B为不同浓度的化合物13a对肿瘤细胞中LC3B基因的表达水平影响结果图;其中,*、**和***分别是与对照组比较p<0.05,p<0.01,p<0.001,NS表示无显著性差异;
图21本发明测试例中的独脚金内酯衍生物13a联合5-氟尿嘧啶抑制HCT116异种移植瘤的生长影响结果图;
图22本发明测试例中独脚金内酯衍生物13a联合5-氟尿嘧啶抑制HCT116异种移植瘤的生长影响结果图,其中A为不同给药组对小鼠肿瘤质量的影响结果图;B为不同给药组小鼠肿瘤体积差异影响结果图;C为不同给药组的小鼠体重变化图,**是与对照组比较,p<0.01,NS表示无显著性差异。
具体实施方式
以下将结合实施例对本发明的构思及产生的技术效果进行清楚、完整地描述,以充分地理解本发明的目的、特征和效果。显然,所描述的实施例只是本发明的一部分实施例,而不是全部实施例,基于本发明的实施例,本领域的技术人员在不付出创造性劳动的前提下所获得的其他实施例,均属于本发明保护的范围。
实验材料:DMEM,胎牛血清(FBS),青霉素-链霉素溶液(PS),购自BI(以色列)。二甲基亚砜 (DMSO)和3-(4,5-二甲基噻唑-2-基)-2、5-二苯基溴化四氮唑(MTT)购自安耐吉(中国)。BCL-2一抗(affyina,美国,1:500稀释),鼠二抗(BBI,中国上海,1:5000稀释)。
本发明所涉及的相关肿瘤细胞系都保存在湘雅药学院药物化学系实验中心,置于37℃,5%CO2的培养箱中,使用含有10%胎牛血清(FBS)和1%青霉素-链霉素溶液(PS)的DMEM培养。细胞融合度90%胰酶消化传代。
实施例1
本实施例制备了一种独脚金内酯衍生物,其制备具体过程为:
(1)化合物2a的制备:
称取1-茚酮(6.6g,50mmol)于250mL圆底烧瓶中,加入乙醛酸一水合物(6.9g,75mmol),将混合物搅拌均匀后加热至95℃,反应3h,TLC监测至1-茚酮反应完全,恢复至室温,向其中加入75mL 冰醋酸和15mL水,搅拌均匀后向其中分批缓慢的加入提前活化的锌粉(3.9g,60mmol),锌粉加完后,加热至60℃反应大约3h,TLC监测至原料反应完全,恢复至室温后,真空抽滤未反应完的锌粉。抽滤所得溶液经减压浓缩除去大部分溶剂,再加入乙酸乙酯萃取三次(35mL×3),然后用饱和 NaCl洗涤(18mL×3)并合并有机相,有机层再用无水硫酸钠干燥,减压浓缩,粗产品经快速硅胶柱层析纯化(石油醚:乙酸乙酯=2.5:1,洗脱剂中加入千分之一醋酸),得到化合物2(6.46g,68%)。
1H NMR(400MHz,CD3OD)δ7.70(d,J=7.7Hz,1H),7.68–7.61(m,1H),7.53(d,J=7.7Hz,1H), 7.40(t,J=7.4Hz,1H),3.49–3.39(m,1H),3.00–2.85(m,3H),2.73–2.65(m,1H)。
(2)化合物3a的制备:
将化合物2a(3.23g,17mmol)加入到250mL圆底烧瓶中,加入85mL乙醇,搅拌均匀后,置于冰水浴中,向其中分批次慢慢地加入粉末状硼氢化钠(964mg,25.5mmol),加入完毕后,搅拌反应 2h至TLC监测原料反应完全停止反应,然后减压浓缩除掉溶剂,加入稀HCl(1M)调pH约为3,然后用乙酸乙酯萃取三次(35mL×3),饱和氯化钠溶液洗涤并合并有机相,有机层用无水硫酸钠干燥,减压浓缩,得到粗产品。向所得粗产品中依次加入50mL苯和对甲苯磺酸酸(292mg,1.7mmol),加热至80℃反应1.5h,TLC监测至原料反应完全,自然恢复至室温,将混合物经减压浓缩除去溶剂苯,粗产品经快速硅胶柱层析纯化(石油醚:乙酸乙酯=4:1),得到化合物3a(2.13g,72%)。
1H NMR(500MHz,CDCl3)δ7.48(d,J=7.4Hz,1H),7.36(t,J=7.4Hz,1H),7.30(dd,J=10.3,7.1 Hz,2H),5.89(d,J=7.0Hz,1H),3.35(ddd,J=24.4,14.3,8.6Hz,2H),2.91(dd,J=18.1,10.1Hz,2H), 2.39(dd,J=18.2,5.3Hz,1H)。
(3)化合物4a的制备:
向250mL三口圆底烧瓶中分别加入含有40%H2O的乙二醛(7.98g,54.1mmol),H2O(45mL),混合均匀后加入甲基丙二酸(4.5g,38.8mmol),然后添加H2SO4(10滴),将反应混合物加热回流。大约反应16h,TLC监测至原料反应完全,向反应混合物加入固体NaCl使其饱和,用乙酸乙酯(3×25mL) 萃取。将合并的有机相经无水Na2SO4干燥,真空浓缩。所得粗产品通过快速硅胶柱色谱法纯化(石油醚:乙酸乙酯=3:1),得到酸酐粗产物。
向50mL圆底烧瓶中加入上一步的酸酐粗产品(342mg,3mmol)和8mL无水二氯甲烷,搅拌均匀置于冰水浴中,然后向其中缓慢加入PBr3(0.14mL,1.5mmol),反应1.5h,TLC监测至原料反应完全,将反应物缓慢倒入冰水中,分出有机层,再用二氯甲烷(3×10mL)萃取水层,饱和碳酸氢钠溶液(3×10mL)洗涤,饱和食盐水(3×10mL)洗涤,无水Na2SO4干燥,旋蒸得产物4a(480mg,92%)为黄色油状液体,不经纯化可直接用于下一步反应。
(4)化合物5a、6a的制备:
在0℃下,向化合物3a(200mg,1.056mmol)的甲酸乙酯(12mL)溶液中分批加入叔丁醇钾(714.6mg,6.3mmol),并使反应恢复至室温。大约反应3h,TLC监测至原料反应完全,加入1M HCl(15mL) 淬灭反应混合物,并用乙酸乙酯(3×10mL)萃取,合并的有机相经饱和NaCl(3×10mL)洗涤,无水硫酸钠干燥,过滤并真空浓缩。将粗制的产物溶于DMF(9mL)中,并在室温下加入无水碳酸钾 (219.6mg,1.6mmol)。反应混合物冷却至0℃,缓慢加入化合物4a(305mg,1.72mmol)的DMF(3mL) 溶液。16h后,TLC监测至原料反应完全后,向其中加入饱和NH4Cl(15mL)淬灭反应混合物,并用乙酸乙酯(3×10mL)萃取。合并的有机相用饱和NaCl(3×10mL)洗涤,无水Na2SO4干燥,过滤并真空浓缩。经快速柱色谱法纯化(石油醚:乙酸乙酯=2.5:1)。首先分离得到(±)-GR-24,我们将其标记为 5a(110mg,35%),后分离得到的化合物为(±)-epi-GR-24,将它标记为6a(110mg,35%)。
5a:1H NMR(500MHz,CDCl3)δ7.53(d,J=7.5Hz,1H),7.51(d,J=2.5Hz,1H),7.36(dt,J=7.4, 3.7Hz,1H),7.31(t,J=7.4Hz,1H),7.26(d,J=7.5Hz,1H),7.01–6.97(m,1H),6.22–6.18(m,1H), 5.98(d,J=7.8Hz,1H),4.01–3.93(m,1H),3.46(dd,J=16.9,9.4Hz,1H),3.13(dd,J=16.9,3.2Hz, 1H),2.06(s,3H)。
6a:1H NMR(500MHz,CDCl3)δ7.52–7.48(m,2H),7.34(t,J=7.2Hz,1H),7.31–7.22(m,2H), 7.02–6.94(m,1H),6.21(s,1H),5.96(d,J=7.9Hz,1H),3.94(ddd,J=8.1,5.9,3.0Hz,1H),3.43(dd,J =16.9,9.3Hz,1H),3.10(dd,J=16.9,3.0Hz,1H),2.04(s,3H)。
(5)化合物5b
(±)-(E)-7-methyl-3-((((S)-4-methyl-5-oxo-2,5-dihydrofuran-2-yl)oxy)methylene)-3,3a,4,8b-tetrahydro-2H-in deno[1,2-b]furan-2-one(5b):
White solid,75mg,31%。
1H NMR(400MHz,CDCl3)δ7.50(d,J=2.5Hz,1H),7.31(s,1H),7.14(q,J=7.9Hz,2H),7.01–6.96 (m,1H),6.21(s,1H),5.93(d,J=7.9Hz,1H),3.98–3.90(m,1H),3.38(dd,J=16.7,9.3Hz,1H),3.06 (dd,J=16.8,2.7Hz,1H),2.36(s,3H),2.05(s,3H)。
下述化合物参照5a和6a的制备方法得到。
(6)化合物6b
(±)-(E)-7-methyl-3-((((R)-4-methyl-5-oxo-2,5-dihydrofuran-2-yl)oxy)methylene)-3,3a,4,8b-tetrahydro-2H-i ndeno[1,2-b]furan-2-one(6b):
White solid,75mg,31%。
1H NMR(400MHz,CDCl3)δ7.50(d,J=2.5Hz,1H),7.31(s,1H),7.14(q,J=7.9Hz,2H),6.99(d,J= 1.3Hz,1H),6.21(s,1H),5.93(d,J=7.9Hz,1H),3.98–3.89(m,1H),3.38(dd,J=16.7,9.3Hz,1H), 3.06(dd,J=16.8,2.7Hz,1H),2.36(s,3H),2.05(s,3H)。
(7)化合物5c
(±)-(E)-6-fluoro-3-((((S)-4-methyl-5-oxo-2,5-dihydrofuran-2-yl)oxy)methylene)-3,3a,4,8b-tetrahydro-2H-in deno[1,2-b]furan-2-one(5c):
Yellow solid,42mg,27%。
1H NMR(400MHz,CDCl3)δ7.51(d,J=2.5Hz,1H),7.44(dd,J=8.4,5.2Hz,1H),7.00–6.98(m,1H), 6.96(dd,J=8.7,2.3Hz,1H),6.92–6.88(m,1H),6.25–6.18(m,1H),5.90(d,J=7.9Hz,1H),4.02– 3.93(m,1H),3.40(dd,J=17.2,9.3Hz,1H),3.07(dd,J=17.2,3.1Hz,1H),2.03(s,3H)。
(8)化合物6c
(±)-(E)-6-fluoro-3-((((R)-4-methyl-5-oxo-2,5-dihydrofuran-2-yl)oxy)methylene)-3,3a,4,8b-tetrahydro-2H-in deno[1,2-b]furan-2-one(6c):
Yellow solid,42mg,27%。
1H NMR(500MHz,CDCl3)δ7.51(d,J=2.5Hz,1H),7.47(dd,J=8.4,5.2Hz,1H),7.03–6.97(m,2H), 6.93(d,J=8.8Hz,1H),6.20(s,1H),5.93(d,J=7.8Hz,1H),4.02–3.96(m,1H),3.42(dd,J=17.2,9.3 Hz,1H),3.10(dd,J=17.2,3.0Hz,1H),2.07(s,3H)。
(9)化合物5d
(±)-(E)-7-fluoro-3-((((S)-4-methyl-5-oxo-2,5-dihydrofuran-2-yl)oxy)methylene)-3,3a,4,8b-tetrahydro-2H-in deno[1,2-b]furan-2-one(5d):
Yellow solid,37mg,25%。
1H NMR(500MHz,CDCl3)δ7.49(d,J=2.5Hz,1H),7.43(dd,J=8.4,5.2Hz,1H),7.01–6.85(m,3H), 6.22(s,1H),5.88(d,J=7.9Hz,1H),4.03–3.91(m,1H),3.40(dd,J=17.2,9.3Hz,1H),3.07(dd,J= 17.2,3.1Hz,1H),2.01(s,3H)。
(10)化合物6d
(±)-(E)-7-fluoro-3-((((R)-4-methyl-5-oxo-2,5-dihydrofuran-2-yl)oxy)methylene)-3,3a,4,8b-tetrahydro-2H-in deno[1,2-b]furan-2-one(6d):
Yellow solid,37mg,25%。
1H NMR(400MHz,CDCl3)δ7.51(d,J=2.5Hz,1H),7.44(dd,J=8.4,5.2Hz,1H),7.00–6.94(m,2H), 6.90(d,J=8.8Hz,1H),6.23–6.21(m,1H),5.90(d,J=7.9Hz,1H),4.01–3.93(m,1H),3.40(dd,J= 17.2,9.3Hz,1H),3.07(dd,J=17.2,3.1Hz,1H),2.03(s,3H)。
(11)化合物5e
(±)-(E)-7-bromo-3-((((S)-4-methyl-5-oxo-2,5-dihydrofuran-2-yl)oxy)methylene)-3,3a,4,8b-tetrahydro-2H-in deno[1,2-b]furan-2-one(5e):
Yellow solid,35mg,23%。
1H NMR(400MHz,CDCl3)δ7.66(d,J=1.2Hz,1H),7.51(d,J=2.5Hz,1H),7.47(dd,J=8.1,1.7Hz, 1H),7.13(d,J=8.1Hz,1H),7.00–6.96(m,1H),6.21(s,1H),5.93(d,J=7.9Hz,1H),4.02–3.95(m, 1H),3.39(dd,J=17.1,9.3Hz,1H),3.08(dd,J=17.0,3.1Hz,1H),2.07(s,3H)。
(12)化合物6e
(±)-(E)-7-bromo-3-((((R)-4-methyl-5-oxo-2,5-dihydrofuran-2-yl)oxy)methylene)-3,3a,4,8b-tetrahydro-2H-i ndeno[1,2-b]furan-2-one(6e):
Yellow solid,35mg,23%.
1H NMR(400MHz,CDCl3)δ7.51(d,J=2.5Hz,1H),7.46–7.37(m,3H),7.00–6.97(m,1H),6.20(s, 1H),5.91(d,J=7.8Hz,1H),4.02–3.95(m,1H),3.44(dd,J=17.1,9.3Hz,1H),3.12(dd,J=17.1,3.1 Hz,1H),2.07(s,3H)。
(13)化合物5f
(±)-(E)-6-bromo-3-((((S)-4-methyl-5-oxo-2,5-dihydrofuran-2-yl)oxy)methylene)-3,3a,4,8b-tetrahydro-2H-in deno[1,2-b]furan-2-one(5f):
Yellow solid,32mg,27%。
The spectral data of 5f and 6fare identical to those of a previousreport.5。
1H NMR(400MHz,CDCl3)δ7.51(d,J=2.5Hz,1H),7.45–7.36(m,3H),7.01–6.97(m,1H),6.20(s, 1H),5.91(d,J=7.8Hz,1H),4.02–3.95(m,1H),3.44(dd,J=17.1,9.3Hz,1H),3.12(dd,J=17.1,3.1 Hz,1H),2.07(s,3H)。
(14)化合物6f
(±)-(E)-6-bromo-3-((((R)-4-methyl-5-oxo-2,5-dihydrofuran-2-yl)oxy)methylene)-3,3a,4,8b-tetrahydro-2H-i ndeno[1,2-b]furan-2-one(6f):
Yellow solid,32mg,27%。
1H NMR(400MHz,CDCl3)δ7.51(d,J=2.6Hz,1H),7.47–7.35(m,3H),7.02–6.95(m,1H),6.25– 6.16(m,1H),5.91(d,J=7.9Hz,1H),4.01–3.93(m,1H),3.42(dd,J=17.2,9.3Hz,1H),3.10(dd,J= 17.2,3.1Hz,1H),2.07(s,3H)。
(15)化合物5g
(±)-(E)-3-((((S)-4-methyl-5-oxo-2,5-dihydrofuran-2-yl)oxy)methylene)-3a,4,5,9b-tetrahydronaphtho[1,2-b]f uran-2(3H)-one(5g):
White solid,101mg,37%.
1H NMR(500MHz,CDCl3)δ7.55(d,J=2.0Hz,1H),7.49(dd,J=5.2,3.8Hz,1H),7.30–7.27(m,2H), 7.17(dd,J=5.2,3.7Hz,1H),7.00–6.97(m,1H),6.23–6.20(m,1H),5.44(d,J=7.4Hz,1H),3.55– 3.48(m,1H),2.80–2.62(m,2H),2.12–2.05(m,1H),2.04(s,3H),1.73–1.65(m,1H)。
(16)化合物6g
(±)-(E)-3-((((R)-4-methyl-5-oxo-2,5-dihydrofuran-2-yl)oxy)methylene)-3a,4,5,9b-tetrahydronaphtho[1,2-b] furan-2(3H)-one(6g):
White solid,101mg,37%。
1H NMR(400MHz,CDCl3)δ7.55(d,J=2.0Hz,1H),7.48(dd,J=5.0,4.0Hz,1H),7.30–7.26(m,2H), 7.19–7.14(m,1H),7.00–6.97(m,1H),6.23–6.19(m,1H),5.45(d,J=7.5Hz,1H),3.56–3.48(m, 1H),2.80–2.60(m,2H),2.11–2.05(m,1H),2.04(s,3H),1.77–1.67(m,1H)。
(17)化合物5h
(±)-(E)-7-bromo-3-((((S)-4-methyl-5-oxo-2,5-dihydrofuran-2-yl)oxy)methylene)-3a,4,5,9b-tetrahydronapht ho[1,2-b]furan-2(3H)-one(5h):
Yellow solid,48mg,31%。
1H NMR(400MHz,CDCl3)δ7.62(d,J=1.9Hz,1H),7.55(d,J=2.1Hz,1H),7.39(dd,J=8.2,2.1Hz, 1H),7.04(d,J=8.2Hz,1H),7.01–6.96(m,1H),6.24–6.18(m,1H),5.38(d,J=7.6Hz,1H),3.57– 3.47(m,1H),2.77–2.52(m,2H),2.11–2.05(m,1H),2.05(s,3H),1.73–1.63(m,1H)。
(18)化合物6h
(±)-(E)-7-bromo-3-((((R)-4-methyl-5-oxo-2,5-dihydrofuran-2-yl)oxy)methylene)-3a,4,5,9b-tetrahydronapht ho[1,2-b]furan-2(3H)-one(6h):
Yellow solid,48mg,31%。
1H NMR(400MHz,CDCl3)δ7.62(d,J=1.9Hz,1H),7.55(d,J=2.1Hz,1H),7.39(dd,J=8.2,2.1Hz, 1H),7.04(d,J=8.2Hz,1H),7.00–6.97(m,1H),6.23–6.20(m,1H),5.38(d,J=7.6Hz,1H),3.55– 3.47(m,1H),2.75–2.53(m,2H),2.12–2.05(m,1H),2.04(s,3H),1.74–1.63(m,1H)。
(19)化合物9a
(±)-Tert-butyl((E)-3-((((S)-4-methyl-5-oxo-2,5-dihydrofuran-2-yl)oxy)methylene)-2-oxo-3,3a,4,8b-tetrahydr o-2H-indeno[1,2-b]furan-7-yl)carbamate(9a):
White solid,75mg,34%。
The spectral data of 9a and 10aare identical to those of a previousreport6.
1H NMR(500MHz,DMSO-d6)δ9.42(s,1H),7.72(s,1H),7.63(s,1H),7.45–7.34(m,2H),7.16(d,J= 7.7Hz,1H),6.69(s,1H),5.94(d,J=7.3Hz,1H),3.93(s,1H),3.34(s,1H),2.94(d,J=16.4Hz,1H), 1.92(s,3H),1.48(s,9H)。
(20)化合物10a
(±)-Tert-butyl((E)-3-((((R)-4-methyl-5-oxo-2,5-dihydrofuran-2-yl)oxy)methylene)-2-oxo-3,3a,4,8b-tetrahydr o-2H-indeno[1,2-b]furan-7-yl)carbamate(10a):
White solid,75mg,34%.
1H NMR(500MHz,CDCl3)δ7.55(s,1H),7.46(d,J=2.5Hz,1H),7.28(s,1H),7.09(d,J=9.9Hz,1H), 7.04–6.94(m,1H),6.83(s,1H),6.19(s,1H),5.86(d,J=7.9Hz,1H),3.96–3.86(m,1H),3.32(dd,J= 16.8,9.3Hz,1H),3.00(dd,J=16.7,3.0Hz,1H),2.00(s,3H),1.49(s,9H)。
(21)化合物9b
(±)-Tert-butyl-((E)-3-((((S)-4-methyl-5-oxo-2,5-dihydrofuran-2-yl)oxy)methylene)-2-oxo-3,3a,4,8b-tetrahyd ro-2H-indeno[1,2-b]furan-6-yl)carbamate(9b):
White solid,32mg,27%.
1H NMR(500MHz,CDCl3)δ7.86(d,J=5.8Hz,1H),7.49(d,J=2.5Hz,1H),7.32(t,J=7.8Hz,1H), 7.24(d,J=7.5Hz,1H),7.03–6.99(m,1H),6.25–6.19(m,2H),5.97(d,J=7.9Hz,1H),4.01(ddd,J= 8.0,5.9,3.1Hz,1H),3.35(dd,J=16.3,9.4Hz,1H),2.97(dd,J=16.3,3.2Hz,1H),2.07(s,3H),1.55(s, 9H)。
(22)化合物10b
(±)-Tert-butyl-((E)-3-((((R)-4-methyl-5-oxo-2,5-dihydrofuran-2-yl)oxy)methylene)-2-oxo-3,3a,4,8b-tetrahyd ro-2H-indeno[1,2-b]furan-6-yl)carbamate(10b):
White solid,32mg,27%.
1H NMR(500MHz,CDCl3)δ7.87(d,J=6.6Hz,1H),7.52(d,J=2.5Hz,1H),7.31(t,J=7.9Hz,1H), 7.23(d,J=7.5Hz,1H),7.05–6.95(m,1H),6.22(dd,J=11.8,10.5Hz,2H),5.96(d,J=7.9Hz,1H), 4.02–3.92(m,1H),3.33(dd,J=16.4,9.4Hz,1H),2.94(dd,J=16.4,3.2Hz,1H),2.07(s,3H),1.54(s, 9H)。
(23)化合物9c
(±)-Benzyl-((E)-3-((((S)-4-methyl-5-oxo-2,5-dihydrofuran-2-yl)oxy)methylene)-2-oxo-3,3a,4,8b-tetrahydro- 2H-indeno[1,2-b]furan-7-yl)carbamate(9c):
White solid,35mg,23%.
1H NMR(400MHz,DMSO-d6)δ9.86(s,1H),7.73(d,J=2.5Hz,1H),7.63(s,1H),7.47–7.39(m,6H), 7.38–7.33(m,1H),7.20(d,J=8.4Hz,1H),6.69(s,1H),5.96(d,J=7.9Hz,1H),5.16(s,2H),3.97– 3.90(m,1H),3.30(dd,J=16.8,9.2Hz,1H),2.95(dd,J=16.7,2.4Hz,1H),1.92(s,3H)。
(24)化合物10c
(±)-Benzyl-((E)-3-((((R)-4-methyl-5-oxo-2,5-dihydrofuran-2-yl)oxy)methylene)-2-oxo-3,3a,4,8b-tetrahydro- 2H-indeno[1,2-b]furan-7-yl)carbamate(10c):
White solid,35mg,23%.
1H NMR(400MHz,CDCl3)δ7.56(s,1H),7.49(d,J=2.5Hz,1H),7.42–7.32(m,5H),7.15(d,J=8.3 Hz,1H),7.08(s,1H),7.00–6.96(m,1H),6.19(s,1H),5.91(d,J=7.9Hz,1H),5.20(s,2H),3.97–3.90 (m,1H),3.36(dd,J=16.8,9.3Hz,1H),3.04(dd,J=16.8,2.9Hz,1H),2.04(s,3H)。
(25)化合物9d
(±)-(E)-7-(benzylamino)-3-((((S)-4-methyl-5-oxo-2,5-dihydrofuran-2-yl)oxy)methylene)-3,3a,4,8b-tetrahydr o-2H-indeno[1,2-b]furan-2-one(9d):
White solid,45mg,32%.
1H NMR(500MHz,CDCl3)δ8.52(s,1H),7.50(d,J=2.4Hz,1H),7.32–7.18(m,6H),7.07(dd,J=8.1, 1.9Hz,1H),6.98(d,J=1.3Hz,1H),6.21(s,1H),5.89(d,J=7.9Hz,1H),5.04(d,J=15.1Hz,1H),4.95 (d,J=15.1Hz,1H),4.01–3.94(m,1H),3.41(dd,J=17.1,9.3Hz,1H),3.09(dd,J=16.9,3.1Hz,1H), 2.04(s,3H)。
(26)化合物10d
(±)-(E)-7-(benzylamino)-3-((((S)-4-methyl-5-oxo-2,5-dihydrofuran-2-yl)oxy)methylene)-3,3a,4,8b-tetrahydr o-2H-indeno[1,2-b]furan-2-one(10d):
White solid,45mg,32%.
1H NMR(500MHz,CDCl3)δ8.52(s,1H),7.52(d,J=2.5Hz,1H),7.32–7.19(m,6H),7.07(dd,J=8.1, 2.1Hz,1H),6.99–6.96(m,1H),6.21–6.19(m,1H),5.90(d,J=8.0Hz,1H),5.04(d,J=15.1Hz,1H), 4.95(d,J=15.1Hz,1H),4.00–3.93(m,1H),3.39(dd,J=17.1,9.4Hz,1H),3.08(dd,J=17.1,3.0Hz, 1H),2.05(s,3H)。
(27)化合物9e
(±)-(E)-7-amino-3-((((S)-4-methyl-5-oxo-2,5-dihydrofuran-2-yl)oxy)methylene)-3,3a,4,8b-tetrahydro-2H-in deno[1,2-b]furan-2-one(9e):
1H NMR(400MHz,DMSO-d6)δ7.69(d,J=2.5Hz,1H),7.44–7.38(m,1H),6.92(d,J=8.1Hz,1H), 6.69(s,1H),6.65–6.57(m,2H),5.84(d,J=7.8Hz,1H),5.10(s,2H),3.91–3.81(m,1H),3.18(dd,J= 16.1,9.1Hz,1H),2.84(dd,J=16.0,2.7Hz,1H),1.92(s,3H).
(28)化合物10e
从10a(41mg,1mmol)中得到10e,10e为白色固体,(28mg,90%)。
(±)-(E)-7-amino-3-((((R)-4-methyl-5-oxo-2,5-dihydrofuran-2-yl)oxy)methylene)-3,3a,4,8b-tetrahydro-2H-in deno[1,2-b]furan-2-one(10e):
10e(28mg,90%)was obtained as white solid from 10a(41mg,1mmol).
The spectral data of 12a and 12bare identical to those of a previousreport3.
1H NMR(400MHz,CDCl3)δ7.48(d,J=2.6Hz,1H),7.01(d,J=8.1Hz,1H),6.99–6.95(m,1H), 6.80(d,J=2.0Hz,1H),6.69(dd,J=8.1,2.2Hz,1H),6.19(d,J=1.2Hz,1H),5.87(d,J=7.9Hz,1H), 3.91(ddd,J=11.4,5.8,2.9Hz,1H),3.31(dd,J=16.3,9.2Hz,1H),2.98(dd,J=16.3,3.0Hz,1H),2.05 (s,3H)。
(29)化合物9f
(±)-Tert-butyl-((E)-3-((((S)-4-methyl-5-oxo-2,5-dihydrofuran-2-yl)oxy)methylene)-2-oxo-2,3,3a,4,5,9b-hexa hydronaphtho[1,2-b]furan-8-yl)carbamate(9f):
White solid,78mg,40%。
1H NMR(400MHz,CDCl3)δ7.53(d,J=1.9Hz,1H),7.45(d,J=1.6Hz,1H),7.34(d,J=7.7Hz,1H), 7.08(d,J=8.3Hz,1H),6.99–6.96(m,1H),6.60(s,1H),6.22–6.18(m,1H),5.38(d,J=7.5Hz,1H), 3.52–3.44(m,1H),2.74–2.54(m,2H),2.04(s,3H),1.71–1.60(m,1H),1.52(s,9H)。
(30)化合物10f
(±)-Tert-butyl-((E)-3-((((R)-4-methyl-5-oxo-2,5-dihydrofuran-2-yl)oxy)methylene)-2-oxo-2,3,3a,4,5,9b-hexa hydronaphtho[1,2-b]furan-8-yl)carbamate(10f):
White solid,78mg,40%.
1H NMR(400MHz,CDCl3)δ7.53(d,J=2.0Hz,1H),7.47(d,J=1.5Hz,1H),7.34–7.29(m,1H),7.08 (d,J=8.3Hz,1H),6.99–6.96(m,1H),6.58(s,1H),6.21–6.17(m,1H),5.39(d,J=7.5Hz,1H),3.49 (dddd,J=9.3,7.5,5.5,2.0Hz,1H),2.74–2.54(m,2H),2.05(s,3H),2.03–1.99(m,1H),1.68(ddd,J= 13.4,8.7,3.8Hz,1H),1.52(s,9H).
(31)化合物9g:
(±)-Tert-butyl-((E)-3-((((S)-3,4-dimethyl-5-oxo-2,5-dihydrofuran-2-yl)oxy)methylene)-2-oxo-3,3a,4,8b-tetra hydro-2H-indeno[1,2-b]furan-7-yl)carbamate(9g):
1HNMR(400MHz,DMSO-d6)δ9.43(s,1H),7.68(d,J=26.7Hz,2H),7.39(d,J=8.0Hz,1H),7.17(d,J =8.3Hz,1H),6.54(s,1H),5.94(d,J=7.8Hz,1H),3.94(s,1H),3.32(dd,J=16.8,9.5Hz,1H),2.94(d,J =16.8Hz,1H),2.04(s,3H),1.83(s,3H),1.48(s,9H)。
(32)化合物10g
(±)-Tert-butyl-((E)-3-((((R)-3,4-dimethyl-5-oxo-2,5-dihydrofuran-2-yl)oxy)methylene)-2-oxo-3,3a,4,8b-tetr ahydro-2H-indeno[1,2-b]furan-7-yl)carbamate(10g):
White solid,123mg,41%。
1H NMR(400MHz,CDCl3)δ7.55(s,1H),7.45(d,J=2.5Hz,1H),7.32(d,J=8.2Hz,1H),7.14(d,J= 8.3Hz,1H),6.67(s,1H),6.00(s,1H),5.91(d,J=7.9Hz,1H),4.00–3.91(m,1H),3.36(dd,J=16.7,9.3 Hz,1H),3.03(dd,J=16.7,3.0Hz,1H),2.05(s,3H),1.92(s,3H),1.52(s,9H)。
(33)化合物9h
(±)-Tert-butyl-((E)-3-((((S)-3,4-dimethyl-5-oxo-2,5-dihydrofuran-2-yl)oxy)methylene)-2-oxo-2,3,3a,4,5,9b- hexahydronaphtho[1,2-b]furan-8-yl)carbamate(9h):
White solid,65mg,37%.
1H NMR(500MHz,CDCl3)δ7.51(d,J=1.3Hz,1H),7.44(s,1H),7.33(d,J=7.1Hz,1H),7.06(d,J= 8.3Hz,1H),6.76(s,1H),6.01(s,1H),5.35(d,J=7.5Hz,1H),3.48(dd,J=13.2,7.3Hz,1H),2.75–2.52 (m,2H),2.03(s,3H),1.96(s,1H),1.89(s,3H),1.70–1.61(m,1H),1.50(s,9H)。
(34)化合物10h
(±)-Tert-butyl-((E)-3-((((R)-3,4-dimethyl-5-oxo-2,5-dihydrofuran-2-yl)oxy)methylene)-2-oxo-2,3,3a,4,5,9b- hexahydronaphtho[1,2-b]furan-8-yl)carbamate(10h):
White solid,65mg,37%。
1H NMR(500MHz,CDCl3)δ7.49(d,J=2.0Hz,1H),7.47(s,1H),7.31(d,J=7.9Hz,1H),7.08(d,J= 8.3Hz,1H),6.58(s,1H),6.00(s,1H),5.40(d,J=7.5Hz,1H),3.51(ddd,J=14.8,7.5,1.8Hz,1H),2.73 –2.55(m,2H),2.05(s,3H),2.02(dd,J=7.9,3.9Hz,1H),1.92(s,3H),1.74–1.66(m,1H),1.52(s, 9H)。
实施例2
本实施例制备了一种光活独脚金内酯衍生物,合成路线包括以下步骤:
(1)化合物11a的制备
取100mL两口圆底烧瓶,用氩气抽换气三次,置于冰水浴中,再向其中加入30mL无水甲酸,然后向其中缓慢滴加无水三乙胺20mL,滴加完毕后,自然恢复至室温,搅拌30min备用。另取一洁净的装有回流冷凝管的100mL两口圆底烧瓶,向其中加入化合物2a(1.9g,10mmol),Cat.A(317mg, 0.5mmol),用氩气抽换气三次彻底除去空气,然后在氩气保护下,向其中加入提前配好的甲酸与三乙胺混合溶剂40mL,然后置于60℃油浴锅中反应10h,TLC监测至原料反应完全,加入15mL水淬灭反应,反应混合液用乙酸乙酯萃取(3×20mL),萃取后合并有机相,有机相分别用水(3×10mL) 合饱和氯化钠溶液(3×10mL)洗涤,旋转蒸发仪浓缩的粗产品,粗产品用快速硅胶柱层析纯化(石油醚:乙酸乙酯=4:1),得到化合物11a(817mg,47%)。
[α]D 20=+110(c=1,CHCl3).1H NMR(400MHz,CDCl3)δ7.51(d,J=7.4Hz,1H),7.40–7.34(m,1H),7.33 –7.27(m,2H),5.92(d,J=7.0Hz,1H),3.45–3.30(m,2H),2.97–2.88(m,2H),2.42(dd,J=18.1,5.4 Hz,1H)。
(2)化合物12a的制备
称量化合物11a(1.74g,10mmol)置于100mL圆底烧瓶中,加入NaNO3(3.9g,46mmol)和50mL 三氟乙酸,室温搅拌反应16h,TLC监测至原料反应完全,减压蒸馏除掉三氟乙酸后,用乙酸乙酯重新溶解固体,用饱和碳酸氢钠洗涤(25mL×3),水层用乙酸乙酯(25mL×3)萃取,合并有机层,有机相经饱和NaCl(25mL×3)洗涤,无水硫酸钠干燥后,浓缩,得到的粗产品主要为化合物2-1和2-2 的混合物,比例大约为3:1,该粗产品用快速硅胶柱层析纯化(石油醚:乙酸乙酯=3:1),得到化合物2-1(1.5g,68%)。
向50mL圆底烧瓶中加入氯化亚锡(2.4g,12.5mmol),2.2mL浓盐酸,搅拌下将化合物2-1(1.1g, 5mmol)用20mL乙醇溶解缓慢滴加至圆底烧瓶中,加热回流反应大约1.5h,TLC监测至原料消失后终止反应,再向其中加入饱和NaHCO3水溶液调节pH至7-8,然后用乙酸乙酯萃取三次(18mL×3),合并有机层,有机相经饱和NaCl(18mL×3)洗涤,再用无水硫酸钠干燥后浓缩得化合物7a(945mg, 100%)为白色固体,不经纯化直接用于下一步。
向50mL圆底烧瓶中加入化合物7a(473mg,2.5mmol),二碳酸二叔丁酯(817mg,3.75mmol),三乙胺(379mg,3.75mmol),25mL无水THF,搅拌均匀后置于60℃油浴锅加热反应1.5h,TLC监测原料反应完全,然后恢复至室温,再减压浓缩除去THF,粗产品用快速硅胶柱层析纯化(石油醚: 乙酸乙酯=3:1),得到化合物12a(664mg,92%)。
1H NMR(400MHz,CDCl3)δ7.53(s,1H),7.34(d,J=8.1Hz,1H),7.17(d,J=8.2Hz,1H),6.74(s, 1H),5.83(d,J=7.2Hz,1H),3.43–3.31(m,1H),3.25(dd,J=16.3,8.4Hz,1H),2.89(dd,J=18.2,9.8 Hz,1H),2.82(dd,J=16.3,3.4Hz,1H),2.37(dd,J=18.2,5.7Hz,1H),1.52(s,9H)。
(3)13a和14a的合成
在0℃下,向化合物12a(200mg,1.056mmol)的甲酸乙酯(12mL)溶液中分批加入叔丁醇钾 (714.6mg,6.3mmol),并使反应恢复至室温。大约反应3h,TLC监测至原料反应完全,加入1M HCl (15mL)淬灭反应混合物,并用乙酸乙酯(3×10mL)萃取,合并的有机相经饱和NaCl(3×10mL)洗涤,无水硫酸钠干燥,过滤并真空浓缩。将粗制的产物溶于DMF(9mL)中,并在室温下加入无水碳酸钾 (219.6mg,1.6mmol)。反应混合物冷却至0℃,缓慢加入化合物4a(305mg,1.72mmol)的DMF(3mL) 溶液。16h后,TLC监测至原料反应完全后,向其中加入饱和NH4Cl(15mL)淬灭反应混合物,并用乙酸乙酯(3×10mL)萃取。合并的有机相用饱和NaCl(3×10mL)洗涤,无水Na2SO4干燥,过滤并真空浓缩。经快速柱色谱法纯化(石油醚:乙酸乙酯=2.5:1)。首先分离得到(±)-GR-24,我们将其标记为 13a(75mg,37%),后分离得到的化合物为(±)-epi-GR-24,将它标记为14a(75mg,37%)。
13a:[α]D 20=+355(c=0.5,CHCl3).1H NMR(400MHz,CDCl3)δ7.52(s,1H),7.47(d,J=2.5Hz,1H), 7.37(d,J=7.9Hz,1H),7.15(d,J=8.3Hz,1H),6.67(s,1H),5.99(s,1H),5.91(d,J=7.9Hz,1H),3.99–3.92(m,1H),3.39(dd,J=16.7,9.3Hz,1H),3.05(dd,J=16.6,3.2Hz,1H),2.06(s,3H),1.92(s,3H), 1.52(s,9H).
14a:[α]D 20=+217(c=0.5,CHCl3).1H NMR(400MHz,CDCl3)δ7.55(s,1H),7.44(d,J=2.5Hz,1H), 7.31(dd,J=8.2,1.4Hz,1H),7.13(d,J=8.3Hz,1H),6.70(s,1H),6.00(s,1H),5.90(d,J=7.9Hz,1H), 3.99–3.92(m,1H),3.36(dd,J=16.8,9.3Hz,1H),3.02(dd,J=16.7,3.1Hz,1H),2.04(s,3H),1.91(s, 3H),1.51(s,9H)。
下述化合物参照13a和14a的制备方法得到。
Tert-butyl-((3aR,8bS,E)-3-((((R)-3,4-dimethyl-5-oxo-2,5-dihydrofuran-2-yl)oxy)methylene)-2-oxo-3,3a,4,8b -tetrahydro-2H-indeno[1,2-b]furan-7-yl)carbamate(13b):
White solid,75mg,37%.
[α]D 20=+355(c=0.5,CHCl3).
1H NMR(400MHz,CDCl3)δ7.52(s,1H),7.47(d,J=2.5Hz,1H),7.37(d,J=7.9Hz,1H),7.15(d,J= 8.3Hz,1H),6.67(s,1H),5.99(s,1H),5.91(d,J=7.9Hz,1H),3.99–3.92(m,1H),3.39(dd,J=16.7,9.3 Hz,1H),3.05(dd,J=16.6,3.2Hz,1H),2.06(s,3H),1.92(s,3H),1.52(s,9H)。
Tert-butyl-((3aS,8bS,E)-3-((((S)-3,4-dimethyl-5-oxo-2,5-dihydrofuran-2-yl)oxy)methylene)-2-oxo-3,3a,4,8b- tetrahydro-2H-indeno[1,2-b]furan-7-yl)carbamate(14b):
White solid,75mg,37%.
[α]D 20=+217(c=0.5,CHCl3).
1H NMR(400MHz,CDCl3)δ7.55(s,1H),7.44(d,J=2.5Hz,1H),7.31(dd,J=8.2,1.4Hz,1H),7.13(d, J=8.3Hz,1H),6.70(s,1H),6.00(s,1H),5.90(d,J=7.9Hz,1H),3.99–3.92(m,1H),3.36(dd,J=16.8, 9.3Hz,1H),3.02(dd,J=16.7,3.1Hz,1H),2.04(s,3H),1.91(s,3H),1.51(s,9H)。
((3aS,8bR,E)-3-((((R)-3,4-dimethyl-5-oxo-2,5-dihydrofuran-2-yl)oxy)methylene)-2-oxo-3,3a,4,8b-tetrahydr o-2H-indeno[1,2-b]furan-7-yl)pivalamide(13c):
White solid,42mg,33%.
[α]D 20=-50(c=0.5,CHCl3).
1H NMR(500MHz,CDCl3)δ7.64(s,1H),7.56(s,1H),7.53(d,J=8.4Hz,1H),7.45(d,J=2.3Hz,1H), 7.16(d,J=8.2Hz,1H),6.00(s,1H),5.90(d,J=7.9Hz,1H),4.00–3.93(m,1H),3.37(dd,J=16.8,9.2 Hz,1H),3.08–3.00(m,1H),2.05(s,3H),1.92(s,3H),1.31(s,9H)。
((3aS,8bR,E)-3-((((S)-3,4-dimethyl-5-oxo-2,5-dihydrofuran-2-yl)oxy)methylene)-2-oxo-3,3a,4,8b-tetrahydr o-2H-indeno[1,2-b]furan-7-yl)pivalamide(14c):
White solid,42mg,33%.
[α]D 20=-46(c=0.5,CHCl3).
1H NMR(500MHz,CDCl3)δ7.63(d,J=8.4Hz,1H),7.60(s,1H),7.48(t,J=2.2Hz,1H),7.39(s,1H), 7.21(d,J=8.2Hz,1H),5.99(s,1H),5.94(d,J=7.9Hz,1H),4.03–3.94(m,1H),3.42(dd,J=16.7,9.2 Hz,1H),3.09(d,J=16.8Hz,1H),2.08(s,3H),1.94(s,3H),1.33(d,J=1.7Hz,9H)。
Tert-butyl((3aS,8bR,E)-2-oxo-3-((((R)-3-oxo-1,3-dihydroisobenzofuran-1-yl)oxy)methylene)-3,3a,4,8b-tetr ahydro-2H-indeno[1,2-b]furan-7-yl)carbamate(13d):
White solid,26mg,19%.
[α]D 20=-256(c=0.5,CHCl3)
1H NMR(500MHz,CDCl3)δ8.00(d,J=7.6Hz,1H),7.83(d,J=7.4Hz,1H),7.74(t,J=7.5Hz,1H), 7.69(d,J=7.6Hz,1H),7.56(t,J=3.0Hz,2H),7.31(d,J=8.7Hz,1H),7.13(d,J=8.2Hz,1H),6.74(s, 1H),6.59(s,1H),5.92(d,J=7.8Hz,1H),4.00–3.93(m,1H),3.32(dd,J=16.7,9.2Hz,1H),3.02(dd,J =16.7,3.1Hz,1H),1.53(s,9H)。
Tert-butyl((3aS,8bR,E)-2-oxo-3-((((S)-3-oxo-1,3-dihydroisobenzofuran-1-yl)oxy)methylene)-3,3a,4,8b-tetra hydro-2H-indeno[1,2-b]furan-7-yl)carbamate(14d):
White solid,26mg,19%.
[α]D 20=-116(c=0.5,CHCl3)
1H NMR(500MHz,CDCl3)δ8.00(d,J=7.6Hz,1H),7.83(t,J=7.5Hz,1H),7.74(t,J=7.5Hz,1H), 7.69(d,J=7.6Hz,1H),7.55(d,J=2.1Hz,2H),7.32–7.28(m,1H),7.12(d,J=8.2Hz,1H),6.74(s, 1H),6.57(s,1H),5.92(d,J=7.8Hz,1H),4.01–3.92(m,1H),3.32(dd,J=16.7,9.2Hz,1H),3.08–2.98 (m,1H),1.53(d,J=1.5Hz,9H)。
试验例
1、独脚金内酯衍生物对肿瘤细胞毒活性的测定
(1)独脚金内酯衍生物对不同肿瘤细胞毒活性的测定
采用MTT法测定评估细胞活力。将不同的肿瘤细胞系(3×103细胞/孔)接种在96孔板中并培养过夜。用实施例1制备的不同浓度的独脚金内酯衍生物化合物10a处理细胞72小时。加入10μl/孔 MTT于培养箱孵育2.5h,小心吸走含MTT培养基,用100μl/孔DMSO溶解甲臢结晶,并在摇床上避光摇晃5分钟,使得所有结晶溶解,Gene cytation5(Biotek,美国)测定570nm处的吸光度。
表1
独脚金内酯衍生物对不同肿瘤细胞毒活性的测定的实验结果如表1所示,从表中可以看出,本发明方案对不同的肿瘤细胞的具有一定的细胞毒性,表明本申请方案制备的独脚金内酯可以用于治疗不同的肿瘤。
(2)不同独脚金内酯衍生物对结直肠癌细胞毒活性的影响
将实施例1和实施例2制备的不同类型的独脚金内酯衍生物对结直肠癌细胞进行毒活性测定,采用MTT法测定评估细胞活力。将不同的结直肠癌细胞系(3×103细胞/孔)接种在96孔板中并培养过夜。用不同浓度的不同独脚金内酯衍生物分别处理细胞72小时。加入10μl/孔MTT于培养箱孵育2.5h,小心吸走含MTT培养基,用100μl/孔DMSO溶解甲臢结晶,并在摇床上避光摇晃5分钟,使得所有结晶溶解,Gene cytation5测定570nm处的吸光度。
表2
实验结果如表2所示,从表2中可以看出,本发明方案制备的独脚金内酯衍生物对结直肠癌细胞均有一定的毒活性,其中,独脚金内酯衍生物13a对结肠癌细胞的IC50最低,因此选用独脚金内酯衍生物13a进行以下实验。
2、独脚金内酯衍生物抑制细胞增殖能力的测定
采用平板克隆形成实验测定独脚金内酯衍生物抑制细胞增殖的能力,将将HCT116细胞、SW620 细胞、MC38细胞、HIEC-6细胞分别以3000个/孔接种在96孔板中,并培养过夜。用(0.1、1、10) μM化合物13a处理细胞,每隔2天补充200μL含药培基直到14天,实验结束。弃掉含药培基,PBS 洗2次,4%多聚甲醛溶液室温固定10分钟,弃掉多聚甲醛,PBS洗2次,0.5%结晶紫染色液染30 分钟,PBS洗净多余染色液,拍照,计数。
实验结果如图1-4所示,从图中可以看出独脚金内酯衍生物13a呈浓度依赖性的抑制结直肠癌细胞系HCT116、SW620、MC38单个细胞增殖,而对正常结肠上皮细胞HIEC-6的细胞毒性较小,表明13a具有较高的安全性。
3、独脚金内酯衍生物对HCT116细胞迁移的影响
采用伤口愈合实验测定独脚金内酯衍生物13a对HCT116细胞迁移的影响,将HCT116细胞106个/孔接种在96孔板中,并培养过夜。使用10μL吸头笔直划十字架。用PBS洗涤两次后,血清浓度降至3%,然后加入1,5,10μM化合物,于培养箱孵育,在加药的0h,6h,12h,24h,36h分别用gene cytation5拍照。
实验结果如图5-6所示,从图中可以看出,在伤口愈合迁移实验中13a呈浓度依赖性的降低 HCT116-GFP细胞的迁移。
4、独脚金内酯衍生物对HCT116细胞凋亡的影响
独脚金内酯衍生物对HCT116细胞凋亡的影响采用流式细胞仪进行测定。将5*105个/孔细胞接种在96孔板过夜后,分别用1,5,20μM化合物13a处理HCT116 24h,按照YF488-Annexin V和 PI凋亡试剂盒(US Everbright Inc,货号:Y6002)说明书操作:贴壁细胞:用不含EDTA的胰酶消化后300g,4℃离心5min收集细胞。用预冷的PBS洗涤细胞两次,每次均在300g,4℃下离心5min,收集1-5×105个细胞并用100μL 1×结合缓冲液重悬细胞。每管加5μL的YF488-Annexin V和5 μL的PI工作液。室温避光孵育15min。每管加入400μL 1×结合缓冲液,30min内通过流式细胞仪检测细胞凋亡情况。
实验结果如图7-8所示,从图中可以看出流式细胞检测凋亡实验表明,化合物13a浓度依赖性诱导HCT116细胞凋亡。
5、独脚金内酯衍生物对HCT116细胞周期的影响
独脚金内酯衍生物对HCT116细胞周期的影响采用流式细胞仪进行测定。将5×105个/孔细胞接种在6孔板过夜后,分别用1、5、10μM化合物13a处理HCT116细胞24h,按照细胞周期测试试剂盒(Multi Sciences,货号:CCS012)说明鼠操作:贴壁细胞:用不含EDTA的胰酶消化后1300rpm,4℃离心5min收集细胞。用预冷的PBS洗涤细胞两次,每次均在1300rpm,4℃下离心5min,收集 2×105-1×106个细胞,用1mL预冷的85%乙醇重悬、固定过夜。1300rpm,4℃下离心5min,去除乙醇。加入2-5mL室温下的PBS,放置15分钟使细胞再次水化。1300rpm,4℃下离心5min,弃上清。加入1mL DNA Staining solution和10μLPermeabilization solution,涡旋振荡5-10s混匀。室温避光孵育30min。选择最低上样速度,在流式细胞仪上进行检测。
实验结果如图9-10所示,从图中可以看出细胞周期实验表明,化合物13a浓度依赖性诱导 HCT116细胞周期阻滞在S期。
6、独脚金内酯衍生物13a对HCT116、NCM460、A2780、Hosepic、H358、SW620细胞LC3B、 p62、caspase3、caspase 8、PARP1、LAMP1、p-Parkin、蛋白表达的影响
在96孔板中以2×105个/孔的密度培养细胞过夜。分别用0.1、1、5μM的化合物13a处理细胞 (HCT116、人正常结肠上皮细胞NCM-460、人卵巢癌细胞A2780、人卵巢上皮细胞Hosepic、人非小细胞肺癌细胞NCI-H358)6h;用自噬诱导剂雷帕霉素(RAP)1μM和5μM 13a联用处理人结肠癌细胞HCT-116 6h;自噬抑制剂氯喹(CQ)10μM和5μM的化合物13a联用处理人结肠癌细胞 HCT-116 6h;将处理好的细胞培养板置于冰上,用预冷的PBS洗涤细胞。吸出PBS,然后加入200μL 冰冷的裂解缓冲液(强RIPA裂解液,碧云天生物)。
用预冷的塑料细胞刮棒刮下贴壁细胞,然后轻轻地将细胞悬浮液转移至预冷的微量离心管中。在4℃预冷的离心机中以10,000rpm的转速离心10分钟。轻轻地从离心机中取出离心管,置于冰上。将上清液转移至新离心管中,弃去沉淀。用RIPA法提取蛋白,用BCA法(百泰克公司)定量检测蛋白浓度。Western blot检测LC3B,p62,caspase3,β-actin的蛋白表达水平:用5×SDS还原型上样缓冲液(碧云天生物)煮沸蛋白样品10分钟,每孔上样量40μg。恒流跑至溴酚蓝到底,120V恒压转膜80分钟,5%脱脂奶粉室温封闭1.5h,一抗(1:1000,5% BSA-PBST稀释)4℃孵育过夜,PBST 洗三次,每次10分钟,二抗(1:5000,5%脱脂奶粉-PBST稀释),室温孵育1.5h,PBST洗三次,每次10分钟,ECL发光液进行发光检测信号(Biorad化学发光仪,美国)。
实验结果如图11-13所示,从图中可以看出,A为肿瘤细胞系HCT116的免疫杂交印记结果图; B为正常细胞系NCM 460的免疫杂交印记结果图;C为肿瘤细胞系A2780的免疫杂交印记结果图; D为正常细胞系Hosepic的免疫杂交印记结果图;F为肿瘤细胞系H358的免疫杂交印记结果图,从图中可以看出,化合物13a呈浓度依赖在肿瘤细胞系HCT116、A2780、H358中上调了P62、 cleaved-caspase3的蛋白表达,下调了LC3B-II的蛋白表达水平。同时在HCT116、SW620细胞中呈浓度依赖地上调了cleaved-caspase8、cleaved-PARP1的蛋白表达。化合物13a对正常细胞系NCM 460 和Hosepic的表达水平并没有明显影响。其中,在图E中采用自噬抑制剂氯喹(CQ)和13a联用,自噬负相关蛋白P62进一步表达增加,显示13a抑制自噬的机制可能有别于氯喹通过作用于溶酶体的作用机制,用自噬诱导剂雷帕霉素(RAP)和13a联用,自噬诱导剂部分削弱了13a的上调P62 蛋白表达水平,结果表明化合物13a可以抑制线粒体自噬。13a可以改变线粒体自噬相关蛋白 p-PINK1(S228)和p-Parkin(S65)蛋白的表达水平,说明13a影响的是线粒体自噬水平而不是其他自噬过程。
7、独脚金内酯衍生物13a抑制体内MC-38肿瘤生长
采用裸鼠荷瘤实验评价将对数生长期的MC38重悬于PBS中,调节细胞密度为5×106个细胞,接种于5周龄C57BL/6小鼠腹股沟中上部,接种细胞后,约8天左右流体长至100mm3,开始腹腔注射给药,按100mg/kg和50mg/kg剂量给药(独脚金内酯衍生物溶解于2%DMSO+30%PEG300+2%吐温80的PBS溶液中),阳性对照药为5-氟尿嘧啶(5-FU)(购自安耐吉),三天给药一次,给药至对照组长至1000mm3,终止实验,按照动物伦理要求,脱臼处死老鼠后迅速解剖瘤体,拍照并称重。
实验结果如图14所示,从图中可以看出,化合物13a在100mg/kg的剂量情况下,可显著抑制体小鼠C57BL/6结直肠癌MC38肿瘤的生长,同时,100mg/kg和50mg/kg的13a对小鼠体重都没有明显影响,而治疗结直肠癌的传统化疗药五氟尿嘧啶(5-Fu)明显减轻了小鼠体重,有较大的毒副作用。13a显示出较好的药效和良好的安全性。
8、独脚金内酯衍生物13a抑制HCT116异种移植瘤的生长
采用裸鼠荷瘤实验评价将对数生长期的HCT116细胞重悬于PBS中,调节细胞密度为107个细胞,接种于5周龄雄性BALB/c裸鼠右前肢,接种细胞后,约10天左右瘤体长至100mm3,开始腹腔注射给药,按100mg/kg和50mg/kg剂量给药(独脚金内酯衍生物溶解于5%DMSO+45%PEG300+8%吐温80的PBS溶液中),阳性对照药为5-氟尿嘧啶(5-Fu)(购自安耐吉),每周给药一次,给药至对照组长至1000mm3,终止实验,按照动物伦理要求,脱臼处死老鼠后迅速解剖瘤体,拍照并称重。
实验结果如图15-20所示,从图中可以看出,化合物13a在100mg/kg的剂量情况下,可显著抑制BALB/c裸鼠结直肠癌HCT116肿瘤的生长;50mg/kg的13a对小鼠体重都没有明显影响,13a显示出较好的药效和良好的安全性;13a处理后C-Casepase 3和p62在肿瘤细胞中表达增加;肿瘤细胞中p62和LC3B的蛋白表达水平增加,说明13a抑制BALB/c裸鼠结直肠癌异种移植瘤细胞的自噬。
9、独脚金内酯衍生物13a联合5-氟尿嘧啶抑制HCT116异种移植瘤的生长
采用裸鼠荷瘤实验评价将对数生长期的HCT116细胞重悬于PBS中,调节细胞密度为107个细胞,接种于5周龄雄性BALB/c裸鼠右前肢,接种细胞后,约14天左右瘤体长至100mm3,开始腹腔注射给药,5-氟尿嘧啶(5-Fu)(购自安耐吉)按15mg/kg,每三天给药一次,联合给药按低剂量组 13a(10mg/kg)+5-Fu(15mg/kg),高剂量组13a(50mg/kg)+5-Fu(15mg/kg),每天给给药一次。药物溶解于5%DMSO+45%PEG300+8%吐温80的PBS溶液中,给药第13天,终止实验,按照动物伦理要求,脱臼处死老鼠后迅速解剖瘤体,拍照并称重。
实验结果如图21-22所示,从图中可以看出,化合物13a(50mg/kg)联合5-Fu(15mg/kg)可以抑制BALB/c裸鼠结直肠癌HCT116肿瘤的生长,并且小鼠的体重没有明显的下降,说明13a联合低剂量 5-Fu具有较好的药效和良好的安全性。
上面结合附图对本发明实施例作了详细说明,但是本发明不限于上述实施例,在所属技术领域普通技术人员所具备的知识范围内,还可以在不脱离本发明宗旨的前提下作出各种变化。此外,在不冲突的情况下,本发明的实施例及实施例中的特征可以相互组合。
Claims (10)
1.独脚金内酯衍生物在制备线粒体自噬抑制剂中的应用,其特征在于,所述独脚金内酯衍生物包括如式(I)所述的化合物或其药学上可接受的盐:
其中,R1、R2独立选自氢、甲基、硝基、氨基、取代胺基、氟原子、氯原子、溴原子、取代脲基和取代碳酸酯基中的一种;
R3、R4、R5选自氢、含1-10个碳的直链烷基或苯基;
n为1或2;
X、Y选自-O-、-S-、-NH-和-CH2-中的一种;
或R2、R3组成苯环、环己烷和环戊烷中的一种;表示S或R构型;优选地,所述独脚金内酯衍生物包括消旋独脚金内酯衍生物和光学活性独脚金内酯衍生物;优选地,所述取代胺基选自NHBoc、NHCbz、NHPiv或NHBz;优选地,所述药学上可接受的盐为无机酸、有机酸、碱金属、碱土金属和碱性氨基酸形成的盐;更优选地,所述无机酸包括盐酸、硝酸、硫酸、磷酸和氢溴酸中的至少一种;更优选地,所述有机酸包括马来酸、富马酸、酒石酸、乳酸、柠檬酸、乙酸、甲磺酸、对甲苯磺酸、己二酸、棕榈酸和单宁酸中的至少一种;更优选地,所述碱金属包括锂、钠和钾中至少一种;更优选地,所述碱土金属包括钙和镁中至少一种;更优选地,所述碱性氨基酸包括赖氨酸。
4.一种线粒体自噬抑制剂,其特征在于,所述线粒体自噬抑制剂包括独脚金内酯衍生物或其药学上可接受的盐。
5.根据权利要求4所述的线粒体自噬抑制剂,其特征在于,所述线粒体自噬抑制剂中独脚金内酯衍生物或其药学上可接受的盐的含量为0.1%~99%;优选地,所述含量为0.5%~95%;更优选地,所述含量为10%~20%。
6.根据权利要求4所述的线粒体自噬抑制剂在制备预防或治疗肿瘤的药物或辅助药物中的用途;优选地,所述肿瘤为结直肠癌、卵巢癌、肺癌、肝癌。
7.根据权利要求4所述的线粒体自噬抑制剂在制备化疗药物增敏剂中的应用;优选地,所述化疗药物增敏剂为增强紫杉醇、顺铂或5-氟尿嘧啶抗肿瘤作用的药物。
8.根据权利要求4所述的线粒体自噬抑制剂在制备预防或治疗神经退行性疾病的药物及其组合物中的应用;优选地,所述神经退行性疾病为脑缺血、脑损伤、帕金森病、阿尔兹海默症。
9.根据权利要求4所述的线粒体自噬抑制剂在制备预防或治疗炎症性疾病的药物及其组合物中的应用;优选地,所述炎性疾病为急性肺损伤、慢阻肺、肺动脉高压、动脉瘤、马凡综合征。
10.根据权利要求4所述的线粒体自噬抑制剂在制备抑制线粒体自噬机制研究的试剂中的应用。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110893493 | 2021-08-04 | ||
CN2021108934936 | 2021-08-04 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN115381815A true CN115381815A (zh) | 2022-11-25 |
CN115381815B CN115381815B (zh) | 2023-10-31 |
Family
ID=84119200
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202210909296.3A Active CN115381815B (zh) | 2021-08-04 | 2022-07-29 | 独脚金内酯衍生物在制备线粒体自噬抑制剂中的应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN115381815B (zh) |
-
2022
- 2022-07-29 CN CN202210909296.3A patent/CN115381815B/zh active Active
Non-Patent Citations (4)
Title |
---|
ANAT REIZELMAN等: ""Synthesis and bioactivity of labelled germination stimulants for the isolation and identifification of the strigolactone receptor"", 《ORG. BIOMOL. CHEM.》 * |
BEGUM KURT等: ""Multitarget Profifiling of a Strigolactone Analogue for Early Events of Alzheimer’s Disease: In Vitro Therapeutic Activities against Neuroinflflammation"", 《ACS CHEM. NEUROSCI》 * |
JUN-XIA ZHENG等: ""Strigolactones: a plant phytohormone as novel anti-inflammatory agents"", 《MED. CHEM. COMMUN》 * |
MOHAMMED NIHAL HASAN等: ""Strigolactones—a novel class of phytohormones as anti-cancer agents"", 《J.PESTIC.SCI》 * |
Also Published As
Publication number | Publication date |
---|---|
CN115381815B (zh) | 2023-10-31 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA3007724C (en) | 2-phenyl-3-(piperazinomethyl)imidazo[1,2-a]pyridine derivatives as blockers of task-1 and task-2 channels, for the treatment of sleep-related breathing disorders | |
KR101381454B1 (ko) | 열역학적으로 안정한 형태의 bay 43-9006 토실레이트 | |
US9150530B2 (en) | Esters of 4, 9-dihydroxy-naphtho [2, 3-b] furans for disease therapies | |
RU2571661C2 (ru) | Новые соединения и композиции для нацеливания на злокачественные стволовые клетки | |
CN108699084A (zh) | 取代全氢吡咯并[3,4-c]吡咯衍生物及其用途 | |
JP2022020002A (ja) | がん幹細胞を標的とするための新規の化合物および組成物 | |
AU2009307580B2 (en) | Phenanthroindolizidine derivative and NFkB inhibitor containing same as active ingredient | |
CN107382966B (zh) | 一类荜茇酰胺-川芎嗪杂合物、制备方法及医药用途 | |
JPH026473A (ja) | 置換フラボノイド化合物、それらの塩、製法およびこれらを含有する医薬 | |
WO2011131103A1 (zh) | 含笑内酯衍生物,其药物组合物及其制备方法和用途 | |
EP3798220B1 (en) | P-phenylenediamine derivative as potassium channel regulator and preparation method and medical application thereof | |
US8871802B2 (en) | Naphthoquinones for disease therapies | |
CN110461836B (zh) | 一种选择性抑制激酶化合物及其用途 | |
JPWO2016039398A1 (ja) | 含窒素複素環誘導体、神経保護剤及び癌治療用医薬組成物 | |
CN104230952A (zh) | 含有嘧啶骨架的化合物及其制备方法和用途 | |
CN113248524A (zh) | 一种双吲哚生物碱化合物及其合成方法和用途 | |
WO2011131102A1 (zh) | 含笑内酯的制备方法及其用途 | |
CN115381815A (zh) | 独脚金内酯衍生物在制备线粒体自噬抑制剂中的应用 | |
CN114981275B (zh) | 三环化合物及其制备方法和医药用途 | |
CN109897022A (zh) | 含笑内酯衍生物、其药物组合物及其制备方法和用途 | |
WO2013170694A1 (zh) | 木香烃内酯衍生物,其药物组合物及其制备方法和用途 | |
EP2695884A1 (en) | Camptothecin derivatives having anti-tumor activity | |
CN114805141A (zh) | 4-胍基苯甲酸芳基酯类化合物及其在抗SARS-CoV-2病毒中的用途 | |
WO2019233366A1 (zh) | 选择性a 2a受体拮抗剂 | |
CN101115734A (zh) | 作为脂氧化酶抑制剂的螺环衍生物 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |