CN114874108A - 一种百里醌衍生物及其在制备ampk激活剂和治疗乳腺癌的药物中的用途 - Google Patents
一种百里醌衍生物及其在制备ampk激活剂和治疗乳腺癌的药物中的用途 Download PDFInfo
- Publication number
- CN114874108A CN114874108A CN202110159842.1A CN202110159842A CN114874108A CN 114874108 A CN114874108 A CN 114874108A CN 202110159842 A CN202110159842 A CN 202110159842A CN 114874108 A CN114874108 A CN 114874108A
- Authority
- CN
- China
- Prior art keywords
- cancer
- compound
- tqfl12
- breast cancer
- pharmaceutically acceptable
- 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
- 206010006187 Breast cancer Diseases 0.000 title claims abstract description 57
- 208000026310 Breast neoplasm Diseases 0.000 title claims abstract description 57
- 239000003814 drug Substances 0.000 title claims abstract description 22
- MPLLLQUZNJSVTK-UHFFFAOYSA-N 5-[3-[4-[2-(4-fluorophenyl)ethoxy]phenyl]propyl]furan-2-carboxylic acid Chemical compound O1C(C(=O)O)=CC=C1CCCC(C=C1)=CC=C1OCCC1=CC=C(F)C=C1 MPLLLQUZNJSVTK-UHFFFAOYSA-N 0.000 title claims abstract description 14
- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- KEQHJBNSCLWCAE-UHFFFAOYSA-N thymoquinone Chemical class CC(C)C1=CC(=O)C(C)=CC1=O KEQHJBNSCLWCAE-UHFFFAOYSA-N 0.000 title abstract description 111
- 150000001875 compounds Chemical class 0.000 claims abstract description 50
- 208000003721 Triple Negative Breast Neoplasms Diseases 0.000 claims abstract description 22
- 208000022679 triple-negative breast carcinoma Diseases 0.000 claims abstract description 21
- 238000013508 migration Methods 0.000 claims abstract description 16
- 230000009545 invasion Effects 0.000 claims abstract description 14
- 230000005012 migration Effects 0.000 claims abstract description 14
- 230000012010 growth Effects 0.000 claims abstract description 9
- 206010028980 Neoplasm Diseases 0.000 claims description 55
- 150000003839 salts Chemical class 0.000 claims description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- 201000011510 cancer Diseases 0.000 claims description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 15
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- -1 cyano, hydroxyl Chemical group 0.000 claims description 10
- 230000002401 inhibitory effect Effects 0.000 claims description 10
- 206010031096 Oropharyngeal cancer Diseases 0.000 claims description 8
- 206010057444 Oropharyngeal neoplasm Diseases 0.000 claims description 8
- 206010060862 Prostate cancer Diseases 0.000 claims description 8
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 201000006958 oropharynx cancer Diseases 0.000 claims description 8
- 210000001519 tissue Anatomy 0.000 claims description 8
- 206010005003 Bladder cancer Diseases 0.000 claims description 6
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 6
- 208000024770 Thyroid neoplasm Diseases 0.000 claims description 6
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 6
- 239000013078 crystal Chemical group 0.000 claims description 6
- 201000005202 lung cancer Diseases 0.000 claims description 6
- 208000020816 lung neoplasm Diseases 0.000 claims description 6
- 201000002510 thyroid cancer Diseases 0.000 claims description 6
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 6
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 5
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 5
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 5
- 230000009471 action Effects 0.000 claims description 5
- 239000004480 active ingredient Substances 0.000 claims description 5
- 208000024447 adrenal gland neoplasm Diseases 0.000 claims description 5
- 201000004101 esophageal cancer Diseases 0.000 claims description 5
- 206010017758 gastric cancer Diseases 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 201000010536 head and neck cancer Diseases 0.000 claims description 5
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 5
- 201000005787 hematologic cancer Diseases 0.000 claims description 5
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 claims description 5
- 239000004615 ingredient Substances 0.000 claims description 5
- 230000000955 neuroendocrine Effects 0.000 claims description 5
- 201000002120 neuroendocrine carcinoma Diseases 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 201000011549 stomach cancer Diseases 0.000 claims description 5
- 208000002874 Acne Vulgaris Diseases 0.000 claims description 4
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 claims description 4
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 4
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 4
- 206010009944 Colon cancer Diseases 0.000 claims description 4
- 208000001976 Endocrine Gland Neoplasms Diseases 0.000 claims description 4
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 claims description 4
- 208000032612 Glial tumor Diseases 0.000 claims description 4
- 206010018338 Glioma Diseases 0.000 claims description 4
- 206010020112 Hirsutism Diseases 0.000 claims description 4
- 208000031226 Hyperlipidaemia Diseases 0.000 claims description 4
- 206010020772 Hypertension Diseases 0.000 claims description 4
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 4
- 206010025323 Lymphomas Diseases 0.000 claims description 4
- 208000003445 Mouth Neoplasms Diseases 0.000 claims description 4
- 208000001894 Nasopharyngeal Neoplasms Diseases 0.000 claims description 4
- 206010061306 Nasopharyngeal cancer Diseases 0.000 claims description 4
- 206010033128 Ovarian cancer Diseases 0.000 claims description 4
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 4
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 4
- 208000000821 Parathyroid Neoplasms Diseases 0.000 claims description 4
- 208000007913 Pituitary Neoplasms Diseases 0.000 claims description 4
- 208000004403 Prostatic Hyperplasia Diseases 0.000 claims description 4
- 208000015634 Rectal Neoplasms Diseases 0.000 claims description 4
- 206010038389 Renal cancer Diseases 0.000 claims description 4
- 206010039491 Sarcoma Diseases 0.000 claims description 4
- 208000000453 Skin Neoplasms Diseases 0.000 claims description 4
- 208000024313 Testicular Neoplasms Diseases 0.000 claims description 4
- 206010057644 Testis cancer Diseases 0.000 claims description 4
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 4
- 208000002495 Uterine Neoplasms Diseases 0.000 claims description 4
- 206010000496 acne Diseases 0.000 claims description 4
- 201000009036 biliary tract cancer Diseases 0.000 claims description 4
- 208000020790 biliary tract neoplasm Diseases 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 210000003169 central nervous system Anatomy 0.000 claims description 4
- 201000010881 cervical cancer Diseases 0.000 claims description 4
- 208000029742 colonic neoplasm Diseases 0.000 claims description 4
- 230000002124 endocrine Effects 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 108010038795 estrogen receptors Proteins 0.000 claims description 4
- 206010016629 fibroma Diseases 0.000 claims description 4
- 201000001421 hyperglycemia Diseases 0.000 claims description 4
- 201000010982 kidney cancer Diseases 0.000 claims description 4
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 claims description 4
- 201000007270 liver cancer Diseases 0.000 claims description 4
- 208000014018 liver neoplasm Diseases 0.000 claims description 4
- 208000029559 malignant endocrine neoplasm Diseases 0.000 claims description 4
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 4
- 208000026045 malignant tumor of parathyroid gland Diseases 0.000 claims description 4
- 239000000463 material Substances 0.000 claims description 4
- 201000001441 melanoma Diseases 0.000 claims description 4
- 206010027191 meningioma Diseases 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 201000008968 osteosarcoma Diseases 0.000 claims description 4
- 201000002528 pancreatic cancer Diseases 0.000 claims description 4
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 4
- 201000002530 pancreatic endocrine carcinoma Diseases 0.000 claims description 4
- 210000001428 peripheral nervous system Anatomy 0.000 claims description 4
- 208000010916 pituitary tumor Diseases 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- 206010038038 rectal cancer Diseases 0.000 claims description 4
- 201000001275 rectum cancer Diseases 0.000 claims description 4
- 201000000849 skin cancer Diseases 0.000 claims description 4
- 201000003120 testicular cancer Diseases 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 206010044285 tracheal cancer Diseases 0.000 claims description 4
- 206010046766 uterine cancer Diseases 0.000 claims description 4
- 101100314454 Caenorhabditis elegans tra-1 gene Proteins 0.000 claims description 3
- 102000052575 Proto-Oncogene Human genes 0.000 claims description 3
- 108700020978 Proto-Oncogene Proteins 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 239000003098 androgen Substances 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 208000013403 hyperactivity Diseases 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- 238000005576 amination reaction Methods 0.000 claims description 2
- 150000005840 aryl radicals Chemical class 0.000 claims description 2
- 208000028591 pheochromocytoma Diseases 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 102000005962 receptors Human genes 0.000 claims description 2
- 108020003175 receptors Proteins 0.000 claims description 2
- 201000007048 respiratory system cancer Diseases 0.000 claims description 2
- 210000002229 urogenital system Anatomy 0.000 claims description 2
- 102100038595 Estrogen receptor Human genes 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000000583 progesterone congener Substances 0.000 claims 1
- 102100036009 5'-AMP-activated protein kinase catalytic subunit alpha-2 Human genes 0.000 abstract description 30
- 101000783681 Homo sapiens 5'-AMP-activated protein kinase catalytic subunit alpha-2 Proteins 0.000 abstract description 30
- 230000000694 effects Effects 0.000 abstract description 28
- 238000011282 treatment Methods 0.000 abstract description 21
- 229940079593 drug Drugs 0.000 abstract description 11
- 230000005764 inhibitory process Effects 0.000 abstract description 8
- 102000004169 proteins and genes Human genes 0.000 abstract description 7
- 108090000623 proteins and genes Proteins 0.000 abstract description 7
- 231100000135 cytotoxicity Toxicity 0.000 abstract description 4
- 230000003013 cytotoxicity Effects 0.000 abstract description 4
- 230000019491 signal transduction Effects 0.000 abstract description 4
- 230000000087 stabilizing effect Effects 0.000 abstract description 3
- 238000010189 synthetic method Methods 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 66
- 238000002474 experimental method Methods 0.000 description 19
- YPHMISFOHDHNIV-FSZOTQKASA-N cycloheximide Chemical compound C1[C@@H](C)C[C@H](C)C(=O)[C@@H]1[C@H](O)CC1CC(=O)NC(=O)C1 YPHMISFOHDHNIV-FSZOTQKASA-N 0.000 description 14
- 241000699670 Mus sp. Species 0.000 description 13
- 210000004072 lung Anatomy 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 241000699666 Mus <mouse, genus> Species 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- 230000022131 cell cycle Effects 0.000 description 7
- 230000010261 cell growth Effects 0.000 description 7
- 230000004709 cell invasion Effects 0.000 description 7
- 230000012292 cell migration Effects 0.000 description 7
- 231100000673 dose–response relationship Toxicity 0.000 description 7
- 230000006907 apoptotic process Effects 0.000 description 6
- 231100000331 toxic Toxicity 0.000 description 6
- 230000002588 toxic effect Effects 0.000 description 6
- 101800005151 Cholecystokinin-8 Proteins 0.000 description 5
- 102400000888 Cholecystokinin-8 Human genes 0.000 description 5
- 206010027476 Metastases Diseases 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- 230000009401 metastasis Effects 0.000 description 5
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 5
- 102100022528 5'-AMP-activated protein kinase catalytic subunit alpha-1 Human genes 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 125000000753 cycloalkyl group Chemical group 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 230000003993 interaction Effects 0.000 description 4
- 238000001262 western blot Methods 0.000 description 4
- 238000011725 BALB/c mouse Methods 0.000 description 3
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 125000003342 alkenyl group Chemical group 0.000 description 3
- 238000010171 animal model Methods 0.000 description 3
- 230000001093 anti-cancer Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 102000015694 estrogen receptors Human genes 0.000 description 3
- 239000012091 fetal bovine serum Substances 0.000 description 3
- 125000001183 hydrocarbyl group Chemical group 0.000 description 3
- 230000005661 hydrophobic surface Effects 0.000 description 3
- 231100000053 low toxicity Toxicity 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 108020004999 messenger RNA Proteins 0.000 description 3
- 238000003032 molecular docking Methods 0.000 description 3
- 108091005981 phosphorylated proteins Proteins 0.000 description 3
- 102000003998 progesterone receptors Human genes 0.000 description 3
- 108090000468 progesterone receptors Proteins 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- AVPYQKSLYISFPO-UHFFFAOYSA-N 4-chlorobenzaldehyde Chemical compound ClC1=CC=C(C=O)C=C1 AVPYQKSLYISFPO-UHFFFAOYSA-N 0.000 description 2
- 206010055113 Breast cancer metastatic Diseases 0.000 description 2
- 238000007808 Cell invasion assay Methods 0.000 description 2
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 2
- 101000677993 Homo sapiens 5'-AMP-activated protein kinase catalytic subunit alpha-1 Proteins 0.000 description 2
- 101150060880 PRKAA1 gene Proteins 0.000 description 2
- 229930040373 Paraformaldehyde Natural products 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 208000008385 Urogenital Neoplasms Diseases 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 210000000577 adipose tissue Anatomy 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 210000000481 breast Anatomy 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000000547 effect on apoptosis Effects 0.000 description 2
- 210000002919 epithelial cell Anatomy 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000000684 flow cytometry Methods 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- 230000006303 immediate early viral mRNA transcription Effects 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 206010061289 metastatic neoplasm Diseases 0.000 description 2
- 229920002866 paraformaldehyde Polymers 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000003753 real-time PCR Methods 0.000 description 2
- 230000000241 respiratory effect Effects 0.000 description 2
- 230000011664 signaling Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 230000036962 time dependent Effects 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- BUDBBFQVIINEGZ-UHFFFAOYSA-N 3-amino-2-methyl-5-propan-2-ylcyclohexa-2,5-diene-1,4-dione Chemical compound CC(C)C1=CC(=O)C(C)=C(N)C1=O BUDBBFQVIINEGZ-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 102000000452 Acetyl-CoA carboxylase Human genes 0.000 description 1
- 108010016219 Acetyl-CoA carboxylase Proteins 0.000 description 1
- 102000007469 Actins Human genes 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- 108010018763 Biotin carboxylase Proteins 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 229910014455 Ca-Cb Inorganic materials 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- GJYRCHPTBGWUDC-DJKKODMXSA-N ClC1=CC=C(\C=N\C2=C(C(C=C(C2=O)C(C)C)=O)C)C=C1 Chemical compound ClC1=CC=C(\C=N\C2=C(C(C=C(C2=O)C(C)C)=O)C)C=C1 GJYRCHPTBGWUDC-DJKKODMXSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 208000030453 Drug-Related Side Effects and Adverse reaction Diseases 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 108010040476 FITC-annexin A5 Proteins 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 102100031181 Glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 1
- 101000699762 Homo sapiens RNA 3'-terminal phosphate cyclase Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 206010027458 Metastases to lung Diseases 0.000 description 1
- 239000000020 Nitrocellulose Substances 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 102100029143 RNA 3'-terminal phosphate cyclase Human genes 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- ZSLZBFCDCINBPY-ZSJPKINUSA-N acetyl-CoA Chemical class O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 ZSLZBFCDCINBPY-ZSJPKINUSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 201000005188 adrenal gland cancer Diseases 0.000 description 1
- 125000005210 alkyl ammonium group Chemical group 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 230000001640 apoptogenic effect Effects 0.000 description 1
- 238000003782 apoptosis assay Methods 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 229930101531 artemisinin Natural products 0.000 description 1
- BLUAFEHZUWYNDE-NNWCWBAJSA-N artemisinin Chemical compound C([C@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2OC(=O)[C@@H]4C BLUAFEHZUWYNDE-NNWCWBAJSA-N 0.000 description 1
- 229960004191 artemisinin Drugs 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 239000012867 bioactive agent Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 210000000069 breast epithelial cell Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003560 cancer drug Substances 0.000 description 1
- 230000005907 cancer growth Effects 0.000 description 1
- 238000003783 cell cycle assay Methods 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 238000002701 cell growth assay Methods 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 239000013043 chemical agent Substances 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 210000003737 chromaffin cell Anatomy 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000001351 cycling effect Effects 0.000 description 1
- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 238000002784 cytotoxicity assay Methods 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 238000009650 gentamicin protection assay Methods 0.000 description 1
- 108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000007490 hematoxylin and eosin (H&E) staining Methods 0.000 description 1
- 235000008216 herbs Nutrition 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000002114 high-resolution electrospray ionisation mass spectrometry Methods 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 201000010066 hyperandrogenism Diseases 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 108010082117 matrigel Proteins 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000004630 mental health Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000010232 migration assay Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000009456 molecular mechanism Effects 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000004112 neuroprotection Effects 0.000 description 1
- 229920001220 nitrocellulos Polymers 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000000861 pro-apoptotic effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000003757 reverse transcription PCR Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 208000012190 sympathetic paraganglioma Diseases 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 229940126680 traditional chinese medicines Drugs 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C251/02—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups
- C07C251/24—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups bound to carbon atoms of six-membered aromatic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/10—Anti-acne agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/14—Drugs for dermatological disorders for baldness or alopecia
-
- 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
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- 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
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/28—Antiandrogens
-
- 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
- A61P9/12—Antihypertensives
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Dermatology (AREA)
- Endocrinology (AREA)
- Oncology (AREA)
- Emergency Medicine (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Pain & Pain Management (AREA)
- Psychiatry (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
技术领域
本发明属于生物医药技术领域,具体涉及一种百里醌衍生物及其在制备 AMPK激活剂和治疗乳腺癌的药物中的用途。
背景技术
恶性肿瘤是肿瘤患者的主要死因,对肿瘤转移机制的研究也是近年来研 究的热点。乳腺癌是严重威胁妇女身心健康的恶性肿瘤。三阴性乳腺癌 (TNBC)和转移性乳腺癌(mBC)是一种高侵袭性、高度异质性的乳腺癌 亚型,预后差,是女性癌症死亡的主要原因。三阴性乳腺癌即雌激素受体(ER)、 孕激素受体(PR)和原癌基因Her-2均为阴性的乳腺癌。近年来尽管死亡率 有所降低,但晚期TNBC的5年生存率仍然很低。科学家们正试图应对这一 挑战。许多研究和实验正在为这些乳腺癌患者研究治疗方案。在各种肿瘤临 床治疗方法中,包括小分子化合物在内的靶向治疗是目前最有效的策略。
从天然产物中提取的生物活性剂引起了研究人员和临床医生的极大关注, 并将其作为中药用于抗癌、抗炎、神经保护等方面。青蒿素就是其中最成功 的天然药物之一,它被科学家屠呦呦视为中药的礼物。然而,这类药物并没 有被完全接受,主要是由于其作用有限,分子机制不明确和费用昂贵。
此外,恶性肿瘤对传统化疗药物容易产生耐药性和副作用,因此寻找低 毒、高效、天然的新型抗乳腺癌药物已成为亟待解决的问题之一。百里醌 (thymoloquinone,TQ)是从黑籽油中分离出来的主要活性成分,已被报道 用于多种疾病的治疗,具有潜在的抗癌作用。TQ还具有抑制肿瘤转移的作 用,如可抑制前列腺癌、乳腺癌、膀胱癌、肺癌和其他恶性肿瘤的转移。因 此,TQ可能具有临床治疗的潜力。
但是TQ的有效药物浓度在某些乳腺癌细胞中仍然较高,其IC50高于 165μM。这限制了其在相关药物中的应用。
发明内容
针对现有技术中存在的问题,本发明提供一种百里醌衍生物及其在制备 AMPK激活剂和治疗乳腺癌的药物中的用途,其目的在于设计合成并筛选出 更有效、低毒的TQ抗癌衍生物。从而为临床治疗乳腺癌等癌症提供更多的 临床用药选择。
式Ⅰ所示的化合物、或其立体异构体、或其药学上可接受的盐、或其晶 型:
其中,n=0-5;
R独立选自取代或未取代的C1~C10烷基、取代或未取代的C6~C20芳基、 取代或未取代的C1~C10烷氧基、取代或未取代的C1~C10酯基、氰基、羟基、 羧基、卤素或硝基;其中,所述取代基是C1~C10烷基、C6~C20芳基、C1~C10烷氧基、C1~C10酯基、氰基、羟基、羧基、卤素或硝基。
优选的,式Ⅰ所述化合物为:
本发明还提供上述化合物的制备方法,包括如下步骤:
(a)化合物TQ经氨基化反应,得到化合物NTQ;
优选的,步骤(a)中,将化合物TQ与NaN3进行反应,优选的所述化 合物TQ与NaN3的用量摩尔比为1:1.2-1.5;和/或,所述反应以乙醇或四氢 呋喃作为溶剂;和/或,所述反应在乙酸作用下进行,优选的所述化合物TQ 与乙酸的用量比为1mmol:6-10ml,优选为1mmol:10ml;和/或,所述 反应的温度为75~85℃,优选为80℃;和/或,所述反应的时间为6-8h,优选为6h。
优选的,步骤(b)中,所述化合物NTQ与化合物的摩尔比为1:1;和/或,所述反应以乙醇或四氢呋喃作为溶剂;和/或,所述 反应在HCl作用下进行,优选的,所述化合物NTQ与浓度36-38%的HCl 的用量比例为1mmol:0.5ml;和/或,所述反应的温度为75~85℃,优选 为80℃;和/或,所述反应的时间为8-12h,优选为8h。
本发明还提供上述化合物、或其立体异构体、或其药学上可接受的盐、 或其晶型在制备用于抑制乳腺癌的生长和/或侵袭和/或迁移的药物中的用途。
优选的,所述乳腺癌为三阴性乳腺癌,优选的,所述三阴性乳腺癌为雌 激素受体、孕激素受体和原癌基因Her-2均为阴性的乳腺癌。
本发明还提供一种用于抑制乳腺癌的生长和/或侵袭和/或迁移的药物, 它是以权利要求1所述的化合物、或其立体异构体、或其药学上可接受的盐、 或其晶型为活性成分,加上药学上可接受的辅料或者辅助性成分制备而成。
本发明还提供上述化合物、或其立体异构体、或其药学上可接受的盐、 或其晶型在制备AMPK激活剂中的用途。
优选的,所述AMPK激活剂用于治疗高血压、高血脂、高血糖、雄性激 素过高、痤疮、多毛症、前列腺增生、抑郁症、乳腺癌、口腔癌、口咽癌、 鼻咽癌、呼吸系统癌、泌尿生殖系统癌、胃肠癌、中枢神经系统或周围神经 系统组织癌、内分泌或神经内分泌癌或造血系统癌、胶质瘤、肉瘤、肿瘤、 淋巴瘤、黑色素瘤、纤维瘤、脑膜瘤、脑癌、口咽癌、肾癌、胆道癌、嗜铬细胞瘤、胰岛细胞癌、Li-Fraumeni肿瘤、甲状腺癌、甲状旁腺癌、垂体瘤、 肾上腺肿瘤、成骨肉瘤、I型多发性神经内分泌和II型肿瘤、肺癌、头颈癌、 前列腺癌、食道癌、气管癌、肝癌、膀胱癌、胃癌、胰腺癌、卵巢癌、子宫 癌、宫颈癌、睾丸癌、结肠癌、直肠癌或皮肤癌中的一种或多种。
本发明还提供一种AMPK激活剂,它是以权利要求1所述的化合物、或 其立体异构体、或其药学上可接受的盐、或其晶型为活性成分,加上药学上 可接受的辅料或者辅助性成分制备而成。
本发明中提供的化合物和衍生物可以根据IUPAC(国际纯粹与应用化 学联合会)或CAS(化学文摘服务社,Columbus,OH)命名系统命名。
关于本发明的使用术语的定义:除非另有说明,本文中基团或者术语提 供的初始定义适用于整篇说明书的该基团或者术语;对于本文没有具体定义 的术语,应该根据公开内容和上下文,给出本领域技术人员能够给予它们的 含义。
“取代”是指分子中的氢原子被其它不同的原子或分子所替换。
碳氢基团中碳原子含量的最小值和最大值通过前缀表示,例如,前缀 Ca-Cb烷基表明任何含“a”至“b”个碳原子的烷基。因此,例如,“C1-C4烷基” 是指包含1-4个碳原子的烷基。
“烷基”是指具有指定数目的成员原子的饱和烃链。例如,C1-C6烷基是指 具有1至6个成员原子,例如1至4个成员原子的烷基基团。烷基基团可 以是直链或支链的。代表性的支链烷基基团具有一个、两个或三个支链。烷 基基团可任选地被一个或多个如本文所定义的取代基取代。烷基包括甲基、 乙基、丙基(正丙基和异丙基)、丁基(正丁基、异丁基和叔丁基)、戊基(正戊 基、异戊基和新戊基)和己基。烷基基团也可以是其他基团的一部分,所述其 他基团为例如C1-C6烷氧基。
“环烷基”是指具有3至14个碳原子且没有环杂原子且具有单个环或多个 环(包括稠合、桥连和螺环体系)的饱和或部分饱和的环状基团。对于具有不 含环杂原子的芳族和非芳族环的多环体系,当连接点位于非芳族碳原子时, 适用术语“环烷基”(例如5,6,7,8,-四氢化萘-5-基)。术语“环烷基”包括环烯基 基团,诸如环己烯基。环烷基基团的实例包括例如,金刚烷基、环丙基、环 丁基、环己基、环戊基、环辛基、环戊烯基和环己烯基。
“烯基”是指具有2至10个碳原子和在一些实施方案中2至6个碳原子或 2至4个碳原子且具有至少1个乙烯基不饱和位点(>C=C<)的直链或支链烃基 基团。例如,(Ca-Cb)烯基是指具有a至b个碳原子的烯基基团并且意在包括 例如乙烯基、丙烯基、异丙烯基、1,3-丁二烯基等。
“卤素”为氟、氯、溴或碘。
“立体异构体”包括对映异构体和非对映异构体。
术语“药学上可接受的”是指某载体、运载物、稀释剂、辅料,和/或所形 成的盐通常
在化学上或物理上与构成某药物剂型的其它成分相兼容,并在生理上与 受体相兼容。
术语“盐”和“可药用的盐”是指上述化合物或其立体异构体,与无机和/或 有机酸和碱形成的酸式和/或碱式盐,也包括两性离子盐(内盐),还包括季 铵盐,例如烷基铵盐。这些盐可以是在化合物的最后分离和纯化中直接得到。 也可以是通过将上述化合物,或其立体异构体,与一定数量的酸或碱适当(例 如等当量)进行混合而得到。这些盐可能在溶液中形成沉淀而以过滤方法收 集,或在溶剂蒸发后回收而得到,或在水介质中反应后冷冻干燥制得。本发 明中所述盐可以是化合物的盐酸盐、硫酸盐、枸橼酸盐、苯磺酸盐、氢溴酸盐、氢氟酸盐、磷酸盐、乙酸盐、丙酸盐、丁二酸盐、草酸盐、苹果酸盐、 琥珀酸盐、富马酸盐、马来酸盐、酒石酸盐或三氟乙酸盐。
本发明设计合成了一类新的百里醌衍生物。实验表明,该衍生物相比于 百里醌,对乳腺癌细胞的生长、侵袭和迁移具有更好的抑制作用。该抑制作 用产生的机理是由于其激活了AMPK/ACC通路。本发明提供的百里醌衍生 物为治疗乳腺癌等疾病提供了一种新的临床用药选择。
本领域公知的,AMPK激活剂可以治疗高血压、高血脂、高血糖、雄性 激素过高、痤疮、多毛症、前列腺增生、抑郁症、乳腺癌、口腔癌、口咽癌、 鼻咽癌、呼吸系统癌、泌尿生殖系统癌、胃肠癌、中枢神经系统或周围神经 系统组织癌、内分泌或神经内分泌癌或造血系统癌、胶质瘤、肉瘤、肿瘤、 淋巴瘤、黑色素瘤、纤维瘤、脑膜瘤、脑癌、口咽癌、肾癌、胆道癌、嗜铬 细胞瘤、胰岛细胞癌、Li-Fraumeni肿瘤、甲状腺癌、甲状旁腺癌、垂体瘤、 肾上腺肿瘤、成骨肉瘤、I型多发性神经内分泌和II型肿瘤、肺癌、头颈癌、 前列腺癌、食道癌、气管癌、肝癌、膀胱癌、胃癌、胰腺癌、卵巢癌、子宫 癌、宫颈癌、睾丸癌、结肠癌、直肠癌以及皮肤癌。
因此,本发明药物作为AMPK激活剂,还可以治疗高血压、高血脂、高 血糖、雄性激素过高、痤疮、多毛症、前列腺增生、抑郁症、乳腺癌、口腔 癌、口咽癌、鼻咽癌、呼吸系统癌、泌尿生殖系统癌、胃肠癌、中枢神经系 统或周围神经系统组织癌、内分泌或神经内分泌癌或造血系统癌、胶质瘤、 肉瘤、肿瘤、淋巴瘤、黑色素瘤、纤维瘤、脑膜瘤、脑癌、口咽癌、肾癌、 胆道癌、嗜铬细胞瘤、胰岛细胞癌、Li-Fraumeni肿瘤、甲状腺癌、甲状旁腺 癌、垂体瘤、肾上腺肿瘤、成骨肉瘤、I型多发性神经内分泌和II型肿瘤、 肺癌、头颈癌、前列腺癌、食道癌、气管癌、肝癌、膀胱癌、胃癌、胰腺癌、 卵巢癌、子宫癌、宫颈癌、睾丸癌、结肠癌、直肠癌以及皮肤癌。
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段, 在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、 替换或变更。
以下通过实施例形式的具体实施方式,对本发明的上述内容再作进一步 的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。 凡基于本发明上述内容所实现的技术均属于本发明的范围。
附图说明
图1为TQFL12和TQ对不同的三阴性乳腺癌细胞系活力的生物学影响。 A和B:CCK8测定显示了TQFL12和TQ作用16h(A)和24h(B)对4T1 细胞系中的影响;C和D:TQFL12和TQ作用16h(C)和48h(D)对 MDA-MB-231细胞系的影响;E&F:TQFL12和TQ作用16h(E)和48h (F)对BT549细胞系的影响;G&H:TQFL12和TQ对正常乳腺上皮细胞 系MCF-10A在24h(G)和48h(H)的作用。结果表示为平均值±果表(n =3,*p<0.05,0.05<**p<0.001,***p<0.001)。
图2为TQFL12对乳腺癌细胞生长,迁移,侵袭,细胞周期和凋亡中的 作用。A~C:在指定的TQFL12浓度下,TQFL12抑制乳腺癌细胞的生长 (A),迁移(B)和侵袭(C);D:在指定的TQFL12浓度下对4T1细胞 周期的影响;E:TQFL12在指定的浓度下对4T1细胞凋亡的影响;F.在指定 的TQFL12浓度下对MDA-MB-231(MDA231)细胞凋亡的影响。
图3为在动物模型中,TQFL12对乳腺癌生长的抑制作用。A:TQ治疗 组小鼠的存活曲线;B:TQ和TQFL12对小鼠的体重的影响;C:TQ和 TQFL12通过剂量依赖性的方式抑制肿瘤的体积;D和E:TQ(D)和TQFL12 (E)通过剂量依赖性方式以抑制肿瘤的大小;F:TQ和TQFL12通过剂量 依赖性的方式抑制肿瘤的重量。
图4为TQFL12治疗抑制乳腺癌向肺转移的效果。A:TQFL12治疗组的 肺转移菌落大小小于TQ治疗组;B:TQFL12治疗组的肺转移结节数少于 TQ治疗组;C:未经TQFL12治疗的肺部转移性肿瘤的代表性图像;D:用 TQFL12治疗的肺转移性肿瘤的代表性图像;E:未经(左图)和经(右图) TQFL12治疗的原位肿瘤代表图像。
图5为TQFL12在乳腺癌细胞中影响AMPK细信号传导。A:浓度依 赖性的AMPK性的总蛋白和磷酸化蛋白水平;B:时间依赖性的AMPKα 总蛋白和磷酸化蛋白水平;C.环己酰亚胺(CHX)和TQFL12的治疗。D: AMPK1的mRNA的半定量RT-PCR结果。
图6为化合物TQFL12和AMPKα蛋白的分子对接结果。A:TQFL12 与AMPK1的结合方式;B:TQFL12和AMPK1相互作用的二维模式;C: TQFL12结合在AMPK1上的疏水表面。
具体实施方式
以下实施例和实验例所用的试剂和细胞:
NaN3(DDN)来自西雅试剂(中国山东)。4-氯苯甲醛来自能源化工(中 国上海)。盐酸(HCl,分析级)来自株洲石英玻璃有限公司(中国株洲), 无水乙醇(EtOH)来自国药集团化学试剂有限公司(中国上海)。
TQ和基质胶是从美国Sigma公司购买。CCK8试剂购自上海同仁化学科 技有限公司。胎牛血清(FBS)购自德国PAN-Biotech生物科技公司。DMEM 和RPMI 1640培养基购自美国Gibco。MCF-10A细胞专用培养基购自上海赛 哲生物科技有限公司。抗生素、胰蛋白酶和4%多聚甲醛从上海碧云天生物 科技有限公司购买。细胞凋亡及周期试剂盒购自美国BD公司。一抗 p-AMPKα(Thr172,2535)、AMPKα(2532)、p-ACC(S79,530298)、兔 源二抗(7074)、鼠源二抗(7076)均购自CST公司,内参Actin抗体(A1978) 购自Sigma。Schrodinger分子对接软件购自美国Schrodinger公司。环己酰亚 胺购自美国Sigma公司。BALB/c小鼠购自北京腾信生物科技有限公司。
所有乳腺癌细胞系(BT549,MDA-MB-231,4T1)和正常乳腺上皮细胞 系(MCF-10A)均来自美国ATCC细胞库,并于10%FBS的培养基中,在 37℃、5%CO2培养箱中培养。
实施例1TQFL12的合成
本实施例通过如下方式合成TQFL12:
包括如下步骤:
(a)合成3-氨基-5-异丙基-2-甲基环己烷-2,5-二烯-1,4-二酮(NTQ): 将TQ(1.640g,10mmol)溶液溶解于无水NaN3和无水EtOH(80mL)的混 合物中,然后添加乙酸(30mL)。在80℃加热搅拌6h后,将反应混合物冷 却至室温(RT),薄层色谱显示TQ已完全反应。在硅胶上电泳分离反应混 合物以获得纯产物(NTQ)。NTQ显示红色固体,收率1.16g(65%);
1H NMR(500MHz,DMSO-d6):δH 1.37(6H,d),2.31(3H,s),3.23(1H,m), 6.53(1H,d),6.73(1H,s),7.34(1H,d).13C NMR(125MHz,DMSO-d6):δC 10.5, 22.9,29.2,103.0,108.9,110.4,110.9,117.8,128.5,133.6,140.0,140.1,148.2, 151.0,153.0,162.3。
(b)合成(E)-3-((4-氯亚苄基)氨基)-5-异丙基-2-甲基环己烷-2,5- 二烯-1,4-二酮(TQFL12):化合物NTQ(0.179g,1mmol)和4-氯苯甲醛(0.144, 1mmol)在乙醇(20ml)中与浓盐酸(0.5mL)混合,80合搅拌8h,将所得 混合物过滤以获得滤液。滤液在减压下浓缩得到粗产物,并从乙醇中再结晶 得到纯化合物TQFL12。TQFL12呈淡黄色固体,产率255mg(85.1%);
化合物TQFL12:1H NMR(500MHz,DMSO-d6):δH 1.33(6H,d),2.33 (3H,s),3.24(1H,m),6.77(1H,d),7.62(2H,m),8.14(2H,m),9.22(1H,s)13C NMR(125MHz,DMSO-d6):δC 10.6,22.9,29.3,111.3,112.1,126.3,128.7, 129.1,136.5,142.1,152.8,161.0。(C17H16ClNO2+H)+302.0948的HRESIMS 计算结果为302.0957。
实验例1TQFL12对乳腺癌细胞的作用
1、实验方法
(1)CCK8分析
96孔板培养细胞,每孔3000-5000个细胞,用不同浓度的TQ或TQFL12 处理16h、24h、48h,每孔加入10μL CCK8试剂,37℃,孵育1h,用酶标仪 检测每孔450nm的吸光度。每个实验分别重复三次。
(2)细胞生长、迁移和侵袭试验
将含有100μl(1001×104个细胞/ml)的细胞悬浮液接种于16孔板上, 检测细胞生长。细胞迁移和侵袭指数分析采用CMI板,下腔孔加入含10% 血清的培养基,上腔加入细胞悬液(1×104细胞/ml)。细胞侵袭试验: 在细胞侵袭试验前,将1:40稀释于1×PBS的基质凝胶接种于CMI平板上。 细胞生长8h后,加入2.5μM或5μM TQFL12或DMSO。用实时细胞分析仪(xCELLigence RTCA DP,Roche,Germany)检测细胞迁移和侵袭过程,直 至结束(详见《精编医学分子生物学实验指导》(中国医药科技出版社,2012 年,主编:傅俊江)。每个实验分别重复三次。
(3)细胞凋亡和细胞周期检测
将4T1或MDA-MB-231细胞(1.5×105个/孔)接种于6孔板中,用不 同浓度(0、2.5、5.0μM)TQFL12处理24小时,用Annexin-V FITC和PI 染色,流式细胞仪检测凋亡细胞。细胞周期分析:细胞在300μl PI溶液中暗 染,流式细胞仪分析细胞周期的各个阶段。
2、实验结果
(1)TQFL12和TQ对乳腺癌细胞的细胞毒性
为了确定TQFL12是否比TQ对乳腺癌细胞有更特异的细胞毒作用,用 TQFL12和TQ对TNBC细胞系进行细胞毒性实验进行分析。采用不同浓度 的TQFL12和TQ对人的正常乳腺细胞(MCF10A)、人乳腺癌细胞系 (MDA-MB-231和BT549)和小鼠乳腺癌细胞系(4T1)进行不同时间的处 理,并用CCK8法测定不同时期的细胞存活率,结果如图1所示。此外, TQFL12和TQ对各细胞系的IC50如表1和表2所示。
表1TQFL12和TQ对4T1细胞系的IC50值
表2TQFL12和TQ对人乳腺癌细胞系或正常乳腺细胞的IC50值
结果表明,TQFL12对这些细胞系的毒性作用是呈时间依赖性的。此外 TQFL12对不同TNBC细胞的细胞毒性比TQ敏感。
TQFL12对TNBC细胞的IC50显著低于TQ对TNBC细胞的IC50。说明 TQFL12对乳腺癌细胞具有更强的毒性。特别的,TQ12对TNBC细胞4T1 的IC50低至20.24μM有,说明TQFL12对TNBC细胞的毒性作用比TQ敏 感。
TQFL12对正常乳腺上皮细胞系(MCF10A)的IC50测量值明显高于所 有TNBC细胞系(<100μM),说明TQFL12对MCF10A的作用没有突出的 效果。
由此可见,TQFL12对肿瘤细胞有毒性而正常细胞无或者低毒性。证明 TQFL12的毒性作用对癌症细胞具有特异性。
(2)TQFL12抑制乳腺癌细胞生长、迁移和侵袭,促进细胞凋亡
为了确定TQFL12的特异性作用,利用实时细胞分析仪系统评价TQFL12 对癌细胞生长、迁移和侵袭的影响。图2为不同浓度(0,2.5,5.0μM)的 TQFL12对4T1细胞的影响。细胞指数结果显示,TQFL12在2.5μM和5.0 μM时对癌细胞生长(图2A)、迁移(图2B)和侵袭(图2C)有明显的抑 制作用。
鉴于TQFL12治疗不仅能抑制癌细胞的迁移和侵袭,而且能促进细胞死 亡,通过流式细胞术检测TQFL12对4T1和MDA-MB-231乳腺癌细胞系的 促凋亡作用。结果表明,TQFL12对细胞周期有轻微影响(图2D),但对4T1 细胞的细胞凋亡有显著影响(图2E);对MDA-MB-231细胞的细胞周期无 影响(数据未显示),对细胞凋亡影响较小(图2F)。
这些结果表明TQFL12能显著抑制乳腺癌细胞的迁移和侵袭,但是对细 胞周期影响较小。
实验例2TQFL12在体内对乳腺癌细胞源性异种移植瘤的作用
1、实验方法
小鼠的动物实验符合机构动物伦理指南,并遵循大学委员会批准的方案。
建立乳腺癌动物模型,将小鼠三阴性乳腺癌(4T1)细胞注射到雌性 BALB/c小鼠的乳腺脂肪垫中,每5天测量一次肿瘤大小。注射细胞后第4 天,将小鼠随机分为7组,每组6只,分别给予0、3.75kg/mg、7.5mg/kg、 15mg/kg的TQFL12和0、3.75kg/mg、7.5mg/kg、15mg/kg的TQ。通过测量 肿瘤的大小连续监测肿瘤。在27天治疗结束时,处死小鼠,解剖肿瘤组织, 测量肿瘤组织的重量。(详见《精编医学分子生物学实验指导》(中国医药 科技出版社,2012年,主编:傅俊江)
2、实验结果
图3A显示了TQ组小鼠的周期,高浓度TQ(15mg/kg)毒性更大,实 验进行一半时间后,小鼠全部死亡,而高浓度TQFL12实验全部小鼠无死亡。 同时,图3B中数据显示TQFL12处理对小鼠的体重没有影响,而TQ在7.5mg /kg时使小鼠的体重降低。可见TQ比TQFL12的毒性作用更显著。
图3C-E展示了TQ和TQFL12通过剂量依赖性的方式以抑制肿瘤的体积, 图3F展示了TQ和TQFL12通过剂量依赖性方式抑制肿瘤的重量。从图中可 以看出,TQFL12对肿瘤的大小和重量的抑制效果显著优于TQ,说明TQFL12 对肿瘤的抑制效果更好。
实验例3TQFL12在体内对乳腺癌细胞侵袭和迁移的抑制作用
1、实验方法
小鼠的动物实验符合机构动物伦理指南,并遵循大学委员会批准的方案。
建立乳腺癌动物模型,将小鼠三阴性乳腺癌(4T1)细胞注射到雌性 BALB/c小鼠的乳腺脂肪垫中,每5天测量一次肿瘤大小。注射细胞后第4 天,将小鼠随机分为7组,每组6只,分别给予0、3.75kg/mg、7.5mg/kg、 15mg/kg的TQFL12和0、3.75kg/mg、7.5mg/kg、15mg/kg的TQ。通过测量 肿瘤的大小连续监测肿瘤。在27天治疗结束时,处死小鼠,解剖肿瘤组织。 为了评估TQFL12和TQ对肿瘤细胞迁移/侵袭的影响,在治疗结束时解剖动 物的肺,并计算肺部转移的肿瘤数。(详见《精编医学分子生物学实验指导》 (中国医药科技出版社,2012年,主编:傅俊江)
HE染色:肿瘤组织在4%多聚甲醛中固定24小时,包埋在石蜡中,每5μm 切片一次。在二甲苯中脱蜡,不同浓度酒精脱水,并用苏木精和伊红染色。
2、实验结果
本实验例通过肺部转移形成的肿瘤菌落数来估算TQFL12在体内对乳腺 癌细胞侵袭和迁移的抑制作用。根据图4A可见,非治疗组的肺中存在大量 肿瘤菌落,而TQFL12治疗组中仅发现少量菌落。此外,图4B显示,当用TQ治疗小鼠时,代表癌细胞迁移和侵袭的每只小鼠的平均菌落数以剂量依 赖性方式减少。同时,与TQFL12治疗组相比,相同浓度的TQ治疗组肺内 菌落数量多、体积大(图4C&D)。此外,与对照组相比,TQFL12治疗的 原位肿瘤图像显示出更多的气泡(图4E,从右到左)。这些体内数据清楚地 表明TQFL12能够更好地抑制乳腺癌的生长、迁移和侵袭。
实验例4TQFL12影响乳腺癌细胞AMPK信号转导和自我稳定
1、实验方法
(1)蛋白质免疫印迹和半定量PCR:
将4T1和BT549细胞接种于6孔板中培养24h,然后用不同浓度(0、 2.5、5.0μM)TQFL12处理,加入裂解缓冲液使细胞裂解。上样40μg蛋白 进行8%、10%和12%的SDS-PAGE分离,转移到硝酸纤维素膜上。分别孵 育一抗及二抗。用LI-COR Odesy成像扫描仪检测每一条带的强度。每个实 验分别重复三次。
将BT549细胞接种于6孔板中培养24h,加入不同浓度(0、2.5、5μM) TQFL12处理,提取RNA并反转录为cDNA,设计PRKAA1和GAPDH引 物,进行半定量PCR。每个实验分别重复三次。
(2)环己酰亚胺和TQFL12处理方法的测定:
4T1或BT549细胞加入TQFL12(5μM)进行处理,且设置不加药组进 行对照。并在添加0.1mg/ml放线菌酮(CHX)之前培养24小时。收集细胞, 提取蛋白进行Western blot。用密度计半定量分析条带强度,并用成像扫描仪 进行分析。
2、实验结果
为研究受TQFL12影响的潜在信号通路,在不同的乳腺癌细胞系中作用 TQFL12并进行western blotting,结果如图5所示。
与TQ相似,TQFL12对4T1细胞(图5A,左图)和BT-549(图5B, 右)的AMPKα总蛋白水平和磷酸化蛋白水平都有剂量依赖性的增加。相应 地,AMPKα下游p-ACC(磷酸化乙酰辅酶A羧化酶)也相应的增加(图5A)。
进行不同时间的TQFL12处理,发现与0小时(不进行TQFL12处理) 相比,AMPKα比总蛋白水平和磷酸化AMPKα从1小时开始逐渐增加,4 小时达到最高水平(图6B)。这些结果表明TQFL12可能直接影响AMPK 蛋白的稳定性。
然后,进行环己酰亚胺(CHX)和TQFL12共同处理,以检测TQFL12 是否稳定AMPKα,结果如图5C所示,TQFL12处理显著增加AMPKα蛋 白水平(图5C,左,western blots;右,定量曲线)。AMPKα(PRKAA1) 的mRNA水平没有变化(图5D),表明TQFL12蛋白水平的增加不是由于其mRNA转录的增加。
本实验例证实TQFL12是通过直接稳定AMPK来影响AMPK信号通路。
实验例5TQFL12与AMPKα疏水表面相互作用
本实验例为了确定TQFL12是否与AMPKα相互作用,进行了分子对接 分析,发现TQFL12和AMPK1的分子对接分数为-5.08kcal/mol。TQFL12 可以与AMPKα的侧链羟基残基Val24形成一个距离为的强氢键(图 6A)。此外,TQFL12的苯环可与残基Leu22形成显著的疏水相互作用(图 6B)。进一步二维模式(2D)显示TQFL12和AMPKα之间的相互作用在AMPKα上的疏水表面(图6C)。
综上所述,本发明提供的化合物TQFL12能够显著抑制乳腺癌细胞的生 长、迁移和侵袭,且对于三阴性乳腺癌(TNBC)细胞具有特异性的细胞毒 性。且TQFL12对乳腺癌细胞的抑制作用显著强于TQ。因此,TQFL12具有 作为治疗乳腺癌的药物的潜力。此外,TQFL12在蛋白水平通过稳定AMPK α而激活AMPK/ACC信号通路表达。因此,TQFL12也能够作为AMPK激 活剂。
Claims (10)
4.按照权利要求3所述的制备方法,其特征在于:步骤(a)中,将化合物TQ与NaN3进行反应,优选的所述化合物TQ与NaN3的用量摩尔比为1:1.2-1.5;和/或,所述反应以乙醇或四氢呋喃作为溶剂;和/或,所述反应在乙酸作用下进行,优选的所述化合物TQ与乙酸的用量比为1mmol:6-10ml,优选为1mmol:10ml;和/或,所述反应的温度为75~85℃,优选为80℃;和/或,所述反应的时间为6-8h,优选为6h。
6.权利要求1所述的化合物、或其立体异构体、或其药学上可接受的盐、或其晶型在制备用于抑制乳腺癌的生长、侵袭和/或迁移的药物中的用途。
7.按照权利要求6所述的用途,其特征在于:所述乳腺癌为三阴性乳腺癌,优选的,所述三阴性乳腺癌为雌激素受体、孕激素受体和原癌基因Her-2均为阴性的乳腺癌。
8.一种用于抑制乳腺癌的生长、侵袭和/或迁移的药物,其特征在于:它是以权利要求1所述的化合物、或其立体异构体、或其药学上可接受的盐、或其晶型为活性成分,加上药学上可接受的辅料或者辅助性成分制备而成。
9.权利要求1所述的化合物、或其立体异构体、或其药学上可接受的盐、或其晶型在制备AMPK激活剂中的用途;
优选的,所述AMPK激活剂用于治疗高血压、高血脂、高血糖、雄性激素过高、痤疮、多毛症、前列腺增生、抑郁症、乳腺癌、口腔癌、口咽癌、鼻咽癌、呼吸系统癌、泌尿生殖系统癌、胃肠癌、中枢神经系统或周围神经系统组织癌、内分泌或神经内分泌癌或造血系统癌、胶质瘤、肉瘤、肿瘤、淋巴瘤、黑色素瘤、纤维瘤、脑膜瘤、脑癌、口咽癌、肾癌、胆道癌、嗜铬细胞瘤、胰岛细胞癌、Li-Fraumeni肿瘤、甲状腺癌、甲状旁腺癌、垂体瘤、肾上腺肿瘤、成骨肉瘤、I型多发性神经内分泌和II型肿瘤、肺癌、头颈癌、前列腺癌、食道癌、气管癌、肝癌、膀胱癌、胃癌、胰腺癌、卵巢癌、子宫癌、宫颈癌、睾丸癌、结肠癌、直肠癌或皮肤癌中的一种或多种。
10.一种AMPK激活剂,其特征在于:它是以权利要求1所述的化合物、或其立体异构体、或其药学上可接受的盐、或其晶型为活性成分,加上药学上可接受的辅料或者辅助性成分制备而成。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110159842.1A CN114874108B (zh) | 2021-02-05 | 2021-02-05 | 一种百里醌衍生物及其在制备ampk激活剂和治疗乳腺癌的药物中的用途 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110159842.1A CN114874108B (zh) | 2021-02-05 | 2021-02-05 | 一种百里醌衍生物及其在制备ampk激活剂和治疗乳腺癌的药物中的用途 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN114874108A true CN114874108A (zh) | 2022-08-09 |
CN114874108B CN114874108B (zh) | 2024-03-22 |
Family
ID=82668023
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202110159842.1A Active CN114874108B (zh) | 2021-02-05 | 2021-02-05 | 一种百里醌衍生物及其在制备ampk激活剂和治疗乳腺癌的药物中的用途 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN114874108B (zh) |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102285934A (zh) * | 2009-01-08 | 2011-12-21 | 四川大学 | 螺环二烯酮衍生物及其制备方法和用途 |
WO2017159877A1 (en) * | 2016-03-18 | 2017-09-21 | Eisai R&D Management Co., Ltd. | Use of eribulin and 3-quinuclidinone derivatives in the treatment of cancer |
CN110123809A (zh) * | 2018-12-31 | 2019-08-16 | 中国科学院昆明植物研究所 | 5-甲基-二氢苯并呋喃-咪唑盐类化合物在制药中的应用 |
US20190315742A1 (en) * | 2018-04-13 | 2019-10-17 | Ankh Life Sciences Limited | Thymoquinone/harmaline and related reaction products |
CN110396071A (zh) * | 2019-09-10 | 2019-11-01 | 陈昱西 | 一种百里醌衍生物及其制备方法和用途 |
-
2021
- 2021-02-05 CN CN202110159842.1A patent/CN114874108B/zh active Active
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102285934A (zh) * | 2009-01-08 | 2011-12-21 | 四川大学 | 螺环二烯酮衍生物及其制备方法和用途 |
WO2017159877A1 (en) * | 2016-03-18 | 2017-09-21 | Eisai R&D Management Co., Ltd. | Use of eribulin and 3-quinuclidinone derivatives in the treatment of cancer |
US20190315742A1 (en) * | 2018-04-13 | 2019-10-17 | Ankh Life Sciences Limited | Thymoquinone/harmaline and related reaction products |
CN110123809A (zh) * | 2018-12-31 | 2019-08-16 | 中国科学院昆明植物研究所 | 5-甲基-二氢苯并呋喃-咪唑盐类化合物在制药中的应用 |
CN110396071A (zh) * | 2019-09-10 | 2019-11-01 | 陈昱西 | 一种百里醌衍生物及其制备方法和用途 |
Non-Patent Citations (10)
Title |
---|
AUMEERUDDY MZ,ET AL: "Combating breast cancer using combination therapy with 3 phytochemicals: Piperine, sulforaphane, and thymoquinone", 《CANCER》, vol. 125, no. 10, pages 1600 - 1611, XP071147299, DOI: 10.1002/cncr.32022 * |
KIMBERLY M. SUTTON,ET AL: "NADPH quinone oxidoreductase 1 mediates breast cancer cell resistance to thymoquinone-induced apoptosis", 《BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS》, vol. 426, no. 03, pages 421 * |
MUJAHID YUSUFI,ET AL: "Synthesis, characterization and anti-tumor activity of novel thymoquinone analogs against pancreatic cancer", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》, vol. 23, no. 10, pages 6 - 11 * |
NASHWA KABIL,ET AL: "Thymoquinone inhibits cell proliferation, migration, and invasion by regulating the elongation factor 2 kinase (eEF-2K) signaling axis in triple-negative breast cancer", 《BREAST CANCER RESEARCH AND TREATMENT》, vol. 171, no. 03, pages 593 - 605, XP036581181, DOI: 10.1007/s10549-018-4847-2 * |
封伟亮,等: "百里醌对体内外乳腺癌细胞生长和凋亡的作用", 《医学研究杂志》, vol. 42, no. 06, pages 178 - 188 * |
徐元,等: "百里醌调控M2型巨噬细胞表型极化的机制研究", 中成药, vol. 38, no. 02, pages 13 - 18 * |
慕刚刚,等: "百里醌抑制人胰腺癌BxPC-3细胞体外运动和侵袭的研究", 胃肠病学, vol. 19, no. 11, pages 650 - 655 * |
沈诗怡,等: "百里醌抑制乳腺癌细胞的迁移和侵袭的分子机制", 《2019 年中国肿瘤标志物学术 大会暨第十三届肿瘤标志物 青年科学家论坛论文集》, no. 01, pages 122 * |
董莹,等: "AMPK在肿瘤发生发展中的研究现状", 中国生物化学与分子生物学报, vol. 16, no. 10, pages 167 - 171 * |
许梦川,等: "AMPK的功能调控及其与肿瘤之间的关系", 生理科学进展, no. 01, pages 63 - 66 * |
Also Published As
Publication number | Publication date |
---|---|
CN114874108B (zh) | 2024-03-22 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN110637011B (zh) | 法尼醇x受体激动剂及其用途 | |
Zhu et al. | Design, synthesis, and evaluation of chalcone analogues incorporate α, β-Unsaturated ketone functionality as anti-lung cancer agents via evoking ROS to induce pyroptosis | |
CN102234259B (zh) | 含笑内酯衍生物,其药物组合物及其制备方法和用途 | |
KR20110031370A (ko) | 염산 icotinib, 합성, 결정형, 약학적 조성물 및 이의 사용 | |
CN102311449B (zh) | 棉酚衍生物在制备抗肿瘤药物中的应用 | |
CN103159646B (zh) | 一种异羟肟酸类化合物及其制备方法和应用 | |
CN111039847B (zh) | 厚朴酚衍生物及其制备方法和应用 | |
Wei et al. | TQFL12, a novel synthetic derivative of TQ, inhibits triple‐negative breast cancer metastasis and invasion through activating AMPK/ACC pathway | |
WO2009067891A1 (fr) | Composés de triterpènephénol solubles dans l'eau ayant une activité anti-tumorale et leur préparation | |
Kletskov et al. | Synthesis and biological activity of novel comenic acid derivatives containing isoxazole and isothiazole moieties | |
JP2015501792A (ja) | ベンジリデンベンゾヒドラジドを用いた卵巣がんの治療 | |
CN114874108B (zh) | 一种百里醌衍生物及其在制备ampk激活剂和治疗乳腺癌的药物中的用途 | |
WO2011131102A1 (zh) | 含笑内酯的制备方法及其用途 | |
CN105012307B (zh) | Imb5046化合物在制备抗肿瘤药物中的用途 | |
US9399644B2 (en) | [1,3] dioxolo [4,5-G] quinoline-6(5H)thione derivatives as inhibitors of the late SV40 factor (LSF) for use in treating cancer | |
CN101502506B (zh) | 咖啡酸3,4-二羟基苯乙酯的医药用途 | |
US9518038B2 (en) | Condensation product of theanine derivative and carboxylic acid coumarin derivative, its intermediate, preparation method and use thereof | |
CN112513000A (zh) | 新型联苯衍生物化合物及其用途 | |
CN110003069A (zh) | 一种含硒化合物及其用途 | |
ES2955462T3 (es) | Nuevos tiromiméticos con un esqueleto de bifenilmetano y su uso | |
WO2014169697A1 (zh) | 长春碱类衍生物及其制备方法和应用 | |
CN106995452B (zh) | 一种噻吩并[3,2‑d]嘧啶类EGFR/ErbB2双靶点抑制剂及其制备方法和用途 | |
US20240092793A1 (en) | Chromene-based compounds, methods and uses thereof | |
TW201345920A (zh) | 一種甾醇類衍生物、其製備方法及用途 | |
WO2020226520A1 (en) | A new terpenoid derivative and its use in chemoprevention and supporting cancer chemotherapy |
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 |