CN115697981A - 作为碳酸酐酶ix的抑制剂用于治疗癌症的2-(3-(2-甲基-6-(对甲苯基)吡啶-3-基)脲基)苯磺酰胺及衍生物 - Google Patents
作为碳酸酐酶ix的抑制剂用于治疗癌症的2-(3-(2-甲基-6-(对甲苯基)吡啶-3-基)脲基)苯磺酰胺及衍生物 Download PDFInfo
- Publication number
- CN115697981A CN115697981A CN202080101662.1A CN202080101662A CN115697981A CN 115697981 A CN115697981 A CN 115697981A CN 202080101662 A CN202080101662 A CN 202080101662A CN 115697981 A CN115697981 A CN 115697981A
- Authority
- CN
- China
- Prior art keywords
- cancer
- carbonic anhydrase
- formula
- treatment
- 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.)
- Pending
Links
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 39
- 238000011282 treatment Methods 0.000 title claims abstract description 26
- 201000011510 cancer Diseases 0.000 title claims abstract description 25
- 108700012439 CA9 Proteins 0.000 title claims description 28
- 102100024423 Carbonic anhydrase 9 Human genes 0.000 title claims description 28
- 239000003112 inhibitor Substances 0.000 title abstract description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 41
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 17
- 230000000694 effects Effects 0.000 claims abstract description 16
- 230000002018 overexpression Effects 0.000 claims abstract description 9
- 201000010099 disease Diseases 0.000 claims abstract description 7
- 230000002265 prevention Effects 0.000 claims abstract description 5
- 206010009944 Colon cancer Diseases 0.000 claims description 17
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 17
- 239000003814 drug Substances 0.000 claims description 13
- 230000002401 inhibitory effect Effects 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 4
- 229940121959 Carbonic anhydrase IX inhibitor Drugs 0.000 claims description 2
- 102000003846 Carbonic anhydrases Human genes 0.000 abstract description 20
- 108090000209 Carbonic anhydrases Proteins 0.000 abstract description 20
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 abstract description 16
- 229940124530 sulfonamide Drugs 0.000 abstract description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 abstract description 8
- 150000003456 sulfonamides Chemical class 0.000 abstract description 8
- 230000002062 proliferating effect Effects 0.000 abstract description 7
- 150000003384 small molecules Chemical class 0.000 abstract description 5
- 239000008177 pharmaceutical agent Substances 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 50
- 230000005764 inhibitory process Effects 0.000 description 22
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 16
- 238000000034 method Methods 0.000 description 16
- 108010029485 Protein Isoforms Proteins 0.000 description 12
- 102000001708 Protein Isoforms Human genes 0.000 description 12
- 239000003489 carbonate dehydratase inhibitor Substances 0.000 description 11
- 208000035475 disorder Diseases 0.000 description 9
- 229940122072 Carbonic anhydrase inhibitor Drugs 0.000 description 8
- 230000001640 apoptogenic effect Effects 0.000 description 8
- 230000006907 apoptotic process Effects 0.000 description 8
- 229910002092 carbon dioxide Inorganic materials 0.000 description 8
- -1 diaryl urea derivative Chemical class 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- FNHKPVJBJVTLMP-UHFFFAOYSA-N regorafenib Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=C(F)C(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 FNHKPVJBJVTLMP-UHFFFAOYSA-N 0.000 description 8
- 239000002138 L01XE21 - Regorafenib Substances 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- 229960004836 regorafenib Drugs 0.000 description 7
- 230000001028 anti-proliverative effect Effects 0.000 description 6
- 238000003556 assay Methods 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 239000002146 L01XE16 - Crizotinib Substances 0.000 description 5
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- KTEIFNKAUNYNJU-GFCCVEGCSA-N crizotinib Chemical compound O([C@H](C)C=1C(=C(F)C=CC=1Cl)Cl)C(C(=NC=1)N)=CC=1C(=C1)C=NN1C1CCNCC1 KTEIFNKAUNYNJU-GFCCVEGCSA-N 0.000 description 5
- 229960005061 crizotinib Drugs 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 230000035899 viability Effects 0.000 description 5
- 239000008096 xylene Substances 0.000 description 5
- YJQZNWPYLCNRLP-UHFFFAOYSA-N 1-(4-fluorophenyl)-3-(4-sulfamoylphenyl)urea Chemical compound C1=CC(S(=O)(=O)N)=CC=C1NC(=O)NC1=CC=C(F)C=C1 YJQZNWPYLCNRLP-UHFFFAOYSA-N 0.000 description 4
- 206010052358 Colorectal cancer metastatic Diseases 0.000 description 4
- 108020004414 DNA Proteins 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- BZKPWHYZMXOIDC-UHFFFAOYSA-N acetazolamide Chemical compound CC(=O)NC1=NN=C(S(N)(=O)=O)S1 BZKPWHYZMXOIDC-UHFFFAOYSA-N 0.000 description 4
- 230000004663 cell proliferation Effects 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 210000002889 endothelial cell Anatomy 0.000 description 4
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 4
- 231100000419 toxicity Toxicity 0.000 description 4
- 230000001988 toxicity Effects 0.000 description 4
- 210000004881 tumor cell Anatomy 0.000 description 4
- 210000003606 umbilical vein Anatomy 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- HFFXLYHRNRKAPM-UHFFFAOYSA-N 2,4,5-trichloro-n-(5-methyl-1,2-oxazol-3-yl)benzenesulfonamide Chemical compound O1C(C)=CC(NS(=O)(=O)C=2C(=CC(Cl)=C(Cl)C=2)Cl)=N1 HFFXLYHRNRKAPM-UHFFFAOYSA-N 0.000 description 3
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 239000005511 L01XE05 - Sorafenib Substances 0.000 description 3
- 206010027476 Metastases Diseases 0.000 description 3
- 230000018199 S phase Effects 0.000 description 3
- 229940006133 antiglaucoma drug and miotics carbonic anhydrase inhibitors Drugs 0.000 description 3
- 235000013877 carbamide Nutrition 0.000 description 3
- 238000003570 cell viability assay Methods 0.000 description 3
- 210000001072 colon Anatomy 0.000 description 3
- 230000001086 cytosolic effect Effects 0.000 description 3
- 238000000684 flow cytometry Methods 0.000 description 3
- 238000006703 hydration reaction Methods 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 230000006882 induction of apoptosis Effects 0.000 description 3
- 210000000664 rectum Anatomy 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 229960003787 sorafenib Drugs 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- YAZSBRQTAHVVGE-UHFFFAOYSA-N 2-aminobenzenesulfonamide Chemical compound NC1=CC=CC=C1S(N)(=O)=O YAZSBRQTAHVVGE-UHFFFAOYSA-N 0.000 description 2
- APRZHQXAAWPYHS-UHFFFAOYSA-N 4-[5-[3-(carboxymethoxy)phenyl]-3-(4,5-dimethyl-1,3-thiazol-2-yl)tetrazol-3-ium-2-yl]benzenesulfonate Chemical compound S1C(C)=C(C)N=C1[N+]1=NC(C=2C=C(OCC(O)=O)C=CC=2)=NN1C1=CC=C(S([O-])(=O)=O)C=C1 APRZHQXAAWPYHS-UHFFFAOYSA-N 0.000 description 2
- 102100033793 ALK tyrosine kinase receptor Human genes 0.000 description 2
- 101710168331 ALK tyrosine kinase receptor Proteins 0.000 description 2
- 102100033040 Carbonic anhydrase 12 Human genes 0.000 description 2
- 101710094325 Carbonic anhydrase 12 Proteins 0.000 description 2
- 108010040476 FITC-annexin A5 Proteins 0.000 description 2
- 206010021143 Hypoxia Diseases 0.000 description 2
- 206010061309 Neoplasm progression Diseases 0.000 description 2
- 108091000080 Phosphotransferase Proteins 0.000 description 2
- 208000037062 Polyps Diseases 0.000 description 2
- 208000015634 Rectal Neoplasms Diseases 0.000 description 2
- 229940124639 Selective inhibitor Drugs 0.000 description 2
- 229960000571 acetazolamide Drugs 0.000 description 2
- 230000001093 anti-cancer Effects 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 238000003782 apoptosis assay Methods 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 230000022131 cell cycle Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 208000029742 colonic neoplasm Diseases 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 231100000517 death Toxicity 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000001747 exhibiting effect Effects 0.000 description 2
- 238000013467 fragmentation Methods 0.000 description 2
- 238000006062 fragmentation reaction Methods 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 210000004907 gland Anatomy 0.000 description 2
- 230000036571 hydration Effects 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 239000012948 isocyanate Substances 0.000 description 2
- 150000002513 isocyanates Chemical class 0.000 description 2
- 201000007270 liver cancer Diseases 0.000 description 2
- 208000014018 liver neoplasm Diseases 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 206010061289 metastatic neoplasm Diseases 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 238000011275 oncology therapy Methods 0.000 description 2
- 102000020233 phosphotransferase Human genes 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 238000001959 radiotherapy Methods 0.000 description 2
- 206010038038 rectal cancer Diseases 0.000 description 2
- 201000001275 rectum cancer Diseases 0.000 description 2
- 235000010288 sodium nitrite Nutrition 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 229940090374 stivarga Drugs 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 230000005751 tumor progression Effects 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- SRYALXBZLHTHHG-UHFFFAOYSA-N 1,2,3,4-tetrahydronaphthalene-1-sulfonamide Chemical class C1=CC=C2C(S(=O)(=O)N)CCCC2=C1 SRYALXBZLHTHHG-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- KNIFBVXXQJQCIB-UHFFFAOYSA-N 2-methyl-6-(4-methylphenyl)pyridine-3-carbohydrazide Chemical compound C1=CC(C)=CC=C1C1=CC=C(C(=O)NN)C(C)=N1 KNIFBVXXQJQCIB-UHFFFAOYSA-N 0.000 description 1
- PPHVFMDULQHSTJ-UHFFFAOYSA-N 3-(azidomethyl)pyridine Chemical compound [N-]=[N+]=NCC1=CC=CN=C1 PPHVFMDULQHSTJ-UHFFFAOYSA-N 0.000 description 1
- WUTIWOZYHHSBBU-UHFFFAOYSA-N 3-methoxy-4-nitrobenzaldehyde Chemical compound COC1=CC(C=O)=CC=C1[N+]([O-])=O WUTIWOZYHHSBBU-UHFFFAOYSA-N 0.000 description 1
- FWBHETKCLVMNFS-UHFFFAOYSA-N 4',6-Diamino-2-phenylindol Chemical compound C1=CC(C(=N)N)=CC=C1C1=CC2=CC=C(C(N)=N)C=C2N1 FWBHETKCLVMNFS-UHFFFAOYSA-N 0.000 description 1
- 239000012099 Alexa Fluor family Substances 0.000 description 1
- 229930183010 Amphotericin Natural products 0.000 description 1
- QGGFZZLFKABGNL-UHFFFAOYSA-N Amphotericin A Natural products OC1C(N)C(O)C(C)OC1OC1C=CC=CC=CC=CCCC=CC=CC(C)C(O)C(C)C(C)OC(=O)CC(O)CC(O)CCC(O)C(O)CC(O)CC(O)(CC(O)C2C(O)=O)OC2C1 QGGFZZLFKABGNL-UHFFFAOYSA-N 0.000 description 1
- 108090000672 Annexin A5 Proteins 0.000 description 1
- 102000004121 Annexin A5 Human genes 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 102100033007 Carbonic anhydrase 14 Human genes 0.000 description 1
- 101710094327 Carbonic anhydrase 14 Proteins 0.000 description 1
- 102100024650 Carbonic anhydrase 3 Human genes 0.000 description 1
- 101710167915 Carbonic anhydrase 3 Proteins 0.000 description 1
- 102100024644 Carbonic anhydrase 4 Human genes 0.000 description 1
- 101710167916 Carbonic anhydrase 4 Proteins 0.000 description 1
- 102100036372 Carbonic anhydrase 5A, mitochondrial Human genes 0.000 description 1
- 101710133954 Carbonic anhydrase 5A, mitochondrial Proteins 0.000 description 1
- 102100036376 Carbonic anhydrase 5B, mitochondrial Human genes 0.000 description 1
- 101710203682 Carbonic anhydrase 5B, mitochondrial Proteins 0.000 description 1
- 102100036369 Carbonic anhydrase 6 Human genes 0.000 description 1
- 101710167912 Carbonic anhydrase 6 Proteins 0.000 description 1
- 102100036368 Carbonic anhydrase 7 Human genes 0.000 description 1
- 101710167910 Carbonic anhydrase 7 Proteins 0.000 description 1
- ZEOWTGPWHLSLOG-UHFFFAOYSA-N Cc1ccc(cc1-c1ccc2c(n[nH]c2c1)-c1cnn(c1)C1CC1)C(=O)Nc1cccc(c1)C(F)(F)F Chemical compound Cc1ccc(cc1-c1ccc2c(n[nH]c2c1)-c1cnn(c1)C1CC1)C(=O)Nc1cccc(c1)C(F)(F)F ZEOWTGPWHLSLOG-UHFFFAOYSA-N 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 238000006969 Curtius rearrangement reaction Methods 0.000 description 1
- 238000000116 DAPI staining Methods 0.000 description 1
- 230000004543 DNA replication Effects 0.000 description 1
- 231100001074 DNA strand break Toxicity 0.000 description 1
- 101100481408 Danio rerio tie2 gene Proteins 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 206010058314 Dysplasia Diseases 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- 102100023593 Fibroblast growth factor receptor 1 Human genes 0.000 description 1
- 101710182386 Fibroblast growth factor receptor 1 Proteins 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- 230000010190 G1 phase Effects 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 102100022623 Hepatocyte growth factor receptor Human genes 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000910338 Homo sapiens Carbonic anhydrase 9 Proteins 0.000 description 1
- 101000972946 Homo sapiens Hepatocyte growth factor receptor Proteins 0.000 description 1
- 108010044467 Isoenzymes Proteins 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 101000984244 Mus musculus Carbonic anhydrase 15 Proteins 0.000 description 1
- 101100481410 Mus musculus Tek gene Proteins 0.000 description 1
- 229910017833 NH2NH2.H2O Inorganic materials 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- BELBBZDIHDAJOR-UHFFFAOYSA-N Phenolsulfonephthalein Chemical compound C1=CC(O)=CC=C1C1(C=2C=CC(O)=CC=2)C2=CC=CC=C2S(=O)(=O)O1 BELBBZDIHDAJOR-UHFFFAOYSA-N 0.000 description 1
- 102000018967 Platelet-Derived Growth Factor beta Receptor Human genes 0.000 description 1
- 108010051742 Platelet-Derived Growth Factor beta Receptor Proteins 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 238000012288 TUNEL assay Methods 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 108010053096 Vascular Endothelial Growth Factor Receptor-1 Proteins 0.000 description 1
- 108010053100 Vascular Endothelial Growth Factor Receptor-3 Proteins 0.000 description 1
- 102100033178 Vascular endothelial growth factor receptor 1 Human genes 0.000 description 1
- 102100033179 Vascular endothelial growth factor receptor 3 Human genes 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 208000009956 adenocarcinoma Diseases 0.000 description 1
- 229940009444 amphotericin Drugs 0.000 description 1
- APKFDSVGJQXUKY-INPOYWNPSA-N amphotericin B Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-INPOYWNPSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000002491 angiogenic effect Effects 0.000 description 1
- 230000001772 anti-angiogenic effect Effects 0.000 description 1
- 229940124650 anti-cancer therapies Drugs 0.000 description 1
- 238000011319 anticancer therapy Methods 0.000 description 1
- 239000012131 assay buffer Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000012925 biological evaluation Methods 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000003783 cell cycle assay Methods 0.000 description 1
- 230000006369 cell cycle progression Effects 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000012292 cell migration Effects 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004624 confocal microscopy Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 208000037765 diseases and disorders Diseases 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 102000051505 human CA9 Human genes 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 238000006698 hydrazinolysis reaction Methods 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 230000001146 hypoxic effect Effects 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 238000002357 laparoscopic surgery Methods 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 238000010859 live-cell imaging Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 210000001365 lymphatic vessel Anatomy 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000006510 metastatic growth Effects 0.000 description 1
- VUZPPFZMUPKLLV-UHFFFAOYSA-N methane;hydrate Chemical compound C.O VUZPPFZMUPKLLV-UHFFFAOYSA-N 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 230000002438 mitochondrial effect Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 229940080607 nexavar Drugs 0.000 description 1
- 150000002828 nitro derivatives Chemical class 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 229960003531 phenolsulfonphthalein Drugs 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 208000037920 primary disease Diseases 0.000 description 1
- 230000000861 pro-apoptotic effect Effects 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 238000012342 propidium iodide staining Methods 0.000 description 1
- 230000004952 protein activity Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- KFUSANSHCADHNJ-UHFFFAOYSA-N pyridine-3-carbohydrazide Chemical compound NNC(=O)C1=CC=CN=C1 KFUSANSHCADHNJ-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229940124617 receptor tyrosine kinase inhibitor Drugs 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 238000013042 tunel staining Methods 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea group Chemical group NC(=O)N XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 229910001868 water Inorganic materials 0.000 description 1
- 229940049068 xalkori Drugs 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
Abstract
本发明涉及2‑(3‑(2‑甲基‑6‑(对甲苯基)吡啶‑3‑基)脲基)苯磺酰胺(式I)化合物及相关的基于吡啶的磺酰胺衍生物。本发明的化合物是靶向碳酸酐酶的小分子，也是碳酸酐酶活性和过表达的抑制剂，因此可用作药剂，特别是用于治疗和/或预防与增殖性疾病相关的病症，例如癌症。
Description
技术领域
本发明公开并要求保护新型基于吡啶的磺酰胺衍生物小分子形式的2-(3-(2-甲基-6-(对甲苯基)吡啶-3-基)脲基)苯磺酰胺(式I)，其作为酶碳酸酐酶IX (CA IX)的抑制剂，碳酸酐酶IX是一种在癌症组织中过表达的蛋白质。本发明还包括式I的合成程序。本发明中所述的人碳酸酐酶IX的抑制剂可作为活性成分用于癌症疗法中所用的药物中。还公开并要求保护包含式I的药物组合物和制备式(I)的方法。
背景技术
在当前的医学时代，基于磺酰胺的小分子已作为用于开发具有有效的促细胞凋亡活性的新型抗癌剂的有吸引力和前景的类别而受到关注。不同的基于吡啶的衍生物已被批准作为癌症疗法，仅举几例：瑞戈非尼(Regorafenib)(Stivarga®)、克唑替尼(Crizotinib)(Xalkori®)和索拉非尼(Sorafenib)(Nexavar®)[1-3]。瑞戈非尼是抑制几种血管生成激酶(如VEGFR-1/3、PDGFRb、FGFR1和Tie-2)的含吡啶的二芳基脲衍生物[4]。瑞戈非尼于2012年9月获批准作为转移性结肠直肠癌(mCRC)的疗法[5]。据报道，除了其抗血管生成和抗增殖作用之外，瑞戈非尼的抗肿瘤活性还经由诱导细胞凋亡来介导[6，7]。
克唑替尼(Xalkori®)是口服活性的多受体酪氨酸激酶抑制剂；所述激酶如(ALK)、(HGFR，c-Met)和(RON) [8]。FDA批准克唑替尼用于治疗既往接受过治疗的ALK阳性晚期非小细胞肺癌成人患者[9]。克唑替尼被认为通过细胞凋亡和其它机制发挥其抗癌活性[10]。
此外，二芳基脲是用于开发小分子抗癌剂的重要片段/药效团。脲官能代表了不同抗癌疗法如利尼伐尼(Linifanib)、索拉非尼和瑞戈非尼中的主要药效团特征[11]。
碳酸酐酶(CA)是锌金属酶，在催化二氧化碳和水向碳酸氢根和质子的互变中发挥重要作用[11]。迄今为止，已知有七个不同的CA家族(α-、β-、γ-、δ-、ζ-、η-和θ-CA) [11]。它们以人(h)中分离的15种不同的α-CA同工型存在，特征在于一些是胞质的(CA I、CA II、CA III、CA VII和CA XIII)，其它是膜结合的(CA IV、CA IX、CA XII、CA XIV和CA XV)，它们中的两种是线粒体的(CA VA和CA VB)，并且一种同工酶在唾液中分泌(CA VI) [12]。hCAIX的过表达通常由不同实体瘤类型如乳腺癌、神经胶质瘤和结肠癌中的缺氧触发[13-15]。因此，抑制hCA IX与显著抑制原发性肿瘤阶段和转移瘤的生长密切相关，这使得hCA IX成为治疗多样性肿瘤的经验证靶标[15]。因此，hCA IX选择性抑制剂的开发作为揭开有效癌症治疗的关键步骤而受到关注，其没有由同工型hCA I和II抑制所引起的经典副作用。
SLC-0111是I/II期临床试验中用于治疗晚期缺氧肿瘤并发转移瘤的基于二芳基脲的磺酰胺衍生物。SLC-0111对抑制跨膜肿瘤相关的同工型hCA IX和XII (相对于胞质同工型hCA I和II)具有良好的选择性[16-18]。
结肠直肠癌是全世界第三致命的癌症，并且它被认为是第四大致死原因。它占所有癌症发病率的超过9% [19]。现在在西方国家，它占癌症相关死亡率的大约10% [20]，并且在澳大利亚、新西兰、加拿大、美国和欧洲部分地区具有最高的发病率[19]。此外，根据The American Cancer的2019统计资料，结肠直肠癌在美国被分类为在男性和女性中诊断出的第三大最常见的癌症，在美国有大约101,420例新发结肠癌病例和44,180例新发直肠癌病例，并且预期在2019年期间导致约51,020例死亡[21]。
结肠直肠癌被认为是缓慢发展的癌症，它开始为在直肠或结肠的内壁(innerlining)上生长的肿瘤(称为息肉)，并最终发展为癌症。这种息肉可以在直肠或结肠的壁上形成肿瘤，然后进入血液循环或淋巴管，并扩散到其它解剖学部位，导致转移瘤。绝大多数(超过95%)的结肠直肠癌被分类为腺癌。这些开始于结肠和直肠内壁的粘液形成腺体(mucus-making glands)[22]。
在国际专利文献WO2008071421A1中，碳酸酐酶抑制剂的硝基衍生物试剂被描述为几种碳酸酐酶同工型(包括同工型IX和XII)的潜在抑制剂。然而，这些化合物中没有一个是吡啶或磺酰胺衍生物，并且没有一个对CA IX和/或CA XII具有高度选择性。
在国际专利文献WO2012087115A1中，提出了许多芳族磺酰胺作为用于化疗和放疗的碳酸酐酶IX抑制剂。在国际专利文献WO2012175654A1中，描述了四氢化萘磺酰胺衍生物作为CA IX和XII相对于CA I和II的选择性抑制剂。
尽管存在针对原发性和转移性结肠直肠癌的各种先进的外科手术和医药疗法，例如针对原发性疾病的腹腔镜手术；转移性疾病的切除；针对直肠癌的放疗；和姑息性化疗，但治愈率和长期生存率比过去几十年仅变化了多一点点的百分比[20]。尽管开发或发现了大量不同的酶碳酸酐酶抑制剂，但主要问题是它们的非特异性和非选择性。由于非特异性抑制人体中存在的所有人碳酸酐酶形式，临床研究中使用的抑制剂具有包括毒性在内的许多副作用。此外，这些疗法引起影响患者生活质量的严重副作用。因此，开发对人碳酸酐酶的特定同工型具有特异性的抑制剂仍然是当前且重要的任务。本发明满足了这些需求和其它需求。
发明内容
根据本发明的第一方面，提供了式I的新型碳酸酐酶抑制剂或其药学上可接受的盐。此外，这种新型小分子(式I)是基于吡啶的磺酰胺衍生物和肿瘤相关的特异性碳酸酐酶抑制剂，其中这种抑制剂对同工型IX具有特异性。
本发明的另一方面是提供碳酸酐酶抑制剂，其特征在于其对碳酸酐酶IX具有高选择性，显著抑制原发性肿瘤阶段和转移瘤的生长，并且由于用于诱导50%的癌细胞凋亡的药物浓度对健康人体细胞没有影响，因此显示出非常轻微的毒性。
本发明的另一方面是提供无毒的碳酸酐酶IX抑制剂式I，或其药学上可接受的盐。这些化合物不会产生任何有害和不合意的作用。
因此，本发明的一个宽泛的实施方案涉及式I的新型碳酸酐酶抑制剂化合物或其药学上可接受的盐：
本发明的另一方面是提供用于治疗和/或预防增殖性病症的特异性碳酸酐酶抑制剂，所述增殖性病症例如癌症，优选选自乳腺癌、宫颈癌、卵巢癌、肾癌、肺癌、食道癌、结肠直肠癌、膀胱癌、前列腺癌、脑癌的癌症，更优选结肠直肠癌，其中所述化合物的特征在于靶向碳酸酐酶IX。
本发明的另一方面是提供用于制备式I的有机合成方法。
本发明可以用于制备因抑制碳酸酐酶IX过表达而可用于治疗和/或预防病症的药物。
本发明的另一方面是提供一种药物组合物，其包含药物载体和治疗有效量的式I化合物或其药学上可接受的盐。
本发明的另一方面涉及式I用于诊断和/或监测增殖性病症，例如癌症，优选结肠直肠癌的非治疗性用途。
本发明的这个目的和其它目的从下面对本发明的详细讨论中变得显而易见。
附图说明
本发明在附图中进行了图示，其中；
图1是用式1处理的存活的HCT116细胞的百分比的图示：(a) 24小时后 (P＜0.0001)，(b) 48小时后 (P＜0.0001)，(c) 72小时后 (P＜0.0001)。
图2是用式I处理72小时的HUVEC细胞的百分比活力的图示(非显著性)。
图3是Annexin V细胞凋亡检测的图示：(a)和(b) 用式I处理24小时的HCT116细胞(P＞0.001)，(c)和(d) 用式I处理48小时的HCT116细胞 (P＞0.0001)，(e)和(f) 用式I处理72小时的HCT116细胞 (P＞0.0001)。
图4是细胞周期检测的图示：(a) 用式I处理48小时的HCT116细胞 (P＜0.05)，(b)用式I处理72小时的HCT 116细胞 (P＜0.0001)。
图5是通过TUNEL检测呈现凋亡细胞的图示。细胞用TUNEL染色和DAPI染色来标记，凋亡细胞呈绿色。(a) 未处理的阴性对照细胞，和(b) 用式I处理的细胞 (比例尺代表20 μm)。
发明详述
本发明描述了新的基于吡啶的磺酰胺衍生物及其对碳酸酐酶IX的特异性抑制作用，碳酸酐酶IX是一种在癌症组织中过表达的酶。本发明还包括合成程序。
本发明涉及碳酸酐酶抑制剂(式I)。
除非另有说明，否则术语“式I”或“化合物”或“小分子”或“抑制剂”指式I的化合物、其前药、化合物和/或前药的盐、化合物的水合物或溶剂合物、式I的立体异构体、互变异构体、同位素标记的化合物、多晶型物和衍生物。
本发明的一个目的是提供一种特异性碳酸酐酶抑制剂化合物，其化学名为2-(3-(2-甲基-6-(对甲苯基)吡啶-3-基)脲基)苯磺酰胺，作为碳酸酐酶IX的活性和/或过表达的抑制剂。
根据本发明的(一个或多个)目的，如本文所体现和宽泛描述的，本发明涉及能够抑制碳酸酐酶IX的活性和/或过表达的特异性碳酸酐酶抑制剂化合物。在这方面，本发明涉及具有下式I的化合物：
或其药学上可接受的盐。
本发明的2-(3-(2-甲基-6-(对甲苯基)吡啶-3-基)脲基)苯磺酰胺(式I)可按照一般合成方案A-D获得。该方案显示了在合成根据本发明的式I中所遵循的一般程序。
A) 通过酯1经由与水合肼在乙醇中反应的肼解开始合成，得到2-甲基-6-(对-甲苯基)烟酸酰肼(nicotinohydrazide) 2。((i)；乙醇，NH2NH2•H2O，回流3小时)
B) 在冷盐酸中用亚硝酸钠处理烟酸酰肼2，提供烟酰基叠氮化物3。((ii)；NaNO2，HCl，搅拌2小时)
C) 然后在回流的无水二甲苯中搅拌下使烟酰基叠氮化物3进行Curtius重排，以产生相应的异氰酸酯衍生物4。((ⅲ)；二甲苯，回流1小时)
D) 最后，通过异氰酸酯4与2-氨基苯磺酰胺5在回流的二甲苯中反应得到目标磺酰胺式I，收率为83%。((iv)；二甲苯，回流7小时)
本文所述化合物的盐可通过常规化学方法由母体化合物合成。
测量式I对碳酸酐酶同工型(I、II、IV和IX)的抑制常数，显示该化合物对所述肿瘤相关的酶同工型碳酸酐酶IX具有特异性。(表1)
使用用于测定CA催化的CO2水合活性的应用光物理(applied photophysics)停流光谱仪(stopped-flow instrument)，评价式I对生理学相关的hCA同工型hCA I、II (胞质的)以及hCA IX和XII (跨膜、肿瘤相关的同工型)的碳酸酐酶抑制活性[24]。将它们的抑制活性与SLC-0111和临床使用的标准碳酸酐酶抑制剂乙酰唑胺(AAZ)进行比较。抑制数据显示在表1中。
表1. 式1的人CA同工型hCA I、II、IV和IX的抑制数据，使用SLC-0111和乙酰唑胺(AAZ)作为参照药物，通过停流CO2水合酶检测来测定。
*通过停流技术，来自3次不同检测的平均值(误差在报告值的5-10%的范围内)。
从表中我们可以注意到，这种特异性抑制剂(式I)对增强肿瘤细胞增殖和肿瘤[26]的hCA IX的抑制常数(KI；nM)为55.9 nM，其显著低于对hCA I、hCA II和/或hCA IV的抑制常数(KI；nM)。此外，这种特异性抑制剂(式I)对hCA IX的抑制常数(KI = 55.9 nM)大约接近参照药物(SLC-001和AAZ)对hCA IX的抑制常数(分别为KI = 45 nM和25.8 nM)。根据表中的数据，特异性抑制剂(式I)显示出对hCA IX的高亲和性。
根据本发明，发现式I表现出针对人结肠直肠癌细胞系(HCT 116)的抗增殖活性。这些发现与实施例中所示的细胞活力检测一致。
已经发现本文所述的磺酰胺衍生物化合物具有抗肿瘤和抗癌活性，并且可用于受试者增殖性病症的治疗、诊断和/或预后。
根据本发明，发现式I具有针对某些癌症类型，特别是人结肠直肠癌的抗增殖和细胞凋亡作用。
此外，发现由于这种抑制，式I调节碳酸酐酶IX的表达，导致其功能受到抑制。式I作为经由诱导细胞凋亡介导的抗增殖剂而起作用。
在另一方面，本发明涉及抑制碳酸酐酶IX蛋白并负调节其活性的化合物(式I)。
在本发明的一个实施方案中，所公开的化合物表现出对碳酸酐酶蛋白的选择性和高亲和性。因此，抑制是有效的。
根据文献，通过化合物WES-1与碳酸酐酶IX的结合抑制在肿瘤细胞增殖和肿瘤进展中起作用的碳酸酐酶IX导致对肿瘤细胞增殖和迁移的抑制。
如本文所用，术语“抑制”是指给定病况、症状或病症或疾病的减少或抑制，或者生物活性或过程如碳酸酐酶的基线活性的显著降低。
本发明化合物的术语“治疗有效量”是指无毒且足量的本发明化合物，其将引起受试者的生物学或医学反应，例如抑制蛋白质活性，或改善症状、减轻病况、减缓或延迟疾病进展，或预防疾病或病症等。
本文公开的本发明的所有各种实施方案涉及治疗和/或预防本文所述的各种疾病和病症的方法。如本文所述，本发明方法中使用的化合物能够抑制碳酸酐酶IX酶活性。
本发明还提供了治疗或预防增殖性病症的方法。在本发明中，术语“增殖性病症”包括瘤和癌症、发育异常、癌变前或癌前病变、异常细胞生长、良性肿瘤、恶性肿瘤或转移瘤，优选指癌症。
此外，本发明涉及包含此类化合物的药物组合物、此类化合物在治疗和/或预防与碳酸酐酶IX酶的过表达相关的病症中的用途和使用方法。在本发明的另一实施方案中，包含所述化合物的药物组合物由于抑制碳酸酐酶IX活性而可用于治疗和/或预防增殖性病症。
本发明涉及药物组合物，其包含药物载体和治疗有效量的式I的化合物或其药学上可接受的盐。
在一方面，本公开涉及用于制备抑制哺乳动物中碳酸酐酶IX活性和/或过表达的药物的方法，包括将治疗有效量的所公开的化合物与药学上可接受的载体或稀释剂组合。
这些实施例旨在代表本发明的具体实施方案，而不是旨在限制本发明的范围。
具体实施方式
在这些实施方案中，应用有机合成程序以提供特异性抑制碳酸酐酶IX蛋白的小分子式I。在通过方案A-D中所示的合成方法获得候选分子后，实验研究导致得以确定特异性结合碳酸酐酶IX的化合物(式I)。此外，在体外研究了式I的抑制活性的表征。
实施例
实施例1 合成根据本发明的化合物
化学部分
熔点用Stuart熔点仪测量，未校正。使用Schimadzu FT-IR 8400S分光光度计以KBr压片(KBr disks)记录红外(IR)光谱。使用Bruker NMR波谱仪(400/100 MHz)进行1H-NMR和13C-NMR实验。报告相对于作为内标的TMS的化学位移(δH)。所有耦合常数(J)值均以赫兹为单位给出。化学位移(δC)报告如下：s，单峰；d，双峰；m，多重峰。所有试剂和溶剂通过标准技术干燥和纯化。预先制备化合物1和2 [23]。
制备式I的目标磺酰胺的一般程序
将2-甲基-6-(对甲苯基)烟酸酰肼2 (1.2 g，5 mmol)和亚硝酸钠(0.5 g，7 mmol)的盐酸溶液在冰浴中搅拌1小时，然后在室温下继续搅拌另外1小时，并倾倒在碎冰上。将获得的固体过滤并风干，得到2-甲基-6-(对甲苯基)烟酰基叠氮化物3，其不经进一步纯化即用于下一步骤。将2-甲基-6-(对甲苯基)烟酰基叠氮化物3在回流的无水二甲苯中加热1小时，然后将2-氨基苯磺酰胺5 (0.86 g，5 mmol)加入到该溶液中。然后将反应混合物在回流温度下加热7小时。在冷却至室温后，滤出得到的固体，用乙醚洗涤，并从二氧杂环己烷中重结晶，以提供目标磺酰胺式I。
2-(3-(2-甲基-6-(对甲苯基)吡啶-3-基)脲基)苯磺酰胺(式I).
白色晶体(收率83%)，m.p. 213-215℃；IR (KBr，ν cm-1)：3207 (NH2), 1713 (C=O)和1342, 1161 (SO2)；1H NMR (DMSO-d6, 400MHz) δ ppm: 2.33 (s, 3H, CH3), 2.53(s, 3H, CH3), 7.15 (dt, 1H, 2-(H2NO2S)-C6H4的H-4, J = 8.4, 1.2 Hz), 7.24 (d,2H, 4-(H3C)-C6H4的H-3和H-5, J = 8.0 Hz), 7.49 (dt, 1H, 2-(H2NO2S)-C6H4的H-5,J = 8.4, 1.2 Hz), 7.71 (d, 1H, H-5吡啶, J = 8.4 Hz), 7.79 (dd, 1H, 2-(H2NO2S)-C6H4的H-3, J = 8.0, 1.2 Hz), 7.92 (d, 2H, 4-(H3C)-C6H4的H-2和H-6, J= 8.0 Hz), 7.96 (d, 1H, 2-(H2NO2S)-C6H4的H-6, J = 8.4 Hz), 8.03 (d, 1H, H-4吡啶, J = 8.4 Hz), 8.24 (s, 1H, NH, D2O可交换), 8.27 (s, 1H, NH, D2O可交换)；13CNMR (DMSO-d6, 100MHz) δ ppm: 21.25 (CH3), 22.03 (CH3), 117.70, 122.88,124.29, 126.41 (2C), 127.81, 129.68 (2C), 131.13, 132.65, 132.71, 132.90,136.22, 136.59, 138.18, 149.91, 150.47, 153.26 (C=O)。
实施例2 式I对碳酸酐酶IX的特异性抑制作用
CA抑制检测
应用光物理(Applied Photophysics)停流光谱仪已用于检测CA催化的CO2水合活性。酚红(浓度为0.2 mM)已用作指示剂，在557 nm的吸光度最大值下工作，使用20 mMHepes (pH 7.5)作为缓冲液，以及20 mM Na2SO4 (用于保持离子强度恒定)，按照CA催化的CO2水合反应的初始速率持续10-100 s的时间段。CO2浓度在1.7至17 mM范围内以确定动力学参数和抑制常数。对于每种抑制剂，至少六道的初始5-10%的反应已用于确定初始速度。以相同方式确定未催化的速率，并从总的实测速率中减去。在蒸馏去离子水中制备抑制剂的储备溶液(0.1 mM)，并用检测缓冲液稀释至0.01 nM。在检测前，将抑制剂和酶溶液一起在室温下预温育15分钟，以便使得能够形成E-I复合物。抑制常数通过使用PRISM 3和Cheng-Prusoff方程的非线性最小二乘法获得，并代表至少三次不同测定的平均值。
实施例3 生物学评价
细胞培养
HCT 116(一种人结肠直肠癌细胞系)和人脐静脉内皮细胞(HUVEC)获自ATCC,USA，并在含有10%热灭活胎牛血清1%青霉素/链霉素/两性霉素的高葡萄糖DMEM培养基(Invitrogen)(Life Technologies™，USA)中生长。
细胞活力检测
通过3-(4,5-二甲基噻唑-2-基)-5-(3-羧基甲氧基苯基)-2-(4-磺基苯基)-2H-四唑鎓(MTS)还原检测法(Cell titer 96® Aqueous MTS粉剂, Promega®)测定在用不同浓度的式I (50 μM、25 μM、12.5 μM、6.25 μM、3.125 μM、1 μM)分别处理24、48和72小时，在温度37℃、80%相对湿度和5% CO2 (这是正常细胞培养条件)下温育后存活的结肠直肠癌细胞(HCT 116细胞)和人脐静脉内皮细胞(HUVEC)的百分比。此外，通过使用GraphPad软件确定式I药物的IC50，即引起HCT 116细胞的50%细胞死亡的剂量。
在将HUVEC细胞(健康细胞)与不同浓度的式I药物一起分别温育24小时、48小时(数据未显示)和72小时(图2)后，我们发现用50 μM浓度的式I处理后的平均活力为80.53%，而用浓度(25 μM、12.5 μM、6.25 μM、3.125 μM、1 μM)处理后的平均活力范围为92.07%至96.89%。另一方面，用浓度(50 μM、25 μM、12.5 μM、6.25 μM、3.125 μM、1 μM)的式I处理24小时后，HCT 116细胞(人结肠直肠癌细胞系)的平均活力范围为69.28%至97.31% (图1a)，而处理48小时后，该范围为57.60%至99.96% (图1b)，此外，处理72小时后的活力范围为38.15%至97.82% (图1c)。从上述HCT 116细胞活力的结果，通过GraphPad软件计算IC50，其为约24 μM。
Annexin V-FITC细胞凋亡检测分析
HCT 116细胞用IC50的式I分别处理24、48和72小时，在温度37℃、80%相对湿度和5% CO2下温育。根据制造商的方案，使用ApoDETECT™ Annexin V-FITC试剂盒(LifeTechnologies™, USA)，通过流式细胞术(Beckman流式细胞仪)检测凋亡细胞。
用式I处理HCT 116细胞24小时诱导早期凋亡细胞的百分比增加约30% (图3a-3b)，而在温育48小时后，经历早期凋亡的细胞的百分比变为约33% (图3c-3d)。此外，用式I处理HCT 116细胞72小时后，我们发现早期凋亡细胞的百分比变为25%，而晚期凋亡细胞的百分比为约16.5% (图3e-3f)。这些发现与细胞活力检测一致，这表明式I药物表现出针对人结肠直肠癌(HCT 116)细胞系的抗增殖活性。
通过流式细胞术进行的细胞周期分析
HCT 116细胞用IC50的式I分别处理48和72小时，在温度37℃，80%相对湿度和5%CO2下温育。通过碘化丙锭染色定量DNA含量来分析细胞周期，以测定式I对细胞周期进程的影响。
在HCT 116细胞用式I分别处理48和72小时后(图4a-4b)，注意到G1期细胞百分比减少，而S期细胞百分比增加。这些发现表明细胞被阻滞在S期，并且细胞在S期的积累提供了DNA复制的阻断，这导致诱导细胞凋亡[25]。
TUNEL (DNA片段化)检测
通过检测DNA片段化的TUNEL检测法证实细胞凋亡，DNA片段化是细胞凋亡晚期的特征。将HCT 116细胞接种在盖玻片上，用IC50的式I处理，在温度37℃、80%相对湿度和5%CO2下温育72小时。在处理后，使用带有Alexa Fluor™ 488染料(绿色)的Click-iT™ PlusTUNEL检测试剂盒(invitrogen™)检测片段化的DNA，并用DAPI ()复染细胞。在共聚焦显微镜下分析染色的细胞。
如图5b中所示，与阴性对照细胞相比，用式I处理72小时的HCT 116细胞显示出TUNEL阳性(绿色荧光) DNA链断裂(图5a)。这些发现证实了式I对HCT 116细胞的凋亡作用。
体外活细胞成像
将HCT 116细胞接种在6孔板中，用IC50的式I药物处理，在温度37℃、80%相对湿度和5% CO2下温育72小时，通过使用Olympus显微镜拍摄视频来监测细胞的行为72小时。
结论
从先前的发现，根据碳酸酐酶检测，我们发现新合成的hCA IX抑制性式I显示出对诱导肿瘤细胞增殖和肿瘤进展的hCA IX酶的高亲和性。此外，基于用式I处理HCT 116癌细胞后的细胞凋亡检测结果，我们注意到式1诱导细胞的凋亡，而在处理HUVEC (健康人脐静脉内皮细胞)后显示超过94%的活力，这表明轻微毒性。最后，我们可以得出结论，新合成的新型化合物(2-(3-(2-甲基-6-(对甲苯基)吡啶-3-基)脲基)苯磺酰胺)(式I)具有针对人结肠直肠癌细胞系HCT 116的抗增殖和细胞凋亡作用，而对健康人脐静脉内皮细胞(HUVEC)细胞具有非常轻微的毒性。
参考文献
1.U.S. FOOD & DRUG ADMINISTRATION. FDA expands approved use of Stivarga to treat liver cancer. 2017, April 27; Available from https://www.fda.gov/news-events/press-announcements/fda-expands-approved-use-stivarga-treat-liver-cancer.
2.Cui, J.J., et al., Structure-based drug design of crizotinib (PF- 02341066), a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK). J MedChem, 2011. 54(18): p. 6342-63.
3.Wilhelm, S., et al., Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov, 2006. 5(10):p. 835-44.
4.Wilhelm; Scott; (Orange, C.D.J.B., CT) ; Ladouceur; Gaetan;(Guilford, CT) ; Lynch; Mark; (Madison, CT) ; Scott; William J.; (Guilford,CT), Diaryl ureas with kinase inhibiting activity 2007, January 25: U.S.
5.Roed Skarderud, M., et al., Efficacy and safety of regorafenib in the treatment of metastatic colorectal cancer: A systematic review. CancerTreat Rev, 2018. 62: p. 61-73.
6.Zhang, L. and J. Yu, Role of apoptosis in colon cancer biology, therapy, and prevention. Curr Colorectal Cancer Rep, 2013. 9(4): p. 013-0188.
7.Chen, D. et al., Regorafenib inhibits colorectal tumor growth through PUMA-mediated apoptosis. Clinical cancer research : an officialjournal of the American Association for Cancer Research, 2014. 20(13): p.3472-3484.
8.Sahu, A., et al., Crizotinib: A comprehensive review. South Asian JCancer, 2013. 2(2): p. 91-7.
9.Frampton, J.E., Crizotinib: a review of its use in the treatment of anaplastic lymphoma kinase-positive, advanced non-small cell lung cancer.Drugs, 2013. 73(18): p. 2031-51.
10.Dai, X. et al., (S)-crizotinib induces apoptosis in human non- small cell lung cancer cells by activating ROS independent of MTH1. J ExpClin Cancer Res, 2017. 36(1): p. 017-0584.
11.Supuran, C.T., Carbonic anhydrases: novel therapeutic applications for inhibitors and activators. Nat Rev Drug Discov, 2008. 7(2): p. 168-81.
12.Ozensoy Guler, O., C. Capasso, and C.T. Supuran, A magnificent enzyme superfamily: carbonic anhydrases, their purification and characterization. J Enzyme Inhib Med Chem, 2016. 31(5): p. 689-94.
13.Supuran, C.T., Carbonic Anhydrase Inhibition and the Management of Hypoxic Tumors. Metabolites, 2017. 7(3).
14.De Simone, G. and C.T. Supuran, Carbonic anhydrase IX: Biochemical and crystallographic characterization of a novel antitumor target. BiochimBiophys Acta, 2010. 2: p. 404-9.
15.Pastorek, J. and S. Pastorekova, Hypoxia-induced carbonic anhydrase IX as a target for cancer therapy: from biology to clinical use.Semin Cancer Biol, 2015. 31: p. 52-64.
16.Lou, Y., et al., Targeting tumor hypoxia: suppression of breast tumor growth and metastasis by novel carbonic anhydrase IX inhibitors. CancerRes, 2011. 71(9): p. 3364-76.
17.Pacchiano, F. et al., Selective hydrophobic pocket binding observed within the carbonic anhydrase II active site accommodate different 4-substituted-ureido-benzenesulfonamides and correlate to inhibitor potency.Chem Commun, 2010. 46(44): p. 8371-3.
18.Pacchiano, F., et al., Ureido-substituted benzenesulfonamides potently inhibit carbonic anhydrase IX and show antimetastatic activity in a model of breast cancer metastasis. J Med Chem, 2011. 54(6): p. 1896-902.
19.Haggar, F.A. and R.P. Boushey, Colorectal cancer epidemiology: incidence, mortality, survival, and risk factors. Clinics in colon and rectalsurgery, 2009. 22(4): p. 191-197.
20.Kuipers, E.J., et al., Colorectal cancer. Nature reviews. Diseaseprimers, 2015. 1: p. 15065-15065.
21.American Cancer Society. Key statistics for colorectal cancer.2019; Available from https://www.cancer.org/cancer/colon-rectal-cancer/about/key-statistics.html.
22.Marley, A.R. and H. Nan, Epidemiology of colorectal cancer.International journal of molecular epidemiology and genetics, 2016. 7(3): p.105-114.
23.Eldehna, W.M., et al., Design, synthesis and QSAR study of certain isatin-pyridine hybrids as potential anti-proliferative agents. Eur J MedChem, 2015. 90: p. 684-94.
24.Khalifah, R.G., The carbon dioxide hydration activity of carbonic anhydrase. I. Stop-flow kinetic studies on the native human isoenzymes B and C. J Biol Chem, 1971. 246(8): p. 2561-73.
25.Xu, X., et al., Inhibition of DNA replication and induction of S phase cell cycle arrest by G-rich oligonucleotides. J Biol Chem, 2001. 276(46): p. 43221-30.
26.Okuno, K., et al., Carbonic anhydrase IX enhances tumor cell proliferation and tumor progression in osteosarcoma. Onco Targets Ther, 2018.11: p. 6879-6886.
Claims (8)
1.化合物，2-(3-(2-甲基-6-(对甲苯基)吡啶-3-基)脲基)苯磺酰胺，
或其药学上可接受的盐。
2.根据权利要求1所述的化合物，其用作碳酸酐酶IX抑制剂。
3.根据权利要求2所述的化合物，其用作药物。
4.根据权利要求1-4所述的化合物用于制备抑制碳酸酐酶IX酶活性和/或过表达的药物的用途。
5.根据权利要求1-4所述的化合物用于制备可用于治疗和/或预防以碳酸酐酶IX酶过表达为特征的疾病或病症的药物的用途。
6.根据权利要求5所述的化合物的用途，其中所述疾病或病症是癌症。
7.根据权利要求6所述的化合物的用途，其中所述疾病或病症是结肠直肠癌。
8.药物组合物，其包含药物载体和治疗有效量的根据前述权利要求中任一项所述的化合物或其药学上可接受的盐。
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/TR2020/050477 WO2021246974A1 (en) | 2020-06-02 | 2020-06-02 | 2-(3-(2-methyl-6-(p-tolyl) pyridine-3-yl) ureido) benzenesulfonamide and derivatives as inhibitor of carbonic anhydrase ix for the treatment of cancer |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN115697981A true CN115697981A (zh) | 2023-02-03 |
Family
ID=78831369
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202080101662.1A Pending CN115697981A (zh) | 2020-06-02 | 2020-06-02 | 作为碳酸酐酶ix的抑制剂用于治疗癌症的2-(3-(2-甲基-6-(对甲苯基)吡啶-3-基)脲基)苯磺酰胺及衍生物 |
Country Status (6)
| Country | Link |
|---|---|
| US (1) | US20230234926A1 (zh) |
| EP (1) | EP4161910A4 (zh) |
| JP (1) | JP7514036B2 (zh) |
| CN (1) | CN115697981A (zh) |
| CA (1) | CA3178176A1 (zh) |
| WO (1) | WO2021246974A1 (zh) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103443083A (zh) * | 2010-12-24 | 2013-12-11 | 马斯特里赫特放射肿瘤学基金会"Maastro诊所" | 使用碳酸酐酶同工酶ix抑制剂的癌症靶向 |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008017932A2 (en) | 2006-08-09 | 2008-02-14 | Pfizer Products Inc. | Heterocycles useful as inhibitors of carbonic anhydrase |
| WO2008071421A1 (en) | 2006-12-15 | 2008-06-19 | Nicox S.A. | Nitrate esters of carbonic anhydrase inhibitors |
| WO2012175654A1 (en) | 2011-06-23 | 2012-12-27 | Facultes Universitaires Notre-Dame De La Paix | Tetraline sulfonamide derivatives for use in the treatment of proliferative disorders |
| BR112018000065B1 (pt) | 2015-07-01 | 2023-11-07 | Signalchem Lifesciences Corporation | Compostos de aril sulfonamida como inibidores de anidrase carbônica, composição farmacêutica compreendendo os ditos compostos e usos terapêuticos dos mesmos no tratamento de câncer |
-
2020
- 2020-06-02 EP EP20939077.2A patent/EP4161910A4/en active Pending
- 2020-06-02 WO PCT/TR2020/050477 patent/WO2021246974A1/en active Application Filing
- 2020-06-02 JP JP2022574320A patent/JP7514036B2/ja active Active
- 2020-06-02 CA CA3178176A patent/CA3178176A1/en active Pending
- 2020-06-02 US US18/007,749 patent/US20230234926A1/en active Pending
- 2020-06-02 CN CN202080101662.1A patent/CN115697981A/zh active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103443083A (zh) * | 2010-12-24 | 2013-12-11 | 马斯特里赫特放射肿瘤学基金会"Maastro诊所" | 使用碳酸酐酶同工酶ix抑制剂的癌症靶向 |
Non-Patent Citations (4)
| Title |
|---|
| CARTA F.等: "Synthesis and carbonic anhydrase inhibition of a series of SLC-0111 analogs", 《BIOORGANIC & MEDICINAL CHEMISTRY》, vol. 25, no. 9, pages 2569 - 2576, XP029972309, DOI: 10.1016/j.bmc.2017.03.027 * |
| CLAUDIU T.SUPURAN等: "Carbonic Anhydrase Inhibitors", 《MEDICINAL RESEARCH REVIEWS》, vol. 23, no. 2, pages 146 - 189 * |
| HALISE INCI GUL等: "New anticancer drug candidates sulfonamides as selective hCA IX or hCA XII inhibitors", 《BIOORGANIC CHEMISTRY》, vol. 77, pages 411 - 419, XP055883499, DOI: 10.1016/j.bioorg. 2018.01.02 1 * |
| WAGDY M.ELDEHNA等: "Synthesis and in vitro anticancer activity of certain novel 1-(2-methyl-6-arylpyridin-3-yl)-3-phenylureas as apoptosis-inducing agents", 《JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY》, vol. 34, no. 1, pages 322 - 332 * |
Also Published As
| Publication number | Publication date |
|---|---|
| US20230234926A1 (en) | 2023-07-27 |
| CA3178176A1 (en) | 2021-12-09 |
| JP7514036B2 (ja) | 2024-07-10 |
| JP2023536388A (ja) | 2023-08-25 |
| WO2021246974A1 (en) | 2021-12-09 |
| EP4161910A1 (en) | 2023-04-12 |
| EP4161910A4 (en) | 2023-08-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| TWI816881B (zh) | 用於治療三陰性乳癌之組合療法 | |
| EP2970221B1 (en) | Cdc7 inhibitors | |
| KR20190095355A (ko) | 암의 치료를 위한 조성물 및 방법 | |
| TWI837478B (zh) | 用於治療ｂｒａｆ相關的疾病和病症之化合物 | |
| US20210077486A1 (en) | Method for Treating Diseases Using SMARCA2/4 Degraders | |
| CN106946812B (zh) | 作为个性化抗癌药的胱天蛋白酶原活化化合物的设计、合成和评价 | |
| EP1919889A2 (en) | Sulfonamide derivatives having carbonic anhydrase inhibiting activity and their use as therapeutic and diagnostic agents | |
| KR20220133258A (ko) | 화합물 및 이의 용도 | |
| Allam et al. | Application of hydrazino and hydrazido linkers to connect benzenesulfonamides with hydrophilic/phobic tails for targeting the middle region of human carbonic anhydrases active site: Selective inhibitors of hCA IX | |
| EP4165035A1 (en) | Heteroaryl alkylene substituted 2-oxoquinazoline derivatives as methionine adenosyltransferase 2a inhibitors | |
| Kardile et al. | Design, synthesis, and biological evaluation of novel quinoline derivatives as small molecule mutant EGFR inhibitors targeting resistance in NSCLC: In vitro screening and ADME predictions | |
| CA2922542A1 (en) | Arylquinoline and analog compounds and use thereof to treat cancer | |
| WO2021252679A1 (en) | 2-aminoquinazolinone derivatives as methionine adenosyltransferase 2a inhibitors | |
| EP3180004B1 (en) | Cancer therapeutics | |
| AU2022203204A1 (en) | Use of heterocyclic pdk1 inhibitors | |
| CN103396417B (zh) | 新型羟肟酸衍生物及其医疗应用 | |
| Szeliga et al. | Design, synthesis and biological evaluation of novel 1, 3, 4-thiadiazole derivatives as anti-glioblastoma agents targeting the AKT pathway | |
| Liu et al. | Development of highly potent and specific AKR1C3 inhibitors to restore the chemosensitivity of drug-resistant breast cancer | |
| Brzozowski et al. | Carbonic anhydrase inhibitors. Synthesis, molecular structures, and inhibition of the human cytosolic isozymes I and II and transmembrane isozymes IX, XII (cancer-associated) and XIV with novel 3-pyridinesulfonamide derivatives | |
| RU2815012C1 (ru) | 2-(3-(2-метил-6-(п-толил)пиридин-3-ил)уреидо)бензолсульфонамид и производные в качестве ингибиторов карбоангидразы ix для лечения рака | |
| JP7514036B2 (ja) | 癌の治療のための炭酸脱水酵素ＩＸ阻害剤としての２－（３－（２－メチル－６－（ｐ－トリル）ピリジン－３－イル）ウレイド）ベンゼンスルホンアミドおよびその誘導体 | |
| Wang et al. | Novel metronidazole-sulfonamide derivatives as potent and selective carbonic anhydrase inhibitors: design, synthesis and biology analysis | |
| Brzozowski et al. | Carbonic anhydrase inhibitors. Regioselective synthesis of novel series 1-substituted 1, 4-dihydro-4-oxo-3-pyridinesulfonamides and their inhibition of the human cytosolic isozymes I and II and transmembrane cancer-associated isozymes IX and XII | |
| Xi et al. | Modification of osimertinib to discover new potent EGFRC797S-TK inhibitors | |
| Kuczak et al. | 4-furanylvinylquinoline derivative as a new scaffold for the design of oxidative stress initiator and glucose transporters inhibitor drugs |
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 |