CN107921047A - 芳基喹啉衍生物作为血管生成拟态抑制剂的新用途 - Google Patents
芳基喹啉衍生物作为血管生成拟态抑制剂的新用途 Download PDFInfo
- Publication number
- CN107921047A CN107921047A CN201680031932.XA CN201680031932A CN107921047A CN 107921047 A CN107921047 A CN 107921047A CN 201680031932 A CN201680031932 A CN 201680031932A CN 107921047 A CN107921047 A CN 107921047A
- Authority
- CN
- China
- Prior art keywords
- purposes
- disease
- independently
- cancer
- trx
- 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
- 230000000982 vasogenic effect Effects 0.000 title claims abstract description 35
- -1 aryl quinoline derivatives Chemical class 0.000 title claims abstract description 31
- 229940027991 antiseptic and disinfectant quinoline derivative Drugs 0.000 title abstract description 6
- 239000003112 inhibitor Substances 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 38
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 37
- 201000010099 disease Diseases 0.000 claims abstract description 32
- 239000003814 drug Substances 0.000 claims abstract description 15
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 10
- 230000001394 metastastic effect Effects 0.000 claims abstract description 10
- 206010061289 metastatic neoplasm Diseases 0.000 claims abstract description 10
- 235000018259 Solanum vestissimum Nutrition 0.000 claims abstract description 9
- 240000002825 Solanum vestissimum Species 0.000 claims abstract description 9
- 230000001093 anti-cancer Effects 0.000 claims abstract description 6
- 239000003667 hormone antagonist Substances 0.000 claims abstract description 4
- 230000003463 hyperproliferative effect Effects 0.000 claims abstract description 4
- 208000020296 Abnormal vascular morphology Diseases 0.000 claims abstract description 3
- 229940121363 anti-inflammatory agent Drugs 0.000 claims abstract description 3
- 239000002260 anti-inflammatory agent Substances 0.000 claims abstract description 3
- 230000001028 anti-proliverative effect Effects 0.000 claims abstract description 3
- 210000004027 cell Anatomy 0.000 claims description 48
- 206010028980 Neoplasm Diseases 0.000 claims description 38
- 201000001441 melanoma Diseases 0.000 claims description 24
- 201000011510 cancer Diseases 0.000 claims description 22
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- 125000003118 aryl group Chemical group 0.000 claims description 14
- 206010009944 Colon cancer Diseases 0.000 claims description 13
- 229910052801 chlorine Inorganic materials 0.000 claims description 12
- 229910052794 bromium Inorganic materials 0.000 claims description 11
- 206010039491 Sarcoma Diseases 0.000 claims description 10
- 229910052731 fluorine Inorganic materials 0.000 claims description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 10
- 208000027866 inflammatory disease Diseases 0.000 claims description 9
- 230000002757 inflammatory effect Effects 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- 210000003238 esophagus Anatomy 0.000 claims description 8
- 239000011159 matrix material Substances 0.000 claims description 8
- 206010012689 Diabetic retinopathy Diseases 0.000 claims description 7
- 230000008859 change Effects 0.000 claims description 7
- 230000001629 suppression Effects 0.000 claims description 7
- 230000002792 vascular Effects 0.000 claims description 7
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 claims description 6
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 210000000936 intestine Anatomy 0.000 claims description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
- 210000001519 tissue Anatomy 0.000 claims description 6
- 208000022072 Gallbladder Neoplasms Diseases 0.000 claims description 5
- 201000010175 gallbladder cancer Diseases 0.000 claims description 5
- 206010073071 hepatocellular carcinoma Diseases 0.000 claims description 5
- 231100000844 hepatocellular carcinoma Toxicity 0.000 claims description 5
- 206010025135 lupus erythematosus Diseases 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 125000001624 naphthyl group Chemical group 0.000 claims description 5
- 230000002062 proliferating effect Effects 0.000 claims description 5
- 201000007914 proliferative diabetic retinopathy Diseases 0.000 claims description 5
- 201000009410 rhabdomyosarcoma Diseases 0.000 claims description 5
- 206010042863 synovial sarcoma Diseases 0.000 claims description 5
- 206010003571 Astrocytoma Diseases 0.000 claims description 4
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 4
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 claims description 4
- 206010060862 Prostate cancer Diseases 0.000 claims description 4
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 4
- 206010003246 arthritis Diseases 0.000 claims description 4
- 201000001531 bladder carcinoma Diseases 0.000 claims description 4
- 210000004907 gland Anatomy 0.000 claims description 4
- 206010020718 hyperplasia Diseases 0.000 claims description 4
- 210000000867 larynx Anatomy 0.000 claims description 4
- 208000032839 leukemia Diseases 0.000 claims description 4
- 201000008968 osteosarcoma Diseases 0.000 claims description 4
- 230000000505 pernicious effect Effects 0.000 claims description 4
- 208000010570 urinary bladder carcinoma Diseases 0.000 claims description 4
- 208000002874 Acne Vulgaris Diseases 0.000 claims description 3
- 201000001320 Atherosclerosis Diseases 0.000 claims description 3
- 208000023275 Autoimmune disease Diseases 0.000 claims description 3
- 208000006332 Choriocarcinoma Diseases 0.000 claims description 3
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 3
- 206010055665 Corneal neovascularisation Diseases 0.000 claims description 3
- 201000004624 Dermatitis Diseases 0.000 claims description 3
- 206010012735 Diarrhoea Diseases 0.000 claims description 3
- 206010018364 Glomerulonephritis Diseases 0.000 claims description 3
- 206010030113 Oedema Diseases 0.000 claims description 3
- 208000024770 Thyroid neoplasm Diseases 0.000 claims description 3
- 206010052779 Transplant rejections Diseases 0.000 claims description 3
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 3
- 206010047115 Vasculitis Diseases 0.000 claims description 3
- 206010000496 acne Diseases 0.000 claims description 3
- 208000006673 asthma Diseases 0.000 claims description 3
- 208000013507 chronic prostatitis Diseases 0.000 claims description 3
- 208000009060 clear cell adenocarcinoma Diseases 0.000 claims description 3
- 206010009887 colitis Diseases 0.000 claims description 3
- 201000000159 corneal neovascularization Diseases 0.000 claims description 3
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 claims description 3
- 208000030381 cutaneous melanoma Diseases 0.000 claims description 3
- 206010012601 diabetes mellitus Diseases 0.000 claims description 3
- 208000035475 disorder Diseases 0.000 claims description 3
- 229940079593 drug Drugs 0.000 claims description 3
- 208000006454 hepatitis Diseases 0.000 claims description 3
- 231100000283 hepatitis Toxicity 0.000 claims description 3
- 201000001371 inclusion conjunctivitis Diseases 0.000 claims description 3
- 230000007794 irritation Effects 0.000 claims description 3
- 210000000607 neurosecretory system Anatomy 0.000 claims description 3
- 210000004197 pelvis Anatomy 0.000 claims description 3
- 125000001997 phenyl group Chemical class [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 201000007094 prostatitis Diseases 0.000 claims description 3
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 3
- 201000000306 sarcoidosis Diseases 0.000 claims description 3
- 201000003708 skin melanoma Diseases 0.000 claims description 3
- 208000011580 syndromic disease Diseases 0.000 claims description 3
- 201000002510 thyroid cancer Diseases 0.000 claims description 3
- 206010044325 trachoma Diseases 0.000 claims description 3
- 206010008690 Chondrocalcinosis pyrophosphate Diseases 0.000 claims description 2
- 208000009386 Experimental Arthritis Diseases 0.000 claims description 2
- 208000010412 Glaucoma Diseases 0.000 claims description 2
- 201000005569 Gout Diseases 0.000 claims description 2
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 2
- 208000005615 Interstitial Cystitis Diseases 0.000 claims description 2
- 208000003456 Juvenile Arthritis Diseases 0.000 claims description 2
- 206010059176 Juvenile idiopathic arthritis Diseases 0.000 claims description 2
- 208000018737 Parkinson disease Diseases 0.000 claims description 2
- 208000002158 Proliferative Vitreoretinopathy Diseases 0.000 claims description 2
- 206010038933 Retinopathy of prematurity Diseases 0.000 claims description 2
- 206010038934 Retinopathy proliferative Diseases 0.000 claims description 2
- 229920002472 Starch Polymers 0.000 claims description 2
- 208000000260 Warts Diseases 0.000 claims description 2
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
- 208000002849 chondrocalcinosis Diseases 0.000 claims description 2
- 208000019069 chronic childhood arthritis Diseases 0.000 claims description 2
- 230000001684 chronic effect Effects 0.000 claims description 2
- 201000001981 dermatomyositis Diseases 0.000 claims description 2
- 208000007784 diverticulitis Diseases 0.000 claims description 2
- 208000025095 immunoproliferative disease Diseases 0.000 claims description 2
- 201000002215 juvenile rheumatoid arthritis Diseases 0.000 claims description 2
- 208000002780 macular degeneration Diseases 0.000 claims description 2
- 208000021971 neovascular inflammatory vitreoretinopathy Diseases 0.000 claims description 2
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 2
- 210000000056 organ Anatomy 0.000 claims description 2
- 201000008482 osteoarthritis Diseases 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 230000006785 proliferative vitreoretinopathy Effects 0.000 claims description 2
- 231100000241 scar Toxicity 0.000 claims description 2
- 201000010153 skin papilloma Diseases 0.000 claims description 2
- 235000019698 starch Nutrition 0.000 claims description 2
- 239000008107 starch Substances 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 206010064930 age-related macular degeneration Diseases 0.000 claims 2
- 208000024827 Alzheimer disease Diseases 0.000 claims 1
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 claims 1
- 206010020649 Hyperkeratosis Diseases 0.000 claims 1
- 208000001126 Keratosis Diseases 0.000 claims 1
- 208000000172 Medulloblastoma Diseases 0.000 claims 1
- 201000004681 Psoriasis Diseases 0.000 claims 1
- 201000000053 blastoma Diseases 0.000 claims 1
- 229910052804 chromium Inorganic materials 0.000 claims 1
- 239000011651 chromium Substances 0.000 claims 1
- 201000008184 embryoma Diseases 0.000 claims 1
- 201000003142 neovascular glaucoma Diseases 0.000 claims 1
- 210000004498 neuroglial cell Anatomy 0.000 claims 1
- 210000003462 vein Anatomy 0.000 claims 1
- 238000011282 treatment Methods 0.000 abstract description 11
- 230000002491 angiogenic effect Effects 0.000 abstract description 2
- ZDWFMAHQGDEALT-UHFFFAOYSA-N foslinanib Chemical compound C=1C(=O)C2=C(OP(O)(O)=O)C(OC)=CC=C2NC=1C1=CC=CC(F)=C1 ZDWFMAHQGDEALT-UHFFFAOYSA-N 0.000 description 50
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 46
- 108090000623 proteins and genes Proteins 0.000 description 24
- 102000004169 proteins and genes Human genes 0.000 description 22
- 210000004204 blood vessel Anatomy 0.000 description 10
- 208000029742 colonic neoplasm Diseases 0.000 description 10
- 238000000034 method Methods 0.000 description 10
- 108020004999 messenger RNA Proteins 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- 238000002054 transplantation Methods 0.000 description 8
- 102000000905 Cadherin Human genes 0.000 description 7
- 108050007957 Cadherin Proteins 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 239000000460 chlorine Substances 0.000 description 7
- 210000003743 erythrocyte Anatomy 0.000 description 7
- 230000014509 gene expression Effects 0.000 description 7
- 238000011081 inoculation Methods 0.000 description 7
- 230000009545 invasion Effects 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- OVBPIULPVIDEAO-LBPRGKRZSA-N Folic acid Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 6
- 238000012545 processing Methods 0.000 description 6
- 238000011160 research Methods 0.000 description 6
- 0 Cc1c(C)c(*)c(*)c(*)c1C Chemical compound Cc1c(C)c(*)c(*)c(*)c1C 0.000 description 5
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 5
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 5
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical compound ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 5
- 229940087004 mustargen Drugs 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 4
- 102100025751 Mothers against decapentaplegic homolog 2 Human genes 0.000 description 4
- 101710143123 Mothers against decapentaplegic homolog 2 Proteins 0.000 description 4
- 102100024616 Platelet endothelial cell adhesion molecule Human genes 0.000 description 4
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 235000019152 folic acid Nutrition 0.000 description 4
- 239000011724 folic acid Substances 0.000 description 4
- 229960004768 irinotecan Drugs 0.000 description 4
- 208000028591 pheochromocytoma Diseases 0.000 description 4
- 230000026731 phosphorylation Effects 0.000 description 4
- 238000006366 phosphorylation reaction Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 229960001196 thiotepa Drugs 0.000 description 4
- 210000004881 tumor cell Anatomy 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 3
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 description 3
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 3
- WEAHRLBPCANXCN-UHFFFAOYSA-N Daunomycin Natural products CCC1(O)CC(OC2CC(N)C(O)C(C)O2)c3cc4C(=O)c5c(OC)cccc5C(=O)c4c(O)c3C1 WEAHRLBPCANXCN-UHFFFAOYSA-N 0.000 description 3
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 3
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 3
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 3
- 102000044547 Nodal Human genes 0.000 description 3
- 108700024442 Nodal Proteins 0.000 description 3
- 102000007374 Smad Proteins Human genes 0.000 description 3
- 108010007945 Smad Proteins Proteins 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 3
- 238000004925 denaturation Methods 0.000 description 3
- 230000036425 denaturation Effects 0.000 description 3
- 238000004043 dyeing Methods 0.000 description 3
- 229960000304 folic acid Drugs 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 3
- 239000004033 plastic Substances 0.000 description 3
- 229920003023 plastic Polymers 0.000 description 3
- 208000029340 primitive neuroectodermal tumor Diseases 0.000 description 3
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 description 3
- 229960004622 raloxifene Drugs 0.000 description 3
- 206010041823 squamous cell carcinoma Diseases 0.000 description 3
- 238000012546 transfer Methods 0.000 description 3
- NNJPGOLRFBJNIW-HNNXBMFYSA-N (-)-demecolcine Chemical compound C1=C(OC)C(=O)C=C2[C@@H](NC)CCC3=CC(OC)=C(OC)C(OC)=C3C2=C1 NNJPGOLRFBJNIW-HNNXBMFYSA-N 0.000 description 2
- WDQLRUYAYXDIFW-RWKIJVEZSA-N (2r,3r,4s,5r,6r)-4-[(2s,3r,4s,5r,6r)-3,5-dihydroxy-4-[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-6-[[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxymethyl]oxan-2-yl]oxy-6-(hydroxymethyl)oxane-2,3,5-triol Chemical compound O[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)[C@H](O)[C@@H](CO[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)O1 WDQLRUYAYXDIFW-RWKIJVEZSA-N 0.000 description 2
- CGMTUJFWROPELF-YPAAEMCBSA-N (3E,5S)-5-[(2S)-butan-2-yl]-3-(1-hydroxyethylidene)pyrrolidine-2,4-dione Chemical compound CC[C@H](C)[C@@H]1NC(=O)\C(=C(/C)O)C1=O CGMTUJFWROPELF-YPAAEMCBSA-N 0.000 description 2
- XRBSKUSTLXISAB-XVVDYKMHSA-N (5r,6r,7r,8r)-8-hydroxy-7-(hydroxymethyl)-5-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydrobenzo[f][1,3]benzodioxole-6-carboxylic acid Chemical compound COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@H](O)[C@@H](CO)[C@@H]2C(O)=O)=C1 XRBSKUSTLXISAB-XVVDYKMHSA-N 0.000 description 2
- JXVAMODRWBNUSF-KZQKBALLSA-N (7s,9r,10r)-7-[(2r,4s,5s,6s)-5-[[(2s,4as,5as,7s,9s,9ar,10ar)-2,9-dimethyl-3-oxo-4,4a,5a,6,7,9,9a,10a-octahydrodipyrano[4,2-a:4',3'-e][1,4]dioxin-7-yl]oxy]-4-(dimethylamino)-6-methyloxan-2-yl]oxy-10-[(2s,4s,5s,6s)-4-(dimethylamino)-5-hydroxy-6-methyloxan-2 Chemical compound O([C@@H]1C2=C(O)C=3C(=O)C4=CC=CC(O)=C4C(=O)C=3C(O)=C2[C@@H](O[C@@H]2O[C@@H](C)[C@@H](O[C@@H]3O[C@@H](C)[C@H]4O[C@@H]5O[C@@H](C)C(=O)C[C@@H]5O[C@H]4C3)[C@H](C2)N(C)C)C[C@]1(O)CC)[C@H]1C[C@H](N(C)C)[C@H](O)[C@H](C)O1 JXVAMODRWBNUSF-KZQKBALLSA-N 0.000 description 2
- IEXUMDBQLIVNHZ-YOUGDJEHSA-N (8s,11r,13r,14s,17s)-11-[4-(dimethylamino)phenyl]-17-hydroxy-17-(3-hydroxypropyl)-13-methyl-1,2,6,7,8,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-3-one Chemical compound C1=CC(N(C)C)=CC=C1[C@@H]1C2=C3CCC(=O)C=C3CC[C@H]2[C@H](CC[C@]2(O)CCCO)[C@@]2(C)C1 IEXUMDBQLIVNHZ-YOUGDJEHSA-N 0.000 description 2
- LKJPYSCBVHEWIU-KRWDZBQOSA-N (R)-bicalutamide Chemical compound C([C@@](O)(C)C(=O)NC=1C=C(C(C#N)=CC=1)C(F)(F)F)S(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-KRWDZBQOSA-N 0.000 description 2
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 2
- BOMZMNZEXMAQQW-UHFFFAOYSA-N 2,5,11-trimethyl-6h-pyrido[4,3-b]carbazol-2-ium-9-ol;acetate Chemical compound CC([O-])=O.C[N+]1=CC=C2C(C)=C(NC=3C4=CC(O)=CC=3)C4=C(C)C2=C1 BOMZMNZEXMAQQW-UHFFFAOYSA-N 0.000 description 2
- HNXQXTQTPAJEJL-UHFFFAOYSA-N 2-aminopteridin-4-ol Chemical compound C1=CN=C2NC(N)=NC(=O)C2=N1 HNXQXTQTPAJEJL-UHFFFAOYSA-N 0.000 description 2
- VNBAOSVONFJBKP-UHFFFAOYSA-N 2-chloro-n,n-bis(2-chloroethyl)propan-1-amine;hydrochloride Chemical compound Cl.CC(Cl)CN(CCCl)CCCl VNBAOSVONFJBKP-UHFFFAOYSA-N 0.000 description 2
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 2
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 description 2
- HDZZVAMISRMYHH-UHFFFAOYSA-N 9beta-Ribofuranosyl-7-deazaadenin Natural products C1=CC=2C(N)=NC=NC=2N1C1OC(CO)C(O)C1O HDZZVAMISRMYHH-UHFFFAOYSA-N 0.000 description 2
- QMGUSPDJTPDFSF-UHFFFAOYSA-N Aldophosphamide Chemical compound ClCCN(CCCl)P(=O)(N)OCCC=O QMGUSPDJTPDFSF-UHFFFAOYSA-N 0.000 description 2
- CEIZFXOZIQNICU-UHFFFAOYSA-N Alternaria alternata Crofton-weed toxin Natural products CCC(C)C1NC(=O)C(C(C)=O)=C1O CEIZFXOZIQNICU-UHFFFAOYSA-N 0.000 description 2
- 102400000068 Angiostatin Human genes 0.000 description 2
- 108010079709 Angiostatins Proteins 0.000 description 2
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical class C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 2
- VGGGPCQERPFHOB-MCIONIFRSA-N Bestatin Chemical compound CC(C)C[C@H](C(O)=O)NC(=O)[C@@H](O)[C@H](N)CC1=CC=CC=C1 VGGGPCQERPFHOB-MCIONIFRSA-N 0.000 description 2
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 2
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 description 2
- AOCCBINRVIKJHY-UHFFFAOYSA-N Carmofur Chemical compound CCCCCCNC(=O)N1C=C(F)C(=O)NC1=O AOCCBINRVIKJHY-UHFFFAOYSA-N 0.000 description 2
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- MKQWTWSXVILIKJ-LXGUWJNJSA-N Chlorozotocin Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](C=O)NC(=O)N(N=O)CCCl MKQWTWSXVILIKJ-LXGUWJNJSA-N 0.000 description 2
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 2
- NNJPGOLRFBJNIW-UHFFFAOYSA-N Demecolcine Natural products C1=C(OC)C(=O)C=C2C(NC)CCC3=CC(OC)=C(OC)C(OC)=C3C2=C1 NNJPGOLRFBJNIW-UHFFFAOYSA-N 0.000 description 2
- 102400000220 ERBB4 intracellular domain Human genes 0.000 description 2
- 101800001263 ERBB4 intracellular domain Proteins 0.000 description 2
- SAMRUMKYXPVKPA-VFKOLLTISA-N Enocitabine Chemical compound O=C1N=C(NC(=O)CCCCCCCCCCCCCCCCCCCCC)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 SAMRUMKYXPVKPA-VFKOLLTISA-N 0.000 description 2
- OBMLHUPNRURLOK-XGRAFVIBSA-N Epitiostanol Chemical compound C1[C@@H]2S[C@@H]2C[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@H]21 OBMLHUPNRURLOK-XGRAFVIBSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 2
- BLCLNMBMMGCOAS-URPVMXJPSA-N Goserelin Chemical compound C([C@@H](C(=O)N[C@H](COC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NNC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 BLCLNMBMMGCOAS-URPVMXJPSA-N 0.000 description 2
- 108010069236 Goserelin Proteins 0.000 description 2
- 229920002971 Heparan sulfate Polymers 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- MPBVHIBUJCELCL-UHFFFAOYSA-N Ibandronate Chemical compound CCCCCN(C)CCC(O)(P(O)(O)=O)P(O)(O)=O MPBVHIBUJCELCL-UHFFFAOYSA-N 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 108010000817 Leuprolide Proteins 0.000 description 2
- VJRAUFKOOPNFIQ-UHFFFAOYSA-N Marcellomycin Natural products C12=C(O)C=3C(=O)C4=C(O)C=CC(O)=C4C(=O)C=3C=C2C(C(=O)OC)C(CC)(O)CC1OC(OC1C)CC(N(C)C)C1OC(OC1C)CC(O)C1OC1CC(O)C(O)C(C)O1 VJRAUFKOOPNFIQ-UHFFFAOYSA-N 0.000 description 2
- XUMBMVFBXHLACL-UHFFFAOYSA-N Melanin Chemical compound O=C1C(=O)C(C2=CNC3=C(C(C(=O)C4=C32)=O)C)=C2C4=CNC2=C1C XUMBMVFBXHLACL-UHFFFAOYSA-N 0.000 description 2
- IVDYZAAPOLNZKG-KWHRADDSSA-N Mepitiostane Chemical compound O([C@@H]1[C@]2(CC[C@@H]3[C@@]4(C)C[C@H]5S[C@H]5C[C@@H]4CC[C@H]3[C@@H]2CC1)C)C1(OC)CCCC1 IVDYZAAPOLNZKG-KWHRADDSSA-N 0.000 description 2
- 229910002651 NO3 Inorganic materials 0.000 description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 2
- KGTDRFCXGRULNK-UHFFFAOYSA-N Nogalamycin Natural products COC1C(OC)(C)C(OC)C(C)OC1OC1C2=C(O)C(C(=O)C3=C(O)C=C4C5(C)OC(C(C(C5O)N(C)C)O)OC4=C3C3=O)=C3C=C2C(C(=O)OC)C(C)(O)C1 KGTDRFCXGRULNK-UHFFFAOYSA-N 0.000 description 2
- 240000007594 Oryza sativa Species 0.000 description 2
- 235000007164 Oryza sativa Nutrition 0.000 description 2
- 229930012538 Paclitaxel Natural products 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 244000221860 Podophyllum emodi Species 0.000 description 2
- 235000010169 Podophyllum emodi Nutrition 0.000 description 2
- HFVNWDWLWUCIHC-GUPDPFMOSA-N Prednimustine Chemical compound O=C([C@@]1(O)CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)[C@@H](O)C[C@@]21C)COC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 HFVNWDWLWUCIHC-GUPDPFMOSA-N 0.000 description 2
- 229920000519 Sizofiran Polymers 0.000 description 2
- 229940123237 Taxane Drugs 0.000 description 2
- CGMTUJFWROPELF-UHFFFAOYSA-N Tenuazonic acid Natural products CCC(C)C1NC(=O)C(=C(C)/O)C1=O CGMTUJFWROPELF-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 108090000190 Thrombin Proteins 0.000 description 2
- UMILHIMHKXVDGH-UHFFFAOYSA-N Triethylene glycol diglycidyl ether Chemical compound C1OC1COCCOCCOCCOCC1CO1 UMILHIMHKXVDGH-UHFFFAOYSA-N 0.000 description 2
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 2
- SPJCRMJCFSJKDE-ZWBUGVOYSA-N [(3s,8s,9s,10r,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-3-yl] 2-[4-[bis(2-chloroethyl)amino]phenyl]acetate Chemical compound O([C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)C(=O)CC1=CC=C(N(CCCl)CCCl)C=C1 SPJCRMJCFSJKDE-ZWBUGVOYSA-N 0.000 description 2
- XZSRRNFBEIOBDA-CFNBKWCHSA-N [2-[(2s,4s)-4-[(2r,4s,5s,6s)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-2,5,12-trihydroxy-7-methoxy-6,11-dioxo-3,4-dihydro-1h-tetracen-2-yl]-2-oxoethyl] 2,2-diethoxyacetate Chemical compound O([C@H]1C[C@](CC2=C(O)C=3C(=O)C4=CC=CC(OC)=C4C(=O)C=3C(O)=C21)(O)C(=O)COC(=O)C(OCC)OCC)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 XZSRRNFBEIOBDA-CFNBKWCHSA-N 0.000 description 2
- ZOZKYEHVNDEUCO-XUTVFYLZSA-N aceglatone Chemical compound O1C(=O)[C@H](OC(C)=O)[C@@H]2OC(=O)[C@@H](OC(=O)C)[C@@H]21 ZOZKYEHVNDEUCO-XUTVFYLZSA-N 0.000 description 2
- 229950002684 aceglatone Drugs 0.000 description 2
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 2
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 229960001220 amsacrine Drugs 0.000 description 2
- XCPGHVQEEXUHNC-UHFFFAOYSA-N amsacrine Chemical compound COC1=CC(NS(C)(=O)=O)=CC=C1NC1=C(C=CC=C2)C2=NC2=CC=CC=C12 XCPGHVQEEXUHNC-UHFFFAOYSA-N 0.000 description 2
- BBDAGFIXKZCXAH-CCXZUQQUSA-N ancitabine Chemical compound N=C1C=CN2[C@@H]3O[C@H](CO)[C@@H](O)[C@@H]3OC2=N1 BBDAGFIXKZCXAH-CCXZUQQUSA-N 0.000 description 2
- 229950000242 ancitabine Drugs 0.000 description 2
- 230000033115 angiogenesis Effects 0.000 description 2
- 239000004037 angiogenesis inhibitor Substances 0.000 description 2
- FZCSTZYAHCUGEM-UHFFFAOYSA-N aspergillomarasmine B Natural products OC(=O)CNC(C(O)=O)CNC(C(O)=O)CC(O)=O FZCSTZYAHCUGEM-UHFFFAOYSA-N 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 229960002756 azacitidine Drugs 0.000 description 2
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 229960000997 bicalutamide Drugs 0.000 description 2
- HXCHCVDVKSCDHU-LULTVBGHSA-N calicheamicin Chemical compound C1[C@H](OC)[C@@H](NCC)CO[C@H]1O[C@H]1[C@H](O[C@@H]2C\3=C(NC(=O)OC)C(=O)C[C@](C/3=C/CSSSC)(O)C#C\C=C/C#C2)O[C@H](C)[C@@H](NO[C@@H]2O[C@H](C)[C@@H](SC(=O)C=3C(=C(OC)C(O[C@H]4[C@@H]([C@H](OC)[C@@H](O)[C@H](C)O4)O)=C(I)C=3C)OC)[C@@H](O)C2)[C@@H]1O HXCHCVDVKSCDHU-LULTVBGHSA-N 0.000 description 2
- 229930195731 calicheamicin Natural products 0.000 description 2
- 229960004117 capecitabine Drugs 0.000 description 2
- 229960004562 carboplatin Drugs 0.000 description 2
- 229930188550 carminomycin Natural products 0.000 description 2
- XREUEWVEMYWFFA-CSKJXFQVSA-N carminomycin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=C(O)C=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XREUEWVEMYWFFA-CSKJXFQVSA-N 0.000 description 2
- XREUEWVEMYWFFA-UHFFFAOYSA-N carminomycin I Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=C(O)C=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XREUEWVEMYWFFA-UHFFFAOYSA-N 0.000 description 2
- 229960003261 carmofur Drugs 0.000 description 2
- 229960005243 carmustine Drugs 0.000 description 2
- 229950001725 carubicin Drugs 0.000 description 2
- 238000007385 chemical modification Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 2
- 229960004630 chlorambucil Drugs 0.000 description 2
- 229960001480 chlorozotocin Drugs 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 229960000640 dactinomycin Drugs 0.000 description 2
- 239000008367 deionised water Substances 0.000 description 2
- 229910021641 deionized water Inorganic materials 0.000 description 2
- 229960005052 demecolcine Drugs 0.000 description 2
- 229950003913 detorubicin Drugs 0.000 description 2
- WVYXNIXAMZOZFK-UHFFFAOYSA-N diaziquone Chemical compound O=C1C(NC(=O)OCC)=C(N2CC2)C(=O)C(NC(=O)OCC)=C1N1CC1 WVYXNIXAMZOZFK-UHFFFAOYSA-N 0.000 description 2
- 229950002389 diaziquone Drugs 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 229940017825 dromostanolone Drugs 0.000 description 2
- NOTIQUSPUUHHEH-UXOVVSIBSA-N dromostanolone propionate Chemical compound C([C@@H]1CC2)C(=O)[C@H](C)C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](OC(=O)CC)[C@@]2(C)CC1 NOTIQUSPUUHHEH-UXOVVSIBSA-N 0.000 description 2
- 229950000549 elliptinium acetate Drugs 0.000 description 2
- 229950011487 enocitabine Drugs 0.000 description 2
- 239000002532 enzyme inhibitor Substances 0.000 description 2
- 229940125532 enzyme inhibitor Drugs 0.000 description 2
- 102000012803 ephrin Human genes 0.000 description 2
- 108060002566 ephrin Proteins 0.000 description 2
- ITSGNOIFAJAQHJ-BMFNZSJVSA-N esorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)C[C@H](C)O1 ITSGNOIFAJAQHJ-BMFNZSJVSA-N 0.000 description 2
- 229950002017 esorubicin Drugs 0.000 description 2
- 229960005237 etoglucid Drugs 0.000 description 2
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 2
- 229960000390 fludarabine Drugs 0.000 description 2
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 229960002949 fluorouracil Drugs 0.000 description 2
- CHPZKNULDCNCBW-UHFFFAOYSA-N gallium nitrate Chemical compound [Ga+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O CHPZKNULDCNCBW-UHFFFAOYSA-N 0.000 description 2
- 229960005277 gemcitabine Drugs 0.000 description 2
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 2
- 229960002913 goserelin Drugs 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 125000001072 heteroaryl group Chemical group 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 229940015872 ibandronate Drugs 0.000 description 2
- 238000011532 immunohistochemical staining Methods 0.000 description 2
- DBIGHPPNXATHOF-UHFFFAOYSA-N improsulfan Chemical compound CS(=O)(=O)OCCCNCCCOS(C)(=O)=O DBIGHPPNXATHOF-UHFFFAOYSA-N 0.000 description 2
- 229950008097 improsulfan Drugs 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 description 2
- 229960004338 leuprorelin Drugs 0.000 description 2
- 229960003538 lonidamine Drugs 0.000 description 2
- WDRYRZXSPDWGEB-UHFFFAOYSA-N lonidamine Chemical compound C12=CC=CC=C2C(C(=O)O)=NN1CC1=CC=C(Cl)C=C1Cl WDRYRZXSPDWGEB-UHFFFAOYSA-N 0.000 description 2
- MQXVYODZCMMZEM-ZYUZMQFOSA-N mannomustine Chemical compound ClCCNC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CNCCCl MQXVYODZCMMZEM-ZYUZMQFOSA-N 0.000 description 2
- 229950008612 mannomustine Drugs 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 229950009246 mepitiostane Drugs 0.000 description 2
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 2
- VJRAUFKOOPNFIQ-TVEKBUMESA-N methyl (1r,2r,4s)-4-[(2r,4s,5s,6s)-5-[(2s,4s,5s,6s)-5-[(2s,4s,5s,6s)-4,5-dihydroxy-6-methyloxan-2-yl]oxy-4-hydroxy-6-methyloxan-2-yl]oxy-4-(dimethylamino)-6-methyloxan-2-yl]oxy-2-ethyl-2,5,7,10-tetrahydroxy-6,11-dioxo-3,4-dihydro-1h-tetracene-1-carboxylat Chemical compound O([C@H]1[C@@H](O)C[C@@H](O[C@H]1C)O[C@H]1[C@H](C[C@@H](O[C@H]1C)O[C@H]1C[C@]([C@@H](C2=CC=3C(=O)C4=C(O)C=CC(O)=C4C(=O)C=3C(O)=C21)C(=O)OC)(O)CC)N(C)C)[C@H]1C[C@H](O)[C@H](O)[C@H](C)O1 VJRAUFKOOPNFIQ-TVEKBUMESA-N 0.000 description 2
- MXWHMTNPTTVWDM-NXOFHUPFSA-N mitoguazone Chemical compound NC(N)=N\N=C(/C)\C=N\N=C(N)N MXWHMTNPTTVWDM-NXOFHUPFSA-N 0.000 description 2
- 229960004857 mitomycin Drugs 0.000 description 2
- 229960001156 mitoxantrone Drugs 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- FOYWNSCCNCUEPU-UHFFFAOYSA-N mopidamol Chemical compound C12=NC(N(CCO)CCO)=NC=C2N=C(N(CCO)CCO)N=C1N1CCCCC1 FOYWNSCCNCUEPU-UHFFFAOYSA-N 0.000 description 2
- 229950010718 mopidamol Drugs 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 210000005036 nerve Anatomy 0.000 description 2
- YMVWGSQGCWCDGW-UHFFFAOYSA-N nitracrine Chemical compound C1=CC([N+]([O-])=O)=C2C(NCCCN(C)C)=C(C=CC=C3)C3=NC2=C1 YMVWGSQGCWCDGW-UHFFFAOYSA-N 0.000 description 2
- 229950008607 nitracrine Drugs 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- KGTDRFCXGRULNK-JYOBTZKQSA-N nogalamycin Chemical compound CO[C@@H]1[C@@](OC)(C)[C@@H](OC)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=C(O)C=C4[C@@]5(C)O[C@H]([C@H]([C@@H]([C@H]5O)N(C)C)O)OC4=C3C3=O)=C3C=C2[C@@H](C(=O)OC)[C@@](C)(O)C1 KGTDRFCXGRULNK-JYOBTZKQSA-N 0.000 description 2
- 229950009266 nogalamycin Drugs 0.000 description 2
- 229950011093 onapristone Drugs 0.000 description 2
- 229960001592 paclitaxel Drugs 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- NUKCGLDCWQXYOQ-UHFFFAOYSA-N piposulfan Chemical compound CS(=O)(=O)OCCC(=O)N1CCN(C(=O)CCOS(C)(=O)=O)CC1 NUKCGLDCWQXYOQ-UHFFFAOYSA-N 0.000 description 2
- 229950001100 piposulfan Drugs 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 229960004694 prednimustine Drugs 0.000 description 2
- WOLQREOUPKZMEX-UHFFFAOYSA-N pteroyltriglutamic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(=O)NC(CCC(=O)NC(CCC(O)=O)C(O)=O)C(O)=O)C(O)=O)C=C1 WOLQREOUPKZMEX-UHFFFAOYSA-N 0.000 description 2
- RXWNCPJZOCPEPQ-NVWDDTSBSA-N puromycin Chemical compound C1=CC(OC)=CC=C1C[C@H](N)C(=O)N[C@H]1[C@@H](O)[C@H](N2C3=NC=NC(=C3N=C2)N(C)C)O[C@@H]1CO RXWNCPJZOCPEPQ-NVWDDTSBSA-N 0.000 description 2
- BMKDZUISNHGIBY-UHFFFAOYSA-N razoxane Chemical compound C1C(=O)NC(=O)CN1C(C)CN1CC(=O)NC(=O)C1 BMKDZUISNHGIBY-UHFFFAOYSA-N 0.000 description 2
- 229960000460 razoxane Drugs 0.000 description 2
- 210000001957 retinal vein Anatomy 0.000 description 2
- 235000009566 rice Nutrition 0.000 description 2
- 229950004892 rodorubicin Drugs 0.000 description 2
- 229950001403 sizofiran Drugs 0.000 description 2
- 159000000000 sodium salts Chemical group 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 229960001603 tamoxifen Drugs 0.000 description 2
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 2
- 210000001550 testis Anatomy 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 229960004072 thrombin Drugs 0.000 description 2
- WYWHKKSPHMUBEB-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 2
- PXSOHRWMIRDKMP-UHFFFAOYSA-N triaziquone Chemical compound O=C1C(N2CC2)=C(N2CC2)C(=O)C=C1N1CC1 PXSOHRWMIRDKMP-UHFFFAOYSA-N 0.000 description 2
- KVJXBPDAXMEYOA-CXANFOAXSA-N trilostane Chemical compound OC1=C(C#N)C[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@@]32O[C@@H]31 KVJXBPDAXMEYOA-CXANFOAXSA-N 0.000 description 2
- 229960001670 trilostane Drugs 0.000 description 2
- NOYPYLRCIDNJJB-UHFFFAOYSA-N trimetrexate Chemical compound COC1=C(OC)C(OC)=CC(NCC=2C(=C3C(N)=NC(N)=NC3=CC=2)C)=C1 NOYPYLRCIDNJJB-UHFFFAOYSA-N 0.000 description 2
- 229960001099 trimetrexate Drugs 0.000 description 2
- HDZZVAMISRMYHH-LITAXDCLSA-N tubercidin Chemical compound C1=CC=2C(N)=NC=NC=2N1[C@@H]1O[C@@H](CO)[C@H](O)[C@H]1O HDZZVAMISRMYHH-LITAXDCLSA-N 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- 229950009811 ubenimex Drugs 0.000 description 2
- 210000001745 uvea Anatomy 0.000 description 2
- GBABOYUKABKIAF-IELIFDKJSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-IELIFDKJSA-N 0.000 description 2
- 229960002066 vinorelbine Drugs 0.000 description 2
- 238000001262 western blot Methods 0.000 description 2
- FBTUMDXHSRTGRV-ALTNURHMSA-N zorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(\C)=N\NC(=O)C=1C=CC=CC=1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 FBTUMDXHSRTGRV-ALTNURHMSA-N 0.000 description 2
- 229960000641 zorubicin Drugs 0.000 description 2
- FLWWDYNPWOSLEO-HQVZTVAUSA-N (2s)-2-[[4-[1-(2-amino-4-oxo-1h-pteridin-6-yl)ethyl-methylamino]benzoyl]amino]pentanedioic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1C(C)N(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FLWWDYNPWOSLEO-HQVZTVAUSA-N 0.000 description 1
- XRBSKUSTLXISAB-UHFFFAOYSA-N (7R,7'R,8R,8'R)-form-Podophyllic acid Natural products COC1=C(OC)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C(CO)C2C(O)=O)=C1 XRBSKUSTLXISAB-UHFFFAOYSA-N 0.000 description 1
- AESVUZLWRXEGEX-DKCAWCKPSA-N (7S,9R)-7-[(2S,4R,5R,6R)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7H-tetracene-5,12-dione iron(3+) Chemical compound [Fe+3].COc1cccc2C(=O)c3c(O)c4C[C@@](O)(C[C@H](O[C@@H]5C[C@@H](N)[C@@H](O)[C@@H](C)O5)c4c(O)c3C(=O)c12)C(=O)CO AESVUZLWRXEGEX-DKCAWCKPSA-N 0.000 description 1
- HXSHBEIVXXJJIJ-MHEUWTTISA-N (8R,9S,13S,14S)-15-methoxy-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthrene-3,17-diol Chemical compound OC1=CC=C2[C@H]3CC[C@]4(C)C(O)CC(OC)[C@H]4[C@@H]3CCC2=C1 HXSHBEIVXXJJIJ-MHEUWTTISA-N 0.000 description 1
- FPVKHBSQESCIEP-UHFFFAOYSA-N (8S)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol Natural products C1C(O)C(CO)OC1N1C(NC=NCC2O)=C2N=C1 FPVKHBSQESCIEP-UHFFFAOYSA-N 0.000 description 1
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 1
- UHDGCWIWMRVCDJ-UHFFFAOYSA-N 1-beta-D-Xylofuranosyl-NH-Cytosine Natural products O=C1N=C(N)C=CN1C1C(O)C(O)C(CO)O1 UHDGCWIWMRVCDJ-UHFFFAOYSA-N 0.000 description 1
- BTOTXLJHDSNXMW-POYBYMJQSA-N 2,3-dideoxyuridine Chemical compound O1[C@H](CO)CC[C@@H]1N1C(=O)NC(=O)C=C1 BTOTXLJHDSNXMW-POYBYMJQSA-N 0.000 description 1
- UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 description 1
- VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 description 1
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 1
- PWMYMKOUNYTVQN-UHFFFAOYSA-N 3-(8,8-diethyl-2-aza-8-germaspiro[4.5]decan-2-yl)-n,n-dimethylpropan-1-amine Chemical compound C1C[Ge](CC)(CC)CCC11CN(CCCN(C)C)CC1 PWMYMKOUNYTVQN-UHFFFAOYSA-N 0.000 description 1
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 description 1
- DODQJNMQWMSYGS-QPLCGJKRSA-N 4-[(z)-1-[4-[2-(dimethylamino)ethoxy]phenyl]-1-phenylbut-1-en-2-yl]phenol Chemical compound C=1C=C(O)C=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 DODQJNMQWMSYGS-QPLCGJKRSA-N 0.000 description 1
- SGOOQMRIPALTEL-UHFFFAOYSA-N 4-hydroxy-N,1-dimethyl-2-oxo-N-phenyl-3-quinolinecarboxamide Chemical compound OC=1C2=CC=CC=C2N(C)C(=O)C=1C(=O)N(C)C1=CC=CC=C1 SGOOQMRIPALTEL-UHFFFAOYSA-N 0.000 description 1
- JOOXCMJARBKPKM-UHFFFAOYSA-N 4-oxopentanoic acid Chemical compound CC(=O)CCC(O)=O JOOXCMJARBKPKM-UHFFFAOYSA-N 0.000 description 1
- IDPUKCWIGUEADI-UHFFFAOYSA-N 5-[bis(2-chloroethyl)amino]uracil Chemical compound ClCCN(CCCl)C1=CNC(=O)NC1=O IDPUKCWIGUEADI-UHFFFAOYSA-N 0.000 description 1
- VVIAGPKUTFNRDU-UHFFFAOYSA-N 6S-folinic acid Natural products C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-UHFFFAOYSA-N 0.000 description 1
- AOJJSUZBOXZQNB-UHFFFAOYSA-N 7-[(4-amino-5-hydroxy-6-methyl-2-oxanyl)oxy]-6,9,11-trihydroxy-9-(2-hydroxy-1-oxoethyl)-4-methoxy-8,10-dihydro-7H-tetracene-5,12-dione Chemical compound C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(=O)CO)CC1OC1CC(N)C(O)C(C)O1 AOJJSUZBOXZQNB-UHFFFAOYSA-N 0.000 description 1
- 102000007469 Actins Human genes 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- 102000014654 Aromatase Human genes 0.000 description 1
- 108010078554 Aromatase Proteins 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- ZRVVLSGESKEHSA-UHFFFAOYSA-N CC(CC(OC)=C1)(C=C1c1nc(cc2OCOc2c2)c2c(O)c1)O Chemical compound CC(CC(OC)=C1)(C=C1c1nc(cc2OCOc2c2)c2c(O)c1)O ZRVVLSGESKEHSA-UHFFFAOYSA-N 0.000 description 1
- SHHKQEUPHAENFK-UHFFFAOYSA-N Carboquone Chemical compound O=C1C(C)=C(N2CC2)C(=O)C(C(COC(N)=O)OC)=C1N1CC1 SHHKQEUPHAENFK-UHFFFAOYSA-N 0.000 description 1
- XCDXSSFOJZZGQC-UHFFFAOYSA-N Chlornaphazine Chemical compound C1=CC=CC2=CC(N(CCCl)CCCl)=CC=C21 XCDXSSFOJZZGQC-UHFFFAOYSA-N 0.000 description 1
- 102100021809 Chorionic somatomammotropin hormone 1 Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 102100031162 Collagen alpha-1(XVIII) chain Human genes 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 229920000832 Cutin Polymers 0.000 description 1
- 206010063057 Cystitis noninfective Diseases 0.000 description 1
- UHDGCWIWMRVCDJ-PSQAKQOGSA-N Cytidine Natural products O=C1N=C(N)C=CN1[C@@H]1[C@@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-PSQAKQOGSA-N 0.000 description 1
- 108010092160 Dactinomycin Proteins 0.000 description 1
- 208000037162 Ductal Breast Carcinoma Diseases 0.000 description 1
- 108010079505 Endostatins Proteins 0.000 description 1
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 description 1
- 229930189413 Esperamicin Natural products 0.000 description 1
- MPJKWIXIYCLVCU-UHFFFAOYSA-N Folinic acid Natural products NC1=NC2=C(N(C=O)C(CNc3ccc(cc3)C(=O)NC(CCC(=O)O)CC(=O)O)CN2)C(=O)N1 MPJKWIXIYCLVCU-UHFFFAOYSA-N 0.000 description 1
- 102100033299 Glia-derived nexin Human genes 0.000 description 1
- 101000895818 Homo sapiens Chorionic somatomammotropin hormone 1 Proteins 0.000 description 1
- 101000956228 Homo sapiens Chorionic somatomammotropin hormone 2 Proteins 0.000 description 1
- 101000997803 Homo sapiens Glia-derived nexin Proteins 0.000 description 1
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 1
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 1
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 description 1
- 102000006992 Interferon-alpha Human genes 0.000 description 1
- 108010047761 Interferon-alpha Proteins 0.000 description 1
- 102000013462 Interleukin-12 Human genes 0.000 description 1
- 108010065805 Interleukin-12 Proteins 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- 229920001491 Lentinan Polymers 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 102000010750 Metalloproteins Human genes 0.000 description 1
- 108010063312 Metalloproteins Proteins 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- VFKZTMPDYBFSTM-KVTDHHQDSA-N Mitobronitol Chemical compound BrC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CBr VFKZTMPDYBFSTM-KVTDHHQDSA-N 0.000 description 1
- 229930192392 Mitomycin Natural products 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- MSHZHSPISPJWHW-UHFFFAOYSA-N O-(chloroacetylcarbamoyl)fumagillol Chemical compound O1C(CC=C(C)C)C1(C)C1C(OC)C(OC(=O)NC(=O)CCl)CCC21CO2 MSHZHSPISPJWHW-UHFFFAOYSA-N 0.000 description 1
- 229930187135 Olivomycin Natural products 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 108010057150 Peplomycin Proteins 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- KMSKQZKKOZQFFG-HSUXVGOQSA-N Pirarubicin Chemical compound O([C@H]1[C@@H](N)C[C@@H](O[C@H]1C)O[C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1CCCCO1 KMSKQZKKOZQFFG-HSUXVGOQSA-N 0.000 description 1
- 102000004211 Platelet factor 4 Human genes 0.000 description 1
- 108090000778 Platelet factor 4 Proteins 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 241000508269 Psidium Species 0.000 description 1
- 201000001263 Psoriatic Arthritis Diseases 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- AHHFEZNOXOZZQA-ZEBDFXRSSA-N Ranimustine Chemical compound CO[C@H]1O[C@H](CNC(=O)N(CCCl)N=O)[C@@H](O)[C@H](O)[C@H]1O AHHFEZNOXOZZQA-ZEBDFXRSSA-N 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 208000017442 Retinal disease Diseases 0.000 description 1
- 206010038923 Retinopathy Diseases 0.000 description 1
- 208000021386 Sjogren Syndrome Diseases 0.000 description 1
- 208000021712 Soft tissue sarcoma Diseases 0.000 description 1
- 201000002661 Spondylitis Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 241001116498 Taxus baccata Species 0.000 description 1
- 102000002938 Thrombospondin Human genes 0.000 description 1
- 108060008245 Thrombospondin Proteins 0.000 description 1
- 101710183280 Topoisomerase Proteins 0.000 description 1
- IWEQQRMGNVVKQW-OQKDUQJOSA-N Toremifene citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 IWEQQRMGNVVKQW-OQKDUQJOSA-N 0.000 description 1
- FYAMXEPQQLNQDM-UHFFFAOYSA-N Tris(1-aziridinyl)phosphine oxide Chemical compound C1CN1P(N1CC1)(=O)N1CC1 FYAMXEPQQLNQDM-UHFFFAOYSA-N 0.000 description 1
- VGQOVCHZGQWAOI-UHFFFAOYSA-N UNPD55612 Natural products N1C(O)C2CC(C=CC(N)=O)=CN2C(=O)C2=CC=C(C)C(O)=C12 VGQOVCHZGQWAOI-UHFFFAOYSA-N 0.000 description 1
- 201000005969 Uveal melanoma Diseases 0.000 description 1
- 108091008605 VEGF receptors Proteins 0.000 description 1
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 1
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 1
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 1
- IFJUINDAXYAPTO-UUBSBJJBSA-N [(8r,9s,13s,14s,17s)-17-[2-[4-[4-[bis(2-chloroethyl)amino]phenyl]butanoyloxy]acetyl]oxy-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-3-yl] benzoate Chemical compound C([C@@H]1[C@@H](C2=CC=3)CC[C@]4([C@H]1CC[C@@H]4OC(=O)COC(=O)CCCC=1C=CC(=CC=1)N(CCCl)CCCl)C)CC2=CC=3OC(=O)C1=CC=CC=C1 IFJUINDAXYAPTO-UUBSBJJBSA-N 0.000 description 1
- IHGLINDYFMDHJG-UHFFFAOYSA-N [2-(4-methoxyphenyl)-3,4-dihydronaphthalen-1-yl]-[4-(2-pyrrolidin-1-ylethoxy)phenyl]methanone Chemical compound C1=CC(OC)=CC=C1C(CCC1=CC=CC=C11)=C1C(=O)C(C=C1)=CC=C1OCCN1CCCC1 IHGLINDYFMDHJG-UHFFFAOYSA-N 0.000 description 1
- PSDYQSWHANEKRV-UHFFFAOYSA-N [S]N Chemical compound [S]N PSDYQSWHANEKRV-UHFFFAOYSA-N 0.000 description 1
- USDJGQLNFPZEON-UHFFFAOYSA-N [[4,6-bis(hydroxymethylamino)-1,3,5-triazin-2-yl]amino]methanol Chemical compound OCNC1=NC(NCO)=NC(NCO)=N1 USDJGQLNFPZEON-UHFFFAOYSA-N 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 229930188522 aclacinomycin Natural products 0.000 description 1
- USZYSDMBJDPRIF-SVEJIMAYSA-N aclacinomycin A Chemical compound O([C@H]1[C@@H](O)C[C@@H](O[C@H]1C)O[C@H]1[C@H](C[C@@H](O[C@H]1C)O[C@H]1C[C@]([C@@H](C2=CC=3C(=O)C4=CC=CC(O)=C4C(=O)C=3C(O)=C21)C(=O)OC)(O)CC)N(C)C)[C@H]1CCC(=O)[C@H](C)O1 USZYSDMBJDPRIF-SVEJIMAYSA-N 0.000 description 1
- 229960004176 aclarubicin Drugs 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 210000004100 adrenal gland Anatomy 0.000 description 1
- 229940009456 adriamycin Drugs 0.000 description 1
- TXUZVZSFRXZGTL-QPLCGJKRSA-N afimoxifene Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=C(O)C=C1 TXUZVZSFRXZGTL-QPLCGJKRSA-N 0.000 description 1
- 125000002723 alicyclic group Chemical group 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000002521 alkyl halide group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 1
- BSJGASKRWFKGMV-UHFFFAOYSA-L ammonia dichloroplatinum(2+) Chemical compound N.N.Cl[Pt+2]Cl BSJGASKRWFKGMV-UHFFFAOYSA-L 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- VGQOVCHZGQWAOI-HYUHUPJXSA-N anthramycin Chemical compound N1[C@@H](O)[C@@H]2CC(\C=C\C(N)=O)=CN2C(=O)C2=CC=C(C)C(O)=C12 VGQOVCHZGQWAOI-HYUHUPJXSA-N 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 230000002280 anti-androgenic effect Effects 0.000 description 1
- 230000003527 anti-angiogenesis Effects 0.000 description 1
- 230000001833 anti-estrogenic effect Effects 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000000051 antiandrogen Substances 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 229940045719 antineoplastic alkylating agent nitrosoureas Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 150000008209 arabinosides Chemical class 0.000 description 1
- 150000001541 aziridines Chemical class 0.000 description 1
- 150000003851 azoles Chemical class 0.000 description 1
- 229950005567 benzodepa Drugs 0.000 description 1
- VFIUCBTYGKMLCM-UHFFFAOYSA-N benzyl n-[bis(aziridin-1-yl)phosphoryl]carbamate Chemical compound C=1C=CC=CC=1COC(=O)NP(=O)(N1CC1)N1CC1 VFIUCBTYGKMLCM-UHFFFAOYSA-N 0.000 description 1
- 108010051210 beta-Fructofuranosidase Proteins 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 229950008548 bisantrene Drugs 0.000 description 1
- 229960001561 bleomycin Drugs 0.000 description 1
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 1
- 206010006007 bone sarcoma Diseases 0.000 description 1
- 208000014581 breast ductal adenocarcinoma Diseases 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229960002092 busulfan Drugs 0.000 description 1
- IVFYLRMMHVYGJH-PVPPCFLZSA-N calusterone Chemical compound C1C[C@]2(C)[C@](O)(C)CC[C@H]2[C@@H]2[C@@H](C)CC3=CC(=O)CC[C@]3(C)[C@H]21 IVFYLRMMHVYGJH-PVPPCFLZSA-N 0.000 description 1
- 229950009823 calusterone Drugs 0.000 description 1
- 230000004611 cancer cell death Effects 0.000 description 1
- 230000005907 cancer growth Effects 0.000 description 1
- PHDSHKDUDPVVGU-UHFFFAOYSA-N carbamic acid;2h-triazole Chemical compound NC(O)=O.C=1C=NNN=1 PHDSHKDUDPVVGU-UHFFFAOYSA-N 0.000 description 1
- 235000013877 carbamide Nutrition 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 229960002115 carboquone Drugs 0.000 description 1
- 125000004181 carboxyalkyl group Chemical group 0.000 description 1
- 210000000845 cartilage Anatomy 0.000 description 1
- 108010047060 carzinophilin Proteins 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000008619 cell matrix interaction Effects 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 230000008614 cellular interaction Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229940060038 chlorine Drugs 0.000 description 1
- 229950008249 chlornaphazine Drugs 0.000 description 1
- OYMZKNZKZDAMHV-UHFFFAOYSA-N chlorobenzene;1,1-dichloroethane Chemical compound CC(Cl)Cl.ClC1=CC=CC=C1 OYMZKNZKZDAMHV-UHFFFAOYSA-N 0.000 description 1
- ZYVSOIYQKUDENJ-WKSBCEQHSA-N chromomycin A3 Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@@H]1OC(C)=O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@@H](O)[C@H](O[C@@H]3O[C@@H](C)[C@H](OC(C)=O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@@H]1C[C@@H](O)[C@@H](OC)[C@@H](C)O1 ZYVSOIYQKUDENJ-WKSBCEQHSA-N 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 229940127573 compound 38 Drugs 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 229960000684 cytarabine Drugs 0.000 description 1
- UHDGCWIWMRVCDJ-ZAKLUEHWSA-N cytidine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-ZAKLUEHWSA-N 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 229960003901 dacarbazine Drugs 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000002405 diagnostic procedure Methods 0.000 description 1
- 239000012954 diazonium Substances 0.000 description 1
- 125000000950 dibromo group Chemical group Br* 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- MCWXGJITAZMZEV-UHFFFAOYSA-N dimethoate Chemical compound CNC(=O)CSP(=S)(OC)OC MCWXGJITAZMZEV-UHFFFAOYSA-N 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- 230000007783 downstream signaling Effects 0.000 description 1
- ZWAOHEXOSAUJHY-ZIYNGMLESA-N doxifluridine Chemical compound O[C@@H]1[C@H](O)[C@@H](C)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ZWAOHEXOSAUJHY-ZIYNGMLESA-N 0.000 description 1
- 229950005454 doxifluridine Drugs 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- FSIRXIHZBIXHKT-MHTVFEQDSA-N edatrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CC(CC)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FSIRXIHZBIXHKT-MHTVFEQDSA-N 0.000 description 1
- 229950006700 edatrexate Drugs 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 210000003038 endothelium Anatomy 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 229960001904 epirubicin Drugs 0.000 description 1
- 229950002973 epitiostanol Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 229960001842 estramustine Drugs 0.000 description 1
- FRPJXPJMRWBBIH-RBRWEJTLSA-N estramustine Chemical compound ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 FRPJXPJMRWBBIH-RBRWEJTLSA-N 0.000 description 1
- 239000000328 estrogen antagonist Substances 0.000 description 1
- QSRLNKCNOLVZIR-KRWDZBQOSA-N ethyl (2s)-2-[[2-[4-[bis(2-chloroethyl)amino]phenyl]acetyl]amino]-4-methylsulfanylbutanoate Chemical compound CCOC(=O)[C@H](CCSC)NC(=O)CC1=CC=C(N(CCCl)CCCl)C=C1 QSRLNKCNOLVZIR-KRWDZBQOSA-N 0.000 description 1
- 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 229940043168 fareston Drugs 0.000 description 1
- 229960000961 floxuridine Drugs 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 229960002074 flutamide Drugs 0.000 description 1
- MKXKFYHWDHIYRV-UHFFFAOYSA-N flutamide Chemical compound CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 description 1
- 229940064302 folacin Drugs 0.000 description 1
- VVIAGPKUTFNRDU-ABLWVSNPSA-N folinic acid Chemical compound C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-ABLWVSNPSA-N 0.000 description 1
- 235000008191 folinic acid Nutrition 0.000 description 1
- 239000011672 folinic acid Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 229960004783 fotemustine Drugs 0.000 description 1
- YAKWPXVTIGTRJH-UHFFFAOYSA-N fotemustine Chemical compound CCOP(=O)(OCC)C(C)NC(=O)N(CCCl)N=O YAKWPXVTIGTRJH-UHFFFAOYSA-N 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 229940044658 gallium nitrate Drugs 0.000 description 1
- 201000008822 gestational choriocarcinoma Diseases 0.000 description 1
- 229960002972 glutethimide Drugs 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 150000002338 glycosides Chemical class 0.000 description 1
- 239000003163 gonadal steroid hormone Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 235000003642 hunger Nutrition 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 229960001330 hydroxycarbamide Drugs 0.000 description 1
- 230000001969 hypertrophic effect Effects 0.000 description 1
- 229960000908 idarubicin Drugs 0.000 description 1
- 229960001101 ifosfamide Drugs 0.000 description 1
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 1
- 238000003119 immunoblot Methods 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000001573 invertase Substances 0.000 description 1
- 235000011073 invertase Nutrition 0.000 description 1
- IQPQWNKOIGAROB-UHFFFAOYSA-N isocyanate group Chemical group [N-]=C=O IQPQWNKOIGAROB-UHFFFAOYSA-N 0.000 description 1
- 229960004130 itraconazole Drugs 0.000 description 1
- 208000018937 joint inflammation Diseases 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 210000003292 kidney cell Anatomy 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 229940115286 lentinan Drugs 0.000 description 1
- 229960001691 leucovorin Drugs 0.000 description 1
- 229940063740 lexifen Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 210000001161 mammalian embryo Anatomy 0.000 description 1
- 230000000684 melanotic effect Effects 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- HRHKSTOGXBBQCB-VFWICMBZSA-N methylmitomycin Chemical compound O=C1C(N)=C(C)C(=O)C2=C1[C@@H](COC(N)=O)[C@@]1(OC)[C@H]3N(C)[C@H]3CN12 HRHKSTOGXBBQCB-VFWICMBZSA-N 0.000 description 1
- QTFKTBRIGWJQQL-UHFFFAOYSA-N meturedepa Chemical compound C1C(C)(C)N1P(=O)(NC(=O)OCC)N1CC1(C)C QTFKTBRIGWJQQL-UHFFFAOYSA-N 0.000 description 1
- 229950009847 meturedepa Drugs 0.000 description 1
- 230000000116 mitigating effect Effects 0.000 description 1
- 229960005485 mitobronitol Drugs 0.000 description 1
- 229960003539 mitoguazone Drugs 0.000 description 1
- VFKZTMPDYBFSTM-GUCUJZIJSA-N mitolactol Chemical compound BrC[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CBr VFKZTMPDYBFSTM-GUCUJZIJSA-N 0.000 description 1
- 229950010913 mitolactol Drugs 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- NJSMWLQOCQIOPE-OCHFTUDZSA-N n-[(e)-[10-[(e)-(4,5-dihydro-1h-imidazol-2-ylhydrazinylidene)methyl]anthracen-9-yl]methylideneamino]-4,5-dihydro-1h-imidazol-2-amine Chemical compound N1CCN=C1N\N=C\C(C1=CC=CC=C11)=C(C=CC=C2)C2=C1\C=N\NC1=NCCN1 NJSMWLQOCQIOPE-OCHFTUDZSA-N 0.000 description 1
- OHDXDNUPVVYWOV-UHFFFAOYSA-N n-methyl-1-(2-naphthalen-1-ylsulfanylphenyl)methanamine Chemical compound CNCC1=CC=CC=C1SC1=CC=CC2=CC=CC=C12 OHDXDNUPVVYWOV-UHFFFAOYSA-N 0.000 description 1
- 229940086322 navelbine Drugs 0.000 description 1
- 201000008383 nephritis Diseases 0.000 description 1
- 238000003012 network analysis Methods 0.000 description 1
- XWXYUMMDTVBTOU-UHFFFAOYSA-N nilutamide Chemical compound O=C1C(C)(C)NC(=O)N1C1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 XWXYUMMDTVBTOU-UHFFFAOYSA-N 0.000 description 1
- 229960002653 nilutamide Drugs 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 230000008481 normal tissue growth Effects 0.000 description 1
- CZDBNBLGZNWKMC-MWQNXGTOSA-N olivomycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1)O[C@H]1O[C@@H](C)[C@H](O)[C@@H](OC2O[C@@H](C)[C@H](O)[C@@H](O)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@H](O)[C@H](OC)[C@H](C)O1 CZDBNBLGZNWKMC-MWQNXGTOSA-N 0.000 description 1
- 229950005848 olivomycin Drugs 0.000 description 1
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229960002340 pentostatin Drugs 0.000 description 1
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 description 1
- QIMGFXOHTOXMQP-GFAGFCTOSA-N peplomycin Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCCN[C@@H](C)C=1C=CC=CC=1)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1NC=NC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C QIMGFXOHTOXMQP-GFAGFCTOSA-N 0.000 description 1
- 229950003180 peplomycin Drugs 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 150000007965 phenolic acids Chemical class 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- NJBFOOCLYDNZJN-UHFFFAOYSA-N pipobroman Chemical compound BrCCC(=O)N1CCN(C(=O)CCBr)CC1 NJBFOOCLYDNZJN-UHFFFAOYSA-N 0.000 description 1
- 229960000952 pipobroman Drugs 0.000 description 1
- 229960001221 pirarubicin Drugs 0.000 description 1
- 150000003057 platinum Chemical class 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 230000004481 post-translational protein modification Effects 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 229940117820 purinethol Drugs 0.000 description 1
- 229950010131 puromycin Drugs 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 229960002185 ranimustine Drugs 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 229930002330 retinoic acid Natural products 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 201000003068 rheumatic fever Diseases 0.000 description 1
- 229960003522 roquinimex Drugs 0.000 description 1
- VHXNKPBCCMUMSW-FQEVSTJZSA-N rubitecan Chemical compound C1=CC([N+]([O-])=O)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VHXNKPBCCMUMSW-FQEVSTJZSA-N 0.000 description 1
- 229950003647 semaxanib Drugs 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 229950006315 spirogermanium Drugs 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- BUUPQKDIAURBJP-UHFFFAOYSA-N sulfinic acid Chemical compound OS=O BUUPQKDIAURBJP-UHFFFAOYSA-N 0.000 description 1
- 125000003375 sulfoxide group Chemical group 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- FIAFUQMPZJWCLV-UHFFFAOYSA-N suramin Chemical compound OS(=O)(=O)C1=CC(S(O)(=O)=O)=C2C(NC(=O)C3=CC=C(C(=C3)NC(=O)C=3C=C(NC(=O)NC=4C=C(C=CC=4)C(=O)NC=4C(=CC=C(C=4)C(=O)NC=4C5=C(C=C(C=C5C(=CC=4)S(O)(=O)=O)S(O)(=O)=O)S(O)(=O)=O)C)C=CC=3)C)=CC=C(S(O)(=O)=O)C2=C1 FIAFUQMPZJWCLV-UHFFFAOYSA-N 0.000 description 1
- 229960005314 suramin Drugs 0.000 description 1
- 229950001899 tasquinimod Drugs 0.000 description 1
- ONDYALNGTUAJDX-UHFFFAOYSA-N tasquinimod Chemical compound OC=1C=2C(OC)=CC=CC=2N(C)C(=O)C=1C(=O)N(C)C1=CC=C(C(F)(F)F)C=C1 ONDYALNGTUAJDX-UHFFFAOYSA-N 0.000 description 1
- BPEWUONYVDABNZ-DZBHQSCQSA-N testolactone Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(OC(=O)CC4)[C@@H]4[C@@H]3CCC2=C1 BPEWUONYVDABNZ-DZBHQSCQSA-N 0.000 description 1
- 229960005353 testolactone Drugs 0.000 description 1
- CXVCSRUYMINUSF-UHFFFAOYSA-N tetrathiomolybdate(2-) Chemical compound [S-][Mo]([S-])(=S)=S CXVCSRUYMINUSF-UHFFFAOYSA-N 0.000 description 1
- 229960003433 thalidomide Drugs 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000010409 thin film Substances 0.000 description 1
- 125000004149 thio group Chemical group *S* 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 125000000464 thioxo group Chemical group S=* 0.000 description 1
- YFTWHEBLORWGNI-UHFFFAOYSA-N tiamiprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC(N)=NC2=C1NC=N2 YFTWHEBLORWGNI-UHFFFAOYSA-N 0.000 description 1
- 229950011457 tiamiprine Drugs 0.000 description 1
- 229960003087 tioguanine Drugs 0.000 description 1
- XFCLJVABOIYOMF-QPLCGJKRSA-N toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 0.000 description 1
- 229960005026 toremifene Drugs 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- IUCJMVBFZDHPDX-UHFFFAOYSA-N tretamine Chemical compound C1CN1C1=NC(N2CC2)=NC(N2CC2)=N1 IUCJMVBFZDHPDX-UHFFFAOYSA-N 0.000 description 1
- 229950001353 tretamine Drugs 0.000 description 1
- 229960001727 tretinoin Drugs 0.000 description 1
- 229960004560 triaziquone Drugs 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 229950000212 trioxifene Drugs 0.000 description 1
- 229960000875 trofosfamide Drugs 0.000 description 1
- UMKFEPPTGMDVMI-UHFFFAOYSA-N trofosfamide Chemical compound ClCCN(CCCl)P1(=O)OCCCN1CCCl UMKFEPPTGMDVMI-UHFFFAOYSA-N 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
- 230000005641 tunneling Effects 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 229940035893 uracil Drugs 0.000 description 1
- 229960001055 uracil mustard Drugs 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- COFJBSXICYYSKG-FJFFLIEUSA-N vindesine sulfate Chemical compound OS(O)(=O)=O.C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(N)=O)N4C)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 COFJBSXICYYSKG-FJFFLIEUSA-N 0.000 description 1
- CILBMBUYJCWATM-PYGJLNRPSA-N vinorelbine ditartrate Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC CILBMBUYJCWATM-PYGJLNRPSA-N 0.000 description 1
- 229940053867 xeloda Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4741—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having oxygen as a ring hetero atom, e.g. tubocuraran derivatives, noscapine, bicuculline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
- A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- 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
- A61P13/10—Drugs for disorders of the urinary system of the bladder
-
- 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
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- 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
-
- 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
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- 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
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- 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
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Urology & Nephrology (AREA)
- Dermatology (AREA)
- Physical Education & Sports Medicine (AREA)
- Rheumatology (AREA)
- Oncology (AREA)
- Pulmonology (AREA)
- Pain & Pain Management (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Hematology (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Psychology (AREA)
- Ophthalmology & Optometry (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Gastroenterology & Hepatology (AREA)
- Vascular Medicine (AREA)
- Transplantation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种芳基喹啉衍生物,其用于在需要其的对象中抑制血管生成拟态、治疗特征为异常的血管形态或功能和/或存在血管生成拟态的疾病。在本发明的一个具体实例中,该化合物用于治疗转移性肿瘤、过度增生性或血管生成性疾病。在本发明的另一个具体实例中,该化合物的使用可结合使用额外的治疗药物,诸如抗癌剂、抗炎药、抗增殖剂、抗荷尔蒙剂或其任何组合。
Description
技术领域
本发明关于一种芳基喹啉衍生物的新用途;且更特别地,关于一种用来抑制血管生成拟态及治疗与迷管形态及功能相关和/或特征为存在血管生成拟态的疾病或症状的芳基喹啉衍生物。
背景技术
术语“血管生成拟态”描述为由高度侵入性及基因失调的肿瘤细胞形成流体输导管道。已经描述了两种特殊的血管生成拟态类型。管状类型的血管生成拟态可在形态学上与内衬内皮细胞的血管混淆。图案状基质类型的血管生成拟态在形态学或拓扑学上与血管毫不类似。已经在这些图案中鉴别出基质蛋白质,诸如层粘连蛋白、硫酸乙酰肝素(heparansulfate)蛋白糖及胶原蛋白IV及VI。该图案状基质与血管交织。
已经在下列中鉴别出该图案状基质类型的血管生成拟态:葡萄膜、皮肤及黏液薄膜黑色瘤、炎性及导管型乳腺癌(ductal breast carcinoma)、卵巢及前列腺癌、肺癌、肾癌、肝细胞癌、间皮性肉瘤、膀胱癌、骨肉瘤、星细胞瘤、嗜铬细胞瘤、结肠直肠癌、神经管胚细胞瘤、腺癌、食道基质瘤、妊娠性绒毛膜癌、胆囊癌、胃肠癌、喉癌、滑膜肉瘤(synoviosarcoma)、神经胶母细胞瘤、白血病及软组织肉瘤,包括滑膜肉瘤、横纹肌肉瘤、骨肉瘤、尤恩氏(Ewing)肉瘤及嗜铬细胞瘤。
证据显示出血管生成拟态在下列侵袭性转移中发挥作用:喉鳞状细胞癌、肝细胞癌、肾细胞癌、乳房癌、卵巢癌、原发性胆囊癌、恶性食道基质癌、肝细胞癌、间皮性肉瘤及齿槽横纹肌肉瘤。具有黑色素瘤且显示出VM的个体具有差的预后及较高的癌复发风险。可使用VM抑制剂来抑制转移或减慢肿瘤生长。因此,已经假定VM形成的拮抗剂可在抑制肿瘤生长及高度侵袭性转移上具有有益的效果。
WO 2012/009519公开了芳基及杂芳基喹啉衍生物的合成及抗癌活性。
发明内容
在一个方面中,本发明关于如下式I、II、III或IV的化合物或其药学上可接受的盐,用于在需要其的对象中抑制血管生成拟态:
其中
R2’、R3’、R4’、R5’及R6’各自独立地为H、(CH2)nCH3、(CH2)nYH、Y(CH2)nCH3、Y(CH2)nYH、Y(CH2)nNR8R9、X、或(CH2)nNR8R9;或R3’=OP(=O)(O-苄基)2;
其中n为0-4的整数;Y为O或S;X为F、Cl或Br;及R8及R9各自独立地为H、(CH2)nYH、(CH2)nN(CnH2n+1)(CmH2m+1)或(CH2)nCH3,其中n及Y如上述定义及m为0-4的整数;
R2、R3、R4及R5各自独立地为H、(CH2)nCH3、(CH2)nYH、Y(CH2)nCH3、Y(CH2)nYH、Y(CH2)nNR8R9、X、(CH2)nNR8R9、(CH2)nN;或R4与R5一起为-Y(CH2)nY-;或R3与R4一起为-Y(CH2)nY-,其中n、Y、X、R8及R9如上述定义;或R3为O-苄基;及
R1及R1’各自独立地为H、Li+、Na+、K+、Ca++、Mg++、N+R8R9R10R11或苄基,其中R10及R11各自独立地为H、(CH2)nYH、(CH2)nN(CnH2n+1)(CmH2m+1)或(CH2)nCH3,n、m、R8及R9如上述定义。
在本发明的一个具体实例中,R2’、R3’、R4’、R5’及R6’全部为H;或R2’、R3’、R4’、R5’及R6’之一为F、OCH3或(CH2)nNR8R9,及其它为H,其中n、R8及R9如上述定义。
在本发明的另一个具体实例中,R2、R3、R4及R5全部为H;或R2、R3、R4及R5之一为F、OCH3、Y(CH2)nCH3或(CH2)nNR8R9,及其它为H;或R2及R5为H,及R3与R4一起为-O(CH2)nO-,其中n、Y、R8及R9如上述定义。
在本发明的另一个具体实例中,R1及R1’为H、Na+和/或K+。
在本发明的另一个具体实例中,R2及R5为H,及R3与R4一起为-O(CH2)O-;及R2’、R3’、R4’及R5’全部为H,及R6’为F。
在本发明的另一个具体实例中,R2及R5为H,及R3与R4一起为-O(CH2)O-;及R2’、R3’、R4’及R6’全部为H,及R5’为F。
在本发明的另一个具体实例中,R2、R3、R4及R5全部为H;及R2’、R3’、R4’、R5’及R6’全部为H。
在本发明的另一个具体实例中,R4为OCH3,及R2、R3及R5为H;及R5’为F,及R2’、R3’、R4’及R6’为H。
在本发明的另一个具体实例中,R2及R5为H,及R3与R4一起为-O(CH2)O-;及R2’、R3’、R4’及R6’全部为H,及R5’为OCH3。
在本发明的另一个具体实例中,该化合物为选自编号38、43、52、147、A6、B1、B3、C4及C6的化合物中的至少一种。
在本发明的另一个具体实例中,该对象患有特征为异常的血管形态或功能和/或存在血管生成拟态的疾病。
进一步在本发明的另一个具体实例中,该疾病为选自转移性肿瘤、过度增生疾病、炎性疾病及眼科疾病中的至少一种。
该转移性肿瘤可为选自下列各项中的至少一种:黑色素瘤、卵巢癌、前列腺癌、肾细胞癌、尤恩氏肉瘤、乳房癌、神经内分泌系癌、甲状腺癌、喉鳞状细胞癌、肝细胞癌、葡萄膜黑色素瘤、皮肤黑色素瘤、口腔恶性黑色素瘤、绒毛膜癌、原发性胆囊癌、恶性食道基质癌、间皮性肉瘤、齿槽横纹肌肉瘤、膀胱癌、骨肉瘤、星细胞瘤、嗜铬细胞瘤、结肠直肠癌、神经管胚细胞瘤、腺癌、食道基质瘤、喉癌、白血病、滑膜肉瘤、神经胶母细胞瘤及胃肠癌。
该增生过度疾病可为选自下列各项中的至少一种:牛皮癣性关节炎、类风湿性关节炎、狼疮、反应性关节炎、索格伦氏(Sjogren’s)病、炎性肠病、皮肌炎、关节强硬性脊椎炎、幼年型类风湿性关节炎、痛风、炎性骨关节炎、假性痛风、类淀粉变性病、角质变性及角化病、糖尿病性视网膜病、子宫内膜异位、黄斑变性病、瘢瘤、疣、硬化、慢性炎性相关病症、增殖性玻璃体视网膜病变、早产儿视网膜病、肉芽肿病、与器官或组织移殖相关的免疫过度增生、良性前列腺肥大及免疫增生疾病或病症。
该炎性疾病可为选自下列各项中的至少一种:寻常性痤疮、阿兹海默氏(Alzheimer’s)症、关节炎、气喘、动脉粥样硬化、自体免疫病、乳糜泻、慢性前列腺炎、结肠炎、克隆氏(Crohn’s)病、皮肤炎、憩室炎、肾小球肾炎、肝炎、发炎性肠道疾病、间质性膀胱炎、刺激性肠症候群、红斑性狼疮、肾炎、帕金森氏(Parkinson’s)病、骨盆腔发炎性疾病、类风湿性关节炎、肉状瘤病、移植排斥、溃疡性结肠炎及血管炎。
该眼科疾病可为选自下列各项中的至少一种:老年性黄斑部变性(AMD)、增生性糖尿病性视网膜病(PDR)、糖尿病性黄斑部水肿(DME)、中心性视网膜静脉阻塞(CRVO)、新生血管性青光眼、角膜新生血管形成(沙眼)及翼状胬肉。
在另一个方面中,本发明关于如下式Ia或Ib的化合物或其药学上可接受的盐,用于在需要其的对象中来抑制、减少和/或减轻血管生成拟态:
其中
R2’、R3’、R4’、R5’、R6’各自独立地为H、F、Cl、Br、(CH2)nCH3、(CH2n)OH、O-(CH2)nCH3、O(CH2)nOH、(CH2n)SH、S-(CH2)nCH3、S(CH2)nSH、O(CH2)nSH、S(CH2)nOH、(CH2)nNR8R9、O(CH2)nNR8R9、或S(CH2)nNR8R9;或R3’=OP(=O)(O-苄基)2;及
其中R8及R9各自独立地为H、(CH2)nCH3、(CH2n)OH、(CH2n)SH、(CH2)nN(CnH2n+1)(CmH2m+1),及n及m各自为0至4的整数;
R2、R3、R4及R5各自独立地为H、F、Cl、Br、(CH2)nCH3、(CH2)nOH、O(CH2)nCH3、O(CH2)nOH、O(CH2)nNR8R9、(CH2)nSH、S(CH2)nCH3、S(CH2)nSH、S(CH2)nNR8R9,(CH2)nNR8R9、(CH2)nN;或R4与R5一起为-O(CH2)nO-、或-S(CH2)nS-;或R3与R4一起为-O(CH2)nO-、或-S(CH2)nS-,其中n、R8及R9如上述定义;或R3为O-苄基;
或R5为OP=OOR1OR1’,及R1及R1’各自独立地为H、Li+、Na+、K+、Ca++、Mg++、N+R8R9R10R11或苄基,其中R10及R11各自独立地为H、(CH2)nYH、(CH2)nN(CnH2n+1)(CmH2m+1)或(CH2)nCH3,n、m、R8及R9如上述定义。
进一步在另一个方面中,本发明关于如下式(X)的化合物或其药学上可接受的盐,用于在需要其的对象中来抑制、减少和/或减轻血管生成拟态:
其中W为选自下列基团的芳香基团:萘基、喹啉、苯并呋喃基、苯并噻吩、蒽及式(Y)的经取代的苯:
及其中:
R2’、R3’、R4’、R5’、R6’各自独立地为H、F、Cl、Br、(CH2)nCH3、(CH2n)OH、O-(CH2)nCH3、O(CH2)nOH、(CH2n)SH、S-(CH2)nCH3、S(CH2)nSH、O(CH2)nSH、S(CH2)nOH、(CH2)nNR8R9、O(CH2)nNR8R9、或S(CH2)nNR8R9;或R3’=OP(=O)(O-苄基)2;及
其中R8及R9各自独立地为H、(CH2)nCH3、(CH2n)OH、(CH2n)SH、(CH2)nN(CnH2n+1)(CmH2m+1),及n及m各自为0至4的整数;
R2、R3、R4及R5各自独立地为H、F、Cl、Br、(CH2)nCH3、(CH2)nOH、O(CH2)nCH3、O(CH2)nOH、O(CH2)nNR8R9、(CH2)nSH、S(CH2)nCH3、S(CH2)nSH、S(CH2)nNR8R9、(CH2)nN、(CH2)nNR8R9;R4与R5一起为-O(CH2)nO-、或-S(CH2)nS-;或R3与R4一起为-O(CH2)nO-、-S(CH2)nS-,其中n、R8及R9如上述定义;或R3为O-苄基;
或R5为OP=OOR1OR1’,及R1及R1’各自独立地为H、Li+、Na+、K+、Ca++、Mg++、N+R8R9R10R11或苄基,其中R10及R11各自独立地为H、(CH2)nYH、(CH2)nN(CnH2n+1)(CmH2m+1)或(CH2)nCH3,n、m、R8及R9如上述定义。
在本发明的一个具体实例中,所使用的化合物为选自下列化合物中的至少一种:编号16-24、37-45、48-53、124-143、143a、143b、144、144a、144b、146-147、152-153、157-158、166-169及CHM-2133,如在表4中所列出。
再者,本发明关于如上述定义的式I、II、III或IV、或式Ia或Ib、或式(X)的化合物或其药学上可接受的盐的用途,其用来制造用以在需要其的对象中抑制血管生成拟态的药剂。
本发明还关于一种用以抑制血管生成拟态的方法,其包括将治疗有效量的如上述定义的式I、II、III或IV、或式Ia或Ib、或式(X)的化合物给药至需要其的对象。
如上述定义的式I、II、III或IV、或式Ia或Ib、或式(X)的化合物的使用可结合使用额外的治疗药物,其中该额外治疗药物选自下列各项中的至少一种:抗癌剂、抗炎药、抗增殖剂、抗荷尔蒙剂及其任何组合。
将从下列优选具体实例的说明且采用下列相关联的附图使这些及其它方面明了,然而在没有脱离本公开内容的新颖概念的精神及范围的情况下,可在其中产生变化及修改。附图阐明本发明之一或多个具体实例及与书面说明一起提供以解释本发明的原理。只要有可能,附图中使用相同附图标记指代具体实例的相同或类似元素。
附图说明
图1显示出显微照片,其阐明TRX-818抑制C8161侵袭性黑色素瘤细胞中的VM网络形成。
图2显示出显微照片,其阐明TRX-818于浓度≥5至10nM下抑制SK-MEL28癌细胞中的VM网络形成。
图3为典型的二进制影像,其阐明不同浓度的TRX-818的媒剂组中的细胞接合及小管长度的形成的影响。
图4显示出显微照片,其阐明TRX-818M1抑制C8161侵袭性黑色素瘤细胞中的VM网络形成。
图5显示出显微照片,其阐明CHM2133抑制C8161侵袭性黑色素瘤细胞中的VM网络形成。
图6A-D显示出TRX-818对Notch 4ICD、Nodal、CDH5及Eph A2表达的影响。
图7为相片,其阐明TRX-818对Pro-Nodal的蛋白表达的影响。
图8为相片,其阐明TRX-818对Smad的蛋白表达及磷酸化水平的影响。
图9显示出在HCT-116结肠癌正位异种移植模型中,在肿瘤接种后第43天时,TRX-818对肿瘤体积的影响。a:在50毫克/千克QD组中,于研究终止前发现一只动物死亡,及通过β-分布离群值分析检测,一个数据点为离群值。b:在20毫克/千克QOD组中,于研究终止前发现两只动物死亡。c:在依立替康(irinotecan)50Q4D组中,通过β-分布离群值分析检测,一个数据点为离群值。对媒剂来说,*p<0.05;对媒剂来说,**p<0.01。
图10显示出在HCT-116结肠癌正位异种移植模型中,TRX-818对VM管道数目的影响。对媒剂组来说,*p<0.05。
图11显示出显微照片,其阐明TRX-818结构类似化合物对侵袭性黑色素瘤细胞中VM网络形成的影响。
具体实施方式
更特别地以下列实施例来说明本发明,这些实施例仅用于说明目的,因为本发明的许多修改及变化对于本领域的技术人员来说是显而易见的。现在,详细地描述本发明的多个具体实例。参照附图,附图中,类似的数字表示类似的组分。如在本文的说明书及贯穿下列权利要求书所使用,除非上下文有明确指出,否则“一”、“一种”及“该”的意义包括复数个。同样地,如在本文的说明书及贯穿下列权利要求书所使用,除非上下文明确指出,否则“在…内”的意义包括“在…内”及“在…上”。再者,为了读者方便,可在本专利说明书中使用标题或子标题,其应该对本发明的范围不具有影响。另外,下列更特别定义出在本说明书中所使用的某些术语。
定义
在本说明书中,在本发明的上下文中所使用的术语及在每个术语所使用的特定上下文中,其通常具有其在本领域中的普通意义。用来描述本发明的某些术语在下列或在专利说明书别处中讨论,以对从事者提供关于发明说明的额外指导。将理解可以多于一种方式表述相同事情。因此,可对本文所讨论的任何一个或多个术语使用另一种文字及同义字或强调任何特别意义,不论该术语是否于本文中阐述或讨论。提供某些术语的同义字。在本专利说明书中的任何地方所使用的实施例,包括本文中所讨论的任何术语的实施例仅作为例证,且决不限制本发明或任何例示的术语的范围及意义。同样地,本发明不限于在此专利说明书中所提供的多个具体实例。
术语“血管生成拟态”描述由高度侵入性及基因失调的肿瘤细胞形成流体输导管道。术语“转移性肿瘤”指为已从原始位置蔓延至身体的其它部分的癌,包括血管及血管沟(vascular channels)的异常形成。不限于此,在本发明中的转移性肿瘤包括涉及富血管性转移(hypervascular metastasis)的肿瘤,例如,黑色素瘤、卵巢癌、前列腺癌、肾细胞癌、尤恩氏肉瘤、乳房癌、神经内分泌系癌、甲状腺癌、喉鳞状细胞癌、肝细胞癌、葡萄膜黑色素瘤、皮肤黑色素瘤、口腔恶性黑色素瘤、绒毛膜癌、原发性胆囊癌、恶性食道基质癌、间皮性肉瘤、齿槽横纹肌肉瘤、膀胱癌、骨肉瘤、星细胞瘤、嗜铬细胞瘤、结肠直肠癌、神经管胚细胞瘤、腺癌、食道基质瘤、喉癌、白血病、滑膜肉瘤、神经胶母细胞瘤及胃肠癌。
术语“增生过度疾病”指细胞增生比正常组织生长更快速的任何疾病或病症。过度增生细胞是一种比正常细胞更快速增生的细胞。
术语“炎性疾病”指特征为炎性异常的症状,包括寻常性痤疮、阿兹海默氏病、关节炎、气喘、动脉粥样硬化、自体免疫病、乳糜泻、慢性前列腺炎、结肠炎、克隆氏病、皮肤炎、憩室炎、肾小球肾炎、肝炎、发炎性肠道疾病、间质性膀胱炎、刺激性肠症候群、红斑性狼疮、肾炎、帕金森氏病、骨盆腔发炎性疾病、类风湿性关节炎、肉状瘤病、移植排斥、溃疡性结肠炎及血管炎,但不限于此。
如于本文中使用,术语“眼科疾病”包括老年性黄斑部变性(AMD)、增生性糖尿病性视网膜病(PDR)、糖尿病性黄斑部水肿(DME)、中心性视网膜静脉阻塞(CRVO)、新生血管性青光眼、角膜新生血管形成(沙眼)及翼状胬肉,但不限于此。
当在本文中使用时,“抗血管生成剂”指一种试管内或活体内抑制血管生成、抑制血管生长或破坏/移除血管生成的脉管的化合物或组合物。该抗血管生成剂的实例包括VEGF/VEGFR、PDGF/PDEGFR抑制剂、类固醇、激酶抑制剂、沙利窦迈艾妥可那唑(itraconazole)羧基酰胺三唑、TNP-470 CM101、IFN-α、IL-12、血小板因子-4、苏拉明、SU5416、凝血酶致敏蛋白(thrombospondin)、软骨取得的血管生成抑制因子、母质金属蛋白酶抑制剂、安吉欧史达丁(angiostatin)、英多史达丁(endostatin)、2-甲氧基雌二醇(methoxyestradiol)、替可加兰(tecogalan)、四硫钼酸盐、凝血酶致敏蛋白、催乳激素、αvβ3抑制剂、三羧胺基喹啉(linomide)、他喹莫德(tasquinimod)。
术语“化疗剂”及“抗癌剂”可互换。“抗癌剂”指抑制癌细胞生长或引起癌细胞死亡的试剂。该化疗剂的实例包括烷基化试剂,诸如噻替派(thiotepa)及环磷酰胺(cyclosphosphamide);磺酸烷酯,诸如二甲磺酸丁酯(busulfan)、英丙舒凡(improsulfan)及哌泊舒凡(piposulfan);氮杂环丙烷类,诸如苯佐替哌(benzodopa)、卡波醌、美妥替哌(meturedopa)及乌瑞替哌(uredopa);亚乙基亚胺类(ethylenimines)及甲基蜜胺类(methylamelamines),包括六甲蜜胺(altreamine)、三亚乙基蜜胺、三亚乙基磷酰胺(trietylenephosphoramide)、三亚乙基硫代磷酰胺(triethylenethiophosphaoramide)及三羟甲基蜜胺(trimethylolomelamine);氮芥类,诸如苯丁酸氮芥、萘氮芥、氯磷酰胺(cholophosphamide)、雌二醇氮芥、异环磷酸胺、甲氮芥、氧化甲氮芥盐酸、苯丙胺酸氮芥、新氮芥(novembichin)、胆固醇苯乙酸氮芥(phenesterine)、松龙苯芥(prednimustine)、氯乙环磷酰胺(trofosfamide)、尿嘧啶氮芥(uracil mustard);亚硝基脲类(nitrosureas),诸如卡莫司汀(carmustine)、吡葡亚硝脲(chlorozotocin)、福塔氮芥(fotemustine)、环己亚硝脲、尼氮芥、雷尼氮芥(ranimustine);抗生素,诸如阿克拉霉素(aclacinomysins)、放线菌素、氨茴霉素(authramycin)、氮丝胺酸、博莱霉素、放线菌素C、卡奇霉素(calicheamicin)、卡拉比星(carabicin)、洋红霉素(carminomycin)、嗜癌素(carzinophilin)、色霉素、更生霉素(dactinomycin)、柔毛霉素、地托比星(detorubicin)、6-重氮-5-氧代-L-正白胺酸、阿霉素(doxorubicin)、表阿霉素(epirubicin)、依索比星(esorubicin)、去甲氧柔红霉素(idarubicin)、麻西罗霉素(marcellomycin)、丝裂霉素、霉酚酸、诺加霉素(nogalamycin)、橄榄霉素、派来霉素(peplomycin)、甲基丝裂霉素(potfiromycin)、嘌呤霉素、三铁阿霉素(quelamycin)、罗多比星(rodorubicin)、链霉黑素、链霉亚硝基素、杀结核菌素(tubercidin)、乌苯美司(ubenimex)、新制癌菌素、佐柔比星(zorubicin);抗代谢物,诸如胺基甲基叶酸及5-氟尿嘧啶(5-FU);叶酸类似物,诸如二甲叶酸(denopterin)、胺基甲基叶酸、蝶罗呤(pteropterin)、三甲曲沙(trimetrexate);嘌呤类似物,诸如氟达拉宾(fludarabine)、6-巯基嘌呤、硫咪嘌呤(thiamiprine)、硫鸟嘌呤;嘧啶类似物,诸如安西他滨(ancitabine)、阿扎胞苷(azacitidine)、6-硫唑脲嘧啶、卡莫氟(carmofur)、阿糖胞苷、二脱氧尿苷、脱氧氟尿苷(doxifluridine)、依诺他滨(enocitabine)、5-氟脱氧尿苷;雄性激素,诸如二甲睪酮(calusterone)、屈他雄酮(dromostanolone)丙酸盐、环硫雄醇(epitiostanol)、美雄烷(mepitiostane)、睪丸内脂(testolactone);抗肾上腺,诸如胺基苯乙哌啶酮、氯苯二氯乙烷、曲洛司坦(trilostane);叶酸补充剂,诸如亚叶酸(frolinic acid);醋葡醛内酯(aceglatone);醛磷酰胺(aldophosphamide)醣苷;胺乙酰丙酸;安吖啶(amsacrine);贝斯曲布昔(bestrabucil);比生群(bisantrene);依达曲沙(edatraxate);得福安(defofamine);地美可辛(demecolcine);地吖醌(diaziquone);艾福敏(elformithine);依利醋铵(elliptiniumacetate);乙环氧啶(etoglucid);硝酸镓;羟基脲;香菇糖;氯尼达明(lonidamine);丙脒腙(mitoguazone);米托山聪(mitoxantrone);莫哌达醇(mopidamol);二胺硝吖啶(nitracrine);喷脱史达丁(pentostatin);蛋胺氮芥(phenamet);吡喃阿霉素(pirarubicin);鬼臼酸(podophyllinic acid);2-乙基酰肼;普鲁卞肼;PSK.RTM.;雷佐生(razoxane);西佐糖(sizofiran);螺旋锗;细交链孢菌酮酸(tenuazonic acid);三亚胺醌(triaziquone);2,2’,2”-三氯三乙基胺;乌拉坦(urethan);长春地辛;达喀尔巴仁(dacarbazine);甘露醇氮芥(mannomustine);二溴甘露醇;二溴矛醇(mitolactol);哌泊溴烷(pipobroman);加胞苷(gacytosine);阿拉伯糖苷(“Ara-C”);环磷酰胺;噻替派(thiotepa);紫杉醇类(taxanes),例如,太平洋紫杉醇(paclitaxel)及欧洲紫杉醇(docetaxel);苯丁酸氮芥;吉西他宾(gemcitabine);6-硫鸟嘌呤;巯基嘌呤;胺基甲基叶酸;铂类似物,诸如顺氯氨铂及卡铂(carboplatin);长春碱;铂;鬼臼乙叉(VP-16);异环磷酸胺;丝裂霉素C;米托山聪(mitoxantrone);长春新碱;长春瑞宾(vinorelbine);温诺平(navelbine);诺凡酮(novantrone);鬼臼噻吩;柔毛霉素(daunomycin);胺蝶呤;截瘤达(xeloda);伊班膦酸盐(ibandronate);CPT-11;拓扑异构酶抑制剂RFS 2000;二氟甲基鸟胺酸(DMFO);视黄酸;埃斯波霉素(esperamicins);卡培他滨(capecitabine);及上述任何药学上可接受的盐、酸或衍生物。在此定义中亦包括抗荷尔蒙剂,其作用以调节或抑制荷尔蒙在肿瘤上的作用,诸如抗雌激素,包括例如泰莫西芬(tamoxifen)、拉乐西芬(raloxifene)、抑制4(5)-咪唑类的芳香环转化酶(aromatase)、4-羟基他莫昔芬(hydroxytamoxifen)、曲沃昔芬(trioxifene)、雷洛昔芬(keoxifene)、LY 117018、奥那司酮(onapristone)及托瑞米芬(toremifene)(弗瑞斯(Fareston));及抗雄性激素,诸如氟硝丁酰胺、尼鲁米特(niluamide)、比卡鲁胺(bicalutamide)、亮丙瑞林(leuprolide)及戈舍瑞林(goserelin);及上述任何药学上可接受的盐、酸或衍生物。
术语“芳基”指6至20个碳原子具有单环(例如,苯基)或多重稠和(稠合)环的不饱和芳香族碳环基团,其中至少一个环是芳香族(例如,萘基、二氢菲基、芴基或蒽基)。优选的芳基包括苯基、萘基及其类似基团。该芳基可选择性为二价基团,因此提供亚芳基。
该芳基可选择性被一个或多个下列基团取代:烷基、烯基、烷氧基、卤基、卤烷基、羟基、羟烷基、芳基、杂芳基、杂环、环烷基、烷酰基、烷氧基羰基、氨基、亚氨基、烷基氨基、酰基氨基、硝基、三氟甲基、三氟甲氧基、羧基、羧基烷基、酮基、硫代基团(thioxo)、烷硫基、烷基亚砜基、烷基砜基、氰基、乙酰胺基、乙酰氧基、乙酰基、苯酰胺基、苯亚砜基、苯磺酰胺基、苯磺酰基、苯磺酰基氨基、苯甲酰基、苯甲酰基氨基、苯甲酰氧基、苄基、苄氧基、苄氧基羰基、苄硫基、胺甲酰基、胺基甲酸酯、异氰酸基、胺磺酰基、胺亚磺酰基、亚磺酸基、磺基、磺基氨基、硫磺基、NR<x>R<y>和/或COOR<x>,其中每个R<x>及R<y>各自独立地系H、烷基、烯基、芳基、杂芳基、杂环、环烷基或羟基。
术语化合物的“衍生物或类似物”指经化学修饰的化合物,其中该化学修饰发生在该化合物的一个或多个官能团处,及当存在时,在芳香族、脂环族或杂环结构上。但是,预计该衍生物或类似物保留由其衍生的化合物的药物活性。
贯穿本公开内容,多种组分的浓度、量等等经常以范围形式呈现。以范围形式描述仅为了方便及简洁,不应该解释为在所主张的发明范围内非灵活限制。此外,范围的描述应该视为具有在该范围内的特别揭示出的全部可能的次范围和个别数值。例如,范围的描述诸如1%至8%应该视为具有特别公开的次范围,诸如1%至7%、2%至8%、2%至6%、3%至6%、4%至8%、3%至8%等等,和在其范围内的个别数值,诸如2%、5%、7%等等。此架构适用贯穿本公开内容的全部上下文中而不管范围幅度。
在本文中描述出的化合物在WO 2012/009519中公开,其全文在此以引用方式并入本文。
术语“进行治疗”或“治疗”指将有效量的治疗药物给药至需要其的对象,其目的为治愈、减轻、解除、补救、改善或防止疾病、其症状、或具有其倾向性的体质。此对象可由保健专家根据任何合适的诊断方法的结果鉴定出。
“有效量”指在接受治疗的对象上赋予治疗效应所需要的活性试剂的量。如由本领域的技术人员了解,该有效剂量将依给药途径、赋形剂使用及与其它治疗性处理共使用的可能性而变化。
QD×28是指动物一天服用一次28天。QOD×7是指动物每隔一天服用共7次剂量。Q4Dx3是指动物每4天服用一次总共3次剂量。
术语“MED”指“最小有效剂量”。
由U.S.Department of Health and Human Services Food and DrugAdministration出版的“Guidance for Industry and Reviews Estimating the SafeStarting Dose in Clinical Trials for Therapeutics in Adult HealthyVolunteers”公开可通过下列式计算获得“人类当量剂量”:
HED=动物剂量以毫克/千克计×(动物重量以千克计/人类重量以千克计)0.33。
本发明关于一种芳基喹啉衍生物的新用途;及更特别地关于一种芳基喹啉衍生物,其用于在需要其的对象中来抑制血管生成拟态及治疗与迷管形态及功能相关和/或特征为存在血管生成拟态的疾病或症状。特别是,本发明关于一种用来治疗特征为存在血管拟态网络的高度转移性肿瘤、过度增生疾病、炎性疾病及眼科疾病的芳基喹啉衍生物。
本发明可与其它抗转移性肿瘤治疗法组合,或与用以提高抗血管生成、化学治疗或免疫治疗剂在治疗肿瘤细胞或其它增殖性疾病的高度侵袭性转移性蔓延上的治疗效果的治疗法组合施用。
实施例
不意欲限制本发明的范围,以下提供根据本发明的具体实例的范例性仪器、设备、方法及其相关结果。要注意的是,为了读者方便可在实施例中使用标题或子标题,但其决不应该限制本发明的范围。再者,在本文中提出及揭示出某些理论;但是,它们决不应该限制本发明的范围,不论它们是正确或错误,只要本发明根据本发明实施而不考虑作用的任何特别理论或方法。
实施例1
TRX-818抑制侵袭性黑色素瘤细胞中的血管生成拟态网络形成
如下制备TRX-818(磷酸2-(3-氟苯基)-6-甲氧基-4-氧代-1,4-二氢喹啉-5-基酯)的溶液。称出呈钠盐形式的TRX-818的重量,将其溶解在无菌组织培养水中以预先制备10mM贮存溶液。然后,将该贮存溶液分装及贮存冷冻,直到使用。解冻该贮存溶液的新鲜液份,及使用细胞培养基进行一系列稀释以在试验当天制备最后操作溶液。
将侵袭性人类黑色素瘤(C8161或SK-MEL28;1x105)细胞接种在三维聚合的MATRIGELTM(75微升)中用于VM网络分析。在细胞附着后的5或24小时,以0.5、1、5、10、25或50或100nM的TRX-818处理C8161或SK-MEL28细胞24小时。将另一组黑色素瘤细胞接种到塑料平皿上,及在使用Guava Nexin Assay(Millipore,USA)确定C8161或SK-MEL28细胞的细胞活力前,处理相同的时间量。
使用配备有环境舱的共焦激光扫描式显微镜取得VM网络影像以追踪癌细胞对测试化合物的反应。然后,数字化该影像及随后使用Angiosys软件分析。每个样品分析四个影像来定量接合数目及VM形成的总小管长度。变化以相对于媒剂对照的百分比呈现。使用无菌去离子水(组织培养等级)作为媒剂对照。
在C8161或SK-MEL28癌细胞中,VM网络形成受浓度≥5至10nM的TRX-818抑制(图1及2)。全部TRX-818测试浓度均明显减少VM形成所需的细胞接合数目及总小管长度形成(图3)。5nM的TRX-818达到最大细胞接合减少(43%减少),然而50nM的TRX-818达到最大总小管长度减少(48%减少)。这些结果总结在表1中,并提示TRX-818在浓度≥10nM下通过破坏细胞-细胞和/或细胞-基质相互作用来抑制VM网络形成,其中该相互作用可先于TRX-818在癌细胞中的抗增殖性活性。表1显示出TRX-818对于细胞接合数目及总小管长度相对于对照的影响。数据以相对于媒剂组的减少百分比呈现。
表1
对实施例化合物TRX-818M1及CHM-2133进行类似的研究。图解结果分别显示在图4及5中。
实施例2
TRX-818对VM蛋白质的mRNA水平的影响
为了确定TRX-818是否通过改变VM的必需蛋白质水平来减少VM网络形成,使用qRT-PCR确定其对Nodal、Notch4、VE-钙黏附素(cadherin)(CDHE5)或肝配蛋白(ephrin)受体A2(Eph A2)表达的影响。以10nM的TRX-818处理2×106个侵袭性人类黑色素瘤(C8161)细胞8、24、48或72小时。使用无菌去离子水(组织培养等级)作为媒剂。
与对照组比较,在8小时处理后,Notch4细胞内结构域(Notch 4ICD)及Nodal的mRNA水平分别减少75%及80%。在72小时处理后,Notch4ICD及Nodal的mRNA水平分别保持在对照细胞的50%及70%(图6A-D)。与对照组比较,在8小时处理(10nM)后,CDH5的mRNA水平减少70%。在72小时连续暴露至10nM的TRX-818后,CDH5的mRNA水平保持在对照细胞的50%(图6A-D)。这些结果提示TRX-818通过抑制Notch、Nodal及CDHE5,但不是Eph A2的mRNA表达来减少VM网络形成。
实施例3
TRX-818对Nodal及Smad蛋白质水平的影响
为了进一步了解TRX-818如何改变VM网络形成所需要的信号通路,使用免疫印迹分析法来确定Pro-Nodal、Smad2及磷酸化的Smad2(P-Smad2)的蛋白水平。在研究当天,如实施例1中所描述地制备TRX-818。以10nM的TRX-818处理或不处理(对照)C8161细胞1、4、8及24小时。通过免疫印迹分析法来分析Nodal及总Smad2、及P-Smad2的蛋白表达。在10nM的TRX-818存在下,将5×106个侵袭性人类黑色素瘤(C8161)细胞接种到塑料平皿上,并收集总蛋白质用于分析。为了定量Nodal及P-Smad2的蛋白质水平,分别使用40微克及25微克的总蛋白质用于SDS-PAGE及免疫印迹法。使用β-肌动蛋白的蛋白质水平来标准化以保证相等的蛋白质上样。
以10nM的TRX-818处理C8161细胞一小时导致Nodal蛋白质表达减少4%(对Pro-Nodal进行检测,与对照细胞比较)。4至8小时处理导致蛋白质水平减少28%,同时24小时处理导致Pro-Nodal的蛋白质水平减少63%(图7)。24小时处理也降低Smad-2的磷酸化水平(图8)。这些结果提示TRX-818通过减少C8161细胞中的Nodal及磷酰基-Smad2的蛋白质水平来降低VM网络形成,如在表2中所总结的,其显示出TRX-818对Smad蛋白质水平及其磷酸化的影响的总概括。
表2
总之,TRX-818通过减少必需蛋白质的转录、翻译表达及翻译后修饰来抑制侵袭性黑色素瘤细胞中的VM网络形成。首先,TRX-818明显降低Nodal、Notch4ICD及VE-钙黏附素(CDH5)的mRNA水平。其次,TRX-818降低Nodal前驱物Pro-Nodal的蛋白质表达;及Smad2的磷酸化。这些结果提示TRX-818可有效防止用于VM网络形成的上游至下游信号通路。
实施例4
TRX-818在HCT-116正位人类结肠癌异种移植模型中的影响
使用HCT-116正位异种移植模型检验TRX-818对高度转移性结肠肿瘤HCT-116的肿瘤生长及VM形成的抑制效应。使用接种HCT116结肠癌细胞株的正位异种移植人类结肠癌模型,通过免疫组织化学染色(IHC)评估TRX-818对血管或血管样(血管生成拟态,VM)网络形成的影响。
在此研究中设定6组(10只老鼠/组)。于此:群组1,TRX-818,以20毫克/千克口服给药;群组2,TRX-818,以50毫克/千克口服给药;群组3,TRX-818,以100毫克/千克口服给药;群组4,TRX-818,以20毫克/千克静脉内注射给药;群组5,依立替康,以50毫克/千克腹膜内注射给药;群组6,媒剂组。G1、G2、G3及G6的剂量计划表为QD×28,G4为QOD×7。监测体重用于安全性评估。在一生研究结束时测量肿瘤尺寸及肿瘤重量。在用于抗肿瘤效应评估的研究终止时,计算肿瘤生长抑制百分比(TGI%)。研究老鼠的平均体重,其在第1天时为~20克并在研究结束(第42天)时减少至~17-19克。
在28天服用结束时,在该研究中,在肿瘤及肺切除前,使用CO2麻醉(1分钟)接着颈椎脱臼法让老鼠安乐死。首先,进行下腹正中切口及切除及收集含有原发肿瘤的结肠。在安乐死后,于3分钟内完成肿瘤收集。在固定前,用PBS冲洗组织以移除血液。
在显微镜下以5倍光场(200x)为基准,在每组中,在每个样品的全断面上计数含有CD31+/红血球(RBC)+或CD31-/RBC+的管道数目,及计数含有CD31正或负染色的血管数目。血管网由CD31+/RBC+染色表示,而VM网络由CD31-/RBC+染色表示,因为该VM形成与血管内皮细胞各自独立。由不知情(blinded)、客观的观测者进行评分。
在HCT-116正位人类结肠癌异种移植模型(Ortho)中,与媒剂组比较,50毫克/千克的TRX-818明显减少肿瘤体积49%(图9)。口服给药的TRX-818的MED为50毫克/千克。
与媒剂组比较,在群组3(TRX-818 100毫克/千克QD×28,口服)及群组5(依立替康50毫克/千克Q4D×3,腹膜内)二者中,含有CD31-/RBC+的平均管道数目明显减少(图10)。CD31-表示血管生成拟态(VM)形成的形成。这些结果提示化合物TRX-818作为单一试剂在抑制HCT116肿瘤细胞形成血管生成拟态结构上表现出有益的效果。表3显示出在正位HCT116人类结肠癌异种移植模型中的VM管道(CD31-/RBC+)数目。
表3
注释:a.平均±SEM;b.对媒剂对照。P-值为来自2-尾Mann-Whitney U检验,未校正来自多重比较。
实施例5
TRX-818M1抑制侵袭性黑色素瘤细胞中的血管生成拟态网络形成
除了使用TRX-818M1代替呈钠盐形式的TRX-818外,使用与在实施例1中类似的方式制备TRX-818M1(2-(3-氟苯基)-6-甲氧基-4-氧代-1,4-二氢喹啉-5-基)的溶液。
如在实施例1中所公开,接种侵袭性人类黑色素瘤(C8161,7.5×104)细胞。以0.3、1或5nM的TRX-818M1处理C8161细胞4小时或24小时。将另一组黑色素瘤细胞接种到塑料平皿上及在确定C8161细胞的细胞活力前,处理相同的时间量。
全部的TRX-818M1测试浓度均抑制C8161癌细胞中的VM网络形成(图4)。TRX-818M1表现为一种在皮摩尔浓度(~0.3nM)下有效的强效性血管破坏剂(vascular disruptingagents)。在该nM范围内的较高的浓度引发细胞死亡。
实施例6
CHM-2133抑制侵袭性黑色素瘤细胞中的血管生成拟态网络形成
使用与实施例1及5中类似的方式制备CHM-2133(2-(2-氟苯基)-6,7-亚甲基二氧基喹啉-4-酮)的溶液。全部的CHM-2133测试浓度均抑制C8161癌细胞中的VM网络形成(图5)。CHM-2133表现为一种在皮摩尔浓度(~0.3nM)下有效的强效性血管破坏剂。
实施例7
抑制侵袭性黑色素瘤细胞中的血管生成拟态网络形成
根据在美国专利案号8524740中所公开的方法合成显示于表4的化合物16-24、37-45、48-53、124-143、143a、143b、144、144a、144b、146-147、152-153、157-158、166-169。使用如在实施例1中所描述的方法测试其对抑制侵袭性黑色素瘤细胞中的血管生成拟态网络形成的影响。
实施例8
对VM蛋白质的mRNA水平的影响
使用如在实施例2中所描述的方法检验显示在表4中的化合物对VM蛋白质的mRNA水平的影响。
实施例9
对Nodal及Smad蛋白质水平的影响
使用如在实施例3中所描述的方法检验显示在表4中的化合物对Nodal及Smad蛋白质水平的影响。
实施例10
喹啉衍生物在HCT-116正位人类结肠癌异种移植模型中的影响
使用如在实施例4中所描述的HCT-116正位人类结肠癌异种移植模型检验显示在表4中的化合物的影响。
实施例11
TRX-818结构类似化合物对抑制血管生成拟态的影响
测试TRX-818MI(即,化合物编号38)结构类似化合物对抑制血管生成拟态的影响。将侵袭性人类黑色素瘤(SK-MEL-28,来自7.5×104/毫升媒质)细胞接种到三维聚合涂布MATRIGELTM的24井板上。在细胞接种18小时后,形成VM网络。然后,以负对照(未处理及经DMSO处理的对照)、正对照(100nM的TRX-818M1)或每种100nM测试化合物置换该媒质。在0小时、5小时及24小时处理后观察VM网络形成。
已发现TRX-818结构类似化合物在VM网络形成上显示出抑制效应。如与负对照(未处理及经DMSO处理的对照)比较,以化合物TRX-818M1(正对照,化合物38)、43、52、147、A6、B1、B3、C4及C6在100nM下处理的SK-MEL28细胞(人类黑色素瘤细胞株)显示出在处理后5小时中度失去VM网络;及在处理后24小时显著失去VM网络(图11)。要注意的是,虽然该测试化合物在浓度100nM下抑制VM网络形成,其对SK-MEL-28细胞具有轻微的细胞毒性。
表4
其中W=选自以下基团的芳香基团:经取代的苯(式Ia或Ib)、萘基、喹啉、苯并呋喃基、苯并噻吩或蒽;
表5
本发明不限于如所阐明的特别形式,及其未脱离本发明的精神及范围的全部修改在如所附的权利要求所定义的范围内。选择及描述出具体实例及实施例以解释本发明的原理及其可实行的应用,以便能够让其它本领域的技术人员使用本发明及多个具体实例,及多种修改如适合于特别考虑到的用途。本发明所属的领域的技术人员将明了涉及本发明而没有脱离其精神及范围的可替代的具体实例。在本发明的说明中引用及讨论一些参考文献,其可包括专利、专利申请案及多种公告。此等参考文献的引用和/或讨论仅提供阐明本发明的说明及不准许任何此参考文献是本文中所描述的发明的“现有技术”。在本专利说明书中所引用及讨论的全部参考文献其全文以引用的方式并入本文至与如每篇参考文献分别以引用方式并入本文相同的程度。
Claims (20)
1.一种式I、II、III或IV的化合物或其药学上可接受的盐的用途,其用来制造用以在需要其的对象中抑制血管生成拟态的药剂:
其中
R2’、R3’、R4’、R5’及R6’各自独立地为H、(CH2)nCH3、(CH2)nYH、Y(CH2)nCH3、Y(CH2)nYH、Y(CH2)nNR8R9、X、或(CH2)nNR8R9;或R3’=OP(=O)(O-苄基)2;
其中n为0-4的整数;Y为O或S;X为F、Cl或Br;及R8及R9各自独立地为H、(CH2)nYH、(CH2)nN(CnH2n+1)(CmH2m+1)或(CH2)nCH3,其中n及Y如上述定义,及m为0-4的整数;
R2、R3、R4及R5各自独立地为H、(CH2)nCH3、(CH2)nYH、Y(CH2)nCH3、Y(CH2)nYH、Y(CH2)nNR8R9、X、(CH2)nNR8R9、(CH2)nN;或R4与R5一起为-Y(CH2)nY-;或R3与R4一起为-Y(CH2)nY-,其中n、Y、X、R8及R9如上述定义;或R3为O-苄基;及
R1及R1’各自独立地为H、Li+、Na+、K+、Ca++、Mg++、N+R8R9R10R11或苄基,其中R10及R11各自独立地为H、(CH2)nYH、(CH2)nN(CnH2n+1)(CmH2m+1)或(CH2)nCH3,n、m、R8及R9如上述定义。
2.如权利要求1所述的用途,其中R2’、R3’、R4’、R5’及R6’全部为H;或R2’、R3’、R4’、R5’及R6’之一为F、OCH3或(CH2)nNR8R9,及其它为H,其中n、R8及R9如在权利要求1中所定义。
3.如权利要求1所述的用途,其中R2、R3、R4及R5全部为H;或R2、R3、R4及R5之一为F、OCH3、Y(CH2)nCH3或(CH2)nNR8R9,及其它为H;或R2与R5为H;及R3与R4一起为-O(CH2)nO-,其中n、Y、R8及R9如在权利要求1中所定义。
4.如权利要求1所述的用途,其中R1及R1’为H、Na+和/或K+。
5.如权利要求3所述的用途,其中R2及R5为H;及R3与R4一起为-O(CH2)O-;及R2’、R3’、R4’及R5’全部为H;及R6’为F。
6.如权利要求3所述的用途,其中R2及R5为H;及R3与R4一起为-O(CH2)O-;及R2’、R3’、R4’及R6’全部为H;及R5’为F。
7.如权利要求3所述的用途,其中R2、R3、R4及R5全部为H;及R2’、R3’、R4’、R5’及R6’全部为H。
8.如权利要求3所述的用途,其中R4为OCH3;及R2、R3及R5为H;及R5’为F;及R2’、R3’、R4’及R6’为H。
9.如权利要求3所述的用途,其中R2及R5为H;及R3与R4一起为-O(CH2)O-;及R2’、R3’、R4’及R6’全部为H;及R5’为OCH3。
10.如权利要求1所述的用途,其中该化合物为选自下列化合物中的至少一种:
11.如权利要求1所述的用途,其中该药剂用以治疗特征为异常的血管形态或功能和/或存在血管生成拟态的疾病。
12.如权利要求11所述的用途,其中该疾病为选自转移性肿瘤、过度增生疾病、炎性疾病及眼科疾病中的至少一种。
13.如权利要求12所述的用途,其中该转移性肿瘤为选自下列各项中的至少一种:黑色素瘤、卵巢癌、前列腺癌、肾细胞癌、尤恩氏肉瘤、乳房癌、神经内分泌系癌、甲状腺癌、喉鳞状细胞癌、肝细胞癌、葡萄膜黑色素瘤、皮肤黑色素瘤、口腔恶性黑色素瘤、绒毛膜癌、原发性胆囊癌、恶性食道基质癌、间皮性肉瘤、齿槽横纹肌肉瘤、膀胱癌、骨肉瘤、星细胞瘤、嗜铬细胞瘤、结肠直肠癌、神经管胚细胞瘤、腺癌、食道基质瘤、喉癌、白血病、滑膜肉瘤、神经胶母细胞瘤及胃肠癌。
14.如权利要求12所述的用途,其中该增生过度疾病为选自下列病症中的至少一种:牛皮癣性关节炎、类风湿性关节炎、狼疮、反应性关节炎、索格伦氏病、炎性肠病、皮肌炎、关节强硬性脊椎炎、幼年型类风湿性关节炎、痛风、炎性骨关节炎、假性痛风、类淀粉变性病、角质变性及角化病、糖尿病性视网膜病、子宫内膜异位、黄斑变性病、瘢瘤、疣、硬化、慢性炎性相关病症、增殖性玻璃体视网膜病变、早产儿视网膜病、肉芽肿病、与器官或组织移殖相关的免疫过度增生、良性前列腺肥大、及免疫增生疾病或病症。
15.如权利要求12所述的用途,其中该炎性疾病为选自下列各项中的至少一种:寻常性痤疮、阿兹海默症、关节炎、气喘、动脉粥样硬化、自体免疫病、乳糜泻、慢性前列腺炎、结肠炎、克隆氏病、皮肤炎、憩室炎、肾小球肾炎、肝炎、发炎性肠道疾病、间质性膀胱炎、刺激性肠症候群、红斑性狼疮、肾炎、帕金森氏病、骨盆腔发炎性疾病、类风湿性关节炎、肉状瘤病、移植排斥、溃疡性结肠炎及血管炎。
16.如权利要求12所述的用途,其中该眼科疾病为选自下列各项中的至少一种:老年性黄斑部变性(AMD)、增生性糖尿病性视网膜病(PDR)、糖尿病性黄斑部水肿(DME)、中心性视网膜静脉阻塞(CRVO)、新生血管性青光眼、角膜新生血管形成(沙眼)及翼状胬肉。
17.一种式Ia或Ib的化合物或其药学上可接受的盐的用途,其用来制造用以在需要其的对象中抑制、减少和/或减轻血管生成拟态的药剂:
其中
R2’、R3’、R4’、R5’、R6’各自独立地为H、F、Cl、Br、(CH2)nCH3、(CH2n)OH、O-(CH2)nCH3、O(CH2)nOH、(CH2n)SH、S-(CH2)nCH3、S(CH2)nSH、O(CH2)nSH、S(CH2)nOH、(CH2)nNR8R9、O(CH2)nNR8R9、或S(CH2)nNR8R9;或R3’=OP(=O)(O-苄基)2;及
其中R8及R9各自独立地为H、(CH2)nCH3、(CH2n)OH、(CH2n)SH、(CH2)nN(CnH2n+1)(CmH2m+1),及n及m各自为0至4的整数;
R2、R3、R4及R5各自独立地为H、F、Cl、Br、(CH2)nCH3、(CH2)nOH、O(CH2)nCH3、O(CH2)nOH、O(CH2)nNR8R9、(CH2)nSH、S(CH2)nCH3、S(CH2)nSH、S(CH2)nNR8R9、(CH2)nNR8R9、(CH2)nN;或R4与R5一起为-O(CH2)nO-、或-S(CH2)nS-;或R3与R4一起为-O(CH2)nO-、或-S(CH2)nS-,其中n、R8及R9如上述定义;或R3为O-苄基;
或R5为OP=OOR1OR1’,及R1及R1’各自独立地为H、Li+、Na+、K+、Ca++、Mg++、N+R8R9R10R11或苄基,其中R10及R11各自独立地为H、(CH2)nYH、(CH2)nN(CnH2n+1)(CmH2m+1)或(CH2)nCH3,n、m、R8及R9如上述定义。
18.一种式(X)的化合物或其药学上可接受的盐的用途,其用来制造用以在需要其的对象中抑制、减少和/或减轻血管生成拟态的药剂:
其中W为选自下列基团的芳香基团:萘基、喹啉、苯并呋喃基、苯并噻吩、蒽及式(Y)的经取代的苯:
及其中:
R2’、R3’、R4’、R5’、R6’各自独立地为H、F、Cl、Br、(CH2)nCH3、(CH2n)OH、O-(CH2)nCH3、O(CH2)nOH、(CH2n)SH、S-(CH2)nCH3、S(CH2)nSH、O(CH2)nSH、S(CH2)nOH、(CH2)nNR8R9、O(CH2)nNR8R9、或S(CH2)nNR8R9;或R3’=OP(=O)(O-苄基)2;及
其中R8及R9各自独立地为H、(CH2)nCH3、(CH2n)OH、(CH2n)SH、(CH2)nN(CnH2n+1)(CmH2m+1),及n及m各自为0至4的整数;
R2、R3、R4及R5各自独立地为H、F、Cl、Br、(CH2)nCH3、(CH2)nOH、O(CH2)nCH3、O(CH2)nOH、O(CH2)nNR8R9、(CH2)nSH、S(CH2)nCH3、S(CH2)nSH、S(CH2)nNR8R9、(CH2)nN、(CH2)nNR8R9;R4与R5一起为-O(CH2)nO-、或-S(CH2)nS-;或R3与R4一起为-O(CH2)nO-、-S(CH2)nS-,其中n、R8及R9如上述定义;或R3为O-苄基;
或R5为OP=OOR1OR1’,及R1及R1’各自独立地为H、Li+、Na+、K+、Ca++、Mg++、N+R8R9R10R11或苄基,其中R10及R11各自独立地为H、(CH2)nYH、(CH2)nN(CnH2n+1)(CmH2m+1)或(CH2)nCH3,n、m、R8及R9如上述定义。
19.如权利要求17所述的用途,其中该化合物选自下列化合物:
20.如权利要求1及11至19中任一项所述的用途,进一步包括使用选自下列各项的额外治疗药物:抗癌剂、抗炎药、抗增殖剂、抗荷尔蒙剂及其任何组合来制造用以治疗特征为异常的血管形态或功能和/或存在血管生成拟态的疾病的药剂。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201562170425P | 2015-06-03 | 2015-06-03 | |
US62/170,425 | 2015-06-03 | ||
PCT/US2016/035441 WO2016196742A1 (en) | 2015-06-03 | 2016-06-02 | Novel use of aryl-quinolin derivatives as inhibitors of vasculogenic mimicry |
Publications (2)
Publication Number | Publication Date |
---|---|
CN107921047A true CN107921047A (zh) | 2018-04-17 |
CN107921047B CN107921047B (zh) | 2021-06-01 |
Family
ID=57442304
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201680031932.XA Active CN107921047B (zh) | 2015-06-03 | 2016-06-02 | 芳基喹啉衍生物作为血管生成拟态抑制剂的新用途 |
Country Status (11)
Country | Link |
---|---|
US (1) | US9717721B2 (zh) |
EP (1) | EP3302488B1 (zh) |
JP (1) | JP6648160B2 (zh) |
KR (2) | KR102087565B1 (zh) |
CN (1) | CN107921047B (zh) |
AU (1) | AU2016270874B2 (zh) |
BR (1) | BR112017026104A2 (zh) |
CA (1) | CA2983769C (zh) |
RU (1) | RU2685731C1 (zh) |
TW (1) | TWI640311B (zh) |
WO (1) | WO2016196742A1 (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113286820A (zh) * | 2018-08-24 | 2021-08-20 | 特拉斯福特普拉斯公司 | 用于靶向分拣蛋白受体和抑制血管生成拟态的方法和化合物 |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2020529432A (ja) * | 2017-08-04 | 2020-10-08 | アキシャル バイオセラピューティクス, インク.Axial Biotherapeutics, Inc. | 微生物により誘発されるアミロイドの阻害剤 |
WO2019071007A1 (en) * | 2017-10-05 | 2019-04-11 | New York Genome Center, Inc. | METHODS AND COMPOSITIONS FOR TARGETING VASCULAR MIMETTISM |
US20230039185A1 (en) * | 2019-12-19 | 2023-02-09 | Genfit | Phosphate derivatives of rorgamma modulators and uses thereof |
US11938127B2 (en) | 2021-09-28 | 2024-03-26 | Wayne State University | Methods and compositions relating to steroid hormone receptor-dependent proliferative disorders |
TW202334089A (zh) | 2021-11-02 | 2023-09-01 | 美商夫雷爾醫療公司 | Pparg反向激動劑及其用途 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20120129775A1 (en) * | 2009-07-31 | 2012-05-24 | Enrique Zudaire | Antiangiogenic small molecules and methods of use |
US8524740B2 (en) * | 2010-07-15 | 2013-09-03 | Tairx, Inc. | Synthesis and anticancer activity of aryl and heteroaryl-quinolin derivatives |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2796290B2 (ja) | 1987-04-10 | 1998-09-10 | 株式会社日立製作所 | 可逆相変化を用いた情報記録方法 |
JP5102843B2 (ja) * | 2006-12-07 | 2012-12-19 | チャイナ メディカル ユニヴァーシティ | 抗癌剤としての2−アリール−4−キノロンの新規な親水性誘導体 |
JP5816174B2 (ja) | 2009-08-06 | 2015-11-18 | アーケマ・インコーポレイテッド | 液状クリーニング組成物 |
CN102824607B (zh) * | 2012-09-12 | 2014-02-19 | 上海市中医医院 | 一种抑制肠癌血管拟态和微血管形成的中药组合物及其应用 |
-
2016
- 2016-06-02 AU AU2016270874A patent/AU2016270874B2/en active Active
- 2016-06-02 KR KR1020197017881A patent/KR102087565B1/ko active IP Right Grant
- 2016-06-02 EP EP16804399.0A patent/EP3302488B1/en active Active
- 2016-06-02 KR KR1020177035842A patent/KR20180003616A/ko not_active Application Discontinuation
- 2016-06-02 CN CN201680031932.XA patent/CN107921047B/zh active Active
- 2016-06-02 CA CA2983769A patent/CA2983769C/en active Active
- 2016-06-02 JP JP2017562359A patent/JP6648160B2/ja active Active
- 2016-06-02 BR BR112017026104A patent/BR112017026104A2/pt not_active Application Discontinuation
- 2016-06-02 WO PCT/US2016/035441 patent/WO2016196742A1/en active Application Filing
- 2016-06-02 RU RU2017144286A patent/RU2685731C1/ru active
- 2016-06-02 US US15/171,365 patent/US9717721B2/en active Active
- 2016-06-03 TW TW105117651A patent/TWI640311B/zh active
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20120129775A1 (en) * | 2009-07-31 | 2012-05-24 | Enrique Zudaire | Antiangiogenic small molecules and methods of use |
US8524740B2 (en) * | 2010-07-15 | 2013-09-03 | Tairx, Inc. | Synthesis and anticancer activity of aryl and heteroaryl-quinolin derivatives |
Non-Patent Citations (3)
Title |
---|
RICHARD E.B. SEFTOR ET AL.: "Tumor Cell Vasculogenic Mimicry", 《ASIP CENTENNIAL REVIEW》 * |
YU-HSUN CHANG ET AL: "Design and Synthesis of 2-(3-Benzo[b]thienyl)-6,7-methylenedioxyquinolin-4-one Analogues as Potent Antitumor Agents that Inhibit Tubulin Assembly", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
陈俊杰等: "血管生成拟态与翼状胬肉进行期及静止期的相关性研究", 《国际眼科杂志》 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113286820A (zh) * | 2018-08-24 | 2021-08-20 | 特拉斯福特普拉斯公司 | 用于靶向分拣蛋白受体和抑制血管生成拟态的方法和化合物 |
Also Published As
Publication number | Publication date |
---|---|
JP6648160B2 (ja) | 2020-02-14 |
EP3302488A1 (en) | 2018-04-11 |
RU2685731C1 (ru) | 2019-04-23 |
CA2983769A1 (en) | 2016-12-08 |
CN107921047B (zh) | 2021-06-01 |
WO2016196742A1 (en) | 2016-12-08 |
CA2983769C (en) | 2020-09-22 |
US9717721B2 (en) | 2017-08-01 |
TW201642861A (zh) | 2016-12-16 |
KR102087565B1 (ko) | 2020-03-11 |
EP3302488B1 (en) | 2020-09-30 |
KR20180003616A (ko) | 2018-01-09 |
US20160354361A1 (en) | 2016-12-08 |
EP3302488A4 (en) | 2019-01-23 |
BR112017026104A2 (pt) | 2018-08-14 |
AU2016270874A1 (en) | 2017-11-16 |
KR20190077109A (ko) | 2019-07-02 |
JP2018516927A (ja) | 2018-06-28 |
AU2016270874B2 (en) | 2018-12-06 |
TWI640311B (zh) | 2018-11-11 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN107921047A (zh) | 芳基喹啉衍生物作为血管生成拟态抑制剂的新用途 | |
ES2962890T3 (es) | Uso del cannabidiol en el tratamiento del complejo de esclerosis tuberosa | |
US8119116B2 (en) | Therapeutics for cancer using 3-bromopyruvate and other selective inhibitors of ATP production | |
ES2973279T3 (es) | Usos de medicamento de duloxetina·HCl en la preparación de una composición farmacéutica para el tratamiento de cáncer | |
CN107835687A (zh) | 癌症治疗 | |
CN102056607B (zh) | On01910.na促进在抗药性肿瘤中化学治疗剂的活性 | |
CN107949387A (zh) | 用谷氨酰胺酶抑制剂治疗肺癌 | |
CN106963769A (zh) | 含pi3k抑制剂和perk抑制剂的药物组合物及其应用 | |
WO2015178426A1 (ja) | がん幹細胞の増殖抑制剤 | |
CN109562119A (zh) | 癌症治疗 | |
AU2013364893A1 (en) | Apoptosis-inducing agent | |
AU2013202507B2 (en) | Inhibition of drug resistant cancer cells | |
EP3094317B1 (en) | Cyclodextrin compositions encapsulating a selective atp inhibitor and uses thereof | |
WO2019228524A1 (zh) | 用于治疗肾癌的药物组合物及其应用 | |
CN106659705A (zh) | 通过prostratin靶向k‑ras介导的信号转导通路和恶性肿瘤 | |
AU2015242363B2 (en) | Glycolipids and pharmaceutical compositions thereof for use in therapy | |
Patki et al. | In vitro assessment of a synergistic combination of gemcitabine and zebularine in pancreatic cancer cells | |
KR102011105B1 (ko) | 고시폴 및 펜포르민을 유효성분으로 포함하는 췌장암 예방 및 치료용 약학적 조성물 | |
CN101081225A (zh) | 一种通过调节表观遗传修饰防治胃肠肿瘤的药物组合物 | |
Myint et al. | Preclinical evidence for anaplastic lymphoma kinase inhibitors as novel therapeutic treatments for cholangiocarcinoma | |
KR20200005573A (ko) | 암의 치료를 위한 약제학적 조합물 | |
WO2022055748A1 (en) | Encapsulated agents that bind to mct-1 | |
WO2023041978A1 (es) | COMPOSICIONES SINÉRGICAS DE COMPUESTOS CONTRA EL COMPLEJO HETERODIMÉRICO K-RAS4B/PDE6δ PARA EL TRATAMIENTO DE CÁNCER DE PÁNCREAS | |
CN116474104A (zh) | 一种治疗髓母细胞癌的小分子靶向药物组合物 | |
CN106572992A (zh) | 用curaxins进行组合治疗 |
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 |