WO2021190076A1 - Anti-tumor compound capable of overcoming cisplatin resistance, preparation therefor, and application thereof - Google Patents
Anti-tumor compound capable of overcoming cisplatin resistance, preparation therefor, and application thereof Download PDFInfo
- Publication number
- WO2021190076A1 WO2021190076A1 PCT/CN2021/070303 CN2021070303W WO2021190076A1 WO 2021190076 A1 WO2021190076 A1 WO 2021190076A1 CN 2021070303 W CN2021070303 W CN 2021070303W WO 2021190076 A1 WO2021190076 A1 WO 2021190076A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- formula
- tumor
- cisplatin
- reaction
- Prior art date
Links
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 title claims abstract description 81
- 229960004316 cisplatin Drugs 0.000 title claims abstract description 81
- 150000001875 compounds Chemical class 0.000 title claims abstract description 59
- 230000000259 anti-tumor effect Effects 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 52
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 48
- 238000006243 chemical reaction Methods 0.000 claims description 30
- 229940125904 compound 1 Drugs 0.000 claims description 28
- 229940126214 compound 3 Drugs 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- 229940125782 compound 2 Drugs 0.000 claims description 9
- 239000002246 antineoplastic agent Substances 0.000 claims description 8
- 229940041181 antineoplastic drug Drugs 0.000 claims description 8
- 239000012065 filter cake Substances 0.000 claims description 8
- 239000012265 solid product Substances 0.000 claims description 8
- 229940125898 compound 5 Drugs 0.000 claims description 5
- 231100000053 low toxicity Toxicity 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 4
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 3
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 3
- 230000000694 effects Effects 0.000 abstract description 27
- 230000005971 DNA damage repair Effects 0.000 abstract description 9
- 230000001988 toxicity Effects 0.000 abstract description 4
- 231100000419 toxicity Toxicity 0.000 abstract description 4
- 101710092489 Protein kinase 2 Proteins 0.000 abstract description 3
- 102000005403 Casein Kinases Human genes 0.000 abstract 1
- 108010031425 Casein Kinases Proteins 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 97
- 206010033128 Ovarian cancer Diseases 0.000 description 23
- 206010061535 Ovarian neoplasm Diseases 0.000 description 23
- 238000012360 testing method Methods 0.000 description 22
- 229940079593 drug Drugs 0.000 description 21
- 239000003814 drug Substances 0.000 description 21
- 208000016691 refractory malignant neoplasm Diseases 0.000 description 21
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 20
- 201000011510 cancer Diseases 0.000 description 16
- 238000011580 nude mouse model Methods 0.000 description 16
- 230000014509 gene expression Effects 0.000 description 15
- 241000699660 Mus musculus Species 0.000 description 14
- MUOKSQABCJCOPU-UHFFFAOYSA-N 5-(3-chloroanilino)benzo[c][2,6]naphthyridine-8-carboxylic acid Chemical compound C=1C(C(=O)O)=CC=C(C2=CN=CC=C22)C=1N=C2NC1=CC=CC(Cl)=C1 MUOKSQABCJCOPU-UHFFFAOYSA-N 0.000 description 13
- 102000004169 proteins and genes Human genes 0.000 description 10
- 108090000623 proteins and genes Proteins 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 241001465754 Metazoa Species 0.000 description 9
- 230000005764 inhibitory process Effects 0.000 description 9
- 238000000338 in vitro Methods 0.000 description 8
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 8
- 235000018102 proteins Nutrition 0.000 description 8
- 230000033616 DNA repair Effects 0.000 description 7
- 206010059866 Drug resistance Diseases 0.000 description 7
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 7
- 239000011521 glass Substances 0.000 description 7
- 201000005202 lung cancer Diseases 0.000 description 7
- 208000020816 lung neoplasm Diseases 0.000 description 7
- 239000013641 positive control Substances 0.000 description 7
- 238000012546 transfer Methods 0.000 description 7
- 230000005778 DNA damage Effects 0.000 description 6
- 231100000277 DNA damage Toxicity 0.000 description 6
- 230000012010 growth Effects 0.000 description 6
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 5
- 230000000875 corresponding effect Effects 0.000 description 5
- 230000001472 cytotoxic effect Effects 0.000 description 5
- 238000001962 electrophoresis Methods 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 239000003292 glue Substances 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- 238000004364 calculation method Methods 0.000 description 4
- 239000008367 deionised water Substances 0.000 description 4
- 229910021641 deionized water Inorganic materials 0.000 description 4
- UQLDLKMNUJERMK-UHFFFAOYSA-L di(octadecanoyloxy)lead Chemical compound [Pb+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O UQLDLKMNUJERMK-UHFFFAOYSA-L 0.000 description 4
- 238000011156 evaluation Methods 0.000 description 4
- 238000004896 high resolution mass spectrometry Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 230000002018 overexpression Effects 0.000 description 4
- -1 platinum (II) compound Chemical class 0.000 description 4
- 206010005003 Bladder cancer Diseases 0.000 description 3
- 108020004414 DNA Proteins 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 3
- 230000006907 apoptotic process Effects 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 229940093181 glucose injection Drugs 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 229910052697 platinum Inorganic materials 0.000 description 3
- HRGDZIGMBDGFTC-UHFFFAOYSA-N platinum(2+) Chemical class [Pt+2] HRGDZIGMBDGFTC-UHFFFAOYSA-N 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 230000008439 repair process Effects 0.000 description 3
- 201000005112 urinary bladder cancer Diseases 0.000 description 3
- 210000003462 vein Anatomy 0.000 description 3
- 238000001262 western blot Methods 0.000 description 3
- AVXWWBFBRTXBRM-UHFFFAOYSA-N 3-bromopyridine-4-carboxylic acid Chemical compound OC(=O)C1=CC=NC=C1Br AVXWWBFBRTXBRM-UHFFFAOYSA-N 0.000 description 2
- PNPCRKVUWYDDST-UHFFFAOYSA-N 3-chloroaniline Chemical compound NC1=CC=CC(Cl)=C1 PNPCRKVUWYDDST-UHFFFAOYSA-N 0.000 description 2
- 208000031648 Body Weight Changes Diseases 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- PXDVLHAAERULJJ-UHFFFAOYSA-N COC(c1cc2nc(Nc3cccc(Cl)c3)c(ccnc3)c3c2cc1)=O Chemical compound COC(c1cc2nc(Nc3cccc(Cl)c3)c(ccnc3)c3c2cc1)=O PXDVLHAAERULJJ-UHFFFAOYSA-N 0.000 description 2
- 206010008342 Cervix carcinoma Diseases 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 206010023825 Laryngeal cancer Diseases 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- WBYCGXZZFGZOPY-UHFFFAOYSA-N NNC(c1cc2nc(Nc3cccc(Cl)c3)c(ccnc3)c3c2cc1)=O Chemical compound NNC(c1cc2nc(Nc3cccc(Cl)c3)c(ccnc3)c3c2cc1)=O WBYCGXZZFGZOPY-UHFFFAOYSA-N 0.000 description 2
- 208000001894 Nasopharyngeal Neoplasms Diseases 0.000 description 2
- 206010061306 Nasopharyngeal cancer Diseases 0.000 description 2
- 206010060862 Prostate cancer Diseases 0.000 description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 2
- 230000003698 anagen phase Effects 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 230000004579 body weight change Effects 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 239000006143 cell culture medium Substances 0.000 description 2
- 201000010881 cervical cancer Diseases 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 208000029742 colonic neoplasm Diseases 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000012737 fresh medium Substances 0.000 description 2
- 206010017758 gastric cancer Diseases 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 206010023841 laryngeal neoplasm Diseases 0.000 description 2
- 210000005229 liver cell Anatomy 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 201000011549 stomach cancer Diseases 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 230000004565 tumor cell growth Effects 0.000 description 2
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 2
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 1
- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 1
- VOZKAJLKRJDJLL-UHFFFAOYSA-N 2,4-diaminotoluene Chemical compound CC1=CC=C(N)C=C1N VOZKAJLKRJDJLL-UHFFFAOYSA-N 0.000 description 1
- 230000007730 Akt signaling Effects 0.000 description 1
- 0 C*c(c(*)c1)ccc1C(OC)=O Chemical compound C*c(c(*)c1)ccc1C(OC)=O 0.000 description 1
- OKXJYDKHLBHDPH-UHFFFAOYSA-N COC(c1ccc(-c(cncc2)c2C(N2)=O)c2c1)=O Chemical compound COC(c1ccc(-c(cncc2)c2C(N2)=O)c2c1)=O OKXJYDKHLBHDPH-UHFFFAOYSA-N 0.000 description 1
- XCRKEOCRHSQXHV-UHFFFAOYSA-N COC(c1ccc(c2cnccc2c(Cl)n2)c2c1)=O Chemical compound COC(c1ccc(c2cnccc2c(Cl)n2)c2c1)=O XCRKEOCRHSQXHV-UHFFFAOYSA-N 0.000 description 1
- 101100298998 Caenorhabditis elegans pbs-3 gene Proteins 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 102000052052 Casein Kinase II Human genes 0.000 description 1
- 108010010919 Casein Kinase II Proteins 0.000 description 1
- 229940122360 Casein kinase 2 inhibitor Drugs 0.000 description 1
- 230000004543 DNA replication Effects 0.000 description 1
- 102100030013 Endoribonuclease Human genes 0.000 description 1
- 101710199605 Endoribonuclease Proteins 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- 206010059024 Gastrointestinal toxicity Diseases 0.000 description 1
- 239000012981 Hank's balanced salt solution Substances 0.000 description 1
- QGZAOURKKUWMMI-UHFFFAOYSA-N NC1=C(C=CC(=C1)C(=O)OC)OB(O)O Chemical compound NC1=C(C=CC(=C1)C(=O)OC)OB(O)O QGZAOURKKUWMMI-UHFFFAOYSA-N 0.000 description 1
- 108010057466 NF-kappa B Proteins 0.000 description 1
- 102000003945 NF-kappa B Human genes 0.000 description 1
- 206010029155 Nephropathy toxic Diseases 0.000 description 1
- 206010029350 Neurotoxicity Diseases 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 206010033109 Ototoxicity Diseases 0.000 description 1
- 102000015087 Poly (ADP-Ribose) Polymerase-1 Human genes 0.000 description 1
- 108010064218 Poly (ADP-Ribose) Polymerase-1 Proteins 0.000 description 1
- 230000018199 S phase Effects 0.000 description 1
- 101710113029 Serine/threonine-protein kinase Proteins 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- 238000006069 Suzuki reaction reaction Methods 0.000 description 1
- 206010044221 Toxic encephalopathy Diseases 0.000 description 1
- 241000711955 Turkey rhinotracheitis virus Species 0.000 description 1
- 102000013814 Wnt Human genes 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000009949 anti-apoptotic pathway Effects 0.000 description 1
- 238000003782 apoptosis assay Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
- 230000001488 breeding effect Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 190000008236 carboplatin Chemical compound 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 description 1
- 229960002327 chloral hydrate Drugs 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- SLPJGDQJLTYWCI-UHFFFAOYSA-N dimethyl-(4,5,6,7-tetrabromo-1h-benzoimidazol-2-yl)-amine Chemical compound BrC1=C(Br)C(Br)=C2NC(N(C)C)=NC2=C1Br SLPJGDQJLTYWCI-UHFFFAOYSA-N 0.000 description 1
- 230000035622 drinking Effects 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 210000003527 eukaryotic cell Anatomy 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 231100000414 gastrointestinal toxicity Toxicity 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine group Chemical group NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 1
- 230000005917 in vivo anti-tumor Effects 0.000 description 1
- 230000002700 inhibitory effect on cancer Effects 0.000 description 1
- 229940090044 injection Drugs 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 238000010030 laminating Methods 0.000 description 1
- 238000002350 laparotomy Methods 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- 230000007694 nephrotoxicity Effects 0.000 description 1
- 231100000228 neurotoxicity Toxicity 0.000 description 1
- 230000007135 neurotoxicity Effects 0.000 description 1
- 231100000262 ototoxicity Toxicity 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
- 230000004983 pleiotropic effect Effects 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 230000005522 programmed cell death Effects 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 230000028617 response to DNA damage stimulus Effects 0.000 description 1
- 239000000565 sealant Substances 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000012089 stop solution Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000012353 t test Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- 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
- A61K31/28—Compounds containing heavy metals
- A61K31/282—Platinum compounds
-
- 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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
-
- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- 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
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
Definitions
- the present invention relates to an anti-tumor compound that effectively overcomes cisplatin resistance, and specifically relates to bonding a compound having protein kinase 2 (CK2) inhibitory activity to a platinum (II) compound known to have anti-tumor activity to obtain an anti-tumor compound that can effectively overcome cisplatin
- CK2 protein kinase 2
- II platinum
- a new type of platinum-resistant anti-tumor compound also relates to a preparation method and application of this type of compound.
- platinum drugs such as cisplatin, carboplatin and oxaliplatin have been on the market, and they have been widely used in clinical practice.
- platinum (II) compounds bind to the guanine N7 target on the DNA of cancer cells to form DNA cross-linked adducts, which restrict DNA replication and inhibit cancer cells.
- platinum (II) compounds bind to the guanine N7 target on the DNA of cancer cells to form DNA cross-linked adducts, which restrict DNA replication and inhibit cancer cells.
- Cisplatin has the best comprehensive effect among all currently known platinum anti-tumor drugs. It not only has strong anti-tumor activity, but also has broad-spectrum anti-tumor activity.
- cisplatin can be used as a treatment for head and neck cancer, ovarian cancer, esophageal cancer, First-line drugs for cancers such as bladder cancer and lung cancer.
- cisplatin also has obvious defects in clinical application.
- Studies have found that there is a significant DNA repair phenomenon in drug-resistant cancer cells. This is because cancer cells can activate their own DNA damage repair mechanism to repair, thereby developing resistance to DNA damage drugs and reducing the anti-tumor effect of cisplatin drugs. Effect. Therefore, DNA damage repair is considered to be an important factor affecting the efficacy of chemotherapy that targets DNA.
- Casein kinase II (CK2) is a pleiotropic and highly conserved second messenger-independent serine/threonine protein kinase, which is widely present in the cytoplasm and nucleus of eukaryotic cells.
- CK2 has a very important role in a variety of cell activities.
- CK2 involved in cell G 1 / S phase, adjusting the G 2 / M phase, over-expression of CK2 can inhibit programmed cell death induced by anti-cancer drugs.
- CK2 overexpression exists in a variety of drug-resistant cancer cell lines, and inhibition of CK2 can promote cell apoptosis and increase the sensitivity of tumor cells to anticancer drugs and apoptosis stimuli.
- the technical problem to be solved by the present invention is to use compounds that inhibit protein kinase 2 activity to inhibit DNA damage and repair.
- Group of platinum (II) compounds combined, design and synthesize a new platinum (II) compound to obtain an anti-tumor drug that overcomes cisplatin resistance and has high efficiency and low toxicity, and provides the preparation method of this compound and its use in anti-tumor Applications.
- the anti-tumor compound capable of overcoming cisplatin resistance according to the present invention has a structure such as compound 1 or compound 2 shown in formula I.
- reaction formula II For the preparation of the reaction formula shown in formula II, the specific steps are as follows: add equimolar amounts of compound 3 and compound 4 in anhydrous methanol into a reaction flask, add acetic acid dropwise, and react the reaction solution at 30-60°C in the dark After 48-72 hours, it was cooled to room temperature, filtered, and the filter cake was washed three times with anhydrous methanol to obtain compound 1 as a yellow solid product.
- reaction formula shown in formula III is prepared, and the specific steps are as follows: add equimolar amounts of compound 3 and compound 5 in anhydrous methanol into the reaction flask, add acetic acid dropwise, and react the reaction solution at 30-60°C in the dark After 48-72 hours, it was cooled to room temperature, filtered, and the filter cake was washed three times with anhydrous methanol to obtain compound 2 as a yellow solid product.
- reaction formula shown in formula IV the specific steps are as follows: add 1 equivalent of compound 6 into a reaction flask containing methanol, slowly add 2-10 equivalents of hydrazine hydrate at room temperature, and heat the reaction solution to reflux for 24-72 hours After the reaction was completed, it was cooled to room temperature, a large amount of solid was precipitated, and the filter cake was washed three times with ice methanol to obtain a bright yellow solid product—compound 3.
- Compounds 4 and 5 shown in formula II and formula III are known platinum (II) compounds with good anti-tumor activity, prepared according to the method disclosed in the inventor's previous patent (invention patent number: ZL201210422936.4; US9227991B2; EP2913335; Japanese Patent No.
- Compound 6 shown in Formula IV and known antitumor drugs targeting CK2 were prepared according to the methods reported in the literature (J.Med.Chem., 2011,54,635- 54), specifically using 3-bromoisonicotinic acid as the starting material, after esterification, Suzuki coupling reaction with 2-amino-4-carbomethoxyphenyl borate to obtain intermediate 5,6 -Dihydrobenzo[c][2,6]naphthyridine-8-methyl carboxylate, then undergoes chlorination reaction with phosphorus oxychloride, and then undergoes substitution reaction with meta-chloroaniline to obtain compound 6, which is then hydrolyzed Get CX-4945.
- the reaction route is shown in formula V:
- the prepared compounds 1, 2 and 3 were used to treat human laryngeal cancer cells Hep2, nasopharyngeal cancer cells CNE2, gastric cancer cells SGC-7901, colon cancer cells HCT-116, breast cancer cells MCF-7, cervical cancer cells SiHa, and prostate cancer.
- CX-4945, cisplatin, and compounds 4 and 5 were used as positive controls.
- Compound 1 has better activity than CX-4945 and its parent compound 3 in various cancer cell lines tested, especially cancer cell lines with high CK2 expression such as T24, PC-3 and HCT-116, etc., and It is comparable to its other parent compound 4, but the toxicity of compound 1 to normal hepatocytes is lower than that of the positive control drug. It is worth noting that although compound 1 has a slightly lower inhibitory effect on cisplatin-sensitive cancer cells A549 and A2780 than cisplatin, it has a significant inhibitory effect on cisplatin-resistant cancer cells A549/CDDP and A2780/CDDP.
- the activity is significantly better than that of cisplatin, and the drug resistance factor is as low as 0.71 (the ratio of the IC 50 value of the compound against cisplatin-resistant cancer cells to the IC 50 value of cisplatin-sensitive cancer cells).
- compound 2 has a slightly lower IC 50 value for A549 cancer cells than compound 1, its effect on drug-resistant cancer cells A549/CDDP is significantly weaker than compound 1, with a drug resistance factor of 1.52.
- compound 1 and its parent compound 3 have better CK2 inhibitory activity than CX-4945, and compound 1 also shows a better inhibitory effect on cisplatin-resistant cancer cells A549/CDDP and A2780/CDDP, compound 1 was tested follow up research.
- a nude mouse xenograft tumor model of cisplatin-sensitive ovarian cancer cell A2780 and cisplatin-resistant ovarian cancer cell A2780/CDDP was used to test the anti-tumor activity of compound 1 in vivo, and cisplatin was used as a positive control.
- the compound of the present invention has a good inhibitory effect on cancer cells, especially cisplatin-resistant cancer cells.
- the in vivo test results show that compound 1 not only has a strong inhibitory effect on cisplatin-sensitive tumors but also cisplatin-resistant tumors, and has low toxicity, high efficiency and low toxicity, and can be used to prepare antitumor drugs.
- Figure 1a shows the expression of CK2 in lung cancer cell A549 and cisplatin-resistant lung cancer cell A549/CDDP, ovarian cancer cell A2780 and cisplatin-resistant ovarian cancer cell A2780/CDDP;
- Figure 1b is the quantitative value of CK2 expression in lung cancer cell A549 and cisplatin-resistant lung cancer cell A549/CDDP, ovarian cancer cell A2780 and cisplatin-resistant ovarian cancer cell A2780/CDDP.
- Figure 2a is the expression of DNA damage repair related proteins in lung cancer cell A549 by the test sample
- Figure 2b shows the expression of DNA damage repair related proteins in the cisplatin-resistant lung cancer cell A549/CDDP of the tested sample
- Figure 2c is the expression of the test sample on DNA damage repair related proteins in ovarian cancer cell A2780;
- Figure 2d shows the expression of DNA damage repair related proteins in the cisplatin-resistant ovarian cancer cell A2780/CDDP of the tested sample.
- Figure 3 The effect of the test sample on the growth volume of cisplatin-sensitive ovarian cancer cell A2780 nude mice xenograft tumors.
- Figure 4 The effect of the test sample on the tumor weight of cisplatin-sensitive ovarian cancer cell A2780 in nude mice xenograft.
- Figure 5 The effect of the test sample on the weight of nude mice with cisplatin-sensitive ovarian cancer cell A2780 xenograft tumors in nude mice.
- Figure 6 The effect of test samples on the growth volume of cisplatin-resistant ovarian cancer cell A2780/CDDP xenograft tumors in nude mice.
- Figure 7 The effect of the tested sample on the tumor weight of cisplatin-resistant ovarian cancer cell A2780/CDDPP xenograft in nude mice.
- Figure 8 The effect of test samples on the body weight of nude mice with cisplatin-resistant ovarian cancer cell A2780/CDDP xenograft tumors.
- An anti-tumor compound capable of overcoming cisplatin resistance of the present invention has a structure such as compound 1 or compound 2 shown in formula I.
- compound 6 and CX-4945 reference (J. Med. Chem. 2011, 54, 635-654) are prepared by the method reported and verified by the hydrogen nuclear magnetic spectrum.
- CK2 enzyme-linked immunoassay (ELISA) kit was used for detection.
- the standard protein was diluted to a suitable concentration, then added to the microtiter plate coated with purified CK2 capture antibody, and then added to the test compound diluted to a suitable concentration gradient, and a control group without added drug was set for comparison. Put it in the incubator and incubate for 1 hour to make the drug effectively inhibit the binding of protein and antibody, discard the liquid in the microplate, add 200 ⁇ L of the diluted washing solution, leave it for 30s, discard it and repeat the washing 5 times.
- ELISA enzyme-linked immunoassay
- the cytotoxic activity test of the compound prepared by the present invention was carried out using the MTT method. Take the logarithmic phase cell count, were seeded in 96-well culture plate, each well of about 104 cells, at 37 °C, 5% CO 2 incubator for 24h to adherent cell administration, administration group are located And the control group without administration. The control group was replaced with fresh medium, the tested compounds 4 and 5 and cisplatin were dissolved in 5% glucose aqueous solution, and other compounds were prepared into mother liquor with DMSO, and the corresponding cell culture medium was diluted to a suitable concentration gradient before use. For the drug group, 3 parallel groups are set for each concentration.
- the prepared compound was used to treat human laryngeal cancer cells Hep2, nasopharyngeal cancer cells CNE2, gastric cancer cells SGC-7901, colon cancer cells HCT-116, breast cancer cells MCF-7, cervical cancer cells SiHa, and prostate cancer cells.
- PC-3, bladder cancer cell T24, non-small cell lung cancer A549 and its cisplatin-resistant cancer cell A549/CDDP, ovarian cancer cell A2780, cisplatin-resistant cancer cell A2780/CDDP, and normal liver cells LO2 were anti-tumor in vitro
- CX-4945 was used as a positive control. Observe the compound's inhibition of tumor cell growth at different concentrations, calculate its IC 50 value to evaluate the cytotoxic activity of the drug, and the results are shown in Table 2.
- Western Blot test was used to detect the compounds involved in the present invention. Taking the logarithmic growth phase cells were counted, seeded in 6-well culture plate, each well of about 10 5 cells. The cells were cultured at 37°C in a 5% CO 2 incubator for 24 hours until the cells adhered to the wall and then administered. The administration group and the non-administered control group were set up respectively. The control group was replaced with fresh medium, the compound 4 to be tested was dissolved in 5% glucose aqueous solution, and the other compounds were prepared into mother liquor with DMSO, and diluted with the corresponding cell culture medium to an appropriate concentration before use and added to the administration group.
- the cells in the wells were digested, collected by centrifugation into a centrifuge tube and washed with PBS, an appropriate amount of lysate was added dropwise to the cells, and the cells were lysed in an ice box for 2 hours. Centrifuge at 10000rpm for 20-30min, and take the supernatant for later use. The protein content was determined with BCA protein kit (Thermo, Waltham, MA).
- Tested animal BALB/c(nu/nu) nude mouse, weighing 16 ⁇ 18g, female, purchased from Shanghai Xipuer-Bikai Experimental Animal Co., Ltd., raised in an SPF breeding environment, the indoor temperature is controlled at 23 ⁇ 2 °C, free eating and drinking.
- the animals were bred adaptively for 7 days before inoculation.
- Drugs and reagents cisplatin was dissolved in 5% glucose injection by ultrasonic, compound 1 was dissolved in DMF, and then diluted with Tween80 and 5% glucose injection in sequence.
- the groups and dosage regimen are as follows. Model control group: 0.1 mL of 5% glucose injection was injected into the tail vein once a week for 4 consecutive weeks.
- Experimental method Take A2780 or A2780/CDDP cells in logarithmic growth phase, prepare a cell suspension concentration of 5 ⁇ 10 7 cell/mL, inoculate 0.2 mL/mouse under the right armpit of nude mice to establish A2780 or A2780/CDDP nude mice transplanted tumors
- the diameter of the transplanted tumor in nude mice was measured with a vernier caliper. After the tumor grew to 100mm 3, the animals were randomly divided into groups. Use the method of measuring tumor diameter to dynamically observe the anti-tumor effect of the test substance. The number of measurements of tumor diameter was once every 3 days, and the mouse body weight was checked every 3 days.
- mice After 4 weeks, all mice were sacrificed by injection of chloral hydrate, and observed by laparotomy. The tumor was removed and irrelevant tissues were carefully removed. The blood was washed with D-Hanks solution for 2 to 3 times, the blood was washed away, and the water was drained for storage. .
- the relative tumor volume (RTV) is calculated according to the measurement results.
- Evaluation index of anti-tumor activity relative tumor proliferation rate T/C (%), the calculation formula is as follows:
- TRTV treatment group RTV
- C RTV model group RTV.
- the mean value is represented by X ⁇ SD, the analysis between groups is statistically processed by t-test, and the results are statistically analyzed by SPSS (Staffstical Package for the Social Science) 17.0.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims (6)
- 一种如权利要求1所述的具有克服顺铂耐药的抗肿瘤化合物的制备方法,其特征在于式I中的化合物1由式II所示的反应式制备,A method for preparing an antitumor compound capable of overcoming cisplatin resistance according to claim 1, wherein compound 1 in formula I is prepared by the reaction formula shown in formula II,式II所示的反应式制备,具体步骤如下:在反应瓶中加入将等摩尔量的化合物3与化合物4悬浮于无水甲醇中,滴加乙酸,反应液在30-60℃下避光反应48-72小时,然后冷至室温,过滤,滤饼用无水甲醇冲洗三次,得黄色固体产物-化合物1。For the preparation of the reaction formula shown in formula II, the specific steps are as follows: add equimolar amounts of compound 3 and compound 4 in anhydrous methanol into a reaction flask, add acetic acid dropwise, and react the reaction solution at 30-60°C in the dark After 48-72 hours, it was cooled to room temperature, filtered, and the filter cake was washed three times with anhydrous methanol to obtain compound 1 as a yellow solid product.
- 一种如权利要求1所述的具有克服顺铂耐药的抗肿瘤化合物的制备方法,其特征在于式I中的化合物2由式III所示的反应式制备,A method for preparing an anti-tumor compound capable of overcoming cisplatin resistance according to claim 1, wherein compound 2 in formula I is prepared by the reaction formula shown in formula III,式Ⅲ所示的反应式制备,具体步骤如下:在反应瓶中加入将等摩尔量的化合物3与化合物5悬浮于无水甲醇中,滴加乙酸,反应液在30-60℃下避光反应48-72小时,然后冷至室温,过滤,滤饼用无水甲醇冲洗三次,得黄色固体产物-化合物2。The reaction formula shown in formula III is prepared, and the specific steps are as follows: add equimolar amounts of compound 3 and compound 5 in anhydrous methanol into the reaction flask, add acetic acid dropwise, and react the reaction solution at 30-60°C in the dark After 48-72 hours, it was cooled to room temperature, filtered, and the filter cake was washed three times with anhydrous methanol to obtain compound 2 as a yellow solid product.
- 如权利要求2或3所述的具有克服顺铂耐药的抗肿瘤化合物的制备方法,其特征在于式II和式Ⅲ中所示的化合物3由式IV所示的反应式制备,The method for preparing an antitumor compound capable of overcoming cisplatin resistance according to claim 2 or 3, characterized in that the compound 3 shown in formula II and formula III is prepared by the reaction formula shown in formula IV,按照式Ⅳ所示的反应式制备,具体步骤如下:在装有甲醇的反应瓶中加入1当量的化合物6,室温下缓慢滴加2-10当量的水合肼,反应液加热回流24-72小时至反应完全,然后冷至室温,析出大量固体,过滤,滤饼用冰甲醇冲洗三次,得亮黄色固体产物-化合物3。According to the reaction formula shown in formula IV, the specific steps are as follows: add 1 equivalent of compound 6 into a reaction flask containing methanol, slowly add 2-10 equivalents of hydrazine hydrate at room temperature, and heat the reaction solution to reflux for 24-72 hours After the reaction was completed, it was cooled to room temperature, and a large amount of solid precipitated out. The filter cake was washed with ice methanol three times to obtain compound 3 as a bright yellow solid product.
- 一种如权利要求1所述的一类具有克服顺铂耐药的抗肿瘤化合物的应用,其特征在于,所述的化合物不仅对顺铂敏感的肿瘤而且对顺铂耐药的肿瘤具有很强的抑制作用,且毒性较小,具有高效低毒的特点,可用于制备抗肿瘤药物。An application of an anti-tumor compound capable of overcoming cisplatin resistance according to claim 1, wherein the compound is not only sensitive to cisplatin-sensitive tumors, but also highly resistant to cisplatin-resistant tumors. The inhibitory effect, low toxicity, high efficiency and low toxicity, can be used to prepare anti-tumor drugs.
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202010223660.1 | 2020-03-26 | ||
CN202010223660 | 2020-03-26 | ||
CN202010703943.6 | 2020-07-21 | ||
CN202010703943.6A CN113444085B (en) | 2020-03-26 | 2020-07-21 | Antitumor compound capable of overcoming cisplatin resistance and preparation and application thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2021190076A1 true WO2021190076A1 (en) | 2021-09-30 |
Family
ID=77808333
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2021/070303 WO2021190076A1 (en) | 2020-03-26 | 2021-01-05 | Anti-tumor compound capable of overcoming cisplatin resistance, preparation therefor, and application thereof |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN113444085B (en) |
WO (1) | WO2021190076A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114164176A (en) * | 2021-12-13 | 2022-03-11 | 深圳市第二人民医院(深圳市转化医学研究院) | Human bladder cancer cis-platinum drug-resistant cell strain and application thereof |
CN115227715A (en) * | 2021-10-28 | 2022-10-25 | 四川大学 | Combined medicine and pharmaceutical composition for treating cancer |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN116178443A (en) * | 2021-11-26 | 2023-05-30 | 东南大学 | Platinum (II) compound with targeting effect, derivative thereof, preparation method, pharmaceutical composition and application |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102036561A (en) * | 2008-02-29 | 2011-04-27 | 赛林药物股份有限公司 | Protein kinase modulators |
CN102924528A (en) * | 2012-10-29 | 2013-02-13 | 东南大学 | Anti-tumor bivalent platinum complex and preparation method for complex and ligand of complex |
CN104086597A (en) * | 2014-05-26 | 2014-10-08 | 昆明贵金属研究所 | Platinum (II) antitumor compounds taking 3-oxo-cyclobutane-1,1-dicarboxylate as ligand |
-
2020
- 2020-07-21 CN CN202010703943.6A patent/CN113444085B/en active Active
-
2021
- 2021-01-05 WO PCT/CN2021/070303 patent/WO2021190076A1/en active Application Filing
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102036561A (en) * | 2008-02-29 | 2011-04-27 | 赛林药物股份有限公司 | Protein kinase modulators |
CN102924528A (en) * | 2012-10-29 | 2013-02-13 | 东南大学 | Anti-tumor bivalent platinum complex and preparation method for complex and ligand of complex |
CN104086597A (en) * | 2014-05-26 | 2014-10-08 | 昆明贵金属研究所 | Platinum (II) antitumor compounds taking 3-oxo-cyclobutane-1,1-dicarboxylate as ligand |
Non-Patent Citations (1)
Title |
---|
CHEN FEIHONG; PEI SINAN; WANG XING; ZHU QIAN; GOU SHAOHUA: "Emerging JWA-targeted Pt(IV) Prodrugs Conjugated with CX-4945 to Overcome Chemo-immune-resistance", BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, vol. 521, no. 3, 6 November 2019 (2019-11-06), pages 753 - 761, XP085972923, ISSN: 0006-291X, DOI: 10.1016/j.bbrc.2019.10.184 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115227715A (en) * | 2021-10-28 | 2022-10-25 | 四川大学 | Combined medicine and pharmaceutical composition for treating cancer |
CN114164176A (en) * | 2021-12-13 | 2022-03-11 | 深圳市第二人民医院(深圳市转化医学研究院) | Human bladder cancer cis-platinum drug-resistant cell strain and application thereof |
CN114164176B (en) * | 2021-12-13 | 2023-10-13 | 深圳市第二人民医院(深圳市转化医学研究院) | Cisplatin-resistant cell strain for human bladder cancer and application thereof |
Also Published As
Publication number | Publication date |
---|---|
CN113444085A (en) | 2021-09-28 |
CN113444085B (en) | 2022-04-08 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2021190076A1 (en) | Anti-tumor compound capable of overcoming cisplatin resistance, preparation therefor, and application thereof | |
Liang et al. | Synthesis, in vitro and in vivo antitumor activity of symmetrical bis-Schiff base derivatives of isatin | |
US20200031807A1 (en) | Aurkb small-molecule inhibitors and uses thereof | |
Gu et al. | Studies of anticancer activity in vivo and in vitro behaviors of liposomes encapsulated iridium (III) complex | |
CN112656795A (en) | Action mechanism and application of fangchinoline in resisting tuberculosis membrane melanoma | |
Li et al. | Development of a series of flurbiprofen and zaltoprofen platinum (iv) complexes with anti-metastasis competence targeting COX-2, PD-L1 and DNA | |
Chen et al. | Cyclometalated Ru (II) β-carboline complexes induce cell cycle arrest and apoptosis in human HeLa cervical cancer cells via suppressing ERK and Akt signaling | |
Lu et al. | SERD-NHC-Au (I) complexes for dual targeting ER and TrxR to induce ICD in breast cancer | |
Hou et al. | Norcantharidin inhibits renal interstitial fibrosis by downregulating PP2Ac expression | |
CN111484492B (en) | Substituted pyridino-imidazole compound and application thereof in preparation of medicine for treating malignant tumor diseases | |
Sun et al. | Design and synthesis of β-carboline derivatives with nitrogen mustard moieties against breast cancer | |
CN111072725B (en) | Compound with naproxen tetravalent platinum structure, preparation method and application thereof in preparation of antitumor drugs | |
WO2020244253A1 (en) | Application of small molecule compound or pharmaceutically acceptable salt thereof in preparation of anti-tumor metastasis drug | |
CN106905347A (en) | BRD4 inhibitor and its application in anti-tumor medicine | |
CN111961084B (en) | Lung cancer cell inhibitor and preparation method thereof | |
CN112940059B (en) | Glycosyl modified naphthalimide-polyamine conjugate, preparation method and application thereof | |
CN110551156A (en) | specific group modified N1, N3 substituted 4, 5-diaryl imidazole ring carbene rhodium complex and preparation method and application thereof | |
CN112876414B (en) | Polyamine-modified naphthalimide conjugate, and preparation method and application thereof | |
CN114195779A (en) | Synthesis method of 9-0-ethyl ether berberberrubine and application thereof in preparation of antitumor drugs | |
Zhao et al. | Camptothecin derivatives induce apoptosis and inhibit proliferation of prostate cancer PC-3M cells through downregulation of PI3K/Akt signaling pathway | |
US11465986B2 (en) | Crystal form of c-MET inhibitor and salt form thereof and preparation method therefor | |
Zhang et al. | Lanatoside c decelerates proliferation and induces apoptosis through inhibition of stat3 and ros-mediated mitochondrial membrane potential transformation in cholangiocarcinoma | |
CN107998130B (en) | Application of RhoGDI inhibitor in preparation of medicine for treating nasopharyngeal carcinoma | |
CN112898301B (en) | Naphthalimide indole heterocyclic compound, and preparation method and application thereof | |
CN105153055A (en) | Allylbenzene acylation 1,5-diaryl-1,2,4-triazole derivative, preparation method of allylbenzene acylation 1,5-diaryl-1,2,4-triazole derivative and medicine purpose of allylbenzene acylation 1,5-diaryl-1,2,4-triazole derivative |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 21775482 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 21775482 Country of ref document: EP Kind code of ref document: A1 |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 21775482 Country of ref document: EP Kind code of ref document: A1 |
|
32PN | Ep: public notification in the ep bulletin as address of the adressee cannot be established |
Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC, EPO FORM 1205A DATED 10.07.2023 |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 21775482 Country of ref document: EP Kind code of ref document: A1 |