CN113853380A - 用于无核遗传毒性化学治疗的改用型抗生素和包含其的用于抗癌的药物组合物 - Google Patents
用于无核遗传毒性化学治疗的改用型抗生素和包含其的用于抗癌的药物组合物 Download PDFInfo
- Publication number
- CN113853380A CN113853380A CN202080035615.1A CN202080035615A CN113853380A CN 113853380 A CN113853380 A CN 113853380A CN 202080035615 A CN202080035615 A CN 202080035615A CN 113853380 A CN113853380 A CN 113853380A
- Authority
- CN
- China
- Prior art keywords
- cancer
- compound
- cfx
- pharmaceutical composition
- cells
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 16
- 230000003115 biocidal effect Effects 0.000 title abstract description 17
- 230000001093 anti-cancer Effects 0.000 title abstract description 13
- 238000002512 chemotherapy Methods 0.000 title description 3
- 230000001738 genotoxic effect Effects 0.000 title description 3
- 231100000024 genotoxic Toxicity 0.000 title description 2
- 210000004027 cell Anatomy 0.000 claims abstract description 82
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 72
- 201000011510 cancer Diseases 0.000 claims abstract description 66
- 150000001875 compounds Chemical class 0.000 claims abstract description 46
- 210000003470 mitochondria Anatomy 0.000 claims abstract description 16
- 150000002148 esters Chemical class 0.000 claims description 41
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 claims description 22
- 239000002839 antibiotic anticancer agent Substances 0.000 claims description 17
- 150000001408 amides Chemical class 0.000 claims description 14
- -1 ethyleneoxy anions Chemical class 0.000 claims description 14
- 108020005196 Mitochondrial DNA Proteins 0.000 claims description 11
- 229960003405 ciprofloxacin Drugs 0.000 claims description 11
- 206010060862 Prostate cancer Diseases 0.000 claims description 8
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 8
- XUBOMFCQGDBHNK-JTQLQIEISA-N (S)-gatifloxacin Chemical compound FC1=CC(C(C(C(O)=O)=CN2C3CC3)=O)=C2C(OC)=C1N1CCN[C@@H](C)C1 XUBOMFCQGDBHNK-JTQLQIEISA-N 0.000 claims description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 7
- 229960003923 gatifloxacin Drugs 0.000 claims description 7
- GSDSWSVVBLHKDQ-UHFFFAOYSA-N 9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid Chemical compound FC1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)COC3=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-UHFFFAOYSA-N 0.000 claims description 6
- 206010009944 Colon cancer Diseases 0.000 claims description 6
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 6
- 208000029742 colonic neoplasm Diseases 0.000 claims description 6
- 201000005202 lung cancer Diseases 0.000 claims description 6
- 208000020816 lung neoplasm Diseases 0.000 claims description 6
- 230000006820 DNA synthesis Effects 0.000 claims description 5
- 230000027721 electron transport chain Effects 0.000 claims description 5
- 239000003306 quinoline derived antiinfective agent Substances 0.000 claims description 5
- 206010006187 Breast cancer Diseases 0.000 claims description 4
- 208000026310 Breast neoplasm Diseases 0.000 claims description 4
- BPFYOAJNDMUVBL-UHFFFAOYSA-N LSM-5799 Chemical compound C1CN(C)CCN1C1=C(F)C=C2C(=O)C(C(O)=O)=CN3N(C)COC1=C32 BPFYOAJNDMUVBL-UHFFFAOYSA-N 0.000 claims description 4
- GSDSWSVVBLHKDQ-JTQLQIEISA-N Levofloxacin Chemical compound C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-JTQLQIEISA-N 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 4
- 229960002531 marbofloxacin Drugs 0.000 claims description 4
- 208000037819 metastatic cancer Diseases 0.000 claims description 4
- 208000011575 metastatic malignant neoplasm Diseases 0.000 claims description 4
- 229960001180 norfloxacin Drugs 0.000 claims description 4
- 229960001699 ofloxacin Drugs 0.000 claims description 4
- XBHBWNFJWIASRO-UHFFFAOYSA-N 6-fluoro-1-(4-fluorophenyl)-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1=CC=C(F)C=C1 XBHBWNFJWIASRO-UHFFFAOYSA-N 0.000 claims description 3
- DPSPPJIUMHPXMA-UHFFFAOYSA-N 9-fluoro-5-methyl-1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylic acid Chemical compound C1CC(C)N2C=C(C(O)=O)C(=O)C3=C2C1=CC(F)=C3 DPSPPJIUMHPXMA-UHFFFAOYSA-N 0.000 claims description 3
- MGQLHRYJBWGORO-LLVKDONJSA-N Balofloxacin Chemical compound C1[C@H](NC)CCCN1C1=C(F)C=C2C(=O)C(C(O)=O)=CN(C3CC3)C2=C1OC MGQLHRYJBWGORO-LLVKDONJSA-N 0.000 claims description 3
- SPFYMRJSYKOXGV-UHFFFAOYSA-N Baytril Chemical compound C1CN(CC)CCN1C(C(=C1)F)=CC2=C1C(=O)C(C(O)=O)=CN2C1CC1 SPFYMRJSYKOXGV-UHFFFAOYSA-N 0.000 claims description 3
- QMLVECGLEOSESV-RYUDHWBXSA-N Danofloxacin Chemical compound C([C@@H]1C[C@H]2CN1C)N2C(C(=CC=1C(=O)C(C(O)=O)=C2)F)=CC=1N2C1CC1 QMLVECGLEOSESV-RYUDHWBXSA-N 0.000 claims description 3
- QIPQASLPWJVQMH-DTORHVGOSA-N Orbifloxacin Chemical compound C1[C@@H](C)N[C@@H](C)CN1C1=C(F)C(F)=C2C(=O)C(C(O)=O)=CN(C3CC3)C2=C1F QIPQASLPWJVQMH-DTORHVGOSA-N 0.000 claims description 3
- KYGZCKSPAKDVKC-UHFFFAOYSA-N Oxolinic acid Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC2=C1OCO2 KYGZCKSPAKDVKC-UHFFFAOYSA-N 0.000 claims description 3
- NJCJBUHJQLFDSW-UHFFFAOYSA-N Rufloxacin Chemical compound C1CN(C)CCN1C1=C(F)C=C2C(=O)C(C(O)=O)=CN3CCSC1=C32 NJCJBUHJQLFDSW-UHFFFAOYSA-N 0.000 claims description 3
- 229950000805 balofloxacin Drugs 0.000 claims description 3
- 229960004621 cinoxacin Drugs 0.000 claims description 3
- VDUWPHTZYNWKRN-UHFFFAOYSA-N cinoxacin Chemical compound C1=C2N(CC)N=C(C(O)=O)C(=O)C2=CC2=C1OCO2 VDUWPHTZYNWKRN-UHFFFAOYSA-N 0.000 claims description 3
- 229960004385 danofloxacin Drugs 0.000 claims description 3
- NOCJXYPHIIZEHN-UHFFFAOYSA-N difloxacin Chemical compound C1CN(C)CCN1C(C(=C1)F)=CC2=C1C(=O)C(C(O)=O)=CN2C1=CC=C(F)C=C1 NOCJXYPHIIZEHN-UHFFFAOYSA-N 0.000 claims description 3
- 229950001733 difloxacin Drugs 0.000 claims description 3
- 229960002549 enoxacin Drugs 0.000 claims description 3
- IDYZIJYBMGIQMJ-UHFFFAOYSA-N enoxacin Chemical compound N1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 IDYZIJYBMGIQMJ-UHFFFAOYSA-N 0.000 claims description 3
- 229960000740 enrofloxacin Drugs 0.000 claims description 3
- 229960000702 flumequine Drugs 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 229960003376 levofloxacin Drugs 0.000 claims description 3
- 229960002422 lomefloxacin Drugs 0.000 claims description 3
- ZEKZLJVOYLTDKK-UHFFFAOYSA-N lomefloxacin Chemical compound FC1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNC(C)C1 ZEKZLJVOYLTDKK-UHFFFAOYSA-N 0.000 claims description 3
- 230000005787 mitochondrial ATP synthesis coupled electron transport Effects 0.000 claims description 3
- 229960003808 nadifloxacin Drugs 0.000 claims description 3
- JYJTVFIEFKZWCJ-UHFFFAOYSA-N nadifloxacin Chemical compound FC1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)CCC3=C1N1CCC(O)CC1 JYJTVFIEFKZWCJ-UHFFFAOYSA-N 0.000 claims description 3
- 229960000210 nalidixic acid Drugs 0.000 claims description 3
- MHWLWQUZZRMNGJ-UHFFFAOYSA-N nalidixic acid Chemical compound C1=C(C)N=C2N(CC)C=C(C(O)=O)C(=O)C2=C1 MHWLWQUZZRMNGJ-UHFFFAOYSA-N 0.000 claims description 3
- OGJPXUAPXNRGGI-UHFFFAOYSA-N norfloxacin Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 OGJPXUAPXNRGGI-UHFFFAOYSA-N 0.000 claims description 3
- 229960004780 orbifloxacin Drugs 0.000 claims description 3
- 229960000321 oxolinic acid Drugs 0.000 claims description 3
- 229960004236 pefloxacin Drugs 0.000 claims description 3
- FHFYDNQZQSQIAI-UHFFFAOYSA-N pefloxacin Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCN(C)CC1 FHFYDNQZQSQIAI-UHFFFAOYSA-N 0.000 claims description 3
- 229960001732 pipemidic acid Drugs 0.000 claims description 3
- JOHZPMXAZQZXHR-UHFFFAOYSA-N pipemidic acid Chemical compound N1=C2N(CC)C=C(C(O)=O)C(=O)C2=CN=C1N1CCNCC1 JOHZPMXAZQZXHR-UHFFFAOYSA-N 0.000 claims description 3
- 229960004062 rufloxacin Drugs 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 229950007734 sarafloxacin Drugs 0.000 claims description 3
- RXZBMPWDPOLZGW-XMRMVWPWSA-N (E)-roxithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=N/OCOCCOC)/[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 RXZBMPWDPOLZGW-XMRMVWPWSA-N 0.000 claims description 2
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000000739 C2-C30 alkenyl group Chemical group 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 150000001450 anions Chemical class 0.000 claims description 2
- 229910052787 antimony Inorganic materials 0.000 claims description 2
- 229910052785 arsenic Inorganic materials 0.000 claims description 2
- 150000007942 carboxylates Chemical class 0.000 claims description 2
- 125000003827 glycol group Chemical group 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 125000001072 heteroaryl group Chemical group 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229960003702 moxifloxacin Drugs 0.000 claims description 2
- FABPRXSRWADJSP-MEDUHNTESA-N moxifloxacin Chemical compound COC1=C(N2C[C@H]3NCCC[C@H]3C2)C(F)=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 FABPRXSRWADJSP-MEDUHNTESA-N 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 claims description 2
- 229910052698 phosphorus Inorganic materials 0.000 claims description 2
- 229920001515 polyalkylene glycol Chemical group 0.000 claims description 2
- 229960005224 roxithromycin Drugs 0.000 claims description 2
- IIACRCGMVDHOTQ-UHFFFAOYSA-M sulfamate Chemical compound NS([O-])(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-M 0.000 claims description 2
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- QKDHBVNJCZBTMR-LLVKDONJSA-N (R)-temafloxacin Chemical compound C1CN[C@H](C)CN1C(C(=C1)F)=CC2=C1C(=O)C(C(O)=O)=CN2C1=CC=C(F)C=C1F QKDHBVNJCZBTMR-LLVKDONJSA-N 0.000 claims 1
- WUWFMDMBOJLQIV-UHFFFAOYSA-N 7-(3-aminopyrrolidin-1-yl)-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid Chemical compound C1C(N)CCN1C(C(=C1)F)=NC2=C1C(=O)C(C(O)=O)=CN2C1=CC=C(F)C=C1F WUWFMDMBOJLQIV-UHFFFAOYSA-N 0.000 claims 1
- MPORYQCGWFQFLA-ONPDANIMSA-N 7-[(7s)-7-amino-5-azaspiro[2.4]heptan-5-yl]-8-chloro-6-fluoro-1-[(1r,2s)-2-fluorocyclopropyl]-4-oxoquinoline-3-carboxylic acid;trihydrate Chemical compound O.O.O.C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1.C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 MPORYQCGWFQFLA-ONPDANIMSA-N 0.000 claims 1
- AIJTTZAVMXIJGM-UHFFFAOYSA-N Grepafloxacin Chemical compound C1CNC(C)CN1C(C(=C1C)F)=CC2=C1C(=O)C(C(O)=O)=CN2C1CC1 AIJTTZAVMXIJGM-UHFFFAOYSA-N 0.000 claims 1
- XAGMUUZPGZWTRP-ZETCQYMHSA-N LSM-5745 Chemical compound C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1C1(N)CC1 XAGMUUZPGZWTRP-ZETCQYMHSA-N 0.000 claims 1
- PWNMXPDKBYZCOO-UHFFFAOYSA-N Prulifloxacin Chemical compound C1=C2N3C(C)SC3=C(C(O)=O)C(=O)C2=CC(F)=C1N(CC1)CCN1CC=1OC(=O)OC=1C PWNMXPDKBYZCOO-UHFFFAOYSA-N 0.000 claims 1
- 229960004024 besifloxacin Drugs 0.000 claims 1
- QFFGVLORLPOAEC-SNVBAGLBSA-N besifloxacin Chemical compound C1[C@H](N)CCCCN1C1=C(F)C=C2C(=O)C(C(O)=O)=CN(C3CC3)C2=C1Cl QFFGVLORLPOAEC-SNVBAGLBSA-N 0.000 claims 1
- QGPKADBNRMWEQR-UHFFFAOYSA-N clinafloxacin Chemical compound C1C(N)CCN1C1=C(F)C=C2C(=O)C(C(O)=O)=CN(C3CC3)C2=C1Cl QGPKADBNRMWEQR-UHFFFAOYSA-N 0.000 claims 1
- 229950001320 clinafloxacin Drugs 0.000 claims 1
- DYDCPNMLZGFQTM-UHFFFAOYSA-N delafloxacin Chemical compound C1=C(F)C(N)=NC(N2C3=C(Cl)C(N4CC(O)C4)=C(F)C=C3C(=O)C(C(O)=O)=C2)=C1F DYDCPNMLZGFQTM-UHFFFAOYSA-N 0.000 claims 1
- 229950006412 delafloxacin Drugs 0.000 claims 1
- 229960003306 fleroxacin Drugs 0.000 claims 1
- XBJBPGROQZJDOJ-UHFFFAOYSA-N fleroxacin Chemical compound C1CN(C)CCN1C1=C(F)C=C2C(=O)C(C(O)=O)=CN(CCF)C2=C1F XBJBPGROQZJDOJ-UHFFFAOYSA-N 0.000 claims 1
- 229960003170 gemifloxacin Drugs 0.000 claims 1
- ZRCVYEYHRGVLOC-HYARGMPZSA-N gemifloxacin Chemical compound C1C(CN)C(=N/OC)/CN1C(C(=C1)F)=NC2=C1C(=O)C(C(O)=O)=CN2C1CC1 ZRCVYEYHRGVLOC-HYARGMPZSA-N 0.000 claims 1
- 229960000642 grepafloxacin Drugs 0.000 claims 1
- 150000002431 hydrogen Chemical group 0.000 claims 1
- 229960002625 pazufloxacin Drugs 0.000 claims 1
- 229960001224 prulifloxacin Drugs 0.000 claims 1
- 229960003177 sitafloxacin Drugs 0.000 claims 1
- 229960004954 sparfloxacin Drugs 0.000 claims 1
- DZZWHBIBMUVIIW-DTORHVGOSA-N sparfloxacin Chemical compound C1[C@@H](C)N[C@@H](C)CN1C1=C(F)C(N)=C2C(=O)C(C(O)=O)=CN(C3CC3)C2=C1F DZZWHBIBMUVIIW-DTORHVGOSA-N 0.000 claims 1
- 229960004576 temafloxacin Drugs 0.000 claims 1
- 229950008187 tosufloxacin Drugs 0.000 claims 1
- 229960000497 trovafloxacin Drugs 0.000 claims 1
- WVPSKSLAZQPAKQ-CDMJZVDBSA-N trovafloxacin Chemical compound C([C@H]1[C@@H]([C@H]1C1)N)N1C(C(=CC=1C(=O)C(C(O)=O)=C2)F)=NC=1N2C1=CC=C(F)C=C1F WVPSKSLAZQPAKQ-CDMJZVDBSA-N 0.000 claims 1
- 108090000623 proteins and genes Proteins 0.000 abstract description 25
- 230000006378 damage Effects 0.000 abstract description 13
- 108091093105 Nuclear DNA Proteins 0.000 abstract description 10
- 230000008685 targeting Effects 0.000 abstract description 9
- 238000011319 anticancer therapy Methods 0.000 abstract description 6
- 230000001225 therapeutic effect Effects 0.000 abstract description 6
- 206010059866 Drug resistance Diseases 0.000 abstract description 4
- 238000011254 conventional chemotherapy Methods 0.000 abstract description 4
- 230000007850 degeneration Effects 0.000 abstract 1
- 238000002626 targeted therapy Methods 0.000 abstract 1
- 229940041181 antineoplastic drug Drugs 0.000 description 29
- 238000011282 treatment Methods 0.000 description 24
- 239000002246 antineoplastic agent Substances 0.000 description 21
- 239000000203 mixture Substances 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- 102000004169 proteins and genes Human genes 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 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 12
- 238000001727 in vivo Methods 0.000 description 10
- 238000002474 experimental method Methods 0.000 description 9
- 239000003642 reactive oxygen metabolite Substances 0.000 description 9
- 239000000523 sample Substances 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 239000003242 anti bacterial agent Substances 0.000 description 7
- 229940088710 antibiotic agent Drugs 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 210000001700 mitochondrial membrane Anatomy 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- 206010055113 Breast cancer metastatic Diseases 0.000 description 6
- 108020004414 DNA Proteins 0.000 description 6
- 230000005778 DNA damage Effects 0.000 description 6
- 231100000277 DNA damage Toxicity 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 230000001640 apoptogenic effect Effects 0.000 description 6
- 238000003556 assay Methods 0.000 description 6
- 229960004679 doxorubicin Drugs 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 230000002829 reductive effect Effects 0.000 description 6
- 210000000130 stem cell Anatomy 0.000 description 6
- 231100000419 toxicity Toxicity 0.000 description 6
- 230000001988 toxicity Effects 0.000 description 6
- 241000894006 Bacteria Species 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- 239000003085 diluting agent Substances 0.000 description 5
- 239000012153 distilled water Substances 0.000 description 5
- 230000005284 excitation Effects 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 230000002438 mitochondrial effect Effects 0.000 description 5
- 239000011259 mixed solution Substances 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- 102000004121 Annexin A5 Human genes 0.000 description 4
- 108090000672 Annexin A5 Proteins 0.000 description 4
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- 206010038111 Recurrent cancer Diseases 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000002835 absorbance Methods 0.000 description 4
- 239000000654 additive Substances 0.000 description 4
- 125000003368 amide group Chemical group 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000012091 fetal bovine serum Substances 0.000 description 4
- 238000003753 real-time PCR Methods 0.000 description 4
- 230000008439 repair process Effects 0.000 description 4
- 239000003381 stabilizer Substances 0.000 description 4
- 230000035899 viability Effects 0.000 description 4
- 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 3
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 description 3
- 208000003721 Triple Negative Breast Neoplasms Diseases 0.000 description 3
- 210000004102 animal cell Anatomy 0.000 description 3
- 230000006907 apoptotic process Effects 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- UQLDLKMNUJERMK-UHFFFAOYSA-L di(octadecanoyloxy)lead Chemical compound [Pb+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O UQLDLKMNUJERMK-UHFFFAOYSA-L 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 238000012377 drug delivery Methods 0.000 description 3
- 238000012239 gene modification Methods 0.000 description 3
- 230000005017 genetic modification Effects 0.000 description 3
- 235000013617 genetically modified food Nutrition 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 230000003834 intracellular effect Effects 0.000 description 3
- 230000002147 killing effect Effects 0.000 description 3
- 230000003902 lesion Effects 0.000 description 3
- 230000003859 lipid peroxidation Effects 0.000 description 3
- 230000035772 mutation Effects 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 229960004964 temozolomide Drugs 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 208000022679 triple-negative breast carcinoma Diseases 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 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 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 2
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 108020004638 Circular DNA Proteins 0.000 description 2
- 102100021122 DNA damage-binding protein 2 Human genes 0.000 description 2
- 230000033616 DNA repair Effects 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- 206010018338 Glioma Diseases 0.000 description 2
- 229920000084 Gum arabic Polymers 0.000 description 2
- 101001041466 Homo sapiens DNA damage-binding protein 2 Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- WSMYVTOQOOLQHP-UHFFFAOYSA-N Malondialdehyde Chemical compound O=CCC=O WSMYVTOQOOLQHP-UHFFFAOYSA-N 0.000 description 2
- 206010027476 Metastases Diseases 0.000 description 2
- 229910020808 NaBF Inorganic materials 0.000 description 2
- 239000000205 acacia gum Substances 0.000 description 2
- 235000010489 acacia gum Nutrition 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 238000000540 analysis of variance Methods 0.000 description 2
- 229940124650 anti-cancer therapies Drugs 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 229940095259 butylated hydroxytoluene Drugs 0.000 description 2
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 2
- 230000005907 cancer growth Effects 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 235000014633 carbohydrates Nutrition 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 230000006315 carbonylation Effects 0.000 description 2
- 238000005810 carbonylation reaction Methods 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 239000000975 dye Substances 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000002073 fluorescence micrograph Methods 0.000 description 2
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 102000006602 glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 2
- 108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 229940118019 malondialdehyde Drugs 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 230000009401 metastasis Effects 0.000 description 2
- 238000010172 mouse model Methods 0.000 description 2
- 231100000956 nontoxicity Toxicity 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 230000036542 oxidative stress Effects 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 238000003752 polymerase chain reaction Methods 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- HSSLDCABUXLXKM-UHFFFAOYSA-N resorufin Chemical compound C1=CC(=O)C=C2OC3=CC(O)=CC=C3N=C21 HSSLDCABUXLXKM-UHFFFAOYSA-N 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- PKYCWFICOKSIHZ-UHFFFAOYSA-N 1-(3,7-dihydroxyphenoxazin-10-yl)ethanone Chemical compound OC1=CC=C2N(C(=O)C)C3=CC=C(O)C=C3OC2=C1 PKYCWFICOKSIHZ-UHFFFAOYSA-N 0.000 description 1
- PJUPKRYGDFTMTM-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1 PJUPKRYGDFTMTM-UHFFFAOYSA-N 0.000 description 1
- HORQAOAYAYGIBM-UHFFFAOYSA-N 2,4-dinitrophenylhydrazine Chemical compound NNC1=CC=C([N+]([O-])=O)C=C1[N+]([O-])=O HORQAOAYAYGIBM-UHFFFAOYSA-N 0.000 description 1
- RVBUGGBMJDPOST-UHFFFAOYSA-N 2-thiobarbituric acid Chemical compound O=C1CC(=O)NC(=S)N1 RVBUGGBMJDPOST-UHFFFAOYSA-N 0.000 description 1
- BCHZICNRHXRCHY-UHFFFAOYSA-N 2h-oxazine Chemical compound N1OC=CC=C1 BCHZICNRHXRCHY-UHFFFAOYSA-N 0.000 description 1
- UAIUNKRWKOVEES-UHFFFAOYSA-N 3,3',5,5'-tetramethylbenzidine Chemical compound CC1=C(N)C(C)=CC(C=2C=C(C)C(N)=C(C)C=2)=C1 UAIUNKRWKOVEES-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- WDBQJSCPCGTAFG-QHCPKHFHSA-N 4,4-difluoro-N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclohexane-1-carboxamide Chemical compound FC1(CCC(CC1)C(=O)N[C@@H](CCN1CCC(CC1)N1C(=NN=C1C)C(C)C)C=1C=NC=CC=1)F WDBQJSCPCGTAFG-QHCPKHFHSA-N 0.000 description 1
- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- HCAJQHYUCKICQH-VPENINKCSA-N 8-Oxo-7,8-dihydro-2'-deoxyguanosine Chemical compound C1=2NC(N)=NC(=O)C=2NC(=O)N1[C@H]1C[C@H](O)[C@@H](CO)O1 HCAJQHYUCKICQH-VPENINKCSA-N 0.000 description 1
- 229920000856 Amylose Polymers 0.000 description 1
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 102100035186 DNA excision repair protein ERCC-1 Human genes 0.000 description 1
- 238000007399 DNA isolation Methods 0.000 description 1
- 230000009946 DNA mutation Effects 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 238000008157 ELISA kit Methods 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 239000012981 Hank's balanced salt solution Substances 0.000 description 1
- 101000876529 Homo sapiens DNA excision repair protein ERCC-1 Proteins 0.000 description 1
- 231100000416 LDH assay Toxicity 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 206010053961 Mitochondrial toxicity Diseases 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 102000003992 Peroxidases Human genes 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 238000011316 allogeneic transplantation Methods 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 238000011394 anticancer treatment Methods 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 229960001714 calcium phosphate Drugs 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000000378 calcium silicate Substances 0.000 description 1
- 229910052918 calcium silicate Inorganic materials 0.000 description 1
- 229960003340 calcium silicate Drugs 0.000 description 1
- 235000012241 calcium silicate Nutrition 0.000 description 1
- OYACROKNLOSFPA-UHFFFAOYSA-N calcium;dioxido(oxo)silane Chemical compound [Ca+2].[O-][Si]([O-])=O OYACROKNLOSFPA-UHFFFAOYSA-N 0.000 description 1
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 1
- 229940127093 camptothecin Drugs 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000005779 cell damage Effects 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 238000003570 cell viability assay Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 208000011654 childhood malignant neoplasm Diseases 0.000 description 1
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 1
- 229960004630 chlorambucil Drugs 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000001218 confocal laser scanning microscopy Methods 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 239000012470 diluted sample Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 238000000684 flow cytometry Methods 0.000 description 1
- 238000000799 fluorescence microscopy Methods 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 229940014259 gelatin Drugs 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 231100000025 genetic toxicology Toxicity 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- DXKRGNXUIRKXNR-UHFFFAOYSA-N ibafloxacin Chemical compound C1CC(C)N2C=C(C(O)=O)C(=O)C3=C2C1=C(C)C(F)=C3 DXKRGNXUIRKXNR-UHFFFAOYSA-N 0.000 description 1
- 229950007954 ibafloxacin Drugs 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 238000011503 in vivo imaging Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 210000005061 intracellular organelle Anatomy 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 238000002843 lactate dehydrogenase assay Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 125000005647 linker group Chemical group 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 238000003266 membrane potential measurement method Methods 0.000 description 1
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 230000004898 mitochondrial function Effects 0.000 description 1
- 231100000296 mitochondrial toxicity Toxicity 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- 230000022888 negative regulation of membrane potential Effects 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 238000001543 one-way ANOVA Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 108040007629 peroxidase activity proteins Proteins 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229960004444 piromidic acid Drugs 0.000 description 1
- RCIMBBZXSXFZBV-UHFFFAOYSA-N piromidic acid Chemical compound N1=C2N(CC)C=C(C(O)=O)C(=O)C2=CN=C1N1CCCC1 RCIMBBZXSXFZBV-UHFFFAOYSA-N 0.000 description 1
- 229910052696 pnictogen Inorganic materials 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 210000001236 prokaryotic cell Anatomy 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 239000003531 protein hydrolysate Substances 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 229960003889 rosoxacin Drugs 0.000 description 1
- XBPZXDSZHPDXQU-UHFFFAOYSA-N rosoxacin Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC=C1C1=CC=NC=C1 XBPZXDSZHPDXQU-UHFFFAOYSA-N 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000003260 vortexing Methods 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
-
- 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
本发明涉及用于在最小的核基因损伤情况下治疗癌症的改用型抗生素化合物和包含所述化合物的抗癌药物组合物。由于改用型抗生素化合物以仅靶向癌细胞线粒体的方式具有治疗作用,因此不同于损伤核DNA以杀伤癌细胞的常规化学治疗,经修饰的抗生素化合物不会导致基因变性,从而预防癌症复发。另外,使用根据本发明化合物进行的线粒体靶向治疗可有效地治疗由于一般抗癌治疗而获得药物抗性从而难以治疗的恶性肿瘤。
Description
技术领域
本发明涉及用于在对核基因损伤最小的情况下进行癌症治疗的经修饰的抗生素化合物和包含所述化合物的抗癌药物组合物。
背景技术
世界各地的许多研究组致力于开发不同的药物递送系统,以在降低副作用的情况下提高现有抗癌药物的治疗作用,并且作为结果,成功开发了将现有的高毒性抗癌药物有效地递送至癌组织并使抗癌药物仅在癌症微环境中被激活的药物递送系统,实现了显著提高的癌症治疗安全性。
然而,尽管取得了这些技术性进步,但对具有获得性药物抗性的复发性和转移性癌症的治疗和抑制仍然是对于常规抗癌治疗仍然是挑战。90%的癌症死亡是由复发性癌症而不是原发性癌症导致的。患有过癌症的人即使在存活5年之后,在其一生中仍然具有非常高的癌症复发的可能性。特别地,儿科癌症患者的癌症复发的风险提高更多。最近已经报道了癌症复发自相矛盾地是由于使用抗癌药物引起的。
一般的化学治疗在癌细胞中抑制核DNA的复制并导致核DNA损伤,从而杀伤癌细胞。在这个过程中,突变发生,并将导致癌症复发。发现向2期胶质瘤患者施用替莫唑胺进行抗癌治疗导致更恶性(4期)的胶质瘤作为复发性癌症,并且在复发性癌症中检测到由抗癌药物替莫唑胺诱导的DNA突变。
线粒体是具有其自己的不同于动物中细胞核的环状DNA并以与原核细胞相同的方式分裂和融合的胞内细胞器。由于这些原因,线粒体的起源由内共生学说来解释,在内共生学说中,细菌在进化期间侵入宿主细胞并成为动物细胞中的线粒体。证据是线粒体如细菌一样具有其自己的环状DNA,并且在结构和遗传上类似于细菌。大量研究揭示了,由于线粒体像细菌一样使用酶进行生物合成,因此主要靶向细菌的一些抗生素抑制线粒体功能,导致线粒体毒性,这是它们副作用的原因。已经尝试了通过反向使用抗生素的毒性来杀伤癌细胞。然而,抗生素在低浓度下对人细胞不表现出显著毒性,并且在高浓度下抑制癌细胞和正常细胞二者的分裂(但即使其对正常细胞更具选择性毒性),使得其基本不可能用作抗癌药物。即,研究结果仅限于抗生素对动物细胞的毒性。一些研究还揭示了,用高浓度抗生素处理癌症干细胞抑制了癌症生长。然而,抗生素对占总癌症体积99%的大量癌细胞没有作用,并且其抑制癌症干细胞的分裂和生长而不是杀伤癌症干细胞。即,这些研究仅表明抗生素的可能的治疗作用。
具有高线粒体质量和高线粒体膜电位的癌症干细胞可通过使用线粒体膜电位以递送药物并使药物在线粒体中积累的药物递送系统最有效地消除。特别地,不同于通过核DNA损伤杀伤癌细胞的常规化学治疗,在癌细胞中选择性地靶向线粒体以进行有效的癌症治疗将在不导致遗传修饰的情况下预防癌症复发。
发明内容
技术挑战
本发明旨在提供这样的经修饰的抗生素抗癌药物,其在不损伤正常细胞和正常干细胞的情况下选择性地杀伤癌细胞和癌症干细胞,并且在预定时间过去之后失去其靶向基团从而成为可从身体中安全地释放而没有次级毒性的简单的抗生素药物,因此可用于新癌症治疗策略以抑制癌症复发和转移并使可能的副作用的可能性最小化。
技术方案
本发明的一个方面提供了用于在对核基因损伤最小的情况下进行癌症治疗的经修饰的抗生素化合物,其由式1表示:
[式1]
下面将描述由式1表示的抗生素的结构和取代基。
本发明的经修饰的抗生素抗癌化合物在癌细胞中使对核基因的损伤最小化并在癌细胞中选择性地靶向线粒体,并因此其在癌细胞中抑制线粒体电子传递链(ETC)和线粒体DNA合成。
本发明的另一个方面提供了用于在对核基因损伤最小的情况下预防和治疗癌症疾病的药物组合物,其包括由式1表示的经修饰的抗生素化合物或其盐作为活性成分。
有益效果
本发明的经修饰的抗生素抗癌药物在癌细胞中选择性地靶向线粒体以表现出其治疗作用。因此,不同于用于通过核DNA损伤来杀伤癌细胞的常规化学治疗,本发明的经修饰的抗生素抗癌药物可在不导致遗传修饰的情况下预防癌症复发。另外,本发明的化合物可用于提供线粒体靶向治疗以用于有效治疗由于获得性药物抗性而难以通过一般抗癌治疗来治疗的恶性肿瘤。
附图说明
图1示出了在用本发明化合物(酯Mt-CFX)和商业抗生素(环丙沙星)处理之后转移性乳腺癌细胞(MDA-MB-231)的生存力。
图2示出了在用酯Mt-CFX和酰胺Mt-CFX处理之后转移性乳腺癌细胞(MDA-MB-231)的生存力,所述酰胺Mt-CFX通过用酰胺基替代酯Mt-CFX的结合位点来获得,以得到更好的体内相容性。
图3示出了在用本发明化合物(酯Mt-CFX)处理之后,多种癌细胞类型(包括A549(肺癌细胞)、SW620(结肠癌细胞)、DU145(前列腺癌细胞)和PC3(前列腺癌细胞))的生存力。
图4示出了由用荧光标记(Amplex-red和CM-H2DCFDA)标记的本发明化合物(酯Mt-CFX)进行的在细胞中的活性氧物质(reactive oxidativespecies,ROS)的产生。
图5示出了在用本发明化合物(酯Mt-CFX)处理之后线粒体DNA合成的抑制和膜电位的降低。
图6示出了在用本发明化合物(酯Mt-CFX)处理之后产生的活性氧物质对DNA、蛋白质和脂质的损伤程度。
图7示出了在用本发明化合物(酯Mt-CFX)处理之后随时间推移的线粒体膜电位差的降低(JC-1测定)和凋亡的发生(膜联蛋白V测定)。
图8比较了本发明抗癌化合物(酯Mt-CFX)和商业抗癌药物(多柔比星(DOXO))对核DNA和线粒体DNA的损伤程度。
图9示出了在用本发明化合物(酯Mt-CFX)和商业抗癌药物(多柔比星(DOXO))处理之后DNA修复蛋白的表达水平(其中POLγ是参与线粒体基因修复的蛋白质,并且ERCC1和DDB2是参与核基因修复的蛋白质)。
图10比较了酯Mt-CFX和对核DNA造成损伤的常规抗癌药物对线粒体基因组DNA的损伤程度,这通过Taq1测定来确定。
图11示出了在用本发明化合物(酯Mt-CFX)和常规商业抗癌药物(多柔比星、替莫唑胺、喜树碱、顺铂、苯丁酸氮芥和5-FU)处理之后对核DNA损伤病变和线粒体DNA损伤病变的实时PCR的结果。
图12示出了化合物(酯Mt-CFX)对肿瘤细胞的抑制作用,这使用乳腺癌移植模型,通过在注射化合物之后确定随时间推移的肿瘤靶向作用(体内成像)以及测量肿瘤体积和重量的时间依赖性变化来进行。
用于实施本发明的最佳方式
现在将更详细地描述本发明。
本发明涉及用于抗癌治疗新概念的经修饰的抗生素药物,其可抑制由强遗传毒性导致的复发和转移,这是当前抗癌治疗的主要问题。
本发明的经修饰的抗生素抗癌药物化合物由式1表示:
[式1]
其中D是选自以下的高度稳定的氟喹诺酮抗生素的骨架:氟甲喹(flumequine)、奥索利酸(oxolinic acid)、罗索沙星(rosoxacin)、西诺沙星(cinoxacin)、萘啶酸(nalidixic acid)、吡咯米酸(piromidic acid)、吡哌酸(pipemidic acid)、环丙沙星(ciprofloxacin)、氟洛沙星(fleroxacin)、洛美沙星(lomefloxacin)、那氟沙星(nadifloxacin)、诺氟沙星(norfloxacin)、氧氟沙星(ofloxacin)、培氟沙星(pefloxacin)、芦氟沙星(rufloxacin)、依诺沙星(enoxacin)、巴洛沙星(balofloxacin)、格帕沙星(grepafloxacin)、左氧氟沙星(levofloxacin)、帕珠沙星(pazufloxacin)、司帕沙星(sparfloxacin)、替马沙星(temafloxacin)、托氟沙星(tosufloxacin)、克林沙星(clinafloxacin)、加替沙星(gatifloxacin)、莫西沙星(moxifloxacin)、西他沙星(sitafloxacin)、普卢利沙星(prulifloxacin)、贝西沙星(besifloxacin)、吉米沙星(gemifloxacin)、曲伐沙星(trovafloxacin)、德拉沙星(delafloxacin)、达氟沙星(danofloxacin)、二氟沙星(difloxacin)、恩诺沙星(enrofloxacin)、依巴沙星(ibafloxacin)、马波沙星(marbofloxacin)、奥比沙星(orbifloxacin)和沙氟沙星(sarafloxacin)。
X与氟喹诺酮抗生素的骨架的末端羟基连接,并且选自O、S和NR(其中R选自氢、C1-C30烷基、C6-C30芳基和C2-C30杂芳基),优选O或NR。
L为与靶向基团的连接基团,并且选自C1-C30烷基、C2-C30烯基和聚亚烷基二醇基团。
Q是选自N、P、As和Sb的第15族元素;R1至R3彼此相同或不同,并且各自独立地选自C1-C30烷基、C2-C30烯基、C6-C30芳基和C2-C30杂芳基。
并且A-是选自以下的阴离子:卤素、羟基、羧酸根、硫酸根、氨基磺酸根、磺酸根、磷酸根、膦酸根、硼酸根和(聚)乙烯氧基阴离子。
本发明的经修饰的抗生素抗癌药物化合物使用高度稳定的抗生素的骨架作为基本结构,并且被设计为选择性地靶向线粒体,实现了增强的抗癌治疗效力。另外,本发明的经修饰的抗生素抗癌药物化合物在线粒体靶向基团在体内被水解之后成为安全的抗生素药物,导致最小的副作用。当X为酰胺基(NR)时,确保了由式1表示的化合物更好的在体内的稳定性。
根据本发明的一个示例性实施方案,式1化合物选自但不限于:
[酯Mt-CFX]
其中n为1至30的整数并且A-如式1中所限定;和
[酰胺Mt-CFX]
其中n和A-如上所限定。式1化合物具有作为氟喹诺酮抗生素的环丙沙星的骨架。在随后的实施例部分中,n为6并且A-为氯阴离子。酰胺Mt-CFX是通过用酰胺基替代酯Mt-CFX的结合位点而获得的化合物,以得到更好的体内稳定性。
本发明还涉及用于预防和治疗癌症疾病的药物组合物,其包含由式1表示的经修饰的抗生素抗癌化合物或其盐作为活性成分。
本发明的药物组合物可用于预防和治疗广泛多种的癌症疾病,例如原发性癌症及其转移性癌症。癌症疾病的一些实例包括但不限于乳腺癌、肺癌、结肠癌、前列腺癌,及其转移性癌症。
本发明的药物组合物可在施用之前与用于预防或治疗癌症疾病的其他已知药物复合,或者还可包含选自以下的一种或更多种另外的添加剂:载体、稀释剂、辅料和稳定剂。
根据本发明的组合物的剂型可取决于所期望的施用方式而变化。这样的剂型的一些实例包括但不限于固体、半固体和液体制剂,例如片剂、丸剂、散剂、胶囊剂、凝胶剂、软膏剂、乳剂和混悬剂。本发明的组合物可以以适合于单次施用精确剂量的单位剂型施用。本发明的组合物可经口或肠胃外施用。对于肠胃外施用,本发明的组合物可静脉内、皮下或肌内施用。
取决于所期望的制剂,组合物还可包含一种或更多种可药用的载体、稀释剂、辅料和稳定剂,它们被定义为通常用于配制用于人施用的药物组合物的基于水的载剂。
术语“载体”意指促进化合物并入到细胞或组织中的物质。合适的载体的一些实例包括但不限于基于碳水化合物的化合物(例如乳糖、直链淀粉、右旋糖、蔗糖、山梨糖醇、甘露糖醇、淀粉和纤维素)、阿拉伯胶、磷酸钙、藻酸盐、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆剂、盐溶液、醇类、阿拉伯胶、植物油(例如玉米油、棉籽油、大豆油、橄榄油和椰子油)、聚乙二醇、甲基纤维素、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石、硬脂酸镁和矿物油,它们通常用于配制药物组合物。术语“稀释剂”被定义为在水中稀释的物质,其可溶解目的化合物并使化合物的生物活性形式稳定化。合适的稀释剂的一些实例包括蒸馏水、生理盐水、林格溶液、右旋糖溶液和Hank溶液。稳定剂可选自蛋白质、碳水化合物、缓冲剂,及其混合物。本发明的组合物还可任选地包含一种或更多种添加剂。这样的任选的添加剂的一些实例包括但不限于润滑剂、润湿剂、甜味剂、矫味剂、乳化剂、助悬剂和防腐剂。
这样的另外的添加剂例如载体、稀释剂、辅料和稳定剂可以以有效获得在活性成分的溶解度、生物活性和其它特征等方面可药用的制剂的量使用。
具体实施方式
将参考以下实施例更具体地解释本发明。本领域技术人员将理解,这些实施例仅是举例说明性的并且本发明的范围不限于此。
合成例1:酯Mt-CFX的合成
根据方案1合成酯Mt-CFX:
[方案一]
方案1中所示的化合物1和2根据本领域已知的方法合成。
(1)化合物3的合成
将化合物1(1g,1.975mmol)和化合物2(852mg,1.975mmol)溶解在作为溶剂的二甲基甲酰胺中,并随后向其中缓慢添加碳酸钾(819mg,5.925mmol)。将混合物在50℃下搅拌12小时。将反应混合物在减压下蒸发以去除溶剂。将残余物通过柱色谱进行纯化并溶解在甲醇和蒸馏水(1/9)的50mL混合溶液中。向溶液添加NaBF4,随后搅拌1小时。将反应混合物用二氯甲烷和蒸馏水萃取并将其溶解在甲醇中。在添加1×8氯化物之后,将所得混合物搅拌6小时。将反应混合物过滤并蒸发以去除溶剂。
(2)酯Mt-CFX的合成
将化合物3溶解在1,4-二氧六环和二氯甲烷(4/1)的18mL混合溶液中,并随后在0℃下向其中逐滴添加6mL在二氧六环中的4N HCl。将混合物在室温下搅拌12小时。通过在减压下蒸发将溶剂去除,得到酯Mt-CFX。
1H NMR(CDCl3,500MHz):δ8.50(s,1H),7.87-7.70(m,15H),7.66(d,J=13.1Hz,1H),7.36(d,J=7.1Hz,1H),4.29-4.23(m,2H),3.69-3.60(m,2H),3.59-3.53(m,1H),3.50-3.42(m,4H),3.30-3.20(m,4H),1.78-1.65(m,6H),1.61-1.53(m,2H),1.39(d,J=5.9Hz,2H),1.14-1.07(m,2H)ppm.
合成例2:酰胺Mt-CFX的合成
根据方案2合成酰胺Mt-CFX:
[方案二]
方案2中所示的化合物1和2根据本领域已知方法合成。
(1)化合物4的合成
将化合物1(1g,mmol)溶解在35mL在甲醇中的7N NH3溶液中。将溶液在室温下搅拌3天。此后,在减压下蒸发反应溶液以去除溶剂。将残余物通过柱色谱进行纯化。
(2)化合物5的合成
将化合物2(1g,2.318mmol)、EDC盐酸盐(667mg,3.477mmol)和1-羟基苯并三唑水合物(470mg,3.477mmol)溶解在作为溶剂的二甲基甲酰胺中。将溶液在室温下搅拌30分钟。向反应溶液添加DMAP(425mg,3.477mmol)和化合物4(1.025g,2.318mmol)。将所得混合物搅拌12小时。在减压下蒸发反应混合物以去除溶剂。将残余物通过柱色谱进行纯化并将其溶解在甲醇和蒸馏水(1/9)的50mL混合溶液中。向溶液添加NaBF4,随后搅拌1小时。将反应混合物用二氯甲烷和蒸馏水萃取并溶解在甲醇中。在添加1×8氯化物之后,将所得混合物搅拌6小时。将反应混合物过滤并蒸发以去除溶剂。
(3)酰胺Mt-CFX的合成
将化合物5溶解在1,4-二氧六环和二氯甲烷(4/1)的18mL混合溶液中,并随后在0℃下向其中逐滴添加6mL在二氧六环中的4N HCl。将混合物在室温下搅拌12小时。通过在减压下蒸发将溶剂去除,得到酰胺Mt-CFX。
1H NMR(MeOD,500MHz):δ8.88(s,1H),7.95-7.74(m,17H),7.69(d,J=7.2Hz,1H)3.85-3.79(m,1H),3.69-3.64(m,4H),3.54-3.49(m,4H),3.49-3.41(m,4H),1.77-1.70(m,2H),1.70-1.58(m,4H),1.53-1.42(m,4H)ppm.
实验例
1-1.动物细胞培养
将人转移性乳腺癌细胞系MDA-MB-231(人乳腺癌细胞)、肺癌细胞系A549(人肺癌细胞)、人结肠癌细胞系SW620(人结肠癌细胞)、人前列腺癌细胞系DU145和PC3(人前列腺癌细胞)在RPMI1640培养基和改良的Eagle培养基(modified Eagle’s media,MEM)中培养。所有培养基均补充有10%灭活的胎牛血清(fetal bovine serum,FBS)和1%青霉素-链霉素。所有细胞系均在37℃和5%二氧化碳下培养。
1-2.细胞生存力分析
将MDA-MB-231、A549、SW620、DU145和PC3细胞接种到96孔板中并培养过夜以稳定化。在用0至100μM的不同浓度的酯MT-CFX、酰胺MT-CFX和环丙沙星处理经稳定化细胞48小时之后,测量活细胞中LDH的量以确定细胞生存力。数据示出为三个独立实验的平均值±SE。
1-3.活性氧物质(ROS)测量和分析
通过用Red试剂(10-乙酰基-3,7-二羟基吩嗪;Thermo Fisherscientific)检测来评价细胞中产生的过氧化氢(H2O2)的活性。在此,在细胞中在存在过氧化物酶的情况下,Red试剂与H2O2以1∶1的化学计量比反应,产生作为红色荧光产物的试卤灵(resorufin)。试卤灵的荧光可在分别为571nm和581nm的激发波长和发射波长下分析。将MDA-MB-231细胞系接种到96孔板中并用10μM酯MT-CFX处理48小时。此后,测量过氧化氢的量。在Krebs-Ringer磷酸缓冲液(145mM NaCl、5.7mM磷酸钠、4.86mM KCl、0.54mMCaCl2、1.22mM MgSO4、5.5mM葡萄糖,pH7.35)中制备50μMRed试剂和0.1U/mL HRP的反应混合物。向每个板孔添加100μL反应混合物,随后在37℃下孵育10分钟。使用微板读取仪在530至560nm激发波长和590nm发射波长下测量荧光亮度。将MDA-MB-231细胞系接种到共焦皿中。将细胞用10μM酯MT-CFX处理48小时,随后与10μM CM-H2DCFDA染料孵育30分钟。CM-H2DCFDA染料是细胞中活性氧物质的已知标志物。细胞中产生的活性氧物质的荧光通过共焦激光扫描显微术在492至495nm激发波长和517至527nm发射波长下成像。
1-4.DNA氧化测量
使用市售8-OHdG ELISA试剂盒通过酶联免疫测定来分析氧化应激引起的胞内DNA氧化。在将MDA-MB-231细胞用10μM酯MT-CFX和10μM CFX处理48小时之后,将样品与一抗在37℃下以及与二抗在37℃下孵育1小时。使经孵育的样品在室温下静置15分钟以显色。使用多板读取仪在450nm下测量所得溶液的吸光度值。
1-5.蛋白质羰基化测量
已知蛋白质羰基是氧化应激的重要生理标志物,并且活性氧物质(ROS)易于损伤胞内蛋白质。通过ELISA确定蛋白质羰基化。在将MDA-MB-231细胞用10μM酯MT-CFX和10μMCFX处理48小时之后,用10μL10%(w/v)SDS使来自每个样品的10μL 1μg/μL的蛋白质裂解物变性并用在TPA中制备的20μL 20mM的2,4-二硝基苯肼(DNPH)溶液使其衍生化。在于室温下孵育10分钟且每2分钟进行涡旋之后,用20μL的2M Tris-Cl中和反应产物。将DNP衍生化样品的3μL等分试样用0.25mL吸附缓冲液(20mM NaHCO3、150mM NaCl、0.25%SDS,pH 8.5)稀释,并将100μL经稀释样品加载到96孔板上。将板用铝箔覆盖并在4℃下孵育过夜。在孵育之后,将样品孔用PBST(0.5%吐温20)冲洗5次,并且与200μL封闭缓冲液(吸附缓冲液中1%BSA)在37℃下孵育1小时。然后将样品孔与包含山羊抗DNP抗体的100μL封闭缓冲液在室温下孵育1小时。在孵育之后,将样品孔用PBST冲洗5次,并且与HRP缀合的兔抗山羊IgG抗体在室温下孵育1小时。在用PBST洗涤5次之后,将标准孔与100μL TMB底物在室温下孵育2至3分钟以显色。用100μL的0.5M H2SO4终止反应,并且在450nm和690nm下测量吸光度。在减去690nm下的背景吸光度之后,使用氧化的BSA标准品的标准曲线来确定每个样品中的羰基含量。
1-6.脂质过氧化测量
脂质过氧化是细胞损伤机制的标志之一并且可通过测量丙二醛(malondialdehyde,MDA)(脂质过氧化的产物)来确定。在将MDA-MB-231细胞用10μM酯Mt-CFX和10μM CFX处理48小时之后,将1mg/mL的每个样品置于磷酸缓冲液中并且在恒温浴中于37℃下孵育6小时。将0.5mL 0.75%硫代巴比妥酸添加至10μL用10%TCA淬灭的丁基化羟基甲苯(butylated hydroxytoluene,BHT)的混合溶液中。将混合物在95℃下加热20分钟,冷却并且以780×g离心10分钟。使用多板读取仪在532nm下测量所得溶液的吸光度。
1-7.FACS测量
通过流式细胞术来分析膜联蛋白V阳性凋亡细胞。为此,将MDA-MB-231细胞用10μM酯MT-CFX处理不同的时间段(0、6、12和24小时)并且培养指定的时间段。收获细胞,将其用冰冷的PBS洗涤两次,置于BD FACS管(106/mL)中,并且用包含10%FBS的PBS中的10μg/mL膜联蛋白V在室温下培养30分钟。随后,将细胞用冰冷的PBS洗涤,并且使用FACSCalibur流式细胞仪(BD,USA)在FL-1通道中测量膜联蛋白V荧光。
1-8.线粒体膜电位测量
测量线粒体膜电位差。为此,将MDA-MB-231细胞用10μM酯MT-CFX处理不同的时间段(0、6、12和24小时)并且培养指定的时间段。收获细胞,将其用冰冷的PBS洗涤一次,并且与2M 5,5’,6,6’-四氯-1,1’,3,3’-四乙基-苯并咪唑基碳菁氯化物(JC-1)在37℃下培养20分钟。将经JC-1染色的细胞以1,300g离心3分钟,并用冰冷的PBS洗涤两次。在不同波长段中测量JC-1单体(绿色通道)和聚集体(红色通道)的线粒体膜电位。
1-9.实时PCR分析
使用TRIzol溶液从每个样品中提取RNA。将从分离的RNA合成的cDNA或使用基因组DNA分离试剂盒提取的胞内基因组DNA用于实时聚合酶链反应(PCR)。将实时PCR数据通过甘油醛-3-磷酸脱氢酶(GAPDH)的表达进行归一化。将相对表达水平表示为相对于对照的倍数变化。结果(平均值±SE)以一式三份获得,并且p值<0.05被认为是统计学上显著的。
1-10.动物准备
使用了称重为18至20g的五周龄免疫缺陷型雄性BALB/c-nu-nu小鼠(Orient bio,Korea)。将动物在基于12小时光/暗循环维持30至40%湿度和22±1℃温度的设施中育种并饲养。所有动物实验均由韩国大学动物研究伦理委员会批准。根据伦理委员会批准的方案处理动物。
1-11.体内小鼠异体移植模型
将MDA-MB-231细胞(5×106个细胞)皮下注射到称重为18至20g的6周龄免疫缺陷型BALB/c-nu-nu小鼠中以建立荷瘤小鼠模型。将环丙沙星和酯MT-CFX每周3次地静脉内注射到所建立的荷瘤小鼠模型中。每周测量肿瘤长轴和短轴的长度。在每种化合物的第一次注射之后12周,处死小鼠并收集肿瘤样品用于进一步分析。结果示出为每组中4只小鼠的肿瘤的平均值±SE。每个星号(*)表示与相应对照的显著性差异。
1-12.体内荧光成像
评价了酯MT-CFX的肿瘤靶向能力和酯MT-CFX在每个器官中的分布。使用IVISLumina Series III Preclinical成像系统(PerkinElmer CO.,USA),在通过尾静脉将2μmol/kg酯MT-CFX注射到荷瘤小鼠中之后1小时至48小时获得体内光谱荧光图像。在560nm的激发波长下测量用于获得体内图像的滤光片。使用多激发光谱分析功能对荧光图像去卷积。
1-13.统计学分析
从以一式三份进行的三个独立实验中计算每组的平均值和标准误差(SE)。使用SAS软件(版本9.0,Cary)通过单因素方差分析(ANOVA)评价组间的统计学上显著性差异。当ANOVA显示出显著性差异时,使用Student’s t检验进行组平均值的比较。p值<0.05被认为是统计学上显著的。
实验结果
(1)市售的抗生素环丙沙星对MDA-MB-231转移性乳腺癌细胞几乎没有或没有凋亡作用。相比之下,具有靶向基团的本发明化合物酯Mt-CFX显示出对MDA-MB-231细胞的强凋亡作用,其中IC50为约15μM(图1)。
图1示出了MDA-MB-231肿瘤细胞系(韩国细胞系库)的生存力。MDA-MB-231是三阴性乳腺癌细胞系。目前,没有可有效地治疗三阴性乳腺癌的抗癌药物。将细胞在补充有10%FBS的DMEM中在37℃和5%CO2下培养。通过LDH测定来确定细胞毒性。将细胞在皿中培养约24小时使得其保持稳定地黏附至皿底部,随后用抗生素环丙沙星和本发明的酯Mt-CFX处理48小时。作为重复实验的结果,估计环丙沙星的IC50为1.65M并且酯Mt-CFX的IC50为20至30μM,表明酯Mt-CFX针对癌细胞的凋亡活性比环丙沙星的凋亡活性高约55,000倍。总之,本发明的抗癌药物对三阴性乳腺癌具有优异的抗癌作用。
(2)为了更好的体内稳定性,通过使酯Mt-CFX的结合位点(酯基)转化为酰胺基来合成酰胺Mt-CFX。酰胺Mt-CFX对癌细胞的凋亡作用经证实类似于酯Mt-CFX的凋亡作用(图2)。
对于本发明的酰胺Mt-CFX,重复了与针对酯Mt-CFX(图1)所述的相同的实验程序。结果示于图2中。本发明的酰胺Mt-CFX也显示出对癌细胞的增强的凋亡作用。
(3)本发明的化合物酯Mt-CFX和酰胺Mt-CFX显示出对多种癌细胞类型的凋亡作用,所述癌细胞类型包括A549(肺癌细胞)、SW620(结肠癌细胞)、DU145(前列腺癌细胞)和PC3(前列腺癌细胞)以及MDA-MB-231转移性乳腺癌细胞,表明了其广泛的适用性(图3)。
为了证明本发明抗癌药物对多种癌细胞类型的适用性,对A549、DU145、SW620和PC3肿瘤细胞系(韩国细胞系库)重复了与针对MDA-MB-231转移性乳腺癌细胞(图1)所述的相同实验程序。结果示于图3中。发现本发明抗癌药物对多种癌细胞类型是有效的。特别地,本发明抗癌药物对A549和SW620的IC50值分别为23.77μM和27.05μM。
(4)本发明的经修饰的抗生素Mt-CFX的抗癌作用可通过以下两种机制来解释:(i)化合物Mt-CFX在线粒体中积累以抑制电子传递链(ETC),因此其产生了活性氧物质(图4),以及(ii)抑制线粒体DNA合成(图5)。
图6示出了在本发明化合物酯Mt-CFX处理之后产生的活性氧物质对DNA、蛋白质和脂质的损伤程度。图7示出了在用本发明化合物酯Mt-CFX处理之后随时间推移的线粒体膜电位差的降低(JC-1测定)和凋亡的发生。
(5)图8通过比较本发明抗癌化合物酯Mt-CFX和商业抗癌药物(多柔比星(DOXO))对核DNA和线粒体DNA的损伤程度,示出了本发明抗癌化合物酯Mt-CFX对核基因的无毒性。作为结果,多柔比星显示出对核基因的强毒性,而本发明的抗癌化合物酯Mt-CFX显示出对核基因的无毒性和对线粒体基因的选择性毒性。
图9示出了在用本发明化合物酯Mt-CFX和商业抗癌药物(多柔比星(DOXO))处理之后DNA修复蛋白的表达水平(其中POLγ是参与线粒体基因修复的蛋白质并且ERCCl和DDB2是参与核基因修复的蛋白质)。图10揭示了不同于商业抗癌药物,本发明的酯Mt-CFX靶向线粒体,这通过Taq1测定来确定。
在用本发明的酯Mt-CFX和多种抗癌药物处理之后,通过PCR来分析DNA损伤病变。结果示于图11中。商业抗癌药物在核基因中导致许多突变而酯Mt-CFX诱导线粒体突变。
(6)通过体内实验确定了本发明荧光抗癌化合物酯Mt-CFX仅在癌组织中选择性地积累。与用对照进行的处理相比,用本发明抗癌化合物酯Mt-CFX进行的处理使得癌症体积显著降低,表明本发明抗癌化合物酯Mt-CFX对癌症具有优异的治疗作用(图12)。
工业实用性
本发明的经修饰的抗生素抗癌药物在癌细胞中选择性地靶向线粒体以表现出其治疗作用。因此,不同于通过核DNA损伤来杀伤癌细胞的常规化学治疗,经修饰的抗生素抗癌药物可在不导致遗传修饰的情况下预防癌症复发。另外,本发明的经修饰的抗生素抗癌药物可有效地治疗由于获得性药物抗性而难以通过一般抗癌治疗来治疗的恶性肿瘤。
Claims (9)
2.根据权利要求1所述的经修饰的抗生素抗癌化合物,其中式1中的D为选自以下的氟喹诺酮抗生素:氟甲喹、奥索利酸、罗索沙星、西诺沙星、萘啶酸、吡咯米酸、吡哌酸、环丙沙星、氟洛沙星、洛美沙星、那氟沙星、诺氟沙星、氧氟沙星、培氟沙星、芦氟沙星、依诺沙星、巴洛沙星、格帕沙星、左氧氟沙星、帕珠沙星、司帕沙星、替马沙星、托氟沙星、克林沙星、加替沙星、莫西沙星、西他沙星、普卢利沙星、贝西沙星、吉米沙星、曲伐沙星、德拉沙星、达氟沙星、二氟沙星、恩诺沙星、依巴沙星、马波沙星、奥比沙星和沙氟沙星。
4.根据权利要求1所述的经修饰的抗生素抗癌化合物,其中式1化合物在癌细胞中选择性地靶向线粒体。
5.根据权利要求1所述的经修饰的抗生素抗癌化合物,其中式1化合物在癌细胞中抑制线粒体电子传递链(ETC)和线粒体DNA合成。
6.用于预防和治疗癌症疾病的药物组合物,其包含根据权利要求1所述的经修饰的抗生素抗癌化合物或其盐作为活性成分。
7.根据权利要求6所述的药物组合物,其中所述药物组合物在癌细胞中选择性地靶向线粒体。
8.根据权利要求6所述的药物组合物,其中所述药物组合物在癌细胞中抑制线粒体电子传递链(ETC)和线粒体DNA合成。
9.根据权利要求6所述的药物组合物,其中所述癌症疾病选自乳腺癌、肺癌、结肠癌、前列腺癌,及其转移性癌症。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020190030384A KR102246180B1 (ko) | 2019-03-18 | 2019-03-18 | 핵 유전자 손상을 최소화한 암 치료를 위한 변형 항생제 화합물 및 이를 포함하는 항암 약학 조성물 |
KR10-2019-0030384 | 2019-03-18 | ||
PCT/KR2020/003248 WO2020189937A2 (ko) | 2019-03-18 | 2020-03-09 | 핵 유전자 손상을 최소화한 암 치료를 위한 변형 항생제 화합물 및 이를 포함하는 항암 약학 조성물 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN113853380A true CN113853380A (zh) | 2021-12-28 |
Family
ID=72519302
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202080035615.1A Pending CN113853380A (zh) | 2019-03-18 | 2020-03-09 | 用于无核遗传毒性化学治疗的改用型抗生素和包含其的用于抗癌的药物组合物 |
Country Status (5)
Country | Link |
---|---|
US (1) | US20220000887A1 (zh) |
EP (1) | EP3943112A4 (zh) |
KR (1) | KR102246180B1 (zh) |
CN (1) | CN113853380A (zh) |
WO (1) | WO2020189937A2 (zh) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR102361131B1 (ko) * | 2020-02-25 | 2022-02-10 | 경희대학교 산학협력단 | 항생제 내성 균주에 대해 항균활성을 갖는 항균용 조성물 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107936058A (zh) * | 2017-11-20 | 2018-04-20 | 沈阳药科大学 | 多西紫杉醇衍生物及其制备方法和应用 |
KR20190007239A (ko) * | 2017-07-12 | 2019-01-22 | 고려대학교 산학협력단 | 저산소환경에 의해 활성화되고 미토콘드리아에 대한 특이적 표적화가 가능한 항암 치료진단제 |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR101406278B1 (ko) * | 2011-11-21 | 2014-06-13 | 국립대학법인 울산과학기술대학교 산학협력단 | 독소루비신 및 개미트리닙을 유효성분으로 포함하는 암 치료용 약학 조성물 |
US20130190324A1 (en) * | 2011-12-23 | 2013-07-25 | The Regents Of The University Of Colorado, A Body Corporate | Topical ocular drug delivery |
KR101743399B1 (ko) * | 2016-05-31 | 2017-06-05 | 충남대학교산학협력단 | 폴리에틸렌글리콜과 트리페닐포스포늄이 컨쥬게이트된 물질 및 이를 적용한 미토콘드리아 표적 자기조립형 나노약물 전달체 |
-
2019
- 2019-03-18 KR KR1020190030384A patent/KR102246180B1/ko active IP Right Grant
-
2020
- 2020-03-09 CN CN202080035615.1A patent/CN113853380A/zh active Pending
- 2020-03-09 EP EP20772922.9A patent/EP3943112A4/en active Pending
- 2020-03-09 WO PCT/KR2020/003248 patent/WO2020189937A2/ko unknown
-
2021
- 2021-09-17 US US17/478,462 patent/US20220000887A1/en active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20190007239A (ko) * | 2017-07-12 | 2019-01-22 | 고려대학교 산학협력단 | 저산소환경에 의해 활성화되고 미토콘드리아에 대한 특이적 표적화가 가능한 항암 치료진단제 |
CN107936058A (zh) * | 2017-11-20 | 2018-04-20 | 沈阳药科大学 | 多西紫杉醇衍生物及其制备方法和应用 |
Non-Patent Citations (1)
Title |
---|
JACEK ZIELONKA ET AL.: "Mitochondria-Targeted Triphenylphosphonium-Based Compounds: Syntheses, Mechanisms of Action, and Therapeutic and Diagnostic Applications", 《CHEM. REV.》 * |
Also Published As
Publication number | Publication date |
---|---|
EP3943112A2 (en) | 2022-01-26 |
WO2020189937A9 (ko) | 2021-01-28 |
WO2020189937A3 (ko) | 2020-12-10 |
US20220000887A1 (en) | 2022-01-06 |
EP3943112A4 (en) | 2023-01-11 |
WO2020189937A2 (ko) | 2020-09-24 |
KR102246180B1 (ko) | 2021-04-28 |
KR20200110898A (ko) | 2020-09-28 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN105899491B (zh) | 用于抑制shp2活性的1-哒嗪-/三嗪-3-基-哌(-嗪)/啶/吡咯烷衍生物及其组合物 | |
JP7074761B2 (ja) | 治療用デンドリマー | |
CN117105939A (zh) | 稠合双环sGC刺激剂 | |
CN106659706A (zh) | 铂化合物、组合物及其用途 | |
JP5086497B1 (ja) | ボロン酸化合物を含有したブロック共重合体を含む医薬組成物 | |
TW202039439A (zh) | 4(1h)-奎諾酮衍生物及其用途 | |
CA2522980A1 (en) | Water soluble wortmannin derivatives | |
US20220000887A1 (en) | Repurposed antibiotics for non-nuclear genotoxic chemotherapy and pharmaceutical composition for anti-cancer containing the same | |
JP7389749B2 (ja) | プロテアソーム関連ユビキチン受容体rpn13機能を阻止する低分子およびその使用法 | |
Castanet et al. | Discovery of PIM-1 kinase inhibitors based on the 2, 5-disubstituted 1, 3, 4-oxadiazole scaffold against prostate cancer: Design, synthesis, in vitro and in vivo cytotoxicity investigation | |
CN109310650A (zh) | 用于减少过表达c-myc的癌症中的c-myc的化合物 | |
CA3191593A1 (en) | Polyvalent sting activating compositions and uses thereof | |
Wang et al. | Novel phenanthrene imidazoles as telomeric G-quadruplex ligands trigger potent immunogenic cell death in triple-negative breast cancer | |
JPWO2015125641A1 (ja) | 高分子化カンプトテシン誘導体及び高分子化hsp90阻害剤誘導体を含む医薬組成物 | |
JP6580030B2 (ja) | カンプトテシン誘導体とhsp90阻害剤の結合した高分子化合物及びその用途 | |
JP5721806B2 (ja) | 副作用のない抗癌剤 | |
CN113398276A (zh) | 脑胶质瘤靶向小檗碱与叶酸修饰的脂质材料的制备与应用 | |
KR102362023B1 (ko) | 유전자 비독성 항암 치료를 위한 항생제 변형 항암제 화합물 및 이를 포함하는 항암 약학 조성물 | |
Yuan et al. | Pioneering 4, 11-Dioxo-4, 11-dihydro-1 H-anthra [2, 3-d] imidazol-3-ium Compounds as Promising Survivin Inhibitors by Targeting ILF3/NF110 for Cancer Therapy | |
US20220331437A1 (en) | Conjugated inhibitors of dna damage response | |
US20240009321A1 (en) | Immunogenic nanovesicles for cancer immunotherapy | |
CN116870176A (zh) | PSMA靶向的PSMA-PARPi偶联物及制备方法和应用 | |
KR102142164B1 (ko) | 퀴논 화합물 및 암의 치료를 위한 그것의 용도 | |
JP2017526648A (ja) | 生物学的シグナル伝達を改変するためのイミダゾール及びチアゾール組成物 | |
Manisha et al. | Quantitative estimation of dextran conjugated ppi dendrimer for delivery of doxorubicin hydrochloride as an anticancer drug |
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 | ||
TA01 | Transfer of patent application right |
Effective date of registration: 20220422 Address after: Seoul, South Kerean Applicant after: Diagnostic chemistry Co. Address before: Seoul, South Kerean Applicant before: KOREA University RESEARCH AND BUSINESS FOUNDATION |
|
TA01 | Transfer of patent application right |