CN113171360A - Application of dithiodipyrone and analog thereof in preparation of medicine for preventing and treating heart tissue damage diseases caused by antitumor doxorubicin chemotherapy - Google Patents
Application of dithiodipyrone and analog thereof in preparation of medicine for preventing and treating heart tissue damage diseases caused by antitumor doxorubicin chemotherapy Download PDFInfo
- Publication number
- CN113171360A CN113171360A CN202110282901.4A CN202110282901A CN113171360A CN 113171360 A CN113171360 A CN 113171360A CN 202110282901 A CN202110282901 A CN 202110282901A CN 113171360 A CN113171360 A CN 113171360A
- Authority
- CN
- China
- Prior art keywords
- formula
- use according
- compound
- tert
- tissue damage
- 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
- 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 title claims abstract description 44
- 239000003814 drug Substances 0.000 title claims abstract description 18
- 238000002512 chemotherapy Methods 0.000 title claims abstract description 13
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims abstract description 10
- 210000005003 heart tissue Anatomy 0.000 title claims abstract description 10
- 230000000451 tissue damage Effects 0.000 title claims abstract description 9
- 231100000827 tissue damage Toxicity 0.000 title claims abstract description 9
- 201000010099 disease Diseases 0.000 title claims abstract description 8
- 229960004679 doxorubicin Drugs 0.000 title claims description 14
- 238000002360 preparation method Methods 0.000 title claims description 7
- 230000000259 anti-tumor effect Effects 0.000 title description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 34
- 229940009456 adriamycin Drugs 0.000 claims abstract description 8
- 230000000118 anti-neoplastic effect Effects 0.000 claims abstract description 4
- 230000000694 effects Effects 0.000 claims description 30
- 150000003254 radicals Chemical class 0.000 claims description 21
- 102000019197 Superoxide Dismutase Human genes 0.000 claims description 14
- 108010012715 Superoxide dismutase Proteins 0.000 claims description 14
- -1 C2-C6Alkenyl radical Chemical class 0.000 claims description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- GAABJUNZYPATIQ-UHFFFAOYSA-N 2,6-ditert-butyl-4-[(3,5-ditert-butyl-4-hydroxyphenyl)sulfanylmethylsulfanyl]phenol Chemical compound CC(C)(C)C1=C(O)C(C(C)(C)C)=CC(SCSC=2C=C(C(O)=C(C=2)C(C)(C)C)C(C)(C)C)=C1 GAABJUNZYPATIQ-UHFFFAOYSA-N 0.000 claims description 3
- WJQOZHYUIDYNHM-UHFFFAOYSA-N 2-tert-Butylphenol Chemical group CC(C)(C)C1=CC=CC=C1O WJQOZHYUIDYNHM-UHFFFAOYSA-N 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 3
- 230000006793 arrhythmia Effects 0.000 claims description 3
- 206010003119 arrhythmia Diseases 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- PTZLTPYSUMWAGK-UHFFFAOYSA-N C(C)(C)(C)C1=C(C=CC=C1)O.[S] Chemical group C(C)(C)(C)C1=C(C=CC=C1)O.[S] PTZLTPYSUMWAGK-UHFFFAOYSA-N 0.000 claims description 2
- 208000031229 Cardiomyopathies Diseases 0.000 claims description 2
- 206010019280 Heart failures Diseases 0.000 claims description 2
- 208000013875 Heart injury Diseases 0.000 claims description 2
- 208000025584 Pericardial disease Diseases 0.000 claims description 2
- OUUQCZGPVNCOIJ-UHFFFAOYSA-M Superoxide Chemical compound [O-][O] OUUQCZGPVNCOIJ-UHFFFAOYSA-M 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 125000003302 alkenyloxy group Chemical group 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 230000013632 homeostatic process Effects 0.000 claims description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 2
- 229940002612 prodrug Drugs 0.000 claims description 2
- 239000000651 prodrug Substances 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims 1
- 230000006378 damage Effects 0.000 description 14
- 102000004190 Enzymes Human genes 0.000 description 13
- 108090000790 Enzymes Proteins 0.000 description 13
- 229910052760 oxygen Inorganic materials 0.000 description 9
- 239000001301 oxygen Substances 0.000 description 9
- 239000003963 antioxidant agent Substances 0.000 description 7
- 108090000765 processed proteins & peptides Proteins 0.000 description 7
- 102000004169 proteins and genes Human genes 0.000 description 7
- 108090000623 proteins and genes Proteins 0.000 description 7
- 206010028980 Neoplasm Diseases 0.000 description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 238000001727 in vivo Methods 0.000 description 6
- 235000018102 proteins Nutrition 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 230000003078 antioxidant effect Effects 0.000 description 5
- 235000006708 antioxidants Nutrition 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 230000005779 cell damage Effects 0.000 description 5
- 208000037887 cell injury Diseases 0.000 description 5
- 239000012528 membrane Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- 239000002246 antineoplastic agent Substances 0.000 description 4
- 229940041181 antineoplastic drug Drugs 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 238000007254 oxidation reaction Methods 0.000 description 4
- 239000003642 reactive oxygen metabolite Substances 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 125000000539 amino acid group Chemical group 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 230000000670 limiting effect Effects 0.000 description 3
- 230000003859 lipid peroxidation Effects 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 230000001590 oxidative effect Effects 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- KGRVJHAUYBGFFP-UHFFFAOYSA-N 2,2'-Methylenebis(4-methyl-6-tert-butylphenol) Chemical compound CC(C)(C)C1=CC(C)=CC(CC=2C(=C(C=C(C)C=2)C(C)(C)C)O)=C1O KGRVJHAUYBGFFP-UHFFFAOYSA-N 0.000 description 2
- DKCPKDPYUFEZCP-UHFFFAOYSA-N 2,6-di-tert-butylphenol Chemical compound CC(C)(C)C1=CC=CC(C(C)(C)C)=C1O DKCPKDPYUFEZCP-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 2
- 102000006587 Glutathione peroxidase Human genes 0.000 description 2
- 108700016172 Glutathione peroxidases Proteins 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 108010057466 NF-kappa B Proteins 0.000 description 2
- 102000003945 NF-kappa B Human genes 0.000 description 2
- 102000003923 Protein Kinase C Human genes 0.000 description 2
- 108090000315 Protein Kinase C Proteins 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000003683 cardiac damage Effects 0.000 description 2
- 229940045200 cardioprotective agent Drugs 0.000 description 2
- 239000012659 cardioprotective agent Substances 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 230000001965 increasing effect Effects 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 230000002107 myocardial effect Effects 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 150000002989 phenols Chemical class 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 102000002723 Atrial Natriuretic Factor Human genes 0.000 description 1
- 101800001288 Atrial natriuretic factor Proteins 0.000 description 1
- 101800001890 Atrial natriuretic peptide Proteins 0.000 description 1
- 101800000407 Brain natriuretic peptide 32 Proteins 0.000 description 1
- 102400000667 Brain natriuretic peptide 32 Human genes 0.000 description 1
- 101800002247 Brain natriuretic peptide 45 Proteins 0.000 description 1
- 102000016938 Catalase Human genes 0.000 description 1
- 108010053835 Catalase Proteins 0.000 description 1
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 238000005698 Diels-Alder reaction Methods 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 102100032742 Histone-lysine N-methyltransferase SETD2 Human genes 0.000 description 1
- 101000654725 Homo sapiens Histone-lysine N-methyltransferase SETD2 Proteins 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- UPYKUZBSLRQECL-UKMVMLAPSA-N Lycopene Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1C(=C)CCCC1(C)C)C=CC=C(/C)C=CC2C(=C)CCCC2(C)C UPYKUZBSLRQECL-UKMVMLAPSA-N 0.000 description 1
- 102000010750 Metalloproteins Human genes 0.000 description 1
- 108010063312 Metalloproteins Proteins 0.000 description 1
- 102000003992 Peroxidases Human genes 0.000 description 1
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 description 1
- 229930003268 Vitamin C Natural products 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000003064 anti-oxidating effect Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000001574 biopsy Methods 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 231100001012 cardiac lesion Toxicity 0.000 description 1
- 150000001746 carotenes Chemical class 0.000 description 1
- 235000005473 carotenes Nutrition 0.000 description 1
- NSQLIUXCMFBZME-MPVJKSABSA-N carperitide Chemical compound C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)=O)[C@@H](C)CC)C1=CC=CC=C1 NSQLIUXCMFBZME-MPVJKSABSA-N 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000008809 cell oxidative stress Effects 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000007123 defense Effects 0.000 description 1
- 230000008260 defense mechanism Effects 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000002592 echocardiography Methods 0.000 description 1
- 238000002565 electrocardiography Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000001952 enzyme assay Methods 0.000 description 1
- 230000007760 free radical scavenging Effects 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 1
- 230000003394 haemopoietic effect Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 230000000116 mitigating effect Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 230000003680 myocardial damage Effects 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- HPNRHPKXQZSDFX-OAQDCNSJSA-N nesiritide Chemical compound C([C@H]1C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)CNC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](CCSC)NC(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CO)C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1N=CNC=1)C(O)=O)=O)[C@@H](C)CC)C1=CC=CC=C1 HPNRHPKXQZSDFX-OAQDCNSJSA-N 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 210000004789 organ system Anatomy 0.000 description 1
- 238000012261 overproduction Methods 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 150000002926 oxygen Chemical class 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 108040007629 peroxidase activity proteins Proteins 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000004153 renaturation Methods 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 229910052711 selenium Inorganic materials 0.000 description 1
- 239000011669 selenium Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- NCYCYZXNIZJOKI-UHFFFAOYSA-N vitamin A aldehyde Natural products O=CC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C NCYCYZXNIZJOKI-UHFFFAOYSA-N 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 230000003313 weakening effect Effects 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
- A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
- A61K31/10—Sulfides; Sulfoxides; Sulfones
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
-
- 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
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
-
- 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
- A61K31/4453—Non condensed piperidines, e.g. piperocaine only substituted in position 1, e.g. propipocaine, diperodon
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
Abstract
The invention provides a dithiobis-butylphenol compound and an analogue thereofThe application in preparing the medicine for preventing and/or treating the heart tissue damage disease caused by antineoplastic adriamycin chemotherapy. Specifically, the compounds of the present invention include the following preferred structures:
Description
Technical Field
The invention relates to the field of medicines, in particular to application of dithiodipyr and analogues thereof in preparation of medicines for preventing and/or treating heart tissue damage diseases caused by antitumor doxorubicin chemotherapy.
Background
The incidence of Chinese tumors has been increasing continuously for many years, and has become a public health problem and a social problem which must be paid high attention. To date, antineoplastic therapy remains one of the important means for treating tumors. Part of the antitumor drugs have toxic and side effects on the heart, which can cause the blood pressure change and the arrhythmia of patients, and can cause the myocardial lesion of patients, thereby not only limiting the increase of the drug dosage in the treatment process and influencing the curative effect, but also possibly leading the death of the patients.
In order to prevent and reduce the toxic and side effects of the antitumor drug on the heart, the monitoring is needed in clinic, for example, the evaluation is carried out before the treatment to eliminate the existence of contraindications; evaluating during treatment to decide to terminate treatment if necessary; follow-up was performed after treatment to detect late-onset cardiac lesions as early as possible. Such as cardiac enzyme assays, atrial natriuretic peptide assays, brain natriuretic peptide assays, troponin assays, electrocardiography, echocardiography, endocardial myocardial biopsies, and the like. In addition, cardiac damage can be prevented by limiting cumulative dosing, altering administration methods, pharmaceutical intervention, and the like. The medicine intervention can effectively reduce the toxic and side effects of the antitumor drug on the heart. Drugs capable of protecting the heart in antitumor therapy such as iron ion chelators, lipid-lowering drugs, hematopoietic cytokines, and the like. Several cardioprotective agents have been developed, but the therapeutic effect is not ideal. The development of a protective agent with a new action target and an action mechanism and capable of comprehensively protecting heart tissue from damage is urgently needed.
Scientific research shows that free radicals can cause damage to human organs including myocardial damage, but the damage to human health is not separated from the oxygen-containing substances with stronger activity, and the damage to human bodies caused by active oxygen radicals is actually an oxidation process. Therefore, to reduce the damage of free radicals, the oxidation resistance is required. Numerous studies have demonstrated that the body itself has the capacity to scavenge unwanted free radicals, mainly by means of an endogenous free radical scavenging system comprising enzymes such as superoxide dismutase (SOD), catalase, glutathione peroxidase, and antioxidants such as vitamin C, vitamin E, reduced glutathione, carotene, and selenium. Enzymes can change the active oxygen radicals in the body into less active substances, thereby weakening their offensive power to the body. While the defense action of enzymes is limited to intracellular, antioxidants act on cell membranes, some act extracellularly. These substances are deeply stored in our bodies, and as long as the quantity and the vitality of the substances are kept, the substances can play the role of eliminating redundant free radicals, so that the free radicals in our bodies are kept in balance. Therefore, to reduce the damage of free radicals, the oxidation resistance is required. When active oxygen is excessively generated, macromolecules can be induced to generate oxidation reaction, functional groups on Ser and Cys residues of the oxidized protein are oxidized, and configuration and signal change is caused; can make Cys residue in catalytic structure domain of nuclear factor NF-kB and protein kinase C form disulfide bond, up-regulate NF-kB and protein kinase C activity and catalytically produce H2O2When active oxygen is excessively generated, Cys residues in hypoxia inducible factor HIF-1 can be directly oxidized and activated to promote inflammation and apoptosis; can oxidize [4Fe2+ -4S in certain enzymes]Center, result in Fe2+Release of (1), Fe2+Can be processed by Fenton reactionA large amount of active oxygen should be generated; fe2+Can also cause inactivation of certain metalloproteins. When the active oxygen is excessively generated, it may oxidize signal molecules, cytokines, proteins, nucleic acids, saccharides, lipids, etc., to damage them.
In addition, Superoxide Dismutase (SOD), also known as heparin, is an important antioxidant enzyme in organisms, widely distributed in various organisms such as animals, plants, microorganisms and the like, is an active substance derived from organisms, can eliminate harmful substances generated by organisms in the metabolic process, resists and blocks damage to cells caused by oxygen radicals, repairs damaged cells in time, and restores damage to cells caused by the free radicals. Therefore, the activity of antioxidant enzymes of cells needs to be mobilized, ROS and lipid peroxidation products are eliminated quickly, and exogenous toxicity and relevant oxidative stress injury brought to organs are reduced.
Disulfide bonds (disulfide bonds) are chemical bonds linking the sulfhydryl groups of two different cysteine residues in different peptide chains or in the same peptide chain. Disulfide bonds are relatively stable covalent bonds and serve to stabilize the spatial structure of peptide chains in protein molecules. Disulfide bonds are involved in the biological activity of higher structures of proteins and in the renaturation of proteins. Disulfide bonds are important for the proper folding of proteins and the formation and maintenance of higher order structures. The formation of disulfide bonds forces amino acid residues in different regions of the same or different peptide chains to come together, whereby the peptide chains fold rapidly and form a stable spatial topology, the number of amino acid residues in this region being highly dense; meanwhile, hydrophobic amino acid residues surround the disulfide bonds, so that a local hydrophobic center can be formed, water molecules are rejected to enter the inside of the peptide to destroy hydrogen bonds, and a stable high-level structural region is formed.
Since an important target of free radicals acting on tissues is biological membranes, free radicals which are not cleared by defense mechanisms can induce lipid peroxidation of the membranes, with the result that the function of the membranes is lost, enzymes are inactivated, and the fluidity of the membranes is changed, resulting in cell damage. The function of some preparations to scavenge free radicals may be related to the hydroxyl groups on the phenol ring in their structures, which contain highly reactive hydroxyl groups that can inactivate free radicals, thereby mitigating damage to DNA and biological membranes by free radicals.
Phenolic compounds are commonly used for the research of antioxidant and anti-free radical protective structures.
The tertiary butyl substituent is a very sterically hindered group that is often used in conjunction with other bulky sterically hindered groups for kinetic stabilization in chemical synthesis, such as the related trimethylsilyl group. The effect that tert-butyl exerts on the progress of a chemical reaction is called: "tert-butyl effect". This effect is deduced by the diels-alder reaction as follows:
the reaction rate of the tertiary butyl substituent is increased by 240 times compared with that of a hydrogen atom as the substituent.
In summary, for chemotherapy injury caused by antitumor drug adriamycin, a novel preparation capable of regulating the dynamic balance of the activity of biological enzymes in human bodies and the active oxygen such as oxidative free radicals and the like is needed to be researched and screened based on further development of structures with potential antioxidant anti-free radical physiological activity values for phenols, tert-butyl, disulfide bonds and the like, so that the heart is protected, and the chemotherapy safety is improved.
Disclosure of Invention
The invention provides a compound and a pharmaceutically acceptable salt thereof, and application of a prodrug in preparing a medicament for preventing and/or treating heart tissue damage diseases caused by antitumor doxorubicin chemotherapy, wherein the compound is selected from the following structures:
(1) contains a sulfur-tert-butylphenol structure, which is specifically shown as the following formula I:
wherein, R is1，R2May be the same or different and are each independently selected from H, C1-C6Alkyl radical, C2-C6Alkenyl radical, C1-C6Alkoxy radical, C2-C6An alkenyloxy group; the R is3、R4Selected from H, OH, or-O-C1-C6Alkyl, -O (C ═ O) C1-C6Alkyl, -O-C2-C6Alkenyl, -O (C ═ O) C2-C6An alkenyl group.
(2) containing-S-S-, -S-CH3-a compound of-S-;
(3) containing a tert-butylphenol ring.
According to an embodiment of the present invention, in the structure of formula I, preferably, R1，R2Can be the same or different and are respectively and independently selected from H, methyl, ethyl, propyl, butyl, pentyl and hexyl; more preferably, R1，R2Is tert-butyl, said R3、R4Selected from OH, or methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, -O (C ═ O) CH3、-O(C＝O) CH2CH3、-O(C＝O)CH2-CH2CH3(ii) a Preferably, R3And R4At least one of them is OH; according to an embodiment of the present invention, the structure of formula I is preferably a structure of formula II as follows:
in the structure of the formula II, R1，R2As defined above for formula I.
According to an embodiment of the invention, the structure of formula II is preferably a specific compound as follows: 4, 4' - (methylenebisthio) bis (2, 6-di-tert-butylphenol) with the molecular formula C29H44O2S2The structural formula is as follows:
according to an embodiment of the present invention, there is further provided the following specific compounds shown in compounds (1) to (3):
according to an embodiment of the present invention, the heart injury diseases caused by doxorubicin include arrhythmia, cardiomyopathy, pericardial disease, heart failure, and the like.
According to an embodiment of the present invention, the medicament can treat or alleviate the imbalance of superoxide dismutase-oxidative free radical homeostasis caused by doxorubicin chemotherapy.
According to an embodiment of the present invention, the medicament may act as a modulator of the activity of a superoxide dismutase biological enzyme.
According to an embodiment of the present invention, preferably, the compound is used as the only active ingredient for preparing a medicament for preventing and/or treating heart tissue damage diseases caused by antitumor adriamycin chemotherapy.
The present invention also provides a pharmaceutical composition, which in some embodiments comprises the compound as the sole active ingredient, together with other pharmaceutically acceptable carriers, and in other embodiments further comprises other chemoprotectants, such as cardioprotective agents.
The invention provides application of the pharmaceutical composition in preparing a preparation for preventing and/or treating heart tissue damage diseases caused by antitumor adriamycin chemotherapy.
Advantageous effects
(1) The compound, especially the compound containing the disulfide-tert-butylphenol structure, can continuously induce the concentration of superoxide dismutase to increase in vivo at fixed points for multiple times while having an antioxidation effect, so that each system in vivo keeps dynamic balance, and the heart is effectively protected.
(2) The specific functional group of the compound, such as tert-butyl phenol, disulfide bond or a combined structure thereof is closely related to an antioxidant, and the compound is proved to be beneficial to inhibiting the activity of oxidative free radicals, inhibiting the risk of damage of peroxidized tissues and protecting the safety and activity of human organ systems, particularly hearts, and has more unexpected effects of playing a role in specifically catalyzing and inducing the activity of biological enzymes and regulating and controlling the dynamic balance of the induced superoxide dismutase (SOD) biological enzyme activity, oxidative free radicals and other activated oxygen.
Drawings
FIG. 1 illustrates the activity test of the compounds of the present invention against doxorubicin-induced cell damage in vivo.
Detailed Description
The technical solution of the present invention will be further described in detail with reference to specific embodiments. It is to be understood that the following examples are only illustrative and explanatory of the present invention and should not be construed as limiting the scope of the present invention. All the technologies realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention.
Unless otherwise indicated, the raw materials and reagents used in the following examples are all commercially available products or can be prepared by known methods.
Example 1 Activity test of Compounds of the invention against SOD
Establishing an experimental principle and a model:
doxorubicin can induce the overproduction of Reactive Oxygen Species (ROS), and is closely related to the increase of cellular oxidative stress, and tests on the compound of the present invention show that the compound of the present invention can reduce the inhibitory effect of doxorubicin on intracellular GSH-Px (glutathione peroxidase _) and SOD activity, and simultaneously reduce doxorubicin-induced ROS and lipid peroxidation product MDA, and these results suggest that the compound of the present invention, especially 4, 4' - (methylene bis) bis (2, 6-di-tert-butylphenol), shows an active effect on the superoxide dismutase biological enzyme activity induction target, and is presumed to have higher specificity on the superoxide dismutase biological enzyme activity induction target and human endogenous peptide chain and protein recombination arrangement aggregation.
Example 2 in vivo pharmacokinetic testing of Compounds of the invention
The experimental result shows that the compound has good pharmacokinetic property and is suitable for being used as a patent drug.
Example 3 Activity test of Compounds of the invention for in vivo cell injury
Cell damage model: the chemotherapy drug adriamycin causes cell damage in animal body so as to establish a pathological model.
Experimental results the experimental results shown in table 1 below show that the compounds of the present invention are effective in protecting cells from damage, wherein the compounds are selected from the group consisting of 4, 4' - (methylenebis) bis (2, 6-di-tert-butylphenol).
TABLE 1
TABLE 1 continuation a
TABLE 1 continuation b
Example 4 evaluation of the in vivo protective Effect of the Compound of the present invention in mice.
(1) Establishing a leukemia mouse model: and (3) after the P388 tumor-bearing mouse is killed, taking tumor knots, preparing a tumor cell suspension, transferring and injecting the tumor cell suspension into a normal mouse, and obtaining the mouse successfully realizing tumor transplantation after 4-7 days.
(2) Animal grouping and dosing: tumor mice were divided into four groups, which were a control group, an doxorubicin-treated group alone, a compound-treated group of the present invention (the specific compound was 4, 4' - (methylenebisthio) bis (2, 6-di-tert-butylphenol)), and an doxorubicin + compound-treated group, and were subjected to an intraperitoneal injection administration experiment, respectively.
(3) Evaluation of the effects: experiments prove that the compound can increase the GSH-Px activity and the superoxide dismutase activity of mouse cardiac muscle, correspondingly reduce lipid peroxidase and effectively prevent heart damage caused by adriamycin.
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (9)
1. The application of a compound and a pharmaceutically acceptable salt and a prodrug thereof in preparing a medicament for preventing and/or treating heart tissue damage diseases caused by antineoplastic adriamycin chemotherapy, wherein the compound is selected from the following structures:
(1) contains a sulfur-tert-butylphenol structure, which is specifically shown as the following formula I:
wherein, R is1，R2And may be the same or different,each independently selected from H, C1-C6Alkyl radical, C2-C6Alkenyl radical, C1-C6Alkoxy radical, C2-C6An alkenyloxy group; the R is3、R4Selected from H, OH, or-O-C1-C6Alkyl, -O (C ═ O) C1-C6Alkyl, -O-C2-C6Alkenyl, -O (C ═ O) C2-C6An alkenyl group.
(2) containing-S-S-, -S-CH3-a compound of-S-;
(3) containing a tert-butylphenol ring.
2. Use according to claim 1, characterized in that in the structure of formula I, preferably, R1，R2Can be the same or different and are respectively and independently selected from H, methyl, ethyl, propyl, butyl, pentyl and hexyl; more preferably, R1，R2Is tert-butyl, said R3、R4Selected from OH, or methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, -O (C ═ O) CH3、-O(C＝O)CH2CH3、-O(C＝O)CH2-CH2CH3(ii) a Preferably, R3And R4At least one of which is OH.
3. Use according to claim 1 or 2, wherein the structure of formula I is preferably of formula II:
in the structure of the formula II, R1，R2As defined above for formula I.
4. Use according to claim 3, wherein the structure of formula II is preferably a specific compound as follows: 4, 4' - (methylenebisthio) bis (2, 6-di-tert-butylphenol) with the molecular formula C29H44O2S2The structural formula is as follows:
5. use according to claim 1, characterized in that the compounds and their pharmaceutically acceptable salts are in particular as follows:
6. the use according to any one of claims 1 to 5, wherein the medicament is for the treatment or alleviation of the imbalance in superoxide dismutase-oxidizing free radical homeostasis caused by doxorubicin chemotherapy.
7. The use according to any one of claims 1 to 6, wherein the medicament is useful as a modulator of the activity of superoxide dismutase enzymes.
8. The use according to any one of claims 1 to 7, wherein the compound is used as the sole active ingredient in the preparation of a medicament for the prevention and/or treatment of cardiac tissue damage caused by antineoplastic doxorubicin chemotherapy.
9. The use according to any one of claims 1 to 8, wherein said adriamycin-induced heart injury disease comprises arrhythmia, cardiomyopathy, pericardial disease, heart failure, and the like.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010184090X | 2020-03-16 | ||
| CN202010184090 | 2020-03-16 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN113171360A true CN113171360A (en) | 2021-07-27 |
Family
ID=76922090
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110282901.4A Pending CN113171360A (en) | 2020-03-16 | 2021-03-16 | Application of dithiodipyrone and analog thereof in preparation of medicine for preventing and treating heart tissue damage diseases caused by antitumor doxorubicin chemotherapy |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113171360A (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013138338A2 (en) * | 2012-03-12 | 2013-09-19 | Massachusetts Institute Of Technology | Methods for treating tissue damage associated with ischemia with apoliporotein d |
-
2021
- 2021-03-16 CN CN202110282901.4A patent/CN113171360A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013138338A2 (en) * | 2012-03-12 | 2013-09-19 | Massachusetts Institute Of Technology | Methods for treating tissue damage associated with ischemia with apoliporotein d |
Non-Patent Citations (2)
| Title |
|---|
| N. SIVESKI-LLISKOVIC 等: "Probucol promotes endogenous antioxidants and provides protection against adriamycin-induced cardiomyopathy in rats", 《CIRCULATION》 * |
| N. SIVESKI-LLISKOVIC 等: "Probucol Protects Against Adriamycin Cardiomyopathy Without Interfering With Its Antitumor Effect", 《AMERICAN HEART ASSOCIATION》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Hosseinimehr | Trends in the development of radioprotective agents | |
| RU2157213C2 (en) | Pharmaceutical composition and method of prophylaxis, suppression or treatment of disease associated with presence of free radicals | |
| Dajas et al. | Cell culture protection and in vivo neuroprotective capacity of flavonoids | |
| JP4160115B2 (en) | Synthetic catalytic free radical scavengers useful as antioxidants for disease prevention and treatment | |
| JP2004514724A (en) | Cyclic salen-metal compounds: reactive oxygen species scavengers useful as antioxidants in the treatment and prevention of disease | |
| KR101069959B1 (en) | Liver protection compounds of the cyclohexenone type from Antrodia camphorata | |
| JPH10500657A (en) | Curcumin, curcumin analogs, and their new uses | |
| Georgieva et al. | New isonicotinoylhydrazones with SSA protect against oxidative-hepatic injury of isoniazid | |
| JP2003002840A (en) | Cucumismelo extract coated with and/or microencapsulated within fat-soluble agent containing fat-soluble compound as base material | |
| EP1827136A1 (en) | Formulation for oral administration having a health-promoting effect on the cardiovascular system | |
| CN111388511A (en) | Composition for improving memory and preventing senile dementia and preparation method and application thereof | |
| WO2004075883A1 (en) | Use of curcumin derivatives or cape in the manufacture of a medicament for the treatment of neuroprotective disorders | |
| Verma et al. | Curcumin ameliorates aflatoxin-induced lipid-peroxidation in liver and kidney of mice | |
| JPH09507490A (en) | Vanadate compounds for the treatment of proliferative disorders, metastases and drug resistant tumors | |
| JPH10158156A (en) | Antitumor agent | |
| CN113171360A (en) | Application of dithiodipyrone and analog thereof in preparation of medicine for preventing and treating heart tissue damage diseases caused by antitumor doxorubicin chemotherapy | |
| Miwa et al. | Altered production of the active oxygen species is involved in enhanced cytotoxic action of acylated derivatives of ascorbate to tumor cells | |
| KR20050001899A (en) | Compound showing anti-oxidant and anti-viral activity and extract of Chrysanthemum indicum comprising the same | |
| Spath et al. | Diethyldithiocarbamate inhibits scheduled and unscheduled DNA synthesis of rat thymocytes in vitro and in vivo—dose-effect relationships and mechanisms of action | |
| Levi et al. | Serine derivative with antitumor activity | |
| RU2440128C1 (en) | Method of complex pathogenetic therapy of acute forms of viral hepatitis b and mixed hepatites (b+c, b+d, b+c+d) | |
| Shilova et al. | Hepatoprotective properties of fractions from meadowsweet extract during experimental toxic hepatitis | |
| Veena et al. | Bioactive extract of mycelia biomass of Ganoderma lucidum protects doxorubicin induced cardiomyopathy | |
| KR102506076B1 (en) | Composition for preventing or treating immune diseases comprising zinc sulfate, lactobacillus acidophillus and coenzyme q | |
| Vijayalakshmi et al. | Oxidative stress and their resultant products as the target molecules in clinical diagnosis of age related disease |
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 | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20210727 |