CN112076200A - Application of hederagenin polyethylene glycol derivative - Google Patents
Application of hederagenin polyethylene glycol derivative Download PDFInfo
- Publication number
- CN112076200A CN112076200A CN202011184557.7A CN202011184557A CN112076200A CN 112076200 A CN112076200 A CN 112076200A CN 202011184557 A CN202011184557 A CN 202011184557A CN 112076200 A CN112076200 A CN 112076200A
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- CN
- China
- Prior art keywords
- polyethylene glycol
- hederagenin
- pyrazine
- ester
- glycol derivative
- 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.)
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- 229920001223 polyethylene glycol Polymers 0.000 title claims abstract description 55
- PGOYMURMZNDHNS-MYPRUECHSA-N hederagenin Chemical compound C1C[C@H](O)[C@@](C)(CO)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CCC(C)(C)C[C@H]5C4=CC[C@@H]3[C@]21C PGOYMURMZNDHNS-MYPRUECHSA-N 0.000 title claims abstract description 37
- 239000002202 Polyethylene glycol Substances 0.000 title claims abstract description 36
- NTWLPZMPTFQYQI-UHFFFAOYSA-N (3alpha)-olean-12-ene-3,23-diol Natural products C1CC(O)C(C)(CO)C2CCC3(C)C4(C)CCC5(C)CCC(C)(C)CC5C4=CCC3C21C NTWLPZMPTFQYQI-UHFFFAOYSA-N 0.000 title claims abstract description 34
- GCGBHJLBFAPRDB-UHFFFAOYSA-N Hederagenin Natural products CC1(C)CCC2(CCC3(C)C4CCC5C(C)(CO)C(O)CCC5(C)C4CC=C3C2C1)C(=O)O GCGBHJLBFAPRDB-UHFFFAOYSA-N 0.000 title claims abstract description 34
- GCGBHJLBFAPRDB-KCVAUKQGSA-N Scutellaric acid Natural products CC1(C)CC[C@@]2(CC[C@@]3(C)[C@@H]4CC[C@H]5[C@@](C)(CO)[C@H](O)CC[C@]5(C)[C@H]4CC=C3[C@@H]2C1)C(=O)O GCGBHJLBFAPRDB-KCVAUKQGSA-N 0.000 title claims abstract description 34
- 150000002334 glycols Chemical class 0.000 title claims abstract description 27
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 24
- 206010059866 Drug resistance Diseases 0.000 claims abstract description 20
- 150000003839 salts Chemical class 0.000 claims abstract description 17
- 239000012313 reversal agent Substances 0.000 claims abstract description 11
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims description 30
- 239000002253 acid Substances 0.000 claims description 16
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 claims description 15
- -1 benzyl ester Chemical class 0.000 claims description 14
- MTHSVFCYNBDYFN-UHFFFAOYSA-N anhydrous diethylene glycol Natural products OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 claims description 9
- 150000002148 esters Chemical class 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 31
- 230000002441 reversible effect Effects 0.000 abstract description 8
- 239000003814 drug Substances 0.000 abstract description 5
- 230000000259 anti-tumor effect Effects 0.000 abstract description 4
- 201000010099 disease Diseases 0.000 abstract description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 4
- 208000024891 symptom Diseases 0.000 abstract description 4
- 206010006187 Breast cancer Diseases 0.000 abstract description 3
- 208000026310 Breast neoplasm Diseases 0.000 abstract description 3
- 201000009030 Carcinoma Diseases 0.000 abstract description 3
- 206010008342 Cervix carcinoma Diseases 0.000 abstract description 3
- 206010009944 Colon cancer Diseases 0.000 abstract description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 abstract description 3
- 208000005718 Stomach Neoplasms Diseases 0.000 abstract description 3
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 abstract description 3
- 201000010881 cervical cancer Diseases 0.000 abstract description 3
- 208000029742 colonic neoplasm Diseases 0.000 abstract description 3
- 206010017758 gastric cancer Diseases 0.000 abstract description 3
- 201000005202 lung cancer Diseases 0.000 abstract description 3
- 208000020816 lung neoplasm Diseases 0.000 abstract description 3
- 201000011549 stomach cancer Diseases 0.000 abstract description 3
- 241000124008 Mammalia Species 0.000 abstract description 2
- 239000000969 carrier Substances 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 67
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 26
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 25
- 150000001875 compounds Chemical class 0.000 description 23
- 238000006243 chemical reaction Methods 0.000 description 20
- 239000000243 solution Substances 0.000 description 13
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 12
- 239000008367 deionised water Substances 0.000 description 11
- 229910021641 deionized water Inorganic materials 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- 239000003054 catalyst Substances 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 9
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 238000005406 washing Methods 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 239000002246 antineoplastic agent Substances 0.000 description 5
- 229940041181 antineoplastic drug Drugs 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000012512 characterization method Methods 0.000 description 5
- 238000004821 distillation Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 230000036457 multidrug resistance Effects 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 229930012538 Paclitaxel Natural products 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 238000007865 diluting Methods 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 229960001592 paclitaxel Drugs 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 230000004083 survival effect Effects 0.000 description 4
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 4
- 210000004881 tumor cell Anatomy 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 238000006555 catalytic reaction Methods 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- PIYNUZCGMLCXKJ-UHFFFAOYSA-N 1,4-dioxane-2,6-dione Chemical compound O=C1COCC(=O)O1 PIYNUZCGMLCXKJ-UHFFFAOYSA-N 0.000 description 2
- RIIUAPMWDSRBSH-UHFFFAOYSA-N 1,4-oxathiane-2,6-dione Chemical compound O=C1CSCC(=O)O1 RIIUAPMWDSRBSH-UHFFFAOYSA-N 0.000 description 2
- MPDGHEJMBKOTSU-YKLVYJNSSA-N 18beta-glycyrrhetic acid Chemical compound C([C@H]1C2=CC(=O)[C@H]34)[C@@](C)(C(O)=O)CC[C@]1(C)CC[C@@]2(C)[C@]4(C)CC[C@@H]1[C@]3(C)CC[C@H](O)C1(C)C MPDGHEJMBKOTSU-YKLVYJNSSA-N 0.000 description 2
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 description 2
- YCLSOMLVSHPPFV-UHFFFAOYSA-N 3-(2-carboxyethyldisulfanyl)propanoic acid Chemical compound OC(=O)CCSSCCC(O)=O YCLSOMLVSHPPFV-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 230000003833 cell viability Effects 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 229940014800 succinic anhydride Drugs 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 2
- WCGUUGGRBIKTOS-GPOJBZKASA-N (3beta)-3-hydroxyurs-12-en-28-oic acid Chemical compound C1C[C@H](O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CC[C@@H](C)[C@H](C)[C@H]5C4=CC[C@@H]3[C@]21C WCGUUGGRBIKTOS-GPOJBZKASA-N 0.000 description 1
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 description 1
- YYSCJLLOWOUSHH-UHFFFAOYSA-N 4,4'-disulfanyldibutanoic acid Chemical compound OC(=O)CCCSSCCCC(O)=O YYSCJLLOWOUSHH-UHFFFAOYSA-N 0.000 description 1
- 241000208340 Araliaceae Species 0.000 description 1
- MPDGHEJMBKOTSU-UHFFFAOYSA-N Glycyrrhetinsaeure Natural products C12C(=O)C=C3C4CC(C)(C(O)=O)CCC4(C)CCC3(C)C1(C)CCC1C2(C)CCC(O)C1(C)C MPDGHEJMBKOTSU-UHFFFAOYSA-N 0.000 description 1
- 241000208341 Hedera Species 0.000 description 1
- JWIPGAFCGUDKEY-UHFFFAOYSA-L O[Cr](Cl)(=O)=O.C1=CC=NC=C1 Chemical compound O[Cr](Cl)(=O)=O.C1=CC=NC=C1 JWIPGAFCGUDKEY-UHFFFAOYSA-L 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000010485 coping Effects 0.000 description 1
- 238000012258 culturing Methods 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
- 238000000502 dialysis Methods 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 229960003720 enoxolone Drugs 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 239000012982 microporous membrane Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000002715 modification method Methods 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 1
- 229940057847 polyethylene glycol 600 Drugs 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- UWHCKJMYHZGTIT-UHFFFAOYSA-N tetraethylene glycol Chemical compound OCCOCCOCCOCCO UWHCKJMYHZGTIT-UHFFFAOYSA-N 0.000 description 1
- ZIBGPFATKBEMQZ-UHFFFAOYSA-N triethylene glycol Chemical compound OCCOCCOCCO ZIBGPFATKBEMQZ-UHFFFAOYSA-N 0.000 description 1
- PLSAJKYPRJGMHO-UHFFFAOYSA-N ursolic acid Natural products CC1CCC2(CCC3(C)C(C=CC4C5(C)CCC(O)C(C)(C)C5CCC34C)C2C1C)C(=O)O PLSAJKYPRJGMHO-UHFFFAOYSA-N 0.000 description 1
- 229940096998 ursolic acid Drugs 0.000 description 1
- 229960001722 verapamil Drugs 0.000 description 1
- 231100000747 viability assay Toxicity 0.000 description 1
- 238000003026 viability measurement method Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
-
- 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
- A61K31/74—Synthetic polymeric materials
- A61K31/785—Polymers containing nitrogen
- A61K31/787—Polymers containing nitrogen containing heterocyclic rings having nitrogen 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
- A61K31/74—Synthetic polymeric materials
- A61K31/795—Polymers containing sulfur
-
- 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
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0036—Nitrogen-containing hetero ring
- C07J71/0042—Nitrogen only
- C07J71/0047—Nitrogen only at position 2(3)
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses an application of hederagenin polyethylene glycol derivatives. In particular, the hederagenin polyethylene glycol derivative provided by the invention is applied to preparing a tumor drug resistance reversal agent, and the hederagenin polyethylene glycol derivative with a novel structure type provided by the invention has improved water solubility and excellent tumor drug resistance reversal activity. The hederagenin polyethylene glycol derivative and the medicinal carrier are used for treating diseases or symptoms such as oral epithelial cancer, gastric cancer, lung cancer, cervical cancer, breast cancer or colon cancer and the like by being combined with clinical common antitumor medicaments. The hederagenin polyethylene glycol derivative and the application of the medical acceptable salt thereof are used for preparing tumor drug resistance reversal agents and/or medicinal carriers for treating mammals, preferably human diseases or symptoms.
Description
Technical Field
The invention relates to the field of organic synthesis and pharmaceutical chemistry, in particular to application of hederagenin polyethylene glycol derivatives with novel structures in preparation of tumor drug resistance reversal agents.
Technical Field
The incidence of tumors is rising year by year, and according to statistics, the number of cancer deaths worldwide in 2018 reaches 960 ten thousand. Multidrug resistance (MDR) is one of the major causes of tumor chemotherapy failure. Therefore, the development of novel tumor resistance reversal agents is a key focus of attention in the field of medicinal chemistry. Natural products such as ursolic acid, glycyrrhetinic acid and the like and derivatives thereof have been proved to have MDR reversal activity, so the natural products become one of the important sources of the tumor drug resistance reversal agent.
Hederagenin (H) is derived from Hederagenin (Hederagenin, H) of Hedera of Araliaceae, and is an oleanane-type pentacyclic triterpene compound. The preliminary study of the subject group finds that the hederagenin derivative H6 has certain tumor drug resistance reversal activity in vivo and in vitro, and the action mechanism is preliminarily clarified, so that the hederagenin derivative H6 is expected to be a new drug candidate compound for coping with clinical tumor drug resistance (see Yang YT, Guan DK, Lei L, et al. H6, a novel chemotherapy derivative, variants multidrug resistance in vitro and in vivo [ J ]. drainage & Applied Pharmacology,2018,341: 98-105). However, H6 has low solubility in water and needs to be formulated into liposomes for in vivo administration, which limits its application to some extent. Therefore, further improvement of water solubility and drug-forming property of H6 is an important point in future work.
Disclosure of Invention
The invention aims to provide application of hederagenin polyethylene glycol derivatives in preparation of drugs for tumor drug resistance reversal agents. The invention aims to solve the technical problems of searching a compound which has novel structure type, improved water solubility and excellent tumor drug resistance reversal activity, and further providing a pharmaceutical composition for treating oral epithelial cancer, gastric cancer, lung cancer, cervical cancer, breast cancer, colon cancer and the like by combining with a clinical common antitumor drug.
In order to solve the technical problems, the invention provides the following technical scheme:
the invention relates to an application of hederagenin polyethylene glycol derivatives shown in a general formula I and medically acceptable salts thereof in preparing tumor drug resistance reversal agents, and the compounds provided by the invention are compounds with novel structural types,
wherein,
general formula I: r1Represents R2、R2XR2；
R2Represents a non-substituted linear or branched alkyl group of 1 to 3 carbons;
x represents S, O, S-S;
n is 2 to 13, and n is a natural number.
Preferably, the compounds and their pharmaceutically acceptable salts, wherein,
general formula I: r1Represents R2、R2XR2；
R2Represents a non-substituted linear or branched alkyl group of 1 to 3 carbons;
x represents S, O, S-S;
n＝2、3、4、9、13。
preferably, some of the compounds of the present invention are:
general formula I:
4- (23-oxoolean-12-en-28-oic acid benzyl ester and [3,2-b ] pyrazine) -4-oxo-butyric acid tetraethylene glycol ester;
1 ' - (23-oxoolean-12-en-28-oic acid benzyl ester-23-oxo [3,2-b ] pyrazine) -1 ' -propionyl-3, 3 ' -dithiopropionic acid triethylene glycol ester;
1 ' - (23-oxyolean-12-en-28-oic acid benzyl ester and [3,2-b ] pyrazine) -1 ' -acetyl-2, 2 ' -oxoacetic acid polyethylene glycol (600) ester;
1 ' - (23-oxyolean-12-en-28-oic acid benzyl ester and [3,2-b ] pyrazine) -1 ' -acetyl-2, 2 ' -thioacetic acid polyethylene glycol (400) ester;
1 ' - (23-oxyolean-12-en-28-oic acid benzyl ester and [3,2-b ] pyrazine) -1 ' -butyryl-4, 4 ' -dithio-butyric acid diethylene glycol ester.
The preparation route of the hederagenin polyethylene glycol derivative provided by the invention is as follows:
the hederagenin polyethylene glycol derivative with the general formula I is synthesized and prepared according to the following method:
a. taking hederagenin as a raw material, and protecting carboxyl by benzyl bromide in the presence of inorganic base;
b. protecting the hydroxyl at the 23-position by using tert-butyldimethylsilyl chloride;
c. the intermediate product protected by TBS is oxidized by pyridine chlorochromate to obtain 3-site hydroxyl;
d. reacting with ethylenediamine under the catalysis of sulfur;
e. under the acidic condition, removing the 23-bit protecting group;
f. under the catalysis of DMAP and EDCI, reacting with connecting chains such as succinic anhydride, 3 '-dithiodipropionic acid, diglycolic anhydride, thiodiglycolic anhydride, 4' -dithiodibutyric acid and the like;
g. reacting with polyethylene glycol under the catalysis of DMAP and EDCI to obtain a crude product;
h. and purifying the crude product by using a dialysis method and a column chromatography method in sequence to obtain the target compound.
The hederagenin polyethylene glycol derivative provided by the invention is applied to preparation of tumor drug resistance reversal agents, and the hederagenin polyethylene glycol derivative with a novel structure type provided by the invention has improved water solubility and excellent tumor drug resistance reversal activity.
The hederagenin polyethylene glycol derivative and the optical isomer of the compound or the pharmaceutically acceptable solvate thereof.
The effective amount of the compound of the general formula I or the salt thereof and the pharmaceutically acceptable carrier are used for treating diseases or symptoms such as oral epithelial cancer, gastric cancer, lung cancer, cervical cancer, breast cancer or colon cancer and the like by combining with clinical common antitumor drugs.
The hederagenin polyethylene glycol derivative with the general formula I and the application of the medical acceptable salt thereof are used for preparing tumor drug resistance reversal agents and/or medicinal carriers for treating mammals, preferably human diseases or symptoms.
Detailed Description
The invention is characterized in that the hederagenin polyethylene glycol derivative with the general formula I and the medically acceptable salt thereof have direct anti-tumor activity disappearance and good tumor drug resistance reversion effect compared with the hederagenin; the further innovation lies in that the hederagenin polyethylene glycol derivative and the medically acceptable salt thereof with the general formula I have improved water solubility and improved tumor drug resistance reversal activity compared with the hederagenin derivative H6, and have already been made into drug properties.
The present invention will be described in further detail below by way of examples, but the present invention is not limited to only the following examples.
Example 14 benzyl [3,2-b ] olean-12-en-28-oate]Pyrazine) -4-oxo-butyric acid tetraethylene glycol ester (H6-D-PEG)200) Synthesis and characterization of
Dissolving compound hederagenin (472.0mg, 1.0mmol) in N, N-dimethylformamide (15.0mL), adding potassium carbonate (300.0mg, 2.1mmol) and benzyl bromide (0.2mL, 1.3mmol), and stirring at 50 deg.C for 6-10 h. Diluting the reaction solution with ethyl acetate (25.0mL), washing with water for three times, washing with saturated salt water for two times, drying with anhydrous sodium sulfate, filtering, evaporating under reduced pressure to remove solvent, and performing silica gel column chromatography (V)Petroleum ether:VEthyl acetate10:1-5:1) to give a white solid (470.0mg, 83.0%).
The above compound (460.0mg, 0.8mmol) was dissolved in 20.0mL of dichloromethane, 4-dimethylaminopyridine (122.0mg, 1.0mmol) and tert-butyldimethylsilyl chloride (360.0mg, 2.4mmol) were added, and the mixture was stirred at room temperature for 4-8 h. The dichloromethane was evaporated, diluted with ethyl acetate (20.0mL), washed acidic with 5% HCl, washed neutral with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatographed (V)Petroleum ether:VEthyl acetate30:1-15:1) to obtain white solid(383.0mg，70.0％)。
The above-mentioned compound (380.0mg, 0.6mmol) was dissolved in 15.0mL of dichloromethane, and fresh pyridinium chlorochromate (300.0mg, 1.3mmol) was added thereto and stirred at room temperature for 6 to 10 hours. Evaporating to remove dichloromethane, diluting with ethyl acetate (20.0mL), washing with water, washing with saturated salt water to neutral, drying with anhydrous sodium sulfate, filtering, concentrating, and performing column chromatography (V)Petroleum ether:VEthyl acetate35:1-20:1) to give a white solid (319.0mg, 84.0%).
Dissolving the above compound (500.0mg, 0.7mmol) in morpholine (25.0mL), adding sulfur (0.3g, 10.0mmol) and ethylenediamine (0.3g, 4.5mmol), refluxing for 6-10h, diluting with ethyl acetate (30.0mL), washing with water three times, washing with saturated salt water twice, drying over anhydrous sodium sulfate, filtering, concentrating, and performing column chromatography (V)Petroleum ether:VEthyl acetate30:1-10:1) to give a white solid (357.0mg, 68.0%).
Dissolving the above product (300.0mg, 0.4mmol) in acetone (20.0mL), adding 10% HCl (2.0mL), stirring at room temperature for 3-5h, diluting with ethyl acetate, washing with water to neutrality, washing with saturated salt water, drying with anhydrous sodium sulfate, filtering, concentrating, and performing column chromatography (V)Petroleum ether:VEthyl acetate5:1-8:1) to give H6(225.0mg, 89.0%) as a white solid.
The above compound H6(443.0mg, 0.7mmol) was dissolved in anhydrous dichloromethane (25.0mL), and the catalyst DMAP (453.4mg, 3.7mmol) and succinic anhydride (742.8mg, 7.4mmol) were added to react at room temperature for 2H. After the reaction is finished, dichloromethane is added for dilution, the organic layer is washed once by 5 percent HCl solution and washed twice by deionized water and saturated sodium chloride solution respectively in turn, dried by anhydrous sodium sulfate, filtered, concentrated and chromatographed by silica gel column (V)Chloroform：VMethanol50:1-20:1) to give H6-D as a white solid (466.0mg, 90.2%).
Tetraethylene glycol (180.0. mu.L, 1.1mmol) was dissolved in anhydrous dichloromethane (6.0mL), H6-D (80.0mg, 0.1mmol), DMAP (133.2mg, 1.1mmol) as a catalyst, EDCI (132.0mg, 0.7mmol) were added, and the reaction was stirred at room temperature for about 10 hours. After the reaction is finished, the solvent is removed by reduced pressure distillation, dissolved by methanol, dialyzed by deionized water for 3 days, and subjected to silica gel column chromatography (V)Methylene dichloride:VMethanol150:1) to give H6-D-PEG as a pale yellow oily liquid200(58.0mg，58.0％)。1H NMR(400MHz,CDCl3)8.41(d,J＝2.4Hz,1H,H-pyrazine),8.29(d,J＝2.5Hz,1H,H-pyrazine),7.36-7.30(m,5H,5×H-Ar),5.37(s,1H,H-12),5.13-5.04(m,2H,CH2Ar),4.32(d,J＝10.5Hz,1H,H-23a),4.27(d,J＝10.5Hz,1H,H-23b),4.21-4.16(m,2H,CH2O PEG group),3.74-3.59(m,14H,CH2O PEG group),2.99-2.93(m,2H,H-1a,H-18),2.54(d,J＝16.4Hz,1H,H-1b),2.49-2.34(m,4H,2×CH2),1.27(s,3H,CH3),1.19(s,3H,CH3),0.94(s,3H,CH3),0.91(s,3H,CH3),0.88(s,3H,CH3),0.69(s,3H,CH3).
Example 21' - (23-Oxyhneta-12-en-28-oic acid benzyl ester [3,2-b ]]Pyrazine) -1 '-propionyl-3, 3' -dithiopropionic acid triethylene glycol ester (H6-S-PEG150) Synthesis and characterization of
H6(100.0mg, 0.2mmol) was dissolved in dry dichloromethane (8.0mL), the catalysts DMAP (102.3mg, 0.8mmol), EDCI (160.6mg, 0.8mmol) and 3, 3' -dithiodipropionic acid (352.3mg, 1.7mmol) were added and the reaction was refluxed at 40 ℃ for 7H. After the reaction was completed, dichloromethane was added for dilution, and the organic layer was washed once with 5% HCl solution, twice with deionized water and twice with saturated sodium chloride solution, respectively, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain H6-S (121.9mg, 92.2%) as a white solid.
Triethylene glycol (131.7. mu.L, 1.1mmol) was dissolved in anhydrous dichloromethane (8.0mL), H6-S (88.0mg, 0.1mmol), DMAP (129.4mg, 1.1mmol) as a catalyst, EDCI (128.3mg, 0.7mmol) were added, and the reaction was stirred at room temperature for about 10H. After the reaction is finished, the solvent is removed by reduced pressure distillation, dissolved by methanol, dialyzed by deionized water for 3 days, and subjected to silica gel column chromatography (V)Methylene dichloride:VMethanol180:1) to give H6-S-PEG as a pale yellow oily liquid150(52.0mg，48.7％)。1H NMR(400MHz,CDCl3)8.42(d,J＝2.5Hz,1H,H-pyrazine),8.30(d,J＝2.5Hz,1H,H-pyrazine),7.36-7.29(m,5H,5×H-Ar),5.37(s,1H,H-12),5.13-5.04(m,2H,CH2Ar),4.35(d,J＝10.5Hz,1H,H-23a),4.28(d,J＝10.5Hz,1H,H-23b),4.27-4.25(m,2H,CH2O PEG group),3.74-3.60(m,10H,CH2O PEG group),2.99-2.93(m,2H,H-1a,H-18),2.85(t,J＝7.3Hz,2H,CH2),2.71(t,J＝6.9Hz,2H,CH2),2.70-2.65(m,2H,CH2),2.53(s,1H,H-1b),2.52-2.49(m,2H,CH2),1.28(s,3H,CH3),1.18(s,3H,CH3),0.94(s,3H,CH3),0.91(s,3H,CH3),0.88(s,3H,CH3),0.69(s,3H,CH3).
Example 31' - (23-Oxyhneta-12-en-28-oic acid benzyl ester [3,2-b ]]Pyrazine) -1 '-acetyl-2, 2' -oxoacetic acid polyethylene glycol (600) ester (H6-E-PEG600) Synthesis and characterization of
H6(70.0mg, 0.1mmol) was dissolved in dry dichloromethane (8.0mL), and the catalyst DMAP (71.6mg, 0.6mmol) and diglycolic anhydride (68.0mg, 0.6mmol) were added and reacted at room temperature for 0.5H. After the reaction was completed, dichloromethane was added for dilution, and the organic layer was washed once with 10% HCl solution, twice with deionized water and twice with saturated sodium chloride solution, respectively, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain H6-E (78.0mg, 93.3%) as a white solid.
Polyethylene glycol 600 (543.4. mu.L, 1.2mmol) was dissolved in anhydrous dichloromethane (8.0mL), H6-E (82.0mg, 0.1mmol), DMAP (133.5mg, 1.1mmol) as a catalyst, EDCI (132.3mg, 0.7mmol) were added, and the reaction was stirred at room temperature for about 10H. After the reaction is finished, the solvent is removed by reduced pressure distillation, dissolved by methanol, dialyzed by deionized water for 3 days, and subjected to silica gel column chromatography (V)Methylene dichloride:VMethanol75:1) to give H6-E-PEG as a pale yellow oily liquid600(61.0mg，40.9％)。1H NMR(400MHz,CDCl3)8.42(s,1H,H-pyrazine),8.30(s,1H,H-pyrazine),7.37-7.30(m,5H,5×H-Ar),5.37(s,1H,H-12),5.13-5.04(m,2H,CH2Ar),4.38(d,J＝10.5Hz,1H,H-23a),4.33(d,J＝10.5Hz,1H,H-23b),4.29-4.25(m,2H,CH2O PEG group),4.05-3.90(m,4H,2×CH2),3.74-3.59(m,50H,CH2O PEG group),3.03-2.91(m,2H,H-1a,H-18),2.46(d,J＝16.6Hz,1H,H-1b),1.29(s,3H,CH3),1.18(s,3H,CH3),0.94(s,3H,CH3),0.91(s,3H,CH3),0.88(s,3H,CH3),0.69(s,3H,CH3).
Example 41' - (23-Oxyhneta-12-en-28-oic acid benzyl ester and [3,2-b ]]Pyrazine) -1 '-acetyl-2, 2' -Thioacetic acid polyethylene glycol (400) ester (H6-S1-PEG400) Synthesis and characterization of
H6(100.0mg, 0.2mmol) was dissolved in anhydrous dichloromethane (8.0mL), and the catalyst DMAP (102.3mg, 0.8mmol) and thiodiglycolic anhydride (110.7mg, 0.8mmol) were added and reacted at room temperature for 10 min. After the reaction, dichloromethane was added to dilute the reaction solution, and the organic layer was washed with 10% HCl solution once, and washed with deionized water and saturated sodium chloride solution twice, respectively, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain H6-S1(115.9mg, 95.0%) as a white solid.
Polyethylene glycol 400 (862.9. mu.L, 2.7mmol) was dissolved in anhydrous dichloromethane (8.0mL), H6-S1(200mg, 0.3mmol), DMAP (318.7mg, 2.6mmol) as a catalyst, EDCI (315.8mg, 1.6mmol) were added, and the reaction was stirred at room temperature for about 10H. After the reaction is finished, the solvent is removed by reduced pressure distillation, dissolved by methanol, dialyzed by deionized water for 3 days, and subjected to silica gel column chromatography (V)Methylene dichloride:VMethanol120:1) to give H6-S1-PEG as a pale yellow oily liquid400(146.9mg，48.2％)。1H NMR(400MHz,CDCl3)8.43(d,J＝2.3Hz,1H,H-pyrazine),8.30(d,J＝2.4Hz,1H,H-pyrazine),7.37-7.29(m,5H,5×H-Ar),5.38(s,1H,H-12),5.13-5.04(m,2H,CH2Ar),4.41(d,J＝10.5Hz,1H,H-23a),4.32(d,J＝10.5Hz,1H,H-23b),4.28-4.21(m,2H,CH2O PEG group),3.74-3.64(m,32H,CH2O PEG group),3.23-3.14(m,2H,CH2),3.14-3.00(m,2H,CH2),2.99-2.93(m,2H,H-1a,H-18),2.58(d,J＝16.6Hz,1H,H-1b),1.28(s,3H,CH3),1.17(s,3H,CH3),0.94(s,3H,CH3),0.91(s,3H,CH3),0.89(s,3H,CH3),0.69(s,3H,CH3).
Example 51' - (23-Oxyhneta-12-en-28-oic acid benzyl ester [3,2-b ]]Pyrazine) -1 '-butyryl-4, 4' -dithiobutanoic acid diethylene glycol ester (H6-S4-PEG100) Synthesis and characterization of
H6(100.0mg, 0.2mmol) was dissolved in dry dichloromethane (8.0mL), the catalysts DMAP (102.3mg, 0.8mmol), EDCI (160.6mg, 0.8mmol) and 4, 4' -dithiodibutanoic acid (199.6mg, 0.8mmol) were added and the reaction was refluxed at 40 ℃ for 0.5H. After the reaction, dichloromethane was added to dilute the reaction solution, and the organic layer was washed with 5% HCl solution once, deionized water and saturated sodium chloride solution twice, respectively, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain H6-S4 as a white solid (125.8mg, 92.0%).
Diethylene glycol (144.7. mu.L, 1.8mmol) was dissolved in anhydrous dichloromethane (8.0mL), H6-S4(150mg, 0.2mmol), DMAP (213.2mg, 1.7mmol) as a catalyst, EDCI (211.3mg, 1.1mmol) were added, and the reaction was stirred at room temperature for about 10H. After the reaction is finished, the solvent is removed by reduced pressure distillation, dissolved by methanol, dialyzed by deionized water for 3 days, and subjected to silica gel column chromatography (V)Methylene dichloride:VMethanol200:1) to obtain light yellow oily liquid H6-S4-PEG100(96.4mg，58.0％)。1HNMR(400MHz,CDCl3)8.42(d,J＝2.4Hz,1H,H-pyrazine),8.30(d,J＝2.4Hz,1H,H-pyrazine),7.37-7.29(m,5H,5×H-Ar),5.38(s,1H,H-12),5.13-5.03(m,2H,CH2Ar),4.28(s,2H,H-23),4.27-4.23(m,2H,CH2O PEG group),3.78-3.59(m,6H,CH2O PEG group),2.98(m,2H,H-1a,H-18),2.66(t,J＝7.1Hz,2H,CH2),2.51(d,J＝10.3Hz,1H,H-1b),2.46(t,J＝7.6Hz,4H,2×CH2),2.28-2.14(m,2H,CH2),2.03-1.95(m,4H,2×CH2),1.28(s,3H,CH3),0.94(s,3H,CH3),0.91(s,3H,CH3),0.88(s,3H,CH3),0.69(s,3H,CH3).
The following are the pharmacological tests and data for some of the compounds of the invention.
1 experimental method: examples 1-5 detection of the survival Rate of the antitumor drug paclitaxel in KBV resistant Strain cells
KBV cells in logarithmic phase are digested with 0.25% pancreatin to prepare single cell suspension with certain concentration. Based on the difference in cell growth rate, the cells were seeded at 4000 wells in a 96-well plate, and 100. mu.L of cell suspension was added to each well. After 24h, complete medium was added at various concentrations of compound and 100nM of paclitaxel and corresponding solvent control. mu.L of DMSO (final DMSO concentration < 0.1%) was added to each well, 3 wells were placed in each group, incubation was continued at 37 ℃ for 72h, and the supernatant was discarded. Add 100. mu.L per well of MTT 0.5mg/mLAnd (3) completely culturing the culture medium for 4 hours, removing the supernatant, adding 150 mu L of LDMSO into each well to dissolve MTT formazan precipitate, uniformly mixing the mixture by using a micro oscillator, and measuring an optical density value (OD) by using an enzyme-labeling instrument under the conditions of a reference wavelength of 450nm and a detection wavelength of 570 nm. Using tumor cells treated by solvent control as a control group, and calculating the survival rate of different tumor cells under the action of each compound by using the following formula; tumor cells treated by solvent control are used as a control group, the inhibition rate of the compound on the tumor cells is calculated by the following formula, and the IC is calculated according to the middle effect equation50。
Cell survival rate (%). The average OD value of the administered group/the average OD value of the control group X100%
IC50(control group mean OD value-administration group mean OD value)/control group mean OD value. times.100%
2, experimental results:
examples 1-5 cell viability when administered alone and in combination is shown in Table 1.
TABLE 1 cell viability of examples 1-5 when administered alone and in combination
Examples 1-5 viability assay of anti-tumor drug paclitaxel in KBV resistant strain cells.
The survival rate evaluation results of KBV drug-resistant strain cells of the derivatives show that the examples 1-4 have better tumor drug resistance reversal activity, wherein the activity is the best example 1. Research results show that the synthesized partial compound can obviously increase the antiproliferative activity of the paclitaxel, and the action intensity is superior to verapamil with equal dosage and is superior to H6.
The following are solubility determination tests and data for some of the compounds of the present invention.
1 experimental method: solubility tests were performed on examples 1-5
The excess compound was added to 4mL of deionized water, respectively, and the suspension was placed in a constant temperature shaker, shaken at 37 ℃ for 24 hours, and then centrifuged at 14,000r/min in a centrifuge for 5 minutes. The supernatant was filtered through a 0.45 μm microporous membrane, diluted appropriately, and the concentration of the compound was measured by UV-visible spectrophotometry to obtain the solubility of the compound in water.
2, experimental results:
examples 1-5 solubility data are shown in table 2.
TABLE 2 examples 1-5 solubility
The solubility measurement results of examples 1-5 show that the water solubility of the hederagenin polyethylene glycol derivative is remarkably improved compared with that of the lead compound H6, and particularly, the water solubility of example 3 is improved by about 1000 times.
Pharmacological tests and solubility determination tests prove that the hederagenin polyethylene glycol derivative provided by the invention improves water solubility while maintaining or improving tumor drug resistance reversal activity, can be used for preparing an MDR reversal agent, is used together with common antitumor drugs, and exerts good antitumor activity.
The experiments show that the polyethylene glycol modification method is introduced into the structural modification of H6, and the polyethylene glycol is connected to H6 through a connecting chain, so that the hederagenin polyethylene glycol derivative with the novel structure and improved tumor drug resistance reversion activity and remarkably improved water solubility is obtained, namely the hederagenin polyethylene glycol derivative with the general formula I and the structure modification of the pharmaceutically acceptable salt thereof are successful, the direct anti-tumor activity disappears compared with the hederagenin, the water solubility is remarkably improved on the premise that the hederagenin polyethylene glycol derivative with the general formula I and the pharmaceutically acceptable salt thereof have good tumor drug resistance reversion effect and the activity is better than that of H6, and the hederagenin polyethylene glycol derivative with the general formula I and the pharmaceutically acceptable salt thereof have the drug properties.
Although the preferred embodiments of the present invention have been described in detail, the present invention is not limited to the details of the embodiments, and various equivalent modifications can be made within the technical spirit of the present invention, and the scope of the present invention is also within the scope of the present invention. It should be noted that the various features described in the above embodiments may be combined in any suitable manner without departing from the scope of the invention. The invention is not described in detail in order to avoid unnecessary repetition. In addition, any combination of the various embodiments of the present invention is also possible, and the same should be considered as the disclosure of the present invention as long as it does not depart from the spirit of the present invention.
Claims (3)
1. Application of hederagenin polyethylene glycol derivatives shown in general formula I and medically acceptable salts thereof in preparing tumor drug resistance reversal agents,
wherein,
R1represents R2、R2XR2；
R2Represents a non-substituted linear or branched alkyl group of 1 to 3 carbons;
x represents S, O, S-S;
n is 2 to 13, and n is a natural number.
2. The use according to claim 1, characterized in that the hederagenin polyethylene glycol derivative represented by the general formula I and the pharmaceutically acceptable salt thereof,
R1represents R2、R2XR2；
R2Represents a non-substituted linear or branched alkyl group of 1 to 3 carbons;
x represents S, O, S-S;
n＝2、3、4、9、13。
3. the use according to claim 1, characterized in that the hederagenin polyethylene glycol derivative represented by the general formula I and the pharmaceutically acceptable salt thereof are as follows:
4- (23-oxoolean-12-en-28-oic acid benzyl ester and [3,2-b ] pyrazine) -4-oxo-butyric acid tetraethylene glycol ester;
1 ' - (23-oxoolean-12-en-28-oic acid benzyl ester-23-oxo [3,2-b ] pyrazine) -1 ' -propionyl-3, 3 ' -dithiopropionic acid triethylene glycol ester;
1 ' - (23-oxyolean-12-en-28-oic acid benzyl ester and [3,2-b ] pyrazine) -1 ' -acetyl-2, 2 ' -oxoacetic acid polyethylene glycol (600) ester;
1 ' - (23-oxyolean-12-en-28-oic acid benzyl ester and [3,2-b ] pyrazine) -1 ' -acetyl-2, 2 ' -thioacetic acid polyethylene glycol (400) ester;
1 ' - (23-oxyolean-12-en-28-oic acid benzyl ester and [3,2-b ] pyrazine) -1 ' -butyryl-4, 4 ' -dithio-butyric acid diethylene glycol ester.
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|---|---|---|---|---|
| CN114191439A (en) * | 2022-01-01 | 2022-03-18 | 烟台大学 | Application of C-23 nitrogen-containing heterocyclic derivative of cycloisoxazole ring hederagenin A |
| CN114213501A (en) * | 2022-01-01 | 2022-03-22 | 烟台大学 | C-23 nitrogen-containing heterocyclic derivative of A-ring-fused isoxazole ring hederagenin and preparation method thereof |
| CN114191439B (en) * | 2022-01-01 | 2023-04-25 | 烟台大学 | Application of C-23-position nitrogen-containing heterocyclic derivative of A-cycloisoxazole-ring hederagenin |
| CN117919259A (en) * | 2024-02-04 | 2024-04-26 | 烟台大学 | P-glycoprotein inhibitor composition and preparation method thereof |
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| CN112076200B (en) | 2022-01-11 |
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