CN110872324B - Oxaliplatin-coupled prodrug, preparation method and application thereof - Google Patents
Oxaliplatin-coupled prodrug, preparation method and application thereof Download PDFInfo
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- CN110872324B CN110872324B CN201810996120.XA CN201810996120A CN110872324B CN 110872324 B CN110872324 B CN 110872324B CN 201810996120 A CN201810996120 A CN 201810996120A CN 110872324 B CN110872324 B CN 110872324B
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- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 title claims abstract description 148
- 229960001756 oxaliplatin Drugs 0.000 title claims abstract description 146
- 229940002612 prodrug Drugs 0.000 title claims abstract description 42
- 239000000651 prodrug Substances 0.000 title claims abstract description 42
- 238000002360 preparation method Methods 0.000 title claims abstract description 33
- YGACXVRLDHEXKY-WXRXAMBDSA-N O[C@H](C[C@H]1c2c(cccc2F)-c2cncn12)[C@H]1CC[C@H](O)CC1 Chemical compound O[C@H](C[C@H]1c2c(cccc2F)-c2cncn12)[C@H]1CC[C@H](O)CC1 YGACXVRLDHEXKY-WXRXAMBDSA-N 0.000 claims abstract description 49
- 230000008878 coupling Effects 0.000 claims abstract description 17
- 238000010168 coupling process Methods 0.000 claims abstract description 17
- 238000005859 coupling reaction Methods 0.000 claims abstract description 17
- 239000003814 drug Substances 0.000 claims abstract description 14
- 239000000126 substance Substances 0.000 claims abstract description 13
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 3
- 239000003112 inhibitor Substances 0.000 claims abstract description 3
- 150000003384 small molecules Chemical class 0.000 claims abstract 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 50
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 38
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 30
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 26
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 11
- 238000001291 vacuum drying Methods 0.000 claims description 11
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 claims description 10
- 229940014800 succinic anhydride Drugs 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 9
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- 238000002390 rotary evaporation Methods 0.000 claims description 8
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- 206010033128 Ovarian cancer Diseases 0.000 claims description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 2
- 206010060862 Prostate cancer Diseases 0.000 claims description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 2
- 238000006473 carboxylation reaction Methods 0.000 claims description 2
- 206010017758 gastric cancer Diseases 0.000 claims description 2
- 201000010536 head and neck cancer Diseases 0.000 claims description 2
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 2
- 201000007270 liver cancer Diseases 0.000 claims description 2
- 208000014018 liver neoplasm Diseases 0.000 claims description 2
- 201000005202 lung cancer Diseases 0.000 claims description 2
- 208000020816 lung neoplasm Diseases 0.000 claims description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
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- 229940079593 drug Drugs 0.000 abstract description 12
- 230000000694 effects Effects 0.000 abstract description 7
- 238000005481 NMR spectroscopy Methods 0.000 description 14
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- 239000001257 hydrogen Substances 0.000 description 12
- 239000000693 micelle Substances 0.000 description 11
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- 102100040061 Indoleamine 2,3-dioxygenase 1 Human genes 0.000 description 8
- 101710120843 Indoleamine 2,3-dioxygenase 1 Proteins 0.000 description 8
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 7
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 7
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 7
- 102000008100 Human Serum Albumin Human genes 0.000 description 7
- 108091006905 Human Serum Albumin Proteins 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 238000001228 spectrum Methods 0.000 description 7
- 210000004881 tumor cell Anatomy 0.000 description 7
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 6
- 230000004083 survival effect Effects 0.000 description 6
- YGPSJZOEDVAXAB-UHFFFAOYSA-N kynurenine Chemical compound OC(=O)C(N)CC(=O)C1=CC=CC=C1N YGPSJZOEDVAXAB-UHFFFAOYSA-N 0.000 description 5
- 238000004949 mass spectrometry Methods 0.000 description 5
- KYNFOMQIXZUKRK-UHFFFAOYSA-N 2,2'-dithiodiethanol Chemical compound OCCSSCCO KYNFOMQIXZUKRK-UHFFFAOYSA-N 0.000 description 4
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 231100000820 toxicity test Toxicity 0.000 description 4
- GFLXBRUGMACJLQ-UHFFFAOYSA-N 1-isocyanatohexadecane Chemical compound CCCCCCCCCCCCCCCCN=C=O GFLXBRUGMACJLQ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000002512 chemotherapy Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000011550 stock solution Substances 0.000 description 3
- 206010009944 Colon cancer Diseases 0.000 description 2
- 206010059866 Drug resistance Diseases 0.000 description 2
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 2
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 230000003833 cell viability Effects 0.000 description 2
- 208000029742 colonic neoplasm Diseases 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 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 2
- 238000009169 immunotherapy Methods 0.000 description 2
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- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 229910052697 platinum Inorganic materials 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 238000000527 sonication Methods 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- 238000010267 two-fold dilution method Methods 0.000 description 2
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- 206010051779 Bone marrow toxicity Diseases 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- -1 NLG919 alkylated oxaliplatin Chemical class 0.000 description 1
- 206010029155 Nephropathy toxic Diseases 0.000 description 1
- 230000033540 T cell apoptotic process Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 231100000366 bone marrow toxicity Toxicity 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 150000002019 disulfides Chemical class 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000017188 evasion or tolerance of host immune response Effects 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- JARKCYVAAOWBJS-UHFFFAOYSA-N hexanal Chemical group CCCCCC=O JARKCYVAAOWBJS-UHFFFAOYSA-N 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000007694 nephrotoxicity Effects 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
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- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0086—Platinum compounds
- C07F15/0093—Platinum compounds without a metal-carbon linkage
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- 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
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
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Abstract
The invention discloses an oxaliplatin coupling prodrug which has a structure shown in formula 1 and formula 2, wherein R is-NHR1or-CH2CH2COR2；R1Selected from C2-C16 alkyl; r2Is a group of a micromolecular inhibitor NLG919 containing a dithioethanol active group. The invention also discloses a preparation method and application thereof, and the purpose of improving the curative effect of oxaliplatin and combined medication is hopefully achieved by oxaliplatin and small molecule coupling drug constructed by chemical bonds.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to an oxaliplatin coupled prodrug, and a preparation method and application thereof.
Background
Chemotherapy is one of the main means of current cancer treatment, wherein (bivalent) platinum drugs have the characteristics of good anti-cancer effect, wide indication and the like, and Cisplatin (cissplatin) and Oxaliplatin (Oxaliplatin) are mainly used for treating various malignant tumors in clinic at present. However, oxaliplatin is liable to cause severe gastrointestinal reactions, nephrotoxicity and bone marrow toxicity. Meanwhile, oxaliplatin easily causes acquired drug resistance, the curative effect is seriously reduced, and the clinical use effect of oxaliplatin is limited. A covalent coupling strategy is utilized to construct a coupled prodrug of oxaliplatin and active molecules, so that the use dosage of the oxaliplatin is expected to be reduced, and the toxic and side effects are reduced. Meanwhile, drug resistance is avoided, and the curative effect is improved.
According to the report of the literature, oxaliplatin can induce immune cell death and activate the immune response of the organism. However, the stimulation of chemotherapeutic drugs such as oxaliplatin and the like can cause the over-activation of indoleamine 2, 3-dioxygenase 1(IDO-1) in tumor cells. Indoleamine 2, 3-dioxygenase 1(IDO-1) degrades tryptophan (Trp) to produce kynurenine (Kyn). Tryptophan is a nutrient for cytotoxic T lymphocytes and kynurenine induces T cell apoptosis, so high expression of IDO-1 inhibits differentiation and proliferation, resulting in an immunosuppressive microenvironment. High expression of IDO-1 is associated with poor clinical prognosis in a variety of malignant patients. IDO-1 has become one of the important targets for tumor immunotherapy. NLG919 inhibits tumor cell immune evasion by inhibiting IDO-1 activity. According to the invention, the tetravalent oxaliplatin covalently modified by NLG919 is synthesized, the compound can reduce and release oxaliplatin and NLG919 in cells, and the chemotherapy and immunotherapy combined treatment is realized, so that the invention has good innovation.
Disclosure of Invention
Based on the above background, the present invention aims to provide an oxaliplatin coupling prodrug, which has a structure shown in formula 1 and formula 2:
wherein,
r is-NHR1、-CH2CH2COR2；
R1Selected from C2-C16 alkyl;
R2the structure of the group containing a micromolecular inhibitor NLG919 containing dithioethanol active groups is as follows:
preferably, the oxaliplatin-coupled prodrug is selected from the following compounds:
the invention also provides a preparation method of the oxaliplatin coupling prodrug, which is selected from the following methods:
the method comprises the following steps: when R is-NHR1The preparation method of the oxaliplatin coupling prodrug comprises the following steps:
step a: preparation of oxaliplatin oxide
Suspending oxaliplatin in water to obtain an oxaliplatin solution, adding hydrogen peroxide with the mass fraction of 30% into the oxaliplatin solution according to the molar ratio of hydrogen peroxide contained in hydrogen peroxide to oxaliplatin of 20: 1-100: 1, placing the mixture at any constant temperature of 0-40 ℃ for light-shielding reaction for 6-48 hours, then performing rotary evaporation to remove water, precipitating with diethyl ether, and performing vacuum drying to obtain oxaliplatin oxide;
step b: preparation of monocarboxylated oxaliplatin oxide
B, dissolving the oxaliplatin oxide prepared in the step a in dimethyl sulfoxide, adding succinic anhydride, reacting at any constant temperature of 0-40 ℃ for 1-24h, adding diethyl ether for precipitation, and performing vacuum drying to obtain the single-carboxylation oxaliplatin oxide, wherein the molar ratio of the oxaliplatin oxide to the succinic anhydride is 1:1-1: 5;
step c: r2Preparation of monocarboxylated oxaliplatin
Dissolving the product prepared in the step b in dimethyl sulfoxide, adding DMAP (4-dimethylaminopyridine) and EDCI (carbodiimide) to activate carboxyl, wherein the molar ratio of DMAP to oxaliplatin monocarboxylation oxide is 1:1-1:10, the molar ratio of EDCI to oxaliplatin monocarboxylation oxide is 1:1-1:10, and 1-4 times of the molar amount of oxaliplatin monocarboxylation oxide is added2H, reacting for 1-24H at normal temperature, precipitating with diethyl ether to remove dimethyl sulfoxide (DMSO), and vacuum drying to obtain R2And monocarboxylated oxaliplatin; wherein R is2As defined above;
step d: preparation of oxaliplatin-coupled prodrugs
Dissolving the product obtained in the step c in DMF, adding 1-5 times of equivalent of an alkylating reagent, and reacting at a constant temperature of 0-40 ℃ for 1-24 h; concentrating by rotary evaporation, precipitating by diethyl ether, and drying in vacuum to obtain oxaliplatin coupled prodrug; wherein R is1，R2As defined above; the alkylating reagent is O ═ C ═ N-R1。
The second method comprises the following steps: when R is-CH2CH2COR2The preparation method of the oxaliplatin coupling prodrug comprises the following steps:
step a: preparation of oxaliplatin oxide
Suspending oxaliplatin in water to obtain an oxaliplatin solution, adding hydrogen peroxide with the mass fraction of 30% into the oxaliplatin solution according to the molar ratio of hydrogen peroxide contained in hydrogen peroxide to oxaliplatin of 20: 1-100: 1, placing the mixture at any constant temperature of 0-40 ℃ for light-shielding reaction for 6-48h, and performing vacuum drying to obtain oxaliplatin oxide;
step b: preparation of dicarboxylated oxaliplatin oxide
B, dissolving the product prepared in the step a in dimethyl sulfoxide, adding succinic anhydride with the molar weight 1-5 times that of oxaliplatin oxide, reacting at any constant temperature of 0-60 ℃ for 1-24 hours, precipitating the obtained substance with diethyl ether, and drying in vacuum to obtain dicarboxylated oxaliplatin oxide;
step c: preparation of oxaliplatin-coupled prodrugs
Dissolving the product obtained in the step b in an organic solvent, adding DMAP (4-dimethylaminopyridine) and EDCI (carbodiimide) to activate carboxyl, wherein the molar ratio of DMAP to oxaliplatin dicarboxylated oxide is 1:1-1:10, the molar ratio of EDCI to oxaliplatin dicarboxylated oxide is 1:1-1:10, and 1-4 times of the molar amount of oxaliplatin dicarboxylated oxide is added2H, reacting for 1-24H at normal temperature, adding diethyl ether for precipitation, and drying in vacuum to obtain the oxaliplatin coupling prodrug; wherein R is2As defined above.
Preferably, the organic reagent in step c of method two is selected from N, N-dimethylformamide, N-dimethylacetamide or dimethylsulfoxide.
Another aspect of the invention is to provide the use of said oxaliplatin-coupled prodrug in the manufacture of a medicament for the treatment of cancer.
In the application, after the oxaliplatin coupling prodrug enters the interior of a tumor cell and is reduced by glutathione, the tetravalent oxaliplatin coupling prodrug is reduced into bivalent oxaliplatin and R2H, so that the concentration of a drug in the tumor cell is rapidly increased and the tumor cell is killed, and the tumor chemotherapy effect is effectively improved.
The cancer is selected from lung cancer, gastric cancer, ovarian cancer, prostatic cancer, pancreatic cancer, breast cancer, liver cancer, head and neck cancer, etc.
Drawings
FIG. 1 is a mass spectrum of monocarboxylated oxaliplatin oxide prepared in example 2 of the present invention. The molecular weight of the synthesized product shown by a mass spectrogram is 530, and is consistent with the theoretical molecular weight, so that the monocarboxylated oxaliplatin is successfully prepared.
FIG. 2 is (A) NMR and (B) mass spectra of disulfides of NLG919 prepared in inventive example 3. As shown in the nuclear magnetic resonance hydrogen spectrum in the graph (A), peaks b and c are characteristic peaks of methylene groups adjacent to two sides of a disulfide bond of bis (2-hydroxyethyl) disulfide, and a peak a is characteristic peak of a hexanal ring in NLG919, and the disulfide of the NLG919 is proved to be successfully prepared. (B) The molecular weight of the synthesized product shown in the mass spectrum of the figure is 462, which is consistent with the theoretical molecular weight, and the successful preparation of the disulfide of NLG919 is proved.
FIG. 3 shows (A) NMR spectra and (B) mass spectra of NLG919 and monocarboxylated oxaliplatin prepared in inventive example 4. As shown in the nuclear magnetic resonance hydrogen spectrum in the graph (A), the peak a is a characteristic peak of oxaliplatin and a hexanuclear ring of NLG919, and the peak b is a characteristic peak of bis (2-hydroxyethyl) disulfide adjacent to a disulfide bond methylene, so that the successful preparation of NLG919 and the monocarboxylation of oxaliplatin are proved. (B) The molecular weight of the synthesized product is 976 as shown in the mass spectrum of the figure, further proving that NLG919 is successfully prepared and oxaliplatin is monocarboxylated.
Fig. 4 is (a) nuclear magnetic resonance hydrogen spectrum and (B) mass spectrum of NLG919 and alkylated oxaliplatin-coupled prodrug prepared in example 5 of the present invention. (A) Shown in the figure by nuclear magnetic resonance hydrogen spectrum, the i peak is the terminal methyl peak of hexadecyl isocyanate, which proves that NLG919 is successfully prepared and the oxaliplatin coupling prodrug is alkylated. (B) The molecular weight of the synthesized product shown by a mass spectrogram in the figure is 1244, which accords with a prediction result, and further proves that the NLG919 alkylated oxaliplatin coupling prodrug is successfully prepared.
FIG. 5 shows (A) NMR spectra and (B) mass spectra of dicarboxylated oxaliplatin prepared in example 6 of the present invention. As shown in the nuclear magnetic resonance hydrogen spectrum in the graph (a), the f3 peak is a methylene characteristic peak of succinic anhydride, and the success in preparing the monocarboxylated oxaliplatin is proved; (B) the molecular weight of the synthesized product shown by a mass spectrogram in the figure is 630, and is consistent with the theoretical molecular weight, so that the dicarboxylated oxaliplatin is proved to be successfully prepared.
FIG. 6 shows (A) NMR and (B) mass spectra of NLG919 and dicarboxylated oxaliplatin-coupled prodrug prepared in example 7 of the present invention. As shown in the nuclear magnetic resonance hydrogen spectrum in the graph (A), the peak a is a characteristic peak of the hexacyclic ring of oxaliplatin and NLG919, and the peak b is a characteristic peak of methylene adjacent to disulfide bond of bis (2-hydroxyethyl) disulfide, so that the successful preparation of NLG919 and the double-carboxylated oxaliplatin coupling prodrug are proved; (B) the molecular weight of the synthesized product shown by a mass spectrogram is 1521, and the successful preparation of the NLG919 dicarboxylated oxaliplatin coupling prodrug is proved.
FIG. 7 is MTT toxicity test data of NLG919 and monocarboxylated oxaliplatin micelles prepared in example 4 of the invention on CT26 mouse colon cancer cells. The result shows that when the concentration of the drug is 100 mu M, the cell survival rate of the oxaliplatin proto-drug group is 29 percent, the cell survival rate of the NLG919 proto-drug group is 40 percent, and the cell survival rate of the NLG919 monocarboxylated oxaliplatin micelle group is 30 percent, which shows that the amphiphilic oxaliplatin precursor nanoparticles can obviously inhibit the growth of tumor cells and have cytotoxicity superior to that of oxaliplatin proto. Wherein OXA is oxaliplatin; NSP is NLG919 and monocarboxylated oxaliplatin micelles.
FIG. 8 is MTT toxicity test data of NLG919 and dicarboxylated oxaliplatin-coupled prodrug micelle prepared in example 7 of the invention on CT26 mouse colon cancer cells. The result shows that when the concentration of the drug is 100 mu M, the cell survival rate of the oxaliplatin proto-drug group is 24%, the cell survival rate of the NLG919 proto-drug group is 40%, and the cell survival rate of the NLG919 dicarboxylated oxaliplatin coupled prodrug micelle group is 24%, which indicates that the amphiphilic oxaliplatin precursor nanoparticle can obviously inhibit the growth of tumor cells. Wherein OXA is oxaliplatin; NSSP is NLG919 and a bis-carboxylated oxaliplatin-coupled prodrug.
Detailed Description
The present invention will be described with reference to the following specific examples, but the present invention is not limited to these specific examples.
The hexadecyl isocyanates used in the examples were purchased from sigma aldrich (china). Oxaliplatin was purchased from Shandong platinum sources. Succinic anhydride, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 1-hydroxybenzotriazole were purchased from Chiese chemical industry development Co., Ltd. Solvents N, N-dimethylformamide, dimethyl sulfoxide were purchased from Shanghai Bailingwei science and technology Co. NLG919 is from chemical technology, Inc. of Shanghai if.
In the present application, the rest of the reagents and solvents used are purchased from the national pharmaceutical group (Shanghai) Chemicals, Inc., unless otherwise specified.
In this application, the equipment and the test methods are conventional in the art unless otherwise specified.
Example 1 preparation of oxaliplatin oxide
Weighing 500mg oxaliplatin, suspending in 30ml water, adding 8ml 30% hydrogen peroxide, placing in a 50ml round bottom flask, stirring at 40 ℃ in a dark place for reaction for 10 hours, removing the solvent by rotary evaporation, and drying in vacuum to obtain the oxaliplatin oxide.
Example 2 preparation of monocarboxylated Oxaliplatinum
413mg of oxaliplatin oxide prepared in example 1 is dissolved in 5ml of anhydrous dimethyl sulfoxide, 100mg of succinic anhydride is added, reaction is carried out for 12 hours at normal temperature, ether precipitation is carried out, and vacuum drying is carried out, so as to obtain the oxaliplatin oxide monocarboxylate. The obtained substance was characterized by hydrogen nuclear magnetic resonance spectroscopy and mass spectrometry, and the results are shown in fig. 1.
Example 3 preparation of disulfide of NLG919
300mg of NLG919, 450mg of DMAP were weighed out and dissolved in 15ml of DCM in a 200ml round-bottom flask. 140mg of triphosgene was weighed out and dissolved in 5ml of DCM, and slowly added dropwise with stirring to the round-bottom flask, after 30min of reaction, 500ml of bis (2-hydroxyethyl) disulfide was slowly added dropwise to the reaction system. And reacting for 20h at normal temperature, and spin-drying and vacuum-drying the product to obtain the disulfide of NLG 919. The obtained substance was characterized by hydrogen nuclear magnetic resonance spectroscopy and mass spectrometry, and the results are shown in fig. 2.
Example 4 preparation of NLG919 and monocarboxylated oxaliplatin and micelles thereof
100mg of monocarboxylated oxatiliplatin prepared in example 2 was taken, dissolved in 3ml of anhydrous DMSO, 150mg of disulfide of NLG919 prepared in example 3 was added, 114mg of EDCI (carbodiimide) and 75mg of DMAP (4-dimethylaminopyridine) were added. Stirring and reacting at 25 ℃ overnight, performing rotary evaporation and concentration, removing DMSO from diethyl ether precipitate, washing the obtained precipitate with dichloromethane to remove an activating agent, and performing vacuum drying to obtain NLG919 monocarboxylated oxaliplatin. HSA (human serum albumin) was dissolved in 10ml of PBS (10 mg/ml) to prepare a mother solution of HSA at a concentration of 1 mg/ml. 4mg of NLG919 and monocarboxylated oxaliplatin were weighed, dissolved in 100. mu.l DMSO and a stock solution of NLG919 and monocarboxylated oxaliplatin was prepared at 40. mu.g/. mu.l. 25 μ l of NLG919 monocarboxylated oxaliplatin mother liquor was added dropwise to 1ml of HSA mother liquor with sonication to form uniform and stable NLG919 monocarboxylated oxaliplatin micelles. The prepared substance is characterized by a nuclear magnetic resonance hydrogen spectrum and a mass spectrum, and the result is shown in figure 3.
Example 5 alkylation of NLG919 and monocarboxylated oxaliplatin
Taking NLG919 prepared in example 4 and 100mg of monocarboxylated oxaliplatin, dissolving in 5ml of N, N-dimethylformamide, adding 300ul of hexadecyl isocyanate, placing at 25 ℃, stirring for reaction and activation for 2h, reacting overnight, performing rotary evaporation and concentration, precipitating with diethyl ether, and drying in vacuum to obtain the NLG919 and alkylated oxaliplatin coupled prodrug (namely the oxaliplatin coupled prodrug disclosed by the invention). The obtained material was characterized by hydrogen nuclear magnetic resonance spectroscopy and mass spectrometry, and the results are shown in FIG. 4.
Example 6 preparation of Bicarboxylation Oxaliplatinum
413mg of oxaliplatin oxide prepared in example 1 is taken and dissolved in 5ml of anhydrous dimethyl sulfoxide, 1g of succinic anhydride is added, the mixture reacts for 24 hours at the temperature of 40 ℃, ether is precipitated, the obtained substance is dissolved in methanol, washed with ether and dried in vacuum, and the dicarboxylated oxaliplatin is obtained. The obtained substance was characterized by hydrogen nuclear magnetic resonance spectroscopy and mass spectrometry, and the results are shown in fig. 5.
Example 7 preparation of NLG919 and Dicarboxylated oxaliplatin and micelles thereof
300mg of the dicarboxylated oxaliplatin, prepared in example 6, is dissolved in 5ml of anhydrous dimethyl sulfoxide, 95mg of the disulfide of NLG919, prepared in example 3, are added, 114mg of EDCI (carbodiimide) and 75mg of DMAP (4-dimethylaminopyridine) are added. The reaction was stirred overnight at 25 ℃, concentrated by rotary evaporation, the resulting material was washed with ether and dried under vacuum to give NLG919 and bis-carboxylated oxaliplatin-coupled prodrug (i.e., the oxaliplatin-coupled prodrug of the invention). 10mg of HSA was dissolved in 10ml of PBS to prepare a mother solution of HSA at a concentration of 1 mg/ml. 4mg of NLG919 dicarboxylated oxaliplatin coupled prodrug is weighed out and dissolved in 100. mu.l DMSO to prepare 40. mu.g/. mu.l stock solution of NLG919 dicarboxylated oxaliplatin coupled prodrug (NSSP). 25 μ l of the stock NSSP solution was added dropwise to 1ml of the HSA stock solution with sonication to form a homogeneous stable NLG919 and dicarboxylated oxaliplatin-coupled prodrug micelle. The prepared substance was characterized by hydrogen nuclear magnetic resonance spectroscopy and mass spectrometry, and the results are shown in fig. 6.
Example 8 NLG919 and monocarboxylated oxaliplatin (NSP) toxicity test
The micelles prepared in example 4 were prepared at equimolar concentrations of 100. mu. mol/ml, and then 9 gradient concentrations, i.e., 50, 25, 12.5, 6.25, 3.125, 1.56, and 0.78, 0.39. mu. mol/ml, were prepared in this order by the two-fold dilution method. 4T1 Breast cancer cells were seeded in 96-well cell culture plates (5000 cells/well) with 100. mu.l 1640 medium (10% serum) per well. After 24h of culture, the fresh complete culture solution was replaced, and drugs with different concentration gradients were added, respectively, using PBS as a blank control group. The culture was continued for 48h, and the cell viability was measured by MTT method, the results are shown in FIG. 7.
Example 9 NLG919 and Dicarboxylated oxaliplatin (NSSP for short) toxicity test
The micelles prepared in example 7 were prepared at equimolar concentrations of 100. mu. mol/ml, and then 9 gradient concentrations, i.e., 50, 25, 12.5, 6.25, 3.125, 1.56, and 0.78, 0.39. mu. mol/ml, were prepared in this order by the two-fold dilution method. 4T1 Breast cancer cells were seeded in 96-well cell culture plates (5000 cells/well) with 100. mu.l 1640 medium (10% serum) per well. After 24h of culture, the fresh complete culture solution was replaced, and drugs with different concentration gradients were added, respectively, using PBS as a blank control group. The culture was continued for 48h, and the cell viability was measured by MTT method, the results are shown in FIG. 8.
Claims (5)
1. An oxaliplatin-coupled prodrug having a structure represented by formula 1:
wherein,
r is-NHR1or-CH2CH2COR2；
R1Selected from C2-C16 alkyl;
R2is a group of a small molecule inhibitor NLG919 containing dithioethanol active group, whichThe structure is as follows:
2. the method of preparing an oxaliplatin-coupled prodrug as claimed in claim 1, which is selected from the following methods:
the method comprises the following steps: when R is-NHR1The preparation method of the oxaliplatin coupling prodrug comprises the following steps:
step a: preparation of oxaliplatin oxide
Suspending oxaliplatin in water to obtain an oxaliplatin solution, adding hydrogen peroxide with the mass fraction of 30% into the oxaliplatin solution according to the molar ratio of hydrogen peroxide contained in hydrogen peroxide to oxaliplatin of 20: 1-100: 1, placing the mixture at any constant temperature of 0-40 ℃ for light-shielding reaction for 6-48 hours, then performing rotary evaporation to remove water, precipitating diethyl ether, and performing vacuum drying to obtain oxaliplatin oxide;
step b: preparation of monocarboxylated oxaliplatin oxide
B, dissolving the oxaliplatin oxide prepared in the step a in dimethyl sulfoxide, adding succinic anhydride, reacting at any constant temperature of 0-40 ℃ for 1-24h, adding diethyl ether for precipitation, and performing vacuum drying to obtain the single-carboxylation oxaliplatin oxide, wherein the molar ratio of the oxaliplatin oxide to the succinic anhydride is 1:1-1: 5;
step c: r2Preparation of monocarboxylated oxaliplatin
Dissolving the product obtained in the step b in dimethyl sulfoxide, adding 4-dimethylaminopyridine and carbodiimide to activate carboxyl, wherein the molar ratio of 4-dimethylaminopyridine to oxaliplatin monocarboxylated oxide is 1:1-1:10, the molar ratio of carbodiimide to oxaliplatin monocarboxylated oxide is 1:1-1:10, and 1-4 times of the molar amount of R is added to the oxaliplatin monocarboxylated oxide2H, after reacting for 1-24H at normal temperature, precipitating with diethyl ether to remove dimethyl sulfoxide, and vacuum drying to obtain R2And monocarboxylated oxaliplatin; wherein R is2As defined in claim 1;
step d: preparation of oxaliplatin-coupled prodrugs
Dissolving the product obtained in the step c in DMF, adding 1-5 times of equivalent of an alkylating reagent, and reacting at a constant temperature of 0-40 ℃ for 1-24 h; concentrating by rotary evaporation, precipitating by diethyl ether, and drying in vacuum to obtain oxaliplatin coupled prodrug; wherein R is1，R2As defined in claim 1; the alkylating reagent is O ═ C ═ N-R1；
The second method comprises the following steps: when R is-CH2CH2COR2The preparation method of the oxaliplatin coupling prodrug comprises the following steps:
step a: preparation of oxaliplatin oxide
Suspending oxaliplatin in water to obtain an oxaliplatin solution, adding hydrogen peroxide with the mass fraction of 30% into the oxaliplatin solution according to the molar ratio of hydrogen peroxide contained in hydrogen peroxide to oxaliplatin of 20: 1-100: 1, placing the mixture at any constant temperature of 0-40 ℃ for light-shielding reaction for 6-48h, and performing vacuum drying to obtain oxaliplatin oxide;
step b: preparation of dicarboxylated oxaliplatin oxide
B, dissolving the product prepared in the step a in dimethyl sulfoxide, adding succinic anhydride with the molar weight 1-5 times that of oxaliplatin oxide, reacting at any constant temperature of 0-60 ℃ for 1-24 hours, precipitating the obtained substance with diethyl ether, and drying in vacuum to obtain dicarboxylated oxaliplatin oxide;
step c: preparation of oxaliplatin-coupled prodrugs
Dissolving the product obtained in the step b in an organic solvent, adding 4-dimethylaminopyridine and carbodiimide to activate carboxyl, wherein the molar ratio of the 4-dimethylaminopyridine to the oxaliplatin dicarboxylating oxide is 1:1-1:10, the molar ratio of the carbodiimide to the oxaliplatin dicarboxylating oxide is 1:1-1:10, and adding 1-4 times of the molar amount of R of the oxaliplatin dicarboxylating oxide2H, reacting for 1-24H at normal temperature, adding diethyl ether for precipitation, and drying in vacuum to obtain the oxaliplatin coupling prodrug; wherein R is2Is as defined in claim 1.
3. The method of claim 2, wherein: the organic solvent in step c of method two is selected from N, N-dimethylformamide, N-dimethylacetamide or dimethylsulfoxide.
4. Use of the oxaliplatin-coupled prodrug of claim 1 in the manufacture of a medicament for the treatment of cancer.
5. Use according to claim 4, characterized in that: the cancer is selected from lung cancer, gastric cancer, ovarian cancer, prostate cancer, pancreatic cancer, breast cancer, liver cancer, and head and neck cancer.
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