CN105001291A - Gemcitabine chemical transfer prodrug, preparation method and applications thereof - Google Patents
Gemcitabine chemical transfer prodrug, preparation method and applications thereof Download PDFInfo
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- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 title claims abstract description 79
- 229960005277 gemcitabine Drugs 0.000 title claims abstract description 79
- 239000000651 prodrug Substances 0.000 title claims abstract description 50
- 229940002612 prodrug Drugs 0.000 title claims abstract description 50
- 239000000126 substance Substances 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 239000003814 drug Substances 0.000 claims abstract description 45
- 210000004556 brain Anatomy 0.000 claims abstract description 36
- DJXNJVFEFSWHLY-UHFFFAOYSA-N quinoline-3-carboxylic acid Chemical compound C1=CC=CC2=CC(C(=O)O)=CN=C21 DJXNJVFEFSWHLY-UHFFFAOYSA-N 0.000 claims abstract description 17
- 229940079593 drug Drugs 0.000 claims abstract description 16
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 9
- 239000005515 coenzyme Substances 0.000 claims abstract description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 6
- 230000008685 targeting Effects 0.000 claims abstract description 6
- 238000006479 redox reaction Methods 0.000 claims abstract description 5
- 230000009467 reduction Effects 0.000 claims abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- 238000006243 chemical reaction Methods 0.000 claims description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 15
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 12
- 230000002490 cerebral effect Effects 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 12
- 239000000243 solution Substances 0.000 claims description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- 150000001408 amides Chemical class 0.000 claims description 9
- 239000007810 chemical reaction solvent Substances 0.000 claims description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 9
- 235000021050 feed intake Nutrition 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 6
- 125000004925 dihydropyridyl group Chemical group N1(CC=CC=C1)* 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- 239000012044 organic layer Substances 0.000 claims description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 6
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 claims description 6
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 4
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 239000007795 chemical reaction product Substances 0.000 claims description 3
- 239000007859 condensation product Substances 0.000 claims description 3
- 229960004132 diethyl ether Drugs 0.000 claims description 3
- 238000000605 extraction Methods 0.000 claims description 3
- 238000005984 hydrogenation reaction Methods 0.000 claims description 3
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 claims description 3
- 238000007069 methylation reaction Methods 0.000 claims description 3
- 238000001556 precipitation Methods 0.000 claims description 3
- 230000037452 priming Effects 0.000 claims description 3
- -1 sulfonic acid methyl esters Chemical class 0.000 claims description 3
- 238000001291 vacuum drying Methods 0.000 claims description 3
- 230000005540 biological transmission Effects 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 10
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 abstract description 3
- 238000006722 reduction reaction Methods 0.000 abstract 2
- 210000005013 brain tissue Anatomy 0.000 abstract 1
- 150000002632 lipids Chemical class 0.000 abstract 1
- 241000700159 Rattus Species 0.000 description 11
- 210000001519 tissue Anatomy 0.000 description 11
- 238000004458 analytical method Methods 0.000 description 8
- 230000000857 drug effect Effects 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000011160 research Methods 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- 210000003169 central nervous system Anatomy 0.000 description 3
- 238000012377 drug delivery Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- 206010018338 Glioma Diseases 0.000 description 2
- WWNNZCOKKKDOPX-UHFFFAOYSA-N N-methylnicotinate Chemical compound C[N+]1=CC=CC(C([O-])=O)=C1 WWNNZCOKKKDOPX-UHFFFAOYSA-N 0.000 description 2
- 241001312519 Trigonella Species 0.000 description 2
- WBDLSXCAFVEULB-UHFFFAOYSA-N acetonitrile;methylsulfinylmethane Chemical compound CC#N.CS(C)=O WBDLSXCAFVEULB-UHFFFAOYSA-N 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000036571 hydration Effects 0.000 description 2
- 238000006703 hydration reaction Methods 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 2
- BOPGDPNILDQYTO-NNYOXOHSSA-N nicotinamide-adenine dinucleotide Chemical compound C1=CCC(C(=O)N)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]2[C@H]([C@@H](O)[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)O1 BOPGDPNILDQYTO-NNYOXOHSSA-N 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 239000002831 pharmacologic agent Substances 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 231100000614 poison Toxicity 0.000 description 2
- 230000007096 poisonous effect Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000007634 remodeling Methods 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 238000007910 systemic administration Methods 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 238000005199 ultracentrifugation Methods 0.000 description 2
- 210000003462 vein Anatomy 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
- 208000014644 Brain disease Diseases 0.000 description 1
- 208000014912 Central Nervous System Infections Diseases 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- 208000000094 Chronic Pain Diseases 0.000 description 1
- CTENFNNZBMHDDG-UHFFFAOYSA-N Dopamine hydrochloride Chemical compound Cl.NCCC1=CC=C(O)C(O)=C1 CTENFNNZBMHDDG-UHFFFAOYSA-N 0.000 description 1
- 208000032274 Encephalopathy Diseases 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 241000725303 Human immunodeficiency virus Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000036983 biotransformation Effects 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 208000035269 cancer or benign tumor Diseases 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000009513 drug distribution Methods 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 208000018389 neoplasm of cerebral hemisphere Diseases 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 210000004279 orbit Anatomy 0.000 description 1
- 239000012466 permeate Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000007723 transport mechanism Effects 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention discloses a gemcitabine chemical transfer prodrug, a preparation method and applications thereof, wherein the gemcitabine chemical transfer prodrug mainly comprises gemcitabine and a dihydropyridine chemical delivery system. According to the present invention, based on the dihydropyridine-pyridine ion oxidation-reduction reaction, gemcitabine and a targeting agent 3-quinolinic acid are bonded to prepare the reduced gemcitabine chemical transfer prodrug, the conjugate is promoted to diffuse into the brain tissue through the high lipid solubility, and in the brain, the pyridine part in the dihydropyridine brain-targeting chemical delivery system conjugate is oxidized into the oxidized gemcitabine chemical transfer prodrug by a coenzyme system; and the gemcitabine chemical transfer prodrug has effects of improvement of the amount of the drug entering the brain, enhancement of the drug efficacy, reduction of the drug consumption, and reduction of the drug toxic-side effect.
Description
Technical field
The present invention relates to a kind of prodrug and application thereof, particularly relate to a kind of gemcitabine (Gemcitabine) chemistry and transmit prodrug and its preparation method and application.
Background technology
Encephalopathy is as huge to the healthy effect of people in cerebral tumor, central nervous system infection, chronic pain, epilepsy, neurodegenerative disease and apoplexy etc.Current methods for the treatment of mainly contains: Formulations for systemic administration, in sheath or intracerebral injection and brain implantation etc.Latter two technical requirements is high, easy infection, and has invasive to cerebral tissue, limits its application.During Formulations for systemic administration treatment, drug distribution is extensive, easily causes serious toxicity or untoward reaction.In recent years, the research of brain-targeted drug delivery is becoming target research field the most popular except neoplasm targeted therapy.But namely the obstacle that first brain-targeted drug delivery research runs into is hemato encephalic barrier (BBB).Due to the existence of BBB, make a lot of medicine not enter brain, be also difficult to reach in brain effectively treat concentration even if enter on a small quantity.The brain tumor medicines such as a lot of central nervous system medicine, anti-cerebral glioma are due to limited in one's ability through BBB of the lower reason of lipotropy, effectively cannot diffuse in cerebral tissue and play drug effect, and improving to increase the dose entering brain the enhancing that dosage can cause periphery poisonous side effect of medicine, above-mentioned factor all significantly limit the performance of these pharmacological agent effects.Therefore, the Major Difficulties that BBB is Brain targeting research is overcome.
Realize in the strategy of brain-targeted drug delivery research through BBB, dihydropyridines Brain targeting chemical delivery system (CDS) is the important Brain targeting pro-drug system of a class, this system is based on the redox reaction of dihydropyridine-pyridinium ion, medicine is connected with target agent dihydropyridine and makes CDS binding substances, by force fat-soluble because of medicine CDS binding substances, thus can promote that binding substances is through BBB.Current such CDS system just under study for action comprises the prodrug etc. of the neat Fu Duoding of AIDS virus resisting infection medicine (AZT), Dopamine HCL and dihydropyridine compounds.All 1 is adopted in these researchs, 4-dihydro trigonelline is as CDS carrier, the effect that its transhipment medicine enters brain is confirmed, but the subject matter that such CDS exists is less stable, cannot effectively meet the requirement of transporting in brain, and unstable to the oxygen in air neutralization solution, easily there is hydration and oxygenizement in its double bond of 5,6.Therefore, be necessary to improve to overcome its weak point to this type systematic.
At present the brain tumor medicine such as a lot of central nervous system medicine, anti-cerebral gliomas is due to limited in one's ability through BBB of the lower reason of lipotropy, effectively cannot diffuse in cerebral tissue and play drug effect, and improving to increase the dose entering brain the enhancing that dosage can cause periphery poisonous side effect of medicine, above-mentioned factor all significantly limit the performance of these pharmacological agent effects.
Commonly use at present 1,4-dihydro trigonella bases CDS is unstable to the oxygen in air neutralization solution, and 5, easily there is hydration and oxygenizement in the double bond of 6, therefore the medicine CDS less stable using this system to prepare, effectively cannot transport medicine in brain, fully can not meet the object of clinical treatment.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of gemcitabine chemistry and transmits prodrug and its preparation method and application, and what it can improve medicine enters brain volume, strengthens the drug effect of medicine, reduces the consumption of medicine, reduce the toxic side effect of medicine.
The present invention solves above-mentioned technical problem by following technical proposals: a kind of gemcitabine chemistry transmits prodrug, it is characterized in that, described gemcitabine chemistry transmits prodrug and forms primarily of gemcitabine and dihydropyridines chemical delivery system.
Preferably, it is based on the redox reaction of dihydropyridine-pyridinium ion that described gemcitabine chemistry transmits prodrug, gemcitabine be connected with target agent 3-quinolinic acid make reduced form gemcitabine chemistry transmit prodrug, the fat-solubility of this binding substances impels it to diffuse into cerebral tissue, pyridine moiety in brain in this dihydropyridines Brain targeting chemical delivery system binding substances is oxidized to oxidized form gemcitabine chemistry by coenzyme system and transmits prodrug
Wherein the structural formula of reduced form gemcitabine chemistry transmission prodrug is:
Wherein, R
1be selected from H, CH
3, OMe, OEt; R
2be selected from H, CH
3, OMe, OEt;
Oxidized form gemcitabine chemistry transmit prodrug) structural formula be:
Wherein, R
1be selected from H, CH
3, OMe, OEt; R
2be selected from H, CH
3, OMe, OEt.
The present invention also provides a kind of gemcitabine chemistry to transmit the preparation method of prodrug, and it is characterized in that, described preparation method comprises the following steps:
Step one, amide condensed reaction take methylene dichloride as reaction solvent, 3-quinolinic acid and condensing agent feed intake according to mol ratio 1: 1.2: 1.2: 2, stirring at room temperature priming reaction is after 1 hour, and gemcitabine feeds intake according to 3-quinolinic acid molar weight 1: 1.2, and stirring at room temperature reacts 24 hours; React complete, reaction solution 10% sodium bicarbonate, water, 10% citric acid, saturated nacl aqueous solution wash, organic layer anhydrous magnesium sulfate drying, filtration, concentrating under reduced pressure, silica gel chromatography (moving phase: methylene chloride/methanol 10/1), obtains midbody acid amide condensation product;
Step 2, methylation reaction take methylene dichloride as reaction solvent, and amide condensed reaction product and the trifluoromethayl sulfonic acid methyl esters of step one feed intake according to mol ratio 1:1.2, and stirring at room temperature reacts 2 hours; React complete, concentrating under reduced pressure removing reaction solvent, redissolves with your a small amount of methylene dichloride, adds ether and precipitation is precipitated, after washed with diethylether, namely obtain intermediate methylate after vacuum-drying;
Step 3, hydrogenation reduction take water-methanol as solvent, and the methylate of step 2 and V-Brite B and sodium bicarbonate feed intake according to mol ratio 1:5:6, after lucifuge stirring at room temperature reacts 2 hours, then add the V-Brite B of same amount and sodium bicarbonate continues reaction 30 minutes; React complete, extraction into ethyl acetate reaction solution three times, organic layer washed with water three times, namely obtain gemcitabine chemistry after anhydrous magnesium sulfate drying, filtration, concentrating under reduced pressure and transmit prodrug.
Present invention also offers a kind of gemcitabine chemistry and transmit the application of prodrug in brain drug transport.
Present invention also offers a kind of gemcitabine chemistry and transmit the application of prodrug in treatment brain tumor.
Positive progressive effect of the present invention is: according to gemcitabine 3-quinolinic acid CDS and the gemcitabine analysis of drug content result at rat brain, the content of oxidized form gemcitabine CDS in brain is significantly higher than gemcitabine, and the residence time in cerebral tissue is also greater than gemcitabine, and oxidized form gemcitabine CDS diffuses into by reduced form gemcitabine CDS the product formed after NADH coenzyme system oxidation after in brain, be stranded in brain due to its hydrophilic increase, thus the medicament contg that improve in cerebral tissue, be conducive to the performance of the antitumor drug effect of gemcitabine.
Accompanying drawing explanation
Fig. 1 is the drug transport mechanism figure of institute of the present invention foundation.
Fig. 2 is the chemical preparation reaction scheme figure that gemcitabine chemistry transmits prodrug.
Fig. 3 is the schematic diagram that gemcitabine chemistry transmits prodrug rat Pharmacokinetic experiments result.
Fig. 4 is the schematic diagram that gemcitabine chemistry transmits prodrug rat brain analysis of drug content result.
Embodiment
Present pre-ferred embodiments is provided, to describe technical scheme of the present invention in detail below in conjunction with accompanying drawing.
Medicine operative mechanism of the present invention as shown in Figure 1, it is based on the redox reaction of dihydropyridine-pyridinium ion that described gemcitabine chemistry transmits prodrug, medicine gemcitabine is connected with target agent 3-quinolinic acid and makes CDS binding substances (reduced form gemcitabine chemistry transmits prodrug), the fat-solubility of this binding substances impels it to diffuse into cerebral tissue, and the pyridine moiety in brain in this CDS binding substances is by coenzyme system (such as NAD (P) H ← → NAD (P)
+coenzyme system) be oxidized to water miscible salt (oxidized form gemcitabine chemistry transmits prodrug), and make it not be stranded in central nervous system through BBB, and slowly and constantly discharge medicine through biotransformation.
The structural formula that reduced form gemcitabine chemistry transmits prodrug is:
R
1be selected from H, CH
3, OMe, OEt; R
2be selected from H, CH
3, OMe, OEt.
Oxidized form gemcitabine chemistry transmit prodrug) structural formula be:
R
1be selected from H, CH
3, OMe, OEt; R
2be selected from H, CH
3, OMe, OEt.
Gemcitabine chemistry transmits the chemical preparation reaction scheme of prodrug as shown in Figure 2, and the preparation method that gemcitabine chemistry of the present invention transmits prodrug comprises the following steps:
Step one, amide condensed reaction, take methylene dichloride as reaction solvent, 3-quinolinic acid and condensing agent EDC(1-ethyl-(3-dimethylaminopropyl) carbodiimide), HOBt(1-hydroxybenzotriazole), DIPEA(N, N-diisopropylethylamine) feed intake according to mol ratio 1: 1.2: 1.2: 2, stirring at room temperature priming reaction is after 1 hour, and gemcitabine feeds intake according to 3-quinolinic acid molar weight 1: 1.2, and stirring at room temperature reacts 24 hours; React complete, reaction solution 10% sodium bicarbonate, water, 10% citric acid, saturated nacl aqueous solution wash, organic layer anhydrous magnesium sulfate drying, filtration, concentrating under reduced pressure, silica gel chromatography (moving phase: methylene chloride/methanol 10/1), obtains midbody acid amide condensation product;
Step 2, methylation reaction take methylene dichloride as reaction solvent, and amide condensed reaction product and the trifluoromethayl sulfonic acid methyl esters of step one feed intake according to mol ratio 1:1.2, and stirring at room temperature reacts 2 hours; React complete, concentrating under reduced pressure removing reaction solvent, redissolves with your a small amount of methylene dichloride, adds ether and precipitation is precipitated, after washed with diethylether, namely obtain intermediate methylate after vacuum-drying;
Step 3, hydrogenation reduction, with water-methanol (v:v/1:1) for solvent, the methylate of step 2 and V-Brite B and sodium bicarbonate feed intake according to mol ratio 1:5:6, after lucifuge stirring at room temperature reacts 2 hours, then add the V-Brite B of same amount and sodium bicarbonate continues reaction 30 minutes; React complete, extraction into ethyl acetate reaction solution three times, organic layer washed with water three times, namely obtain gemcitabine 3-quinolinic acid CDS(gemcitabine chemistry after anhydrous magnesium sulfate drying, filtration, concentrating under reduced pressure and transmit prodrug).
Carry out gemcitabine chemistry and transmit the analysis of prodrug rat Pharmacokinetic experiments, gemcitabine, gemcitabine 3-quinolinic acid CDS uses DMSO/ physiological saline (v/v:10/90) mixed solvent to be made into the solution that concentration is 25 ~ 26 mg/ml respectively, SD rat (a kind of mouse kind) (weight in average 200 ~ 250 g) tail vein injection administration, dosage 10 mg/kg, often organize three rats, respectively at 5, 15, 30, 45, 60, 90, 120 minutes, eye socket gets blood 1 ml, add 2 ml acetonitrile-DMSO(V/V:94/6), vortex jolting 1 minute, 4000 rpm ultracentrifugations 10 minutes, get supernatant liquor and carry out high performance liquid chromatography content analysis, analytical results (medicine time front of blood concentration) as shown in Figure 3.
Gemcitabine chemistry transmits prodrug rat brain analysis of drug content: gemcitabine, gemcitabine 3-quinolinic acid CDS use DMSO/ physiological saline (v/v:10/90) mixed solvent to be made into the solution that concentration is 25 ~ 26 mg/ml respectively, (weight in average 200 ~ 250 g) the tail vein injection administration of SD rat, dosage 15 mg/kg, often organize three rats, respectively at 5,10,20,30,45,60,90,120 minutes, disconnected neck puts to death mouse, take out cerebral tissue, 20 ml brine, filter paper suck dry moisture, according to homogenate
:solvent (w/v 1
:2) acetonitrile-DMSO(v/v:94/6 is added) carry out homogenate, 4000 rpm ultracentrifugations 10 minutes, get supernatant liquor and carry out high performance liquid chromatography content analysis.Above-mentioned gemcitabine 3-quinolinic acid CDS rat cerebral tissue analysis of drug content experimental result (brain drug concentration time curve) as shown in Figure 4.
According to gemcitabine 3-quinolinic acid CDS and the gemcitabine analysis of drug content result at rat brain, the content of oxidized form gemcitabine CDS in brain is significantly higher than gemcitabine, and the residence time in cerebral tissue is also greater than gemcitabine, and oxidized form gemcitabine CDS diffuses into by reduced form gemcitabine CDS the product formed after NADH coenzyme system oxidation after in brain, be stranded in brain due to its hydrophilic increase, thus the medicament contg that improve in cerebral tissue, be conducive to the performance of the antitumor drug effect of gemcitabine.
Gemcitabine chemistry of the present invention transmits prodrug and can apply in brain drug transport or apply in treatment brain tumor.
The present invention is directed to traditional anti-tumor medicine wetting ability stronger, the ability of agent permeates therethrough BBB is poor, the shortcoming of the therapeutic action of medicine cannot be given full play in brain, the higher prodrug of lipotropy is made by being combined with CDS by medicine, thus improve medicine enter brain volume, strengthen the drug effect of medicine, reduce the consumption of medicine, reduce the toxic side effect of medicine.The present invention is directed to conventional 1; the oxidizable destruction of 4-dihydro trigonella bases CDS; the shortcoming of poor stability; the present invention adopts 3-quinolinic acid as CDS carrier; by oxidizable pyridine 5; 6 double bonds are protected, and improve the stability of CDS system, ensure that medicine can effectively be transported in brain by CDS and discharge and play drug effect.
Those skilled in the art can carry out various remodeling and change to the present invention.Therefore, present invention covers the various remodeling in the scope falling into appending claims and equivalent thereof and change.
Claims (5)
1. gemcitabine chemistry transmits a prodrug, it is characterized in that, described gemcitabine chemistry transmits prodrug and forms primarily of gemcitabine and dihydropyridines chemical delivery system.
2. gemcitabine chemistry as claimed in claim 1 transmits prodrug, it is characterized in that, it is based on the redox reaction of dihydropyridine-pyridinium ion that described gemcitabine chemistry transmits prodrug, gemcitabine be connected with target agent 3-quinolinic acid make reduced form gemcitabine chemistry transmit prodrug, the fat-solubility of this binding substances impels it to diffuse into cerebral tissue, pyridine moiety in brain in this dihydropyridines Brain targeting chemical delivery system binding substances is oxidized to oxidized form gemcitabine chemistry by coenzyme system and transmits prodrug
Wherein the structural formula of reduced form gemcitabine chemistry transmission prodrug is:
Wherein, R
1be selected from H, CH
3, OMe, OEt; R
2be selected from H, CH
3, OMe, OEt;
Oxidized form gemcitabine chemistry transmit prodrug) structural formula be:
Wherein, R
1be selected from H, CH
3, OMe, OEt; R
2be selected from H, CH
3, OMe, OEt.
3. gemcitabine chemistry transmits a preparation method for prodrug, and it is characterized in that, described preparation method comprises the following steps:
Step one, amide condensed reaction take methylene dichloride as reaction solvent, 3-quinolinic acid and condensing agent feed intake according to mol ratio 1: 1.2: 1.2: 2, stirring at room temperature priming reaction is after 1 hour, and gemcitabine feeds intake according to 3-quinolinic acid molar weight 1: 1.2, and stirring at room temperature reacts 24 hours; React complete, reaction solution 10% sodium bicarbonate, water, 10% citric acid, saturated nacl aqueous solution wash, and namely obtain midbody acid amide condensation product after organic layer anhydrous magnesium sulfate drying, filtration, concentrating under reduced pressure;
Step 2, methylation reaction take methylene dichloride as reaction solvent, and amide condensed reaction product and the trifluoromethayl sulfonic acid methyl esters of step one feed intake according to mol ratio 1:1.2, and stirring at room temperature reacts 2 hours; React complete, concentrating under reduced pressure removing reaction solvent, redissolves with your a small amount of methylene dichloride, adds ether and precipitation is precipitated, after washed with diethylether, namely obtain intermediate methylate after vacuum-drying;
Step 3, hydrogenation reduction take water-methanol as solvent, and the methylate of step 2 and V-Brite B and sodium bicarbonate feed intake according to mol ratio 1:5:6, after lucifuge stirring at room temperature reacts 2 hours, then add the V-Brite B of same amount and sodium bicarbonate continues reaction 30 minutes; React complete, extraction into ethyl acetate reaction solution three times, organic layer washed with water three times, namely obtain gemcitabine chemistry after anhydrous magnesium sulfate drying, filtration, concentrating under reduced pressure and transmit prodrug.
4. gemcitabine chemistry as claimed in claim 1 transmits the application of prodrug in brain drug transport.
5. gemcitabine chemistry as claimed in claim 1 transmits the application of prodrug in treatment brain tumor.
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