CN105001291B - Gemcitabine chemistry transmits prodrug and its preparation method and application - Google Patents
Gemcitabine chemistry transmits prodrug and its preparation method and application Download PDFInfo
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Abstract
The invention discloses a kind of gemcitabine chemistry transmitting prodrug and its preparation method and application, the gemcitabine chemistry transmitting prodrug is mainly made of gemcitabine and dihydropyridines chemical delivery system.The present invention is based on dihydropyridine-pyridinium ion redox reaction, gemcitabine is connected with targeting agent 3- quinolinic acid is made reduced form gemcitabine chemistry transmitting prodrug, the fat-solubility of the conjugate promotes it to diffuse into brain tissue, and the pyridine moiety in the intracerebral dihydropyridines Brain targeting chemical delivery system conjugate is oxidized to oxidized form gemcitabine chemistry transmitting prodrug by coenzyme system.What the present invention can improve drug enters brain volume, enhances the drug effect of drug, reduces the dosage of drug, reduces the toxic side effect of drug.
Description
Technical field
The present invention relates to a kind of prodrug and its applications, pass more particularly to a kind of gemcitabine (Gemcitabine) chemistry
Pass prodrug and its preparation method and application.
Background technique
Brain diseases such as brain tumor, central nervous system infection, chronic ache, epilepsy, neurodegenerative disease and apoplexy etc.
It is huge to the health effect of people.Current treatment method mainly has: Formulations for systemic administration, intrathecal or intracerebral injection and brain implantation etc..Afterwards
Two kinds of technical requirements height, easy infection, and have invasive to brain tissue, it limits its application.Drug distribution when Formulations for systemic administration is treated
Extensively, easily cause serious toxicity or adverse reaction.In recent years, the research of brain-targeted drug delivery is becoming except neoplasm targeted therapy
Targeting research field the most popular in addition.However, the obstacle that brain-targeted drug delivery research initially encounters is blood-brain barrier
(BBB).Due to the presence of BBB, so that many drugs not can enter brain, it is difficult to reach effective in intracerebral a small amount of enter
Treatment concentration.The brain tumors drugs such as many central nervous system drugs, anti-glioma are saturating due to lipophilicity is lower
The ability for crossing BBB is limited, can not effectively diffuse into and play drug effect in brain tissue, and in order to increase enter brain dose mention
High dosage will cause the enhancing of periphery poisonous side effect of medicine again, and above-mentioned factor all significantly limits these drug therapies work
Performance.Therefore, overcoming BBB is the Major Difficulties of Brain targeting research.
In the strategy for realizing brain-targeted drug delivery research through BBB, dihydropyridines Brain targeting chemical delivery system (CDS) is
A kind of important Brain targeting pro-drug system, the system is based on dihydropyridine-pyridinium ion redox reaction, medicine
Object is connected with targeting agent dihydropyridine is made CDS conjugate, fat-soluble strong because of drug CDS conjugate, thus can promote to tie
It closes object and penetrates BBB.Currently research in such CDS system include the neat Fu Duoding of AIDS virus resisting infection medicine (AZT),
Dopamine and the pro-drug of dihydropyridine compounds etc..1,4- dihydro trigonelline is all made of as CDS in these researchs
Carrier, the effect that transhipment drug enters brain has been confirmed, but main problem existing for such CDS is that stability is poor, can not
Effectively meet the requirement transported to intracerebral, and unstable to the oxygen in air and in solution, 5,6 double bonds are easily hydrated
Effect and oxidation.Therefore, it is necessary to be improved to such system to overcome its shortcoming.
The brain tumors drug such as many central nervous system drugs, anti-glioma is saturating due to lipophilicity is lower at present
The ability for crossing BBB is limited, can not effectively diffuse into and play drug effect in brain tissue, and in order to increase enter brain dose mention
High dosage will cause the enhancing of periphery poisonous side effect of medicine again, and above-mentioned factor all significantly limits these drug therapies work
Performance.
Currently used Isosorbide-5-Nitrae-dihydro faenum graecum bases CDS is unstable to the oxygen in air and in solution, and 5,6
Aquation and oxidation easily occur for double bond, therefore poor with the drug CDS stability of system preparation, can not be effective
Drug is transported to intracerebral, cannot sufficiently meet the purpose of clinical treatment.
Summary of the invention
Technical problem to be solved by the invention is to provide a kind of gemcitabine chemistry transmitting prodrug and preparation method thereof and
Using can improve drug enters brain volume, enhances the drug effect of drug, reduces the dosage of drug, reduces the toxic side effect of drug.
The present invention is to solve above-mentioned technical problem by following technical proposals: before a kind of transmitting of gemcitabine chemistry
Medicine, which is characterized in that the gemcitabine chemistry transmitting prodrug is mainly by gemcitabine and dihydropyridines chemical delivery system
It constitutes.
Preferably, the gemcitabine chemistry transmitting prodrug is to be with dihydropyridine-pyridinium ion redox reaction
Basis, gemcitabine is connected with targeting agent 3- quinolinic acid is made reduced form gemcitabine chemistry transmitting prodrug, the conjugate
Fat-solubility promotes it to diffuse into brain tissue, the pyrrole in the intracerebral dihydropyridines Brain targeting chemical delivery system conjugate
Pyridine part is oxidized to oxidized form gemcitabine chemistry transmitting prodrug by coenzyme system,
The wherein structural formula of reduced form gemcitabine chemistry transmitting prodrug are as follows:
Wherein, R1Selected from H, CH3, OMe, OEt；R2Selected from H, CH3, OMe, OEt；
Oxidized form gemcitabine chemistry transmit prodrug) structural formula are as follows:
Wherein, R1Selected from H, CH3, OMe, OEt；R2Selected from H, CH3, OMe, OEt.
The present invention also provides a kind of preparation methods of gemcitabine chemistry transmitting prodrug, which is characterized in that the preparation side
Method the following steps are included:
Step 1, amide condensed reaction, using methylene chloride as reaction dissolvent, 3- quinolinic acid and condensing agent are according to molar ratio 1
: feed intake at 1.2: 1.2: 2, after priming reaction being stirred at room temperature 1 hour, gemcitabine according to 3- quinolinic acid mole 1:
1.2 feed intake, and reaction 24 hours is stirred at room temperature；End of reaction, 10% sodium bicarbonate of reaction solution, water, 10% citric acid, saturation chlorination
Sodium solution washing, organic layer anhydrous magnesium sulfate is dry, filtering, is concentrated under reduced pressure, silica gel chromatography (mobile phase: methylene chloride/
Methanol 10/1) to get midbody acid amide condensation product；
Step 2, methylation reaction, using methylene chloride as reaction dissolvent, the amide condensed reaction product and trifluoro of step 1
Loprazolam methyl esters feeds intake according to molar ratio 1:1.2, and reaction 2 hours is stirred at room temperature；End of reaction is concentrated under reduced pressure except dereaction is molten
Agent is redissolved with your a small amount of methylene chloride, and ether, which is added, makes that precipitating is precipitated, after ether washing, up to intermediate first after vacuum drying
Base product；
Step 3, hydrogenation reduction, using water-methanol as solvent, the methylate and sodium dithionite of step 2
It feeds intake with sodium bicarbonate according to molar ratio 1:5:6, is protected from light after reaction being stirred at room temperature 2 hours, adds two sulfurous of company of same amount
The reaction was continued 30 minutes for sour sodium and sodium bicarbonate；End of reaction, ethyl acetate extract reaction solution three times, and organic layer is washed with water three
Secondary, anhydrous magnesium sulfate is dry, filter, gemcitabine chemistry transmits prodrug to obtain the final product after reduced pressure.
The present invention also provides a kind of application of gemcitabine chemistry transmitting prodrug in brain drug transport.
The present invention also provides a kind of application of gemcitabine chemistry transmitting prodrug in treatment brain tumor.
The positive effect of the present invention is that: according to gemcitabine 3- quinolinic acid CDS and gemcitabine in rat brain
Analysis of drug content result it is found that oxidized form gemcitabine CDS is significantly higher than gemcitabine in the content of intracerebral, and in brain group
Residence time in knitting is also greater than gemcitabine, and oxidized form gemcitabine CDS is diffused by reduced form gemcitabine CDS
The product formed after NADH coenzyme system oxidation after in brain is stranded in intracerebral due to its hydrophilic increase, to improve
Medicament contg in brain tissue, is conducive to the performance of the antitumor drug effect of gemcitabine.
Detailed description of the invention
Fig. 1 is drug transport mechanism figure based on the present invention.
Fig. 2 is the chemical preparation reaction route 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.
Specific embodiment
Present pre-ferred embodiments are provided with reference to the accompanying drawing, in order to explain the technical scheme of the invention in detail.
Drug operative mechanism of the present invention is as shown in Figure 1, the gemcitabine chemistry transmitting prodrug is with dihydropyridine-pyrrole
Based on the redox reaction of pyridine ion, drug gemcitabine is connected with targeting agent 3- quinolinic acid is made CDS conjugate (also
Prototype gemcitabine chemistry transmits prodrug), the fat-solubility of the conjugate promotes it to diffuse into brain tissue, in the intracerebral CDS
Pyridine moiety in conjugate is by coenzyme system (such as NAD (P) H ← → NAD (P)+Coenzyme system) be oxidized to it is water-soluble
Salt (oxidized form gemcitabine chemistry transmits prodrug), and prevent it from being stranded in central nervous system through BBB, and pass through
Biology conversion slowly constantly discharges drug.
The structural formula of reduced form gemcitabine chemistry transmitting prodrug are as follows:
R1Selected from H, CH3, OMe, OEt；R2Selected from H, CH3, OMe, OEt.
Oxidized form gemcitabine chemistry transmit prodrug) structural formula are as follows:
R1Selected from H, CH3, OMe, OEt；R2Selected from H, CH3, OMe, OEt.
Gemcitabine chemistry transmits the chemical preparation reaction route of prodrug as shown in Fig. 2, gemcitabine chemistry of the present invention passes
Pass the preparation method of prodrug the following steps are included:
Step 1, amide condensed reaction, using methylene chloride as reaction dissolvent, 3- quinolinic acid and condensing agent EDC(1- ethyl-
(3- dimethylaminopropyl) carbodiimide), HOBt(1- hydroxybenzotriazole), DIPEA(N, N- diisopropylethylamine) according to
Molar ratio 1: 1.2: 1.2: 2 feeds intake, and after priming reaction being stirred at room temperature 1 hour, gemcitabine rubs according to 3- quinolinic acid
You feed intake at amount 1: 1.2, and reaction 24 hours is stirred at room temperature；End of reaction, 10% sodium bicarbonate of reaction solution, water, 10% citric acid,
Saturated sodium chloride solution washing, organic layer anhydrous magnesium sulfate is dry, filtering, is concentrated under reduced pressure, silica gel chromatography (mobile phase:
Methylene chloride/methanol 10/1) to get midbody acid amide condensation product；
Step 2, methylation reaction, using methylene chloride as reaction dissolvent, the amide condensed reaction product and trifluoro of step 1
Loprazolam methyl esters feeds intake according to molar ratio 1:1.2, and reaction 2 hours is stirred at room temperature；End of reaction is concentrated under reduced pressure except dereaction is molten
Agent is redissolved with your a small amount of methylene chloride, and ether, which is added, makes that precipitating is precipitated, after ether washing, up to intermediate first after vacuum drying
Base product；
Step 3, hydrogenation reduction, with water-methanol (v:v/1:1) for solvent, the methylate of step 2 and even two
Sodium sulfite and sodium bicarbonate feed intake according to molar ratio 1:5:6, are protected from light after reaction being stirred at room temperature 2 hours, add same amount
The reaction was continued 30 minutes for sodium dithionite and sodium bicarbonate；End of reaction, ethyl acetate extract reaction solution three times, and organic layer is used
Water washing three times, anhydrous magnesium sulfate is dry, filtering, be concentrated under reduced pressure after up to a kind of gemcitabine of gemcitabine 3- quinolinic acid CDS(
Chemistry transmitting prodrug).
Carry out the transmitting prodrug rat Pharmacokinetic experiments analysis of gemcitabine chemistry, gemcitabine, gemcitabine 3- quinolinic acid
CDS is made into the solution that concentration is 25 ~ 26 mg/ml, SD rat with DMSO/ physiological saline (v/v:10/90) mixed solvent respectively
A kind of administration of (mouse kind) (200 ~ 250 g of average weight) tail vein injection, 10 mg/kg of dosage, every group of three rats, point
Not in 5,15,30,45,60,90,120 minutes, eye socket takes 1 ml of blood, and 2 ml acetonitrile-DMSO(V/V:94/6 are added), be vortexed vibration
It shakes 1 minute, 4000 rpm ultracentrifugations 10 minutes, supernatant is taken to carry out high performance liquid chromatography content analysis, analyze result (drug
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
It is made into the solution that concentration is 25 ~ 26 mg/ml with DMSO/ physiological saline (v/v:10/90) mixed solvent respectively, SD rat is (average
G) tail vein injection is administered weight 200 ~ 250,15 mg/kg of dosage, every group of three rats, respectively at 5,10,20,30,
45,60,90,120 minutes, neck execution mouse of breaking, taking-up brain tissue, 20 ml brines, filter paper suck dry moisture, according to
Homogenate: acetonitrile-DMSO(v/v:94/6 is added in solvent (w/v 1: 2)) it is homogenized, 4000 rpm ultracentrifugations 10 minutes take
Supernatant carries out high performance liquid chromatography content analysis.Above-mentioned gemcitabine 3- quinolinic acid CDS rat cerebral tissue's medicament contg point
It is as shown in Figure 4 to analyse experimental result (brain drug concentration time graph).
According to gemcitabine 3- quinolinic acid CDS and gemcitabine rat brain analysis of drug content result it is found that oxygen
Change type gemcitabine CDS is significantly higher than gemcitabine in the content of intracerebral, and the residence time in brain tissue is also greater than Ji Xi
His shore, and oxidized form gemcitabine CDS is after being diffused into brain by reduced form gemcitabine CDS through NADH coenzyme system oxidation
The product formed afterwards is stranded in intracerebral due to its hydrophilic increase, to improve the medicament contg in brain tissue, favorably
In the performance of the antitumor drug effect of gemcitabine.
Gemcitabine chemistry transmitting prodrug of the present invention can be applied in brain drug transport or in treatment brain tumor
Using.
The present invention is stronger for traditional anti-tumor drug hydrophily, and drug is poor through the ability of BBB, can not fill in intracerebral
The shortcomings that therapeutic effect of drug is waved in distribution, by the way that drug to be made to the higher prodrug of lipophilicity in conjunction with CDS, to improve medicine
Object enters brain volume, enhances the drug effect of drug, reduces the dosage of drug, reduces the toxic side effect of drug.The present invention is for common
Isosorbide-5-Nitrae-oxidizable the destruction of dihydro faenum graecum bases CDS, the disadvantage of stability difference, the present invention using 3- quinolinic acid as CDS carrier,
Oxidizable 5,6 double bonds of pyridine are protected, the stability of CDS system is improved, ensure that CDS can be effective by drug
Intracerebral is transported to discharge and play drug effect.
Those skilled in the art can carry out various remodel and change to the present invention.Therefore, present invention covers fall into
Various in the range of appended claims and its equivalent remodel and change.
Claims (2)
1. a kind of gemcitabine chemistry transmits prodrug, which is characterized in that the gemcitabine chemistry transmitting prodrug is mainly by Ji Xi
His shore and dihydropyridines chemical delivery system are constituted, the gemcitabine chemistry transmitting prodrug be with dihydropyridine-pyridine from
Based on the redox reaction of son, gemcitabine is connected with targeting agent 3- quinolinic acid is made reduced form gemcitabine chemistry biography
Prodrug is passed, the fat-solubility of the conjugate promotes it to diffuse into brain tissue, passes in the intracerebral dihydropyridines Brain targeting chemistry
Pyridine moiety in delivery system conjugate is oxidized to oxidized form gemcitabine chemistry transmitting prodrug by coenzyme system,
The wherein structural formula of reduced form gemcitabine chemistry transmitting prodrug are as follows:
Wherein, R1Selected from H, CH3, OMe, OEt；R2Selected from H, CH3, OMe, OEt；
The structural formula of oxidized form gemcitabine chemistry transmitting prodrug are as follows:
Wherein, R1Selected from H, CH3, OMe, OEt；R2Selected from H, CH3, OMe, OEt.
2. a kind of preparation method of gemcitabine chemistry transmitting prodrug as described in claim 1, which is characterized in that the preparation
Method the following steps are included:
Step 1, amide condensed reaction, using methylene chloride as reaction dissolvent, 3- quinolinic acid and condensing agent are according to molar ratio 1:1.2
~1.2:2 feeds intake, and after priming reaction being stirred at room temperature 1 hour, gemcitabine feeds intake according to 3- quinolinic acid mole 1:1.2, room
Temperature is stirred to react 24 hours；End of reaction, 10% sodium bicarbonate of reaction solution, water, 10% citric acid, saturated sodium chloride solution are washed
It washs, up to midbody acid amide condensation product after the drying of organic layer anhydrous magnesium sulfate, filtering, reduced pressure；
Step 2, methylation reaction, using methylene chloride as reaction dissolvent, the amide condensed reaction product and fluoroform of step 1
Methylmesylate feeds intake according to molar ratio 1:1.2, and reaction 2 hours is stirred at room temperature；End of reaction is concentrated under reduced pressure and removes reaction dissolvent,
It is redissolved with a small amount of methylene chloride, ether, which is added, makes that precipitating is precipitated, and after ether washing, produces after vacuum drying up to intermediate methylation
Object；
Step 3, hydrogenation reduction, using water-methanol as solvent, the methylate and sodium dithionite and carbon of step 2
Sour hydrogen sodium feeds intake according to molar ratio 1:5:6, is protected from light after reaction being stirred at room temperature 2 hours, adds the sodium dithionite of same amount
The reaction was continued 30 minutes with sodium bicarbonate；End of reaction, ethyl acetate extract reaction solution three times, and organic layer is washed with water three times,
Anhydrous magnesium sulfate is dry, filter, gemcitabine chemistry transmits prodrug to obtain the final product after reduced pressure.
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| CN106279321A (en) | 2016-08-09 | 2017-01-04 | 南京医科大学 | Gemcitabine ProTide weary oxygen activation prodrug and application thereof |
| KR20190090301A (en) * | 2018-01-24 | 2019-08-01 | 에스티팜 주식회사 | Novel nucleoside or nucleotide derivatives, and use thereof |
| JP2021512951A (en) * | 2018-02-02 | 2021-05-20 | メイベリックス オンコロジー インコーポレイテッド | New small molecule drug conjugate of gemcitabine derivative |
| CN112135634A (en) * | 2018-02-02 | 2020-12-25 | 马福瑞克斯肿瘤学股份有限公司 | Small molecule drug conjugate of gemcitabine monophosphate |
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| WO2008030373A2 (en) * | 2006-09-01 | 2008-03-13 | University Of Georgia Research Foundation, Inc. | L- oddc prodrugs for cancer |
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