CN105315294B - 7-Ethyl-10-hydroxycamptothecin prodrug and its preparation method and application - Google Patents
7-Ethyl-10-hydroxycamptothecin prodrug and its preparation method and application Download PDFInfo
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Abstract
The invention discloses 7 ethyl, 10 hydroxycamptothecin prodrug and its preparation method and application.It is that esterification occurs with hydrophobic molecule by 20 hydroxyls of C 10 or C of 7 ethyl, 10 hydroxycamptothecin to generate shown in the structural formula of the prodrug such as formula (I) or formula (II).The prodrug has preferable antitumor activity, in vivo can be with the direct discharge active component of the mode of hydrolysis, it is not necessary to which the catalyzing hydrolysis of carboxy-lesterase, bioavailability are high；The prodrug of the present invention not only has preferable dissolubility in water, but also also has fabulous dissolubility in the amphiphilic surfactants such as Tween 80, and solubility still has higher stability up to more than 30mg/mL after being diluted with water；The present invention can obtain the prodrug by single step esterification process, and yield is high, and manufacturing cost is low, and stability is high, and security is good, meets the requirement of clinical application, meets the requirement of large-scale industrial production, possesses good market prospects and clinical value.
Description
Technical field
The present invention relates to camptothecine precursor, and in particular to a series of 7-Ethyl-10-hydroxycamptothecin prodrugs
And its preparation method and application.
Background technology
Camptothecine is a kind of natural alkaloid extracted from camplotheca acuminata, it mainly acts on DNA topoisomerase Is, has
The ability of extremely strong suppression tumor cell proliferation.7-Ethyl-10-hydroxycamptothecin (SN-38) is one of which derivative, although
The antitumous effect of SN-38 is good, but due to poorly water-soluble, nor be dissolved in acceptable solvent in pharmacy and (such as spit
Temperature 80, Emulsifier EL-60 etc.), therefore cannot be directly used to clinic.The structural formula of 7-Ethyl-10-hydroxycamptothecin is as follows：
The camptothecin cancer therapy drug for clinically going through to apply at present has Irinotecan (Irinotecan, CPT-11)
Deng.Irinotecan is obtained by carrying out modified with functional group to the C10 positions hydroxyl in 7-Ethyl-10-hydroxycamptothecin, its
Structural formula is as follows：
Irinotecan enters the SN-38 competence exertion drug effects that needs in vivo are converted into activity, but Irinotecan turns in vivo
The catalyzing hydrolysis of carboxy-lesterase (Carboxylesterase) is needed when being melted into the SN-38 of activity.The life of Irinotecan in vivo
Thing utilization rate is low, only the conversion ratio of 2-8%.Compared to Irinotecan, the anti tumor activity in vitro of SN-38 is higher than Irinotecan
100-1000 times.
For these reasons, people are developed by connecting hydrophilic radical in 7-Ethyl-10-hydroxycamptothecin in recent years
The macromolecule conjugates of 7-Ethyl-10-hydroxycamptothecin a series of overcomes its water solubility problems, and can avoid as her
It is vertical to need to digest the path that discharge medicine in vivo like that for health.The EZN- developed such as Enzon Pharmaceuticals
2208 polymer drugs.In the medicine, SN-38 is coupled on the polyglycol chain of four arms by the method for organic synthesis,
Improve the water-soluble of medicine and the half-life period being metabolized in vivo.The product is bought by Zhejiang Haizheng Pharmaceutical Co and declares clinic
1.1 kind new medicine.
But the SN-38 medicines of above-mentioned polyethylene glycol conjugation, there is some defects, first, drugloading rate is low (to be about
4%), it is necessary to substantial amounts of auxiliary material；Secondly, required coupling drug is generated, it is necessary to multistep organic reaction, preparation process is cumbersome, matter
Amount is not easy to control.
The content of the invention
The present invention provides a kind of 7-Ethyl-10-hydroxycamptothecin prodrug, which can be dissolved in water
In, it can also be dissolved in the amphiphilic surfactants such as tween, considerably increase the application range of SN-38.
Shown in 7-Ethyl-10-hydroxycamptothecin prodrug, structural formula such as formula (I) or formula (II)：
Wherein, R represents hydrophobic group.
Different from the existing raising water miscible Research Thinking of medicine (connection hydrophilic radical), the present invention exists off the beaten trackly
After connecting hydrophobic group on the C-10 positions of SN-38 or C-20 hydroxyls, the prodrug found can be dissolved in medicament
Acceptable solvent (Tween 80, Emulsifier EL-60 etc.) on, and by that can be injected intravenously after normal saline dilution.
At the same time it has been found that obtained prodrug can directly dissolve in aqueous.The mode medicine connected by ester bond
Precursor can directly discharge effective antitumor component by way of hydrolysis in vivo, and avoiding Irinotecan such as needs carboxylate
Enzymatic hydrolysis could discharge the problem of active medicine.
In the present invention, the hydrophobic group is provided by the one of which in following hydrophobic molecule：
Aliphatic acid, deoxycholic acid, the monoesters that qinghaosu is formed with acid anhydrides, the monoesters that cholesterol is formed with acid anhydrides, tertiary fourth oxygen
The amino acid of carbonyl-protection；
Carboxyl in the hydrophobic molecule participates in being formed ester bond (ester bond and R group phase in formula (I) or formula (II)
Even).
Preferably, the carbon chain lengths of the aliphatic acid are C2~C22.Saturated fatty acid or not may be selected in the aliphatic acid
Saturated fatty acid, is preferably unrighted acid.Compared to saturated fatty acid, the SN-38 of unrighted acid modification tween,
The solubility of higher is respectively provided with water.
The unrighted acid is preferably DHA, leukotrienes, oleic acid or linoleic acid, more preferably DHA, leukotrienes or Asia
Oleic acid, is most preferably leukotrienes or linoleic acid；N-butyric acie, positive enanthic acid or lauric acid/dodecanoic acid can be selected in the saturated fatty acid.
The monoesters that monoesters, cholesterol and the acid anhydrides that qinghaosu is formed with acid anhydrides are formed, the hydrophobicity of this two classes material depend on
The acid anhydrides species (carbon containing number) of monoesters is formed without strict demand in qinghaosu, cholesterol, therefore to participation.Preferably, institute
It is Artesunate to state the monoesters that qinghaosu is formed with acid anhydrides, and the monoesters that the cholesterol is formed with acid anhydrides is cholesterol succinic acid list
Ester.Used succinic anhydride is simple in structure, easily obtains.
Preferably, the amino acid is glycine, serine, valine, leucine, phenylalanine or histidine.Make
To be further preferred, the amino acid is glycine or leucine.In the present invention, the amino of amino acid is protected through tertbutyloxycarbonyl
Hydrophobicity greatly improves afterwards, the prodrug that reaction generates is kept relatively low polarity, is more easy to self assembly in aqueous
And then it is dissolved in water.
Present invention also offers the preparation method of the 7-Ethyl-10-hydroxycamptothecin prodrug, including：
(1) in the presence of condensing agent, the C10 position hydroxyls of 7-Ethyl-10-hydroxycamptothecin are esterified with hydrophobic molecule
Reaction；
Preferably, the hydrophobic molecule is aliphatic acid, deoxycholic acid, qinghaosu and the monoesters of acid anhydrides formation, courage are solid
The monoesters that alcohol is formed with acid anhydrides, the amino acid of tertbutyloxycarbonyl protection；
As further preferred, the aliphatic acid is the unrighted acid that carbon chain lengths are C2~C22, the qinghaosu
The monoesters formed with acid anhydrides is Artesunate, and the monoesters that the cholesterol is formed with acid anhydrides is cholesterol succinate monoester, described
Amino acid is glycine, serine, valine, leucine, phenylalanine or histidine；
Preferably, the condensing agent is N, N '-dicyclohexylcarbodiimide (DCC), 1- (3- dimethylamino-propyls) -3-
Ethyl carbodiimide (EDC) or N, N '-diisopropylcarbodiimide (DIPC)；
(2) crude product is isolated and purified after the completion of reacting, obtains 7- ethyl -10- hydroxyl of the structural formula as shown in formula (I)
Base camptothecin drug precursor；
Purification procedures are used to remove the impurity such as unreacted raw material and condensing agent used, catalyst in dereaction.
Alternatively, including：
(1) protection group is introduced on the C10 positions hydroxyl of 7-Ethyl-10-hydroxycamptothecin；
Preferably, the protection group is tert-butyl diphenyl silicon substrate；
Specifically, by 7-Ethyl-10-hydroxycamptothecin and tert-butyl diphenyl chlorosilane mixed dissolution, at room temperature in nothing
It is refluxed overnight inside water dichloromethane；
(2) in the presence of condensing agent, the C20 position hydroxyls and hydrophobic molecule of step (1) product carry out esterification；
(3) protection group in step (2) product is sloughed；
Step (2) product and tetrabutyl ammonium fluoride (TBAF) are reacted, to slough the uncle that step (1) is connected on C10 positions
Butyl diphenyl silicon substrate；
(4) crude product is isolated and purified after the completion of reacting, obtains 7- ethyl -10- of the structural formula as shown in formula (II)
Hydroxycamptothecin prodrug.
Present invention also offers the 7-Ethyl-10-hydroxycamptothecin prodrug answering in antitumor drug is prepared
With.By the modification of hydrophobic group, 7-Ethyl-10-hydroxycamptothecin prodrug of the invention be both dissolvable in water Tween 80,
In the routine medicinal reagent such as Emulsifier EL-60, nanoparticle can be also self-assembled into water.
Wherein, nanoparticle is self-assembled into by the 7-Ethyl-10-hydroxycamptothecin prodrug in water and receiving for obtaining
It can be used alone after metric system agent is freeze-dried, different excipient post-processings can also be added into any type formulation, including piece
Agent, pill, capsule, granule, oral liquid and liquid drugs injection or powder-injection for intravenous injection.
, can only be in the C10 position hydroxyls of SN-38 or C20 to enable the prodrug to be self-assembled into nanoparticle in water
Hydrophobic group is connected at hydroxyl, it is impossible to connect hydrophobic group at the same time on two positions, i.e., one of hydroxyl must be protected
Free state is held, so that prodrug is with amphipathic；If two hydroxyls are all modified, prodrug can be because cannot be in water
In be self-assembled into nanoparticle so as to causing to precipitate.
Compared with prior art, beneficial effects of the present invention are：
(1) 7-Ethyl-10-hydroxycamptothecin prodrug of the invention has preferably anti-than clinical application Irinotecan
Tumor promotion, in vivo can be with the direct discharge active component of the mode of hydrolysis, it is not necessary to the catalyzing hydrolysis of carboxy-lesterase, biology
Utilization rate is high；
(2) 7-Ethyl-10-hydroxycamptothecin prodrug of the invention not only in water there is preferable dissolubility (to reach
8mg/mL), and in the amphiphilic surfactants such as Tween 80 also there is fabulous dissolubility, solubility is up to 30mg/mL
More than, still there is higher stability after being diluted with water；
(3) present invention can obtain the prodrug by single step esterification process, and yield is high, and manufacturing cost is low, stability
Height, security is good, meets the requirement of clinical application, meets the requirement of large-scale industrial production, possesses good market prospects
With clinical value.
Brief description of the drawings
Fig. 1 is the synthetic route of the SN-38 pro-drugs 1 of the chain compound containing alkane in embodiment 1；
Fig. 2 is the synthetic route of the SN-38 pro-drugs 2 of the chain compound containing alkane in embodiment 2；
Fig. 3 is the synthetic route of the SN-38 pro-drugs 3 of the chain compound containing alkane in embodiment 3；
Fig. 4 is the synthesis of the SN-38 pro-drugs 4 containing unsaturated alkane chain compound in embodiment 4；
Fig. 5 is the synthetic route of the SN-38 pro-drugs 5 containing unsaturated alkane chain compound in embodiment 5；
Fig. 6 is the synthetic route of the pro-drug 6 containing unsaturated alkane chain compound in embodiment 6；
Fig. 7 is the synthetic route of the pro-drug 7 containing unsaturated alkane chain compound in embodiment 7；
Fig. 8 is the synthetic route of the SN-38 pro-drugs 8 that glycine is coupled in embodiment 8；
Fig. 9 is the synthetic route of the SN-38 pro-drugs 9 that valine is coupled in embodiment 9；
Figure 10 is the synthetic route of the SN-38 pro-drugs 10 that leucine is coupled in embodiment 10；
Figure 11 is the synthetic route of the SN-38 pro-drugs 11 that phenylalanine is coupled in embodiment 11；
Figure 12 is the synthetic route of the SN-38 pro-drugs 12 that histidine is coupled in embodiment 12；
Figure 13 is the synthetic route of the SN-38 pro-drugs 13 that Artesunate is coupled in embodiment 13；
Figure 14 is the synthetic route of the SN-38 pro-drugs 15 that cholesterol is coupled in embodiment 14；
Figure 15 is the synthetic route of the SN-38 pro-drugs 16 that deoxycholic acid is coupled in embodiment 15；
Wherein, DMF represents dimethylformamide, and EDC represents 1- (3- dimethylamino-propyls) -3- ethyl carbodiimides,
DMAP represents 4-dimethylaminopyridine, and DIEA represents n,N-diisopropylethylamine, and pyridine represents pyridine.
Embodiment
The present invention is described in further detail with reference to the accompanying drawings and detailed description.
The synthesis of the SN-38 pro-drugs 1 of 1 chain compound containing alkane of embodiment
N-butyric acie (116 μ L, 1.3mmol) and SN-38 (500mg, 1.3mmol), dissolving are added in 100mL round-bottomed flasks
In 28mL anhydrous DMFs (dimethylformamide), EDCHCl (267mg, 1.4mmol), DMAP (4- dimethylamino pyrroles are added
Pyridine) (172mg, 1.4mmol) and DIEA (n,N-diisopropylethylamine) (232 μ L, 1.4mmol).25 DEG C are stirred overnight, and remove anti-
After answering solvent, solid is dissolved in dichloromethane, then respectively with 5% citric acid, saturated sodium bicarbonate, saturated salt solution cleaning；Have
Machine is mutually dried with anhydrous sodium sulfate, and filtering, solvent is removed under reduced pressure after collecting filtrate；Solid is isolated and purified with column chromatography chromatogram
(DCM:MeOH=75:1) product 1 (350mg, yield 59%) is obtained after.
Product 11H NMR nuclear magnetic datas and mass spectrometric data are as follows：
1H NMR (400MHz, CDCl3)：δ1.02-1.05(t,3H),1.08-1.12(t,3H),1.42(t,3H),1.83-
1.90 (m, 4H), 2.64-2.67 (t, 2H), 3.18-3.20 (t, 2H), 5.30 (s, 2H), 5.28-5.32 (d, 1H, J=16),
5.71-5.75 (d, 1H, J=16.4), 7.57-7.59 (d, 1H, J=7.6), 7.84 (s, 1H), 7.86 (s, 1H), 8.35-
8.37 (d, 1H, J=8.4)；
HR-ESI Qq-LTMS：calcd for[C26H27N2O6]+[M+H]+=463.1864, obsd463.1893.
The synthesis of the SN-38 pro-drugs 2 of 2 chain compound containing alkane of embodiment
Positive enanthic acid (108 μ L, 0.76mmol) and SN-38 (300mg, 0.76mmol) are added in 100mL round-bottomed flasks, it is molten
Solution adds EDCHCl (160mg, 0.84mmol), DMAP (103mg, 0.84mmol) and DIEA in 20mL anhydrous DMFs
(149mL,0.84mmol)；25 DEG C are stirred overnight, and after removing reaction dissolvent, solid is dissolved in dichloromethane, then respectively with 5% lemon
Lemon acid, saturated sodium bicarbonate, saturated salt solution cleaning；Organic phase is dried with anhydrous sodium sulfate, filtering, is depressurized and is removed after collection filtrate
Remove solvent；Solid isolates and purifies (DCM with column chromatography chromatogram:MeOH=75:1) product 2 (157mg, yield 41%) is obtained after.
Product 21H NMR nuclear magnetic datas and mass spectrometric data are as follows：
1H NMR(400MHz,CDCl3)：δ0.91-0.94(t,3H),1.00-1.04(t,3H),1.35-1.41(m,6H),
1.43-1.49(t,3H),1.80-1.91(m,4H),2.64-2.68(t,2H),3.17-3.18(q,2H),5.27(s,2H),
5.27-5.31 (d, 1H, J=16.4), 5.70-5.74 (d, 1H, J=16.4), 7.54-7.56 (d, 1H, J=7.6), 7.79
(s, 1H), 7.83 (s, 1H) 8.29-8.31 (d, 1H, J=9.2)；
HR-ESI Qq-LTMS：calcd for[C29H33N2O6]+[M+H]+=505.2333；obsd505.2289.
The synthesis of the SN-38 pro-drugs 3 of 3 chain compound containing alkane of embodiment
Lauric acid/dodecanoic acid (153mg, 0.76mmol) and SN-38 (300mg, 0.76mmol) are added in 100mL round-bottomed flasks, it is molten
Solution adds EDCHCl (160mg, 0.84mmol), DMAP (103mg, 0.84mmol) and DIEA in 20mL anhydrous DMFs
(149μL,0.84mmol)；25 DEG C are stirred overnight, and after removing reaction dissolvent, solid is dissolved in dichloromethane, then respectively with 5% lemon
Lemon acid, saturated sodium bicarbonate, saturated salt solution cleaning；Organic phase is dried with anhydrous sodium sulfate, filtering, is depressurized and is removed after collection filtrate
Remove solvent；Solid isolates and purifies (DCM with column chromatography chromatogram:MeOH=100:1) product 3 (220mg, 50%) is obtained after.
Product 31H NMR nuclear magnetic datas and mass spectrometric data are as follows：
1H NMR(400MHz,CDCl3)：δ0.86-0.90(t,3H),1.01-1.05(t,3H),1.25-1.35(m,
16H),1.40-1.43(t,3H),1.78-1.91(m,4H),2.64-2.68(t,2H),3.15-3.22(q,2H),5.30(s,
2H), 5.27-5.31 (d, 1H, J=16.4), 5.70-5.74 (d, 1H, J=16.4), 7.56-7.58 (d, 1H, J=7.6),
7.85 (s, 1H), 7.86 (s, 1H), 8.34-8.37 (d, 1H, J=9.2)；
HR-ESI Qq-LTMS：calcd for[C34H43N2O6]+[M+H]+=575.3116；obsd575.3091.
The synthesis of SN-38 pro-drug 4 of the embodiment 4 containing unsaturated alkane chain compound
Sorbic acid (85.7mg, 0.76mmol) and SN-38 (300mg, 0.76mmol) are added in 100mL round-bottomed flasks,
It is dissolved in 10mL anhydrous DMFs, adds EDCHCl (160mg, 0.84mmol), DMAP (103mg, 0.84mmol) and DIEA
(149μL,0.84mmol)；30 DEG C are stirred overnight, and after removing reaction dissolvent, solid is dissolved in dichloromethane, then respectively with 5% lemon
Lemon acid, saturated sodium bicarbonate, saturated salt solution cleaning；Organic phase is dried with anhydrous sodium sulfate, filtering, is depressurized and is removed after collection filtrate
Remove solvent；Solid isolates and purifies (DCM with column chromatography chromatogram:MeOH=100:1) product 4 (160mg, 43%) is obtained after.
Product 41H NMR nuclear magnetic datas and mass spectrometric data are as follows：
1H NMR(400MHz,CDCl3)：δ1.02-1.06(t,3H),1.39-1.42(t,3H),1.87-1.94(m,5H),
3.14-3.18 (q, 2H), 5.27 (s, 2H), 5.30-5.34 (d, 1H, J=16.0), 5.72-5.76 (d, 1H, J=16.0),
6.02-6.06 (d, 1H, J=15.2), 6.31-6.34 (m, 2H), 7.50-7.56 (m, 1H), 7.59-7.61 (d, 1H, J=
9.2), 7.68 (s, 1H), 7.87 (s, 1H), 8.23-8.25 (d, 1H, J=8.8)；
HR-ESI Qq-LTMS：calcd for[C28H27N2O6]+[M+H]+=487.1864；obsd487.1859.
The synthesis of SN-38 pro-drug 5 of the embodiment 5 containing unsaturated alkane chain compound
Oleic acid (21mg, 0.076mmol) and SN-38 (30mg, 0.076mmol), dissolving are added in 100mL round-bottomed flasks
In 2mL anhydrous DMFs, EDCHCl (16mg, 0.084mmol), DMAP (10mg, 0.084mmol) and DIEA (15 μ are added
L,0.084mmol)；It is stirred overnight at room temperature, after removing reaction dissolvent, solid is dissolved in dichloromethane, then respectively with 5% lemon
Acid, saturated sodium bicarbonate, saturated salt solution cleaning；Organic phase is dried with anhydrous sodium sulfate, and filtering, is removed under reduced pressure after collecting filtrate
Solvent；Solid isolates and purifies (DCM with column chromatography chromatogram:MeOH=100:1) product 5 (26mg, 52%) is obtained after.
Product 51H NMR nuclear magnetic datas and mass spectrometric data are as follows：
1H NMR(400MHz,CDCl3)：δ0.79-0.82(t,3H),0.95-0.99(t,3H),1.20-1.32(m,
23H),1.73-1.95(m,4H),1.99-2.04(m,4H),2.64-2.68(t,2H),3.15-3.21(q,2H),5.28(s,
2H), 5.30-5.37 (m, 2H), 5.32-5.36 (d, 1H, J=14.8), 5.72-5.76 (d, 1H, J=16.4), 7.55-7.57
(d, 1H, J=7.6), 7.58 (s, 1H), 7.85 (s, 1H), 8.32-8.34 (d, 1H, J=9.2)；
HR-ESI Qq-LTMS：calcd for[C40H53N2O6]+[M+H]+=657.3898；obsd657.3831.
The synthesis of the linoleic SN-38 pro-drugs 6 containing unsaturated alkane chain compound of embodiment 6
Linoleic acid (214mg, 0.76mmol) and SN-38 (300mg, 0.76mmol) are added in 100mL round-bottomed flasks, it is molten
Solution adds EDCHCl (161mg, 0.84mmol), DMAP (103mg, 0.84mmol) and DIEA in 5mL anhydrous DMFs
(140μL,0.84mmol)；It is stirred overnight at room temperature, after removing reaction dissolvent, solid is dissolved in dichloromethane, then respectively with 5% lemon
Lemon acid, saturated sodium bicarbonate, saturated salt solution cleaning；Organic phase is dried with anhydrous sodium sulfate, filtering, is depressurized and is removed after collection filtrate
Remove solvent；Solid isolates and purifies (DCM with column chromatography chromatogram:MeOH=100:1) product 6 (340mg, 68%) is obtained after.
Product 61H NMR nuclear magnetic datas and mass spectrometric data are as follows：
1H NMR(400MHz,CDCl3)：δ0.79-0.84(m,6H),0.95-0.99(t,3H),1.18-1.40(m,
16H),1.73-1.87(m,4H),1.96-2.01(m,4H),2.57-2.61(t,2H),2.70-2.73(t,2H),3.06-
3.12 (q, 2H), 3.69 (s, 1H), 5.19-5.33 (m, 7H), 5.67-5.71 (d, 1H, J=16.4), 7.48-7.55 (d, 1H,
), J=7.6 7.60 (s, 1H), 7.76 (s, 1H), 8.17-8.19 (d, 1H, J=9.2)；
HR-ESI Qq-LTMS：calcd for[C40H51N2O6]+[M+H]+=655.3742；obsd655.3731.
The synthesis of the linolenic SN-38 pro-drugs 7 containing unsaturated alkane chain compound of embodiment 7
Leukotrienes (250mg, 0.9mmol) and SN-38 (352mg, 0.9mmol), dissolving are added in 100mL round-bottomed flasks
In 2mL anhydrous DMFs, add EDCHCl (189mg, 1mmol), DMAP (121mg, 1mmol) and DIEA (163 μ L,
1mmol)；It is stirred overnight at room temperature, after removing reaction dissolvent, solid is dissolved in dichloromethane, then respectively with 5% citric acid, saturation
Sodium acid carbonate, saturated salt solution cleaning；Organic phase is dried with anhydrous sodium sulfate, and filtering, solvent is removed under reduced pressure after collecting filtrate；Gu
Body isolates and purifies (DCM with column chromatography chromatogram:MeOH=100:1) product 7 (318mg, 49%) is obtained after.
Product 71H NMR nuclear magnetic datas and mass spectrometric data are as follows：
1H NMR(400MHz,CDCl3)：δ0.86-0.89(t,3H),0.96-1.00(t,3H),1.02-1.06(t,3H),
1.25-1.47(m,12H),1.78-1.94(m,4H),2.06-2.09(t,2H),2.64-2.68(t,2H),2.80-2.83(t,
2H), 3.13-3.19 (q, 2H), 3.77 (s, 1H), 5.27-5.39 (m, 9H), 5.74-5.78 (d, 1H, J=16.4), 7.54-
7.56 (d, 1H, J=7.6), 7.66 (s, 1H), 7.83 (s, 1H), 8.24-8.26 (d, 1H, J=9.2)；
HR-ESI Qq-LTMS：calcd for[C40H49N2O6]+[M+H]+=653.3585；obsd653.3572.
The synthesis of the SN-38 pro-drugs 8 of 8 glycine of embodiment coupling
In 100mL round-bottomed flasks add Boc-Gly-OH (144.8mg, 0.76mmol) and SN-38 (300mg,
0.76mmol), it is dissolved in 20mL anhydrous DMFs, adds EDCHCl (160mg, 0.84mmol), DMAP (103mg,
0.84mmol) and DIEA (139 μ L, 0.84mmol)；25 DEG C are stirred overnight, and after removing reaction dissolvent, solid is dissolved in dichloromethane,
Then respectively with 5% citric acid, saturated sodium bicarbonate, saturated salt solution cleaning；Organic phase is dried with anhydrous sodium sulfate, filtering,
Solvent is removed under reduced pressure after collecting filtrate；Solid isolates and purifies (DCM with column chromatography chromatogram:MeOH=80:1) product 8 is obtained after
(540mg, 77%).
Product 81H NMR nuclear magnetic datas and mass spectrometric data are as follows：
1H NMR(400MHz,CDCl3)：δ0.97-1.06(t,3H),1.37-1.40(t,3H),1.50(s,9H),1.86-
1.94 (m, 2H), 3.14-3.17 (q, 2H), 4.27-4.28 (d, 2H, J=5.6), 5.16 (br, 1H), 5.26 (s, 2H),
5.39-5.43 (d, 1H, J=17.2), 5.74-5.78 (d, 1H, J=16.4), 7.55-7.58 (d, 1H, J=7.6), 7.64
(s, 1H), 7.85 (s, 1H), 8.22-8.24 (d, 1H, J=9.2)；
HR-ESI Qq-LTMS：calcd for[C29H32N3O8]+[M+H]+=550.2184；obsd550.2222.
The synthesis of the SN-38 pro-drugs 9 of 9 valine of embodiment coupling
In 100mL round-bottomed flasks add Boc-Val-OH (166mg, 0.76mmol) and SN-38 (300mg,
0.76mmol), it is dissolved in 20mL anhydrous DMFs, adds EDCHCl (160mg, 0.84mmol), DMAP (103mg,
0.84mmol) and DIEA (149 μ L, 0.84mmol)；It is stirred overnight at room temperature, after removing reaction dissolvent, solid is dissolved in dichloromethane,
Then respectively with 5% citric acid, saturated sodium bicarbonate, saturated salt solution cleaning；Organic phase is dried with anhydrous sodium sulfate, filtering,
Solvent is removed under reduced pressure after collecting filtrate；Solid isolates and purifies (DCM with column chromatography chromatogram:MeOH=50:1) product 9 is obtained after
(215mg, 46.4%).
Product 91H NMR nuclear magnetic datas and mass spectrometric data are as follows：
1H NMR(400MHz,DMSO)：δ 0.87-0.93 (t, 3H), 1.05-1.07 (d, 6H, J=6.4), 1.27-1.31
(t,3H),1.45(s,9H),1.86-1.90(m,2H),2.24-2.29(m,1H),4.09-4.17(m,1H),3.15-3.20
(m, 2H), 5.34 (s, 2H), 5.44 (s, 2H), 7.24 (s, 1H), 7.55-7.57 (d, 1H, J=7.2), 7.90 (s, 1H),
(8.23-8.25 d, 1H, J=9.2)；
HR-ESI Qq-LTMS：calcd for[C32H38N3O8]+[M+H]+=592.2653；obsd592.2637.
The synthesis of the SN-38 pro-drugs 10 of 10 leucine of embodiment coupling
Boc-Leu-OH (318mg, 1.3mmol) and SN-38 (500mg, 1.3mmol) is added in 100mL round-bottomed flasks,
It is dissolved in 20mL anhydrous DMFs, adds EDCHCl (269mg, 1.4mmol), DMAP (171.4mg, 1.4mmol) and DIEA
(232μL,1.4mmol)；It is stirred overnight at room temperature, after removing reaction dissolvent, solid is dissolved in dichloromethane, then respectively with 5% lemon
Lemon acid, saturated sodium bicarbonate, saturated salt solution cleaning；Organic phase is dried with anhydrous sodium sulfate, filtering, is depressurized and is removed after collection filtrate
Remove solvent；Solid isolates and purifies (DCM with column chromatography chromatogram:MeOH=50:1) product 10 (540mg, 77%) is obtained after.
Product 101H NMR nuclear magnetic datas and mass spectrometric data are as follows：
1H NMR(400MHz,CDCl3)：δ1.02-1.04(t,3H),1.06-1.08(m,6H),1.39-1.43(t,3H),
1.49(s,9H),1.72-1.77(m,1H),1.86-1.93(m,4H),2.11(s,1H),3.15-3.20(q,2H),4.59(br
S, 1H), 5.31 (s, 2H), 5.30-5.34 (d, 1H, J=16.4), 5.71-5.75 (d, 1H, J=16.4), 7.56-7.58 (d,
2H, J=9.2), 7.68 (s, 1H), 7.86 (s, 1H), 8.22-8.25 (d, 2H, J=9.2)；
HR-ESI Qq-LTMS：calcd for[C33H40N3O8]+[M+H]+=606.2810；obsd606.2788.
The synthesis of the SN-38 pro-drugs 11 of 11 phenylalanine of embodiment coupling
Boc-Phe-OH (318mg, 1.3mmol) and SN-38 (500mg, 1.3mmol) is added in 100mL round-bottomed flasks,
It is dissolved in 25mL anhydrous DMFs, adds EDCHCl (269mg, 1.4mmol), DMAP (171.4mg, 1.4mmol) and DIEA
(232μL,1.4mmol)；It is stirred overnight at room temperature, after removing reaction dissolvent, solid is dissolved in dichloromethane, then respectively with 5% lemon
Lemon acid, saturated sodium bicarbonate, saturated salt solution cleaning；Organic phase is dried with anhydrous sodium sulfate, filtering, is depressurized and is removed after collection filtrate
Remove solvent；Solid isolates and purifies (DCM with column chromatography chromatogram:MeOH=75:1) product 11 (450mg, 55%) is obtained after.
Product 111H NMR nuclear magnetic datas and mass spectrometric data are as follows：
1H NMR(400MHz,CDCl3)：δ1.00-1.04(t,3H),1.24-1.26(t,3H),1.46(s,9H),1.90-
1.94(m,2H),3.11-3.16(q,2H),3.25-3.29(m,3H),4.84(s,1H),5.32(s,2H),5.32-5.36(d,
1H, J=16.8), 5.69-5.74 (d, 1H, J=16.8), 7.33-7.38 (m, 5H), 7.40-7.42 (d, 1H, J=7.6),
7.63 (s, 1H), 7.68 (s, 1H), 8.18-8.20 (d, 1H, J=9.6)；
HR-ESI Qq-LTMS：calcd for[C36H38N3O8]+[M+H]+=640.2653；obsd640.2634.
The synthesis of the SN-38 pro-drugs 12 of 12 histidine of embodiment coupling
Added in 100mL round-bottomed flasks Boc-His (Boc)-OH (318mg, 1.3mmol) and SN-38 (500mg,
1.3mmol), it is dissolved in 25mL anhydrous DMFs, adds EDCHCl (269mg, 1.4mmol), DMAP (171.4mg,
1.4mmol) and DIEA (232 μ L, 1.4mmol)；25 DEG C are stirred overnight, and after removing reaction dissolvent, solid is dissolved in dichloromethane, so
Afterwards respectively with 5% citric acid, saturated sodium bicarbonate, saturated salt solution cleaning；Organic phase is dried with anhydrous sodium sulfate, is filtered, and is received
Solvent is removed under reduced pressure after collection filtrate；Solid isolates and purifies (DCM with column chromatography chromatogram:MeOH=75:1) product 12 is obtained after
(575mg, 62.8%).
Product 121H NMR nuclear magnetic datas and mass spectrometric data are as follows：
1H NMR(400MHz,CDCl3)：δ1.02-1.06(t,3H),1.38-1.42(t,3H),1.48(s,9H),1.63
(s,9H),1.86-1.94(m,2H),3.12-3.18(q,2H),3.49-3.78(m,2H),4.90(m,1H),5.26(s,2H),
5.29-5.33 (d, 1H, J=16.0), 5.74-5.78 (d, 1H, J=16.4), 7.29 (s, 1H), 7.59-7.61 (d, 1H, J=
9.2), 7.64 (s, 1H), 7.90 (s, 1H), 8.07 (s, 1H), 8.21-8.23 (d, 1H, J=8.8)；
HR-ESI Qq-LTMS：calcd for[C38H44N5O10]+[M+H]+=730.3083；obsd730.3137.
The synthesis of the SN-38 pro-drugs 13 of 13 Artesunate of embodiment coupling
Artesunate (19mg, 0.051mmol) and SN-38 (20mg, 0.051mmol) are added in 100mL round-bottomed flasks,
It is dissolved in 2mL DMF, adds EDCHCl (12mg, 0.056mmol), DMAP (8mg, 0.056mmol)；It was stirred at room temperature
At night, after removing reaction dissolvent, solid is dissolved in dichloromethane, then respectively with 5% citric acid, saturated sodium bicarbonate, saturated common salt
Water cleans；Organic phase is dried with anhydrous sodium sulfate, and filtering, solvent is removed under reduced pressure after collecting filtrate；Solid column chromatography chromatogram point
From purifying (DCM:MeOH=50:1) product 13 (23mg, 59.5%) is obtained after.
Product 131H NMR nuclear magnetic datas and mass spectrometric data are as follows：
1H NMR(400MHz,CDCl3)：δ0.86-0.87(m,3H),0.94-0.97(m,6H),1.25-1.28(m,3H),
1.29-1.31(m,2H),1.37-1.38(m,4H),1.40(s,2H),1.41-1.43(m,3H),1.62-1.65(m,2H),
1.75(m,1H),1.85-1.89(m,2H),1.90-1.95(m,1H),2.02(s,1H),2.94-2.97(t,2H),2.98-
3.07 (m, 2H), 3.15-3.20 (t, 2H), 5.27 (s, 2H), 5.28-5.32 (d, 1H, J=16), 5.71-5.75 (d, 1H, J
=16.4), 7.58-7.61 (d, 1H, J=7.6), 7.77 (s, 1H), 7.84 (s, 1H), 8.29-8.31 (d, 1H, J=9.2)；
HR-ESI Qq-LTMS：calcd for[C41H46N2O12]+[M+H]+=759.3124；obsd759.3125.
The synthesis of the SN-38 pro-drugs 15 of 14 cholesterol of embodiment coupling
Cholesterol (1.16g, 3mmol) and succinic anhydride (0.902g, 9mmol), dissolving are added in 100mL round-bottomed flasks
In 10mL pyridines, DMAP (367mg, 3mmol) is added；It is stirred overnight at room temperature, after removing reaction dissolvent, solid is dissolved in dichloro
Methane, then respectively with 5% citric acid, saturated sodium bicarbonate, saturated salt solution cleaning；Organic phase is dried with anhydrous sodium sulfate,
Filtering, solvent is removed under reduced pressure after collecting filtrate；Solid isolates and purifies (DCM with column chromatography chromatogram:MeOH=100:1) produced after
Thing 14 (950mg, 65%).
Product 141H NMR nuclear magnetic datas are as follows：
1H NMR(400MHz,CDCl3)：δ0.67-1.57(m,37H),1.83-2.02(m,6H),2.30-2.32(m,
1H), 2.60-2.62 (d, 2H, J=6.8), 2.66-2.68 (d, 2H, J=6.4), 5.36-5.37 (m, 1H).
Product 14 (300mg, 0.62mmol) and SN-38 (241mg, 0.62mmol) are added in 100mL round-bottomed flasks, it is molten
Solution adds EDCHCl (140mg, 0.73mmol), DMAP (80mg, 0.73mmol) and pyridine (200 μ in 18mL DMF
L,1mmol)；It is stirred overnight at room temperature, after removing reaction dissolvent, solid is dissolved in dichloromethane, is then satisfied respectively with 5% citric acid
And sodium acid carbonate, saturated salt solution cleaning；Organic phase is dried with anhydrous sodium sulfate, and filtering, solvent is removed under reduced pressure after collecting filtrate；
Solid isolates and purifies (DCM with column chromatography chromatogram:MeOH=100:1) product 15 (381mg, 71.8%), is obtained.
Product 151H NMR nuclear magnetic datas and mass spectrometric data are as follows：
1H NMR(400MHz,CDCl3)：δ0.64-1.59(m,37H),0.95-0.98(t,3H),1.32-1.43(t,
3H), 1.84-1.89 (m, 2H), 1.87-2.02 (m, 6H), 2.35-2.36 (m, 1H), 2.78-2.80 (d, 2H, J=7.2),
2.96-2.98 (d, 2H, J=6.8), 3.11-3.16 (q, 2H), 5.05-5.15 (m, 1H), 5.23 (s, 2H), 5.26-5.30
(d, 1H, J=16), 5.71-5.75 (d, 1H, J=16.4), 7.53-7.56 (d, 1H, J=9.2), 7.64 (s, 1H), 7.80
(s, 1H), 8.16-8.18 (d, 1H, J=9.2)；
HR-ESI Qq-LTMS：calcd for[C53H69N2O8]+[M+H]+=861.5048；obsd861.5019.
The synthesis of the SN-38 pro-drugs 16 of 15 deoxycholic acid of embodiment coupling
Deoxycholic acid (300mg, 0.76mmol) and SN-38 (300mg, 0.76mmol) are added in 100mL round-bottomed flasks,
It is dissolved in 13mL DMF, adds EDCHCL (160mg, 0.84mmol), DMAP (103mg, 0.84mmol) and DIEA
(149μL,0.84mmol)；It is stirred overnight at room temperature, after removing reaction dissolvent, solid is dissolved in dichloromethane, then respectively with 5% lemon
Lemon acid, saturated sodium bicarbonate, saturated salt solution cleaning；Organic phase is dried with anhydrous sodium sulfate, filtering, is depressurized and is removed after collection filtrate
Remove solvent；Solid isolates and purifies (DCM with column chromatography chromatogram:MeOH=30:1) product 16 (85mg, 14.5%), is obtained.
Product 161H NMR nuclear magnetic datas and mass spectrometric data are as follows：
1H NMR(400MHz,CDCl3)：δ0.73(s,3H),0.91-0.94(t,6H),1.03-1.07(t,3H),1.09-
1.10(m,4H),1.26(s,6H),1.39-1.43(t,7H),1.53-1.59(m,10H),1.77-1.81(m,2H),3.16-
3.18 (q, 2H), 3.64-3.68 (m, 2H), 3.98-4.07 (m, 2H), 5.27 (s, 2H), 5.30-5.34 (d, 1H, J=
16.4), 5.74-5.78 (d, 1H, J=16.4), 7.54-7.57 (dd, 1H, J=9.2,2.8), 7.66 (s, 1H), 7.825-
7.832 (d, 1H, J=2.8), 8.23-8.25 (d, 1H, J=9.2)；
HR-ESI Qq-LTMS：calcd for C46H59N2O9[M+H]+=783.4215；obsd783.3847.
16 dissolubility of embodiment is evaluated
Evaluate obtaining dissolubility of the prodrug in Tween 80 and water in embodiment 1-13, evaluation result is shown in Table
1。
Dissolving situation of 1. prodrug of table in Tween 80 and water
By table 1 as it can be seen that prodrug 5 made of with oleic acid, being made with prodrug made of linoleic acid 6, with leukotrienes
Prodrug 7, be made with prodrug made of leucine 10, with prodrug made of histidine 12, with Artesunate
Prodrug 13, can be dissolved in Tween 80 and water with prodrug made of cholesterol 15, wherein with prodrug 6,7
Dissolubility it is best, its solubility in Tween 80 reaches 30mg/mL, and solubility in water reaches 8mg/mL.
15 antitumor evaluating drug effect of embodiment
To evaluate killing ability of the prodrug obtained in embodiment 1-13 to tumour cell, with colon-cancer cell system HCT-
116th, exemplified by SW480, lung cancer A549 and breast cancer MCF-7, evaluating drug effect has been carried out using mtt assay, and with Irinotecan and SN-
38 as control.A series of prodrugs are shown in Table 2 to the toxicity data of various tumour cells.
Measure (MTT) (IC of cell survival rate after when 2. medicine culture 48 of table is small50±SD inμM)
By table 1 as it can be seen that after when SN-38 prodrugs and cell co-cultivation 48 prepared by the present invention is small, its anti tumor activity in vitro
It is far superior to clinical application Irinotecan, and there is the effect similar with SN-38.
Claims (4)
1.7- ethyl-10-hydroxycamptothecin prodrugs, it is characterised in that shown in structural formula such as formula (I)：
Wherein, R represents hydrophobic group；
The hydrophobic group is linoleic acid or leukotrienes；
Carboxyl in the hydrophobic molecule participates in being formed the ester bond of formula (I).
2. the preparation method of 7-Ethyl-10-hydroxycamptothecin prodrug as claimed in claim 1, including：
(1) in the presence of condensing agent, esterification occurs for C10 position hydroxyls and the hydrophobic molecule of 7-Ethyl-10-hydroxycamptothecin instead
Should；
(2) crude product is isolated and purified after the completion of reacting, obtains 7- ethyl -10- hydroxyl happiness of the structural formula as shown in formula (I)
Set alkali prodrug；
The hydrophobic molecule is linoleic acid or leukotrienes.
3. preparation method as claimed in claim 2, it is characterised in that the condensing agent is N, N '-dicyclohexylcarbodiimide,
1- (3- dimethylamino-propyls) -3- ethyl carbodiimides or N, N '-diisopropylcarbodiimide.
4. application of the 7-Ethyl-10-hydroxycamptothecin prodrug as claimed in claim 1 in antitumor drug is prepared.
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| JP2019094260A (en) * | 2016-03-28 | 2019-06-20 | 国立大学法人東北大学 | Nanoparticulate formulations for cancer disease treatment |
| CN105997943B (en) * | 2016-06-24 | 2019-02-26 | 浙江大学 | A kind of nano particle and its preparation method and application of human serum albumins load camptothecine |
| CN106109415B (en) * | 2016-07-26 | 2019-01-29 | 金华市人民医院 | A kind of load camptothecin antineoplastic agents liposome, preparation method and applications |
| CN106236752A (en) * | 2016-07-29 | 2016-12-21 | 浙江大学 | Drug combination antitumor drug, preparation method and application |
| CN106267227A (en) * | 2016-08-12 | 2017-01-04 | 北京蓝贝望生物医药科技股份有限公司 | Antitumor drug |
| CN109289053B (en) * | 2018-09-30 | 2020-10-13 | 浙江大学 | Cabazitaxel-oligo/polylactic acid coupled prodrug, preparation method and application thereof |
| CN109400826A (en) * | 2018-10-25 | 2019-03-01 | 中国林业科学研究院林产化学工业研究所 | Lignosulfonates-dienoic acid-acrylate copolymer emulsion preparation method |
| CN109400619A (en) * | 2018-12-25 | 2019-03-01 | 东北林业大学 | 10-Methoxycamptothecine soluble derivative, preparation method and purposes |
| AU2020274113A1 (en) | 2019-05-14 | 2021-11-11 | Nuvation Bio Inc. | Anti-cancer nuclear hormone receptor-targeting compounds |
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| CN111253411B (en) * | 2020-03-26 | 2021-03-12 | 山东省科学院生物研究所 | Berberine linoleic acid conjugate and preparation method and application thereof |
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| CN103864810A (en) * | 2012-12-07 | 2014-06-18 | 天津科技大学 | Preparation method of novel 10-hydroxycamptothecine 10-position derivatives and application in antitumor drugs |
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