CN106588946B - 10-hydroxycamptothecine derivative, synthetic method and its application - Google Patents
10-hydroxycamptothecine derivative, synthetic method and its application Download PDFInfo
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- CN106588946B CN106588946B CN201710062516.2A CN201710062516A CN106588946B CN 106588946 B CN106588946 B CN 106588946B CN 201710062516 A CN201710062516 A CN 201710062516A CN 106588946 B CN106588946 B CN 106588946B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
Abstract
The present invention relates to camptothecine fields, specifically, providing a kind of 10-hydroxycamptothecine derivative, synthetic method and its application.The 10-hydroxycamptothecine derivative is the derivative for the structure with ester that 10 in 10-hydroxycamptothecine hydroxyls are formed after being esterified.The molecular polarity of the derivative substantially reduces, and the speed across biomembrane significantly improves, and helps to improve speed and quantity that drug enters tumour cell, improves utilization ratio of drug, plays better antitumous effect, while reducing toxic side effect.
Description
Technical field
The present invention relates to camptothecine fields, in particular to a kind of 10-hydroxycamptothecine derivative, synthesis
Method and its application.
Background technique
10-hydroxycamptothecine (10-Hydroxycamptothecine, 10-HCPT) is Nyssaceae drought Nelumbo deciduous plant
A kind of camptothecin alkaloid for the significant anticancer activity of tool extracted in fruit of camptotheca acuminata and leaf, can also be synthesized by camptothecine.
Its antitumaous effect is equivalent to 30 times of camptothecine.10-HCPT to cancer of pancreas, prostate cancer, bladder cancer, oral squamous cell carcinomas, colorectal cancer,
Gastric cancer, liver cancer, non-small cell lung cancer etc. have obvious curative effects.To oral cavity, neck face cancer, head-neck carcinoma, incidence cylindrical type gland
Cancer and cutaneum carcinoma also have good therapeutic effect；To chorioadenoma, chorioepithelioma, lung cancer, acute and chronic neutrophilic, leukaemia, silver
Hepatosplenomegaly caused by bits disease and snail fever etc. also has certain curative effect.10-hydroxycamptothecine and other common anticancers
Medicine is without crossing drug resistant.
Chemotherapy is the effective therapy and main therapy before and after tumor operation.Due to the hydroxyl in 10-HCPT be polarity compared with
Strong group, therefore 10-HCPT polarity is higher, across biomembrane speed is slower, and dosage is big, and normal tissue organ generates very
Big toxic side effect, clinical application are restricted.
In view of this, the present invention is specifically proposed.
Summary of the invention
The first object of the present invention is to provide a kind of 10-hydroxycamptothecine derivative, and the derivative is by camptothecine 10
Hydroxyl replace with the structure of ester, greatly reduce the molecular polarity of the derivative, improve its speed across biomembrane, facilitate
Speed and quantity that drug enters tumour cell are improved, utilization ratio of drug is improved, plays better antitumous effect, reduce simultaneously
Toxic side effect.
The second object of the present invention is to provide a kind of synthetic method of above-mentioned 10-hydroxycamptothecine derivative, this method
Processing step is scientific and reasonable, has antitumous effect good and malicious using the 10-hydroxycamptothecine derivative that the synthetic method obtains
The low advantage of side effect.
The third object of the present invention is to provide a kind of above-mentioned 10-hydroxycamptothecine derivative in the medicine of preparation treatment tumour
Application in object, gained drug have the advantages that oncotherapy effect is good.
In order to realize above-mentioned purpose of the invention, the following technical scheme is adopted:
In a first aspect, the derivative is 10- hydroxy-camptothecin the present invention provides a kind of 10-hydroxycamptothecine derivative
The derivative for the structure with ester that 10 hydroxyls are formed after being esterified in alkali.
As further preferably technical solution, the structural formula of the derivative is as follows:
Wherein, R is the straight chained alkyl or branched alkyl of the C1-C10 optionally replaced, and/or, the C2-C10's optionally replaced
Alkenyl.
As further preferably technical solution, the straight chained alkyl or branched alkyl of C1-C10 is methyl, ethyl, positive third
Any one in base, normal-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl or positive decyl or at least two
Combination.
As further preferably technical solution, the alkenyl of C2-C10 be vinyl, allyl, acrylic, 1- cyclobutenyl,
2- cyclobutenyl, 3- cyclobutenyl, 1- pentenyl, 2- pentenyl, 3- pentenyl, 2-methyl-1-butene alkenyl, 3-methyl-1-butene base,
2- methyl-2-butene base, 1- hexenyl, 2- hexenyl, 3- hexenyl, 2- methyl-1-pentene alkenyl, 2- methyl -2- pentenyl, 4-
Methyl -2- pentenyl, 4-methyl-1-pentene base, 3- methyl-1-pentene alkenyl, 3- methyl -2- pentenyl, 2- ethyl -1- butylene
Base, 3,3- dimethyl -1- cyclobutenyl, 2,3- dimethyl -1- cyclobutenyl, 2,3- dimethyl -2- butylene, 1- heptenyl, 1- octene
In base, 1- nonenyl or 1- decene base any one or at least two combination.
As further preferably technical solution, the straight chained alkyl of the C1-C10 in R or the alkene of branched alkyl or C2-C10
In base, more than one hydrogen is independently replaced oxygen；
Preferably, R is 4- carbonyl amyl.
As further preferably technical solution, the derivative is any one in following derivative:
Second aspect, the present invention provides a kind of synthetic methods of 10-hydroxycamptothecine derivative, comprising the following steps:
The carboxylic acid that 10-hydroxycamptothecine and structure are RCOOH is dissolved in pyridine, wherein R is the straight chain alkane of the C1-C10 optionally replaced
Base or branched alkyl, and/or, the alkenyl of the C2-C10 optionally replaced；Then EDCI is added, stirs 1-4 hours, obtains described
10-hydroxycamptothecine derivative.
As further preferably technical solution, the synthetic method further include: after 1-4 hours to be mixed, dichloro is added
Methane and water isolate organic layer after stirring 10-50 minutes, finally purify and using body by the residue after dry concentration
Product is than being (5-25): 1 methylene chloride and methanol elution obtains the 10-hydroxycamptothecine derivative.
As further preferably technical solution, comprising the following steps: by 10-hydroxycamptothecine 1-4mmol and 5- carbonyl
Caproic acid 7-9mmol is dissolved in 5-15mL pyridine, and EDCI 8-12mmol is added at 18-28 DEG C, is stirred 1-4 hours；Then it is added
40-60mL methylene chloride and 40-60mL water isolate organic layer, after being then dried under reduced pressure concentration after stirring 10-50 minutes
Residue purified with silicagel column, finally with volume ratio be (5-25): 1 methylene chloride and methanol is eluted, and institute is obtained
State 10-hydroxycamptothecine derivative.
The third aspect, the present invention provides a kind of 10-hydroxycamptothecine derivatives in the drug of preparation treatment tumour
Using.
Compared with prior art, the invention has the benefit that
10-hydroxycamptothecine derivative provided by the invention replaces 10-hydroxycamptothecine 10 hydroxyls after over-churning
It is changed to the structure of ester, greatly reduces the molecular polarity of the derivative, its speed across biomembrane is improved, helps to improve drug
Into the speed and quantity of tumour cell, utilization ratio of drug is improved, better antitumous effect is played, while reducing malicious secondary work
With.
The synthetic method craft step of above-mentioned 10-hydroxycamptothecine derivative provided by the invention is scientific and reasonable, using this
The 10-hydroxycamptothecine derivative that method obtains has the advantages that antitumous effect is good and toxic side effect is low.
Above-mentioned 10-hydroxycamptothecine derivative is applied in the drug of preparation treatment tumour, gained drug has tumour
The good advantage of therapeutic effect.
Detailed description of the invention
It, below will be to specific in order to illustrate more clearly of the specific embodiment of the invention or technical solution in the prior art
Embodiment or attached drawing needed to be used in the description of the prior art be briefly described, it should be apparent that, it is described below
Attached drawing is some embodiments of the present invention, for those of ordinary skill in the art, before not making the creative labor
It puts, is also possible to obtain other drawings based on these drawings.
Fig. 1 is the hydrogen nuclear magnetic resonance spectrogram of 10-hydroxycamptothecine derivative 1 provided by the invention；
Fig. 2 is the carbon spectrogram of 10-hydroxycamptothecine derivative 1 provided by the invention；
Fig. 3 is the high resolution mass spectrum figure of 10-hydroxycamptothecine derivative 1 provided by the invention；
Fig. 4 is the infrared spectrogram of 10-hydroxycamptothecine derivative 1 provided by the invention；
Fig. 5 is the agarose gel electrophoresis figure of 10-hydroxycamptothecine；
Fig. 6 is the agarose gel electrophoresis figure of 10-hydroxycamptothecine derivative 1 provided by the invention；
Fig. 7 is the result figure of laser co-focusing Germicidal efficacy cellular uptake 10-hydroxycamptothecine derivative 1；
Fig. 8 is the gross tumor volume and shape of tumor figure in Tumor growth inhibition experiment；
Fig. 9 is changes of weight curve graph after tumor bearing nude mice administration；
Figure 10 is tumor tissues H&E stained slice figure；
Figure 11 is the chemical structural drawing of 10-hydroxycamptothecine derivative provided by the invention.
Specific embodiment
Embodiment of the present invention is described in detail below in conjunction with embodiment, but those skilled in the art will
Understand, the following example is merely to illustrate the present invention, and is not construed as limiting the scope of the invention.It is not specified in embodiment specific
Condition person carries out according to conventional conditions or manufacturer's recommended conditions.
In a first aspect, the derivative is 10- hydroxy-camptothecin the present invention provides a kind of 10-hydroxycamptothecine derivative
The derivative for the structure with ester that 10 hydroxyls are formed after being esterified in alkali.
As shown in formula (1) and formula (2), 10-hydroxycamptothecine is by pyrroles's quinoline ring, a conjugation pyridine ring and one
Hexa-atomic α hydroxyl base lactonic ring (ring E) composition, molecular formula C20H16N2O5, molal weight 364.357 is that yellow prism-shaped one is hydrated
Object crystallization, is slightly soluble in a small number of organic solvents by 268~270 DEG C of fusing point, not soluble in water, becomes open loop carboxylate in dilute alkaline soln
Form dissolution, solution have blue-fluorescence.
There is stronger polarity in view of 10 in 10-hydroxycamptothecine hydroxyls, will affect the speed across biomembrane of drug
Degree etc., therefore, the present invention form the structure of ester after being esterified 10 hydroxyls, greatly reduce the molecule pole of the derivative
Property, its speed across biomembrane is improved, speed and quantity that drug enters tumour cell are helped to improve, improves drug utilization
Rate plays better antitumous effect, while reducing toxic side effect.
It is preferably carried out in mode in one kind, the structural formula of the derivative is as follows:
Wherein, R is the straight chained alkyl or branched alkyl of the C1-C10 optionally replaced, and/or, the C2-C10's optionally replaced
Alkenyl.
The following are the typical but non-limiting optional embodiments of 10-hydroxycamptothecine derivative provided by the invention:
The straight chained alkyl or branched alkyl of C1-C10 is the straight chained alkyl or branched alkane of C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10
Base；Specifically, the straight chained alkyl of C1-C10 or branched alkyl be methyl, it is ethyl, propyl, isopropyl, normal-butyl, sec-butyl, different
Butyl, tert-butyl, n-pentyl, 2- methyl butyl, 3- methyl butyl, 1- methyl butyl, 2,2- dimethyl propyl, 1,2- dimethyl
Propyl, 1,1- dimethyl propyl, 1- ethyl propyl, n-hexyl, 4- methyl amyl, 3- methyl amyl, 2- methyl amyl, 1- methyl
Amyl, 2,3- dimethylbutyl, 1,3- dimethylbutyl, 3,3- dimethylbutyl, 2,2- dimethylbutyl, 1,1- dimethyl butyrate
Base, 2- ethyl-butyl, 1- ethyl-butyl, 1- Ethyl-2-Methyl propyl, 1,1,2- thmethylpropyl, 1,2,2- thmethylpropyl,
1- methyl-1-ethyl propyl, n-heptyl, 1- methylhexyl, 2- methylhexyl, 3- methylhexyl, 1,2- methyl amyl, 1,3- bis-
Methyl amyl, 1,4- dimethyl amyl group, 2,3- dimethyl amyl group, 2,4- dimethyl amyl group, 1,1- dimethyl amyl group, 2,2- diformazan
Base amyl, 3,3- dimethyl amyl group, 3,4- dimethyl amyl group, 1- ethylpentyl, 2- ethylpentyl, 3- ethylpentyl, 1,2,3-
Trimethyl butyl, 1,1,2- trimethyl butyl, 1,1,3- trimethyl butyl, 1- ethyl 2- methyl butyl, 1- ethyl -3- methyl fourth
It is base, 2,2,3- trimethyl butyl, 2- ethyl -3- methyl butyl, 1,2- diethylpropyl, 1,1,2,2- tetramethyl propyl, just pungent
Base, 1- methylheptyl, 2- methylheptyl, 3- methylheptyl, 4- methylheptyl, 1,1- dimethylhexanyl, 1,2- dimethylhexanyl,
1,3- dimethylhexanyl, 1,4- dimethylhexanyl, 1,5- dimethylhexanyl, 1- ethylhexyl, 2- ethylhexyl, 3- ethyl hexyl
Base, 1,2,3- tri-methyl-amyl, 1,2,4- tri-methyl-amyl, 2,3,4- tri-methyl-amyl, 1,1,2- tri-methyl-amyl, 1,1,3-
Tri-methyl-amyl, 2,2,3- tri-methyl-amyl, 1- Ethyl-2-Methyl amyl, 1- ethyl -3- methyl amyl, 2- ethyl -3- methyl
Amyl, 1,1,2,2- tetramethyl butyl, 1,2- diethyl butyl, 1- ethyl -2,2- dimethylbutyl, 1,1- dimethyl -2- second
Base butyl, 1- propyl -2- methyl butyl, n-nonyl, 1- Methyl Octyl, 2- Methyl Octyl, 3- Methyl Octyl, 4- Methyl Octyl,
5- Methyl Octyl, 1,1- dimethyl heptyl, 1,2- dimethyl heptyl, 1,3- dimethyl heptyl, 1,4- dimethyl heptyl, 1- ethyl
Heptyl, 2- ethylheptyl, 3- ethylheptyl, 4- ethylheptyl, 1,1,2- trimethyl, 1,1,3- trimethyl, 2,2,
3- trimethyl, 1,2,3- trimethyl, 1- Ethyl-2-Methyl hexyl, 1- ethyl -3- methylhexyl, 1- propyl hexyl,
2- propyl hexyl, 3- propyl hexyl, 1- isopropyl hexyl, 2- isopropyl hexyl, 3- isopropyl hexyl, 1,1,2,2- tetramethyl penta
Base, 1,1,3,3- tetramethyl amyl, 1,2,2,3- tetramethyl amyl, 1,2,3,3- tetramethyl amyl, 1- ethyl -2,2- dimethyl
Amyl, 1- ethyl -2,3- dimethyl amyl group, 1,2- dimethyl -1- ethylpentyl, 1- propyl -2- methyl amyl, 1,1,2,2,3-
Trimethyl butyl, 3- methyl-1,2- diethyl butyl, positive decyl, 1- Nonyl, 2- Nonyl, 3- Nonyl, 4- first
Base nonyl, 5- Nonyl, 1,1- dimethyl octyl, 1,3- dimethyl octyl, 1,4- dimethyl octyl, 1,5- dimethyl-octa
Base, 2,2- dimethyl octyl, 2,3- dimethyl octyl, 2,4- dimethyl octyl, 2,5- dimethyl octyl, 3,3- dimethyl-octa
Base, 3,4- dimethyl octyl, 3,5- dimethyl octyl, 4,4- dimethyl octyl, 4,5- dimethyl octyl, 1- ethyloctanyl, 2-
Ethyloctanyl, 3- ethyloctanyl, 4- ethyloctanyl, 1,1,2- trimethyl heptyl, 1,1,3- trimethyl heptyl, 1,1,4- trimethyl
Heptyl, 1- Ethyl-2-Methyl heptyl, 1- methyl -2- ethylheptyl, 1- propylheptyl, 2- propylheptyl, 3- propylheptyl, 1-
Isopropyl heptyl, 2- isopropyl heptyl, 3- isopropyl heptyl, 1,1,2,2- tetramethylhexyl, 1,1,3,3- tetramethylhexyl, 1,
2,2,3- tetramethylhexyl, 1,2,3,3- tetramethylhexyl, 1- ethyl -2,2- dimethylhexanyl, 1- ethyl -2,3- dimethyl oneself
In base, 1,2- dimethyl -1- ethylhexyl or 1- propyl -2- methylhexyl any one or at least two combination；
The alkenyl of C2-C10 is the alkenyl of C2, C3, C4, C5, C6, C7, C8, C9 or C10；Specifically, the alkenyl of C2-C10
For vinyl, allyl, acrylic, 1- cyclobutenyl, 2- cyclobutenyl, 3- cyclobutenyl, 1- pentenyl, 2- pentenyl, 3- pentenyl,
2-methyl-1-butene alkenyl, 3-methyl-1-butene base, 2- methyl-2-butene base, 1- hexenyl, 2- hexenyl, 3- hexenyl, 2-
Methyl-1-pentene alkenyl, 2- methyl -2- pentenyl, 4- methyl -2- pentenyl, 4-methyl-1-pentene base, 3- Methyl-1-pentene
Base, 3- methyl -2- pentenyl, 2- ethyl -1- cyclobutenyl, 3,3- dimethyl -1- cyclobutenyl, 2,3- dimethyl -1- cyclobutenyl, 2,
Any one in 3- dimethyl -2- butylene, 1- heptenyl, 1- octenyl, 1- nonenyl or 1- decene base or at least two
Combination.
Be preferably carried out in mode in one kind, the straight chained alkyl or branched alkyl of C1-C10 be methyl, ethyl, n-propyl,
Normal-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl or positive decyl.
It is preferably carried out in mode in one kind, the alkenyl of C2-C10 is vinyl, allyl, acrylic, 1- cyclobutenyl, 2-
Cyclobutenyl, 3- cyclobutenyl, 1- pentenyl, 2- pentenyl, 3- pentenyl, 2-methyl-1-butene alkenyl, 3-methyl-1-butene base, 2-
Methyl-2-butene base, 1- hexenyl, 2- hexenyl, 3- hexenyl, 2- methyl-1-pentene alkenyl, 2- methyl -2- pentenyl, 4- first
Base -2- pentenyl, 4-methyl-1-pentene base, 3- methyl-1-pentene alkenyl, 3- methyl -2- pentenyl, 2- ethyl -1- cyclobutenyl,
3,3- dimethyl -1- cyclobutenyl, 2,3- dimethyl -1- cyclobutenyl, 2,3- dimethyl -2- butylene, 1- heptenyl, 1- octenyl,
1- nonenyl or 1- decene base.
It is preferably carried out in mode in one kind, the straight chained alkyl or branched alkyl of the C1-C10 in R or the alkenyl of C2-C10
In, more than one hydrogen is independently replaced oxygen.
It is preferably carried out in mode in one kind, R is 4- carbonyl amyl.
It is preferably carried out in mode in one kind, the derivative is any one in following derivative:
Second aspect, the present invention provides a kind of synthetic methods of 10-hydroxycamptothecine derivative, comprising the following steps:
The carboxylic acid that 10-hydroxycamptothecine and structure are RCOOH is dissolved in pyridine, wherein R is the straight chain alkane of the C1-C10 optionally replaced
Base or branched alkyl, and/or, the alkenyl of the C2-C10 optionally replaced；Then EDCI is added, stirs 1-4 hours, obtains described
10-hydroxycamptothecine derivative.
Wherein, EDCI is carbodiimides.
It is preferably carried out in mode in one kind, the synthetic method further include: after 1-4 hours to be mixed, dichloromethane is added
Alkane and water isolate organic layer after stirring 10-50 minutes, finally purify and using volume by the residue after dry concentration
Than for (5-25): 1 methylene chloride and methanol elution obtains the 10-hydroxycamptothecine derivative.
Be preferably carried out in mode in one kind, comprising the following steps: by 10-hydroxycamptothecine 1-4mmol and 5- carbonyl oneself
Sour 7-9mmol is dissolved in 5-15mL pyridine, and EDCI 8-12mmol is added at 18-28 DEG C, is stirred 1-4 hours；Then it is added
40-60mL methylene chloride and 40-60mL water isolate organic layer, after being then dried under reduced pressure concentration after stirring 10-50 minutes
Residue purified with silicagel column, finally with volume ratio be (5-25): 1 methylene chloride and methanol is eluted, and institute is obtained
State 10-hydroxycamptothecine derivative；
Synthetic reaction is as follows:
The third aspect, the present invention provides a kind of 10-hydroxycamptothecine derivatives in the drug of preparation treatment tumour
Using.
It is the chemical structural drawing of 10-hydroxycamptothecine derivative provided by the invention as shown in figure 11.
Embodiment 1
A kind of 10-hydroxycamptothecine derivative 1, structural formula is as follows:
Embodiment 2
Derivative described in embodiment 1 is synthesized by following methods:
10-HCPT (1.00g, 2.7mmol) and 5- carbonyl caproic acid (1.07g, 8.1mmol) are dissolved in 10mL pyridine,
EDCI (2.06g, 10.8mmol) is added at room temperature, stirs 3h, thin-layered chromatography monitoring reaction.It is added into reaction system
50mL methylene chloride and 50mL water separate organic layer after being stirred to react 30 minutes, are dried under reduced pressure the residue silica gel being concentrated to get
Column is purified, and is eluted with methylene chloride and methanol, and the volume ratio of methylene chloride and methanol is 10:1, obtains the solidification of yellow
Close object, i.e. 10-hydroxycamptothecine derivative 1 (1.25g, yield 96%).
Synthetic reaction is as follows:
The structure and performance test for the 10-hydroxycamptothecine derivative 1 that embodiment 2 obtains:
Using the chemistry knot of the technical appraisement such as nuclear magnetic resonance spectroscopy, carbon spectrum, high resolution mass spectrum, infrared spectroscopy derivative
Structure is as shown in Figs 1-4 each test spectrogram.
Using 1H NMR and 13C NMR and high resolution mass spectrometry, infra-red sepectrometry etc. is to 10-hydroxycamptothecine derivative 1
Structure identified.The representative multiplet of abbreviation is as follows: multiplet: s=is unimodal, and d=is bimodal, tri- peak t=, q=quadruple
Peak, m=multiplet, two doublets of dd=, two triplets of dt=.1H NMR spectra and 13C NMR spectra deuterated chloroform
(CDCl3-d6) solvent is made.The following are nuclear magnetic signal results:
1H NMR (400MHz, CDCl3) δ 8.31 (s, 1H), 8.22 (d, J=9.2Hz, 1H), 7.72-7.61 (m, 2H),
7.53 (dt, J=35.3,17.7Hz, 1H), 5.71 (t, J=17.7Hz, 1H), 5.30 (d, J=15.5Hz, 3H), 4.17-
3.96 (m, 1H), 2.68 (dt, J=19.8,7.1Hz, 4H), 2.22 (d, J=9.8Hz, 3H), 2.08 (dt, J=12.0,
6.1Hz, 2H), 2.01-1.85 (m, 2H), 1.03 (t, J=7.4Hz, 3H).
13C NMR(101MHz,CDCl3)δ207.82,173.82,171.53,157.58,152.40,150.15,
149.56,146.81,146.12,131.24,130.69,129.14,128.44,125.91,118.85,118.68,98.16,
72.78,66.30,50.03,42.22,33.37,31.65,30.06,18.70,7.84。
The agarose gel electrophoresis figure of 10-hydroxycamptothecine and 10-hydroxycamptothecine derivative 1 is respectively such as Figures 5 and 6 institute
Show, the results showed that, product is suitable to the inhibiting effect and 10-HCPT of DNA topoisomerase I.
Agarose gel electrophoresis figure, 0 swimming lane are positive control, and 1 swimming lane is negative control, and 2-6 swimming lane is DNA topoisomerase
+ pBR322DNA+100 μM of enzyme I, 200 μM, 300 μM, 400 μM, 500 μM of drug, Fig. 5 drug is 10-HCPT；Fig. 6 is 10- hydroxyl
Base camptothecin derivative 1；R is relaxed DNA, and Sc is super coiled DNA.It is visible with concentration according to the brightness of electrophoretic band in figure
Increase, 10-HCPT completely inhibits the activity of TOPO I at 400 μM, and relaxed type DNA is completely converted into screw type.10- hydroxyl
Camptothecin derivative 1 is active to TOPO I to inhibit substantially suitable with 10-HCPT, completely inhibits TOPO I's at 400 μM
Activity.
10- bit derivant utilizes confocal laser scanning microscope cellular uptake drug to the inhibitory activity of DNA TOPO I
Process, as a result as shown in Figure 7；Its toxicity to MCF-7, HepG2, SW180 cell is detected using mtt assay.The result shows that: it is thin
Born of the same parents absorb the fast speed of product, and the blue-fluorescence of Intracellular drug can be observed after 1 hour, can be observed after 2 hours thin
The blue-fluorescence of drug in karyon, 4 hours fluorescence intensity maximums, drug largely enter nucleus, show the cell internalizing of drug
Rapidly.The IC50 ratio 10-HCPT of product of the present invention is lower.
The tumor cell in vitro growth inhibitory effect of table 1.MTT method measurement 10-hydroxycamptothecine derivative 1 and 10-HCPT
Oxter lotus knurl nude mouse animal model is established with MCF-7 cell, carries out pharmacodynamic study, the results showed that product is in lotus
The intracorporal antitumous effect of tumor nude mouse is better than 10-HCPT；
The foundation of tumor model:
After MCF-7 cell culture to logarithmic growth phase, after centrifugation, cell is resuspended in for pancreatin digestion, sterile PBS washing
In the culture medium of serum-free, cell concentration is adjusted to 107/mL, single cell suspension is made.0.2ml cell suspension is taken, it is subcutaneous to infuse
It is mapped to nude mice oxter.The oxter tumour growing state of nude mice is observed and recorded daily, and measures gross tumor volume.
Animal packet and dosage regimen:
After inoculation, mouse continues raising 7 days, reaches 100mm to gross tumor volume3It is grouped behind left and right, every group 6, point
Not Cai Yong tail vein injection give each group preparation.
(1) physiological saline group；(2) commercially available 10-HCPT injection group；(3) 1 group of 10-hydroxycamptothecine derivative.Various systems
The dosage of 10-HCPT or equivalent dosage are 5.0mg/kg in agent.
Tumor growth inhibition experiment:
The length and width of vernier caliper measurement nude mouse tumor are used during experiment daily.Gross tumor volume is calculated, gross tumor volume-is drawn
Time variation diagram evaluates each administration group to the therapeutic effect of tumour.The 14th day execution animal after administration, removing tumour claim
Amount, knurl weight and nude mice go knurl weight, photograph.Gross tumor volume and tumor control rate calculate as follows respectively:
V=1/2 × a × b2.Wherein, V is gross tumor volume, and a is tumour major diameter；B is tumour minor axis.
Inhibiting rate=(blank group tumor weight-administration group swell tumor weight)/blank group tumor weight × 100%
Pharmacodynamic evaluation carries out statistical procedures using Student ' s t-test.
Tumor growth inhibition experiment:
The gross tumor volume and shape of tumor of 3 groups of preparations change with time and see Fig. 8, wherein (A) is physiological saline group, (B)
For 10-HCPT group, (C) is 1 group of 10-hydroxycamptothecine derivative.The experimental results showed that inhibition rate of tumor growth size order are as follows:
10-hydroxycamptothecine derivative 1 group > 10-HCPT injection group > physiological saline group.10-hydroxycamptothecine derivative 1 compares 10-
HCPT parent drug has embodied higher Tumor growth inhibition efficiency.
Tumor size after each group preparation is administered 14 days:
Such as Fig. 9, versus time curve result is as it can be seen that physiology during the nude mouse of each administration group focuses on pharmacodynamic study
Salt water group nude mouse restarts just variation, and less, decreased later is rapid, and analysis may be due to the growth of tumour, the life state of nude mice
Gradually severe, tumour has drawn a large amount of nutrients, causes nude mice thin rapidly.10-HCPT group is slow compared with physiological saline group weight loss
Slowly.Analysis may obtain a degree of containment due to the therapeutic effect of drug, tumour, and the nutrient that nude mice obtains can maintain body
Weight, but due to the side reaction of the toxic side effect of drug especially gastrointestinal tract, weight is still on a declining curve.10-hydroxycamptothecine
Derivative 1 (10 bit derivant of figure middle finger) is more slow compared with the decline of 10-HCPT group, may be due to the raising of curative effect, the life of tumour
Length obtains the containment of more preferable degree, and nude mice life state is preferable, and weight loss is slow.Illustrate 10-HCPT in antineoplaston mistake
There is certain toxic side effect in journey.10-hydroxycamptothecine derivative 1 is compared to the commercial preparation 10-HCPT, to a certain extent
Reduce toxic side effect.The effect of the anti-subcutaneous tumor of phototherapy is preferable and toxic side effect is low.The effect of phototherapy combination chemotherapy is very
It is good, and toxic side effect is very low.
After effect experiment, nude mice is put to death, takes out Saline, 10-HCPT and 1 group of 10-hydroxycamptothecine derivative
The tumor tissues of (5mg/kg) each preparation group nude mice are fixed after a week with 10% formalin solution, carry out paraffin embedding, slice
It is dyed with H&E.The pathological section dyed is placed in microscopically observation, is photographed to record, the results are shown in Figure 10, wherein (A)
For physiological saline group, (B) is 10-HCPT group, and (C) is 1 group of 10-hydroxycamptothecine derivative.It is cut from the H&E of tumor tissues dyeing
For piece as it can be seen that physiological saline group tumor tissue cell core is largely assembled, form is irregular, is in nodositas, and nuclei dyeing chromaticness increases
And be unevenly distributed, it is in ink droplet sample that nuclear hyperchromatism, particle is thicker, large stretch of necrotic cell debris occurs；10-HCPT group tumor tissues
Feature is typical, and the big deep dye of core, is in nodositas, it also seen that there is a small amount of necrotic cell debris；1 group of 10-hydroxycamptothecine derivative swollen
Tumor tissue feature is typical, and necrosis is less, shows stronger Tumor growth inhibition effect compared to 10-HCPT group.
By each organ-tissue pathological section of experimental animal after analysis administration, the indexs such as experimental animal weight reduces.Preparation
Preliminary toxicity researches show that: invention formulation toxicity is lower compared with commercial reference preparation.
Although illustrate and describing the present invention with specific embodiment, it will be appreciated that without departing substantially from of the invention
Many other change and modification can be made in the case where spirit and scope.It is, therefore, intended that in the following claims
Including belonging to all such changes and modifications in the scope of the invention.
Claims (5)
1. a kind of 10-hydroxycamptothecine derivative, which is characterized in that the structural formula of the derivative is as follows:
2. the synthetic method of 10-hydroxycamptothecine derivative described in claim 1, which comprises the following steps: will
10-hydroxycamptothecine and 5- carbonyl caproic acid are dissolved in pyridine, and EDCI is then added, and are stirred 1-4 hours, are obtained the 10- hydroxyl
Camptothecin derivative.
3. synthetic method according to claim 2, which is characterized in that the synthetic method further include: 1-4 hours to be mixed
Afterwards, methylene chloride and water is added and isolates organic layer after stirring 10-50 minutes, finally carries out the residue after dry concentration pure
Change and use volume ratio for (5-25): 1 methylene chloride and methanol elution obtains the 10-hydroxycamptothecine derivative.
4. synthetic method according to claim 2, which comprises the following steps: by 10-hydroxycamptothecine 1-
4mmol and 5- carbonyl caproic acid 7-9mmol are dissolved in 5-15mL pyridine, and EDCI 8-12mmol is added at 18-28 DEG C, stir 1-4
Hour；Then 40-60mL methylene chloride and 40-60mL water is added to isolate organic layer after stirring 10-50 minutes, then will subtract
Residue after pressing dry dry concentration is purified with silicagel column, and be finally (5-25) with volume ratio: 1 methylene chloride and methanol carries out
Elution, obtains the 10-hydroxycamptothecine derivative.
5. application of the 10-hydroxycamptothecine derivative described in claim 1 in the drug of preparation treatment tumour.
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