CN108148098A - The gemcitabine of target cancer cell high level ROS-aryl nitrogen mustard conjugate and preparation method thereof and medical usage - Google Patents
The gemcitabine of target cancer cell high level ROS-aryl nitrogen mustard conjugate and preparation method thereof and medical usage Download PDFInfo
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Abstract
The invention discloses a kind of the gemcitabine mustargen conjugates and its pharmaceutically acceptable salt of target cancer cell high level ROS, have structure shown in general formula I：
Description
Technical field
The present invention relates to biomedicine fields, and in particular to a kind of gemcitabine-mustargen of target cancer cell high level ROS
Conjugate and its pharmaceutically acceptable salt, their preparation method, containing the Pharmaceutical composition of these derivatives and they
Medical usage, particularly application in preparation of anti-tumor drugs.
Background technology
Gemcitabine (gemcitabine, dFdC) is the new anti-metabolism anticancer drug of U.S. FDA approval in 1996.
DFdC is a kind of cell cycle specific antineoplastic, and dFdC plays the part of a competition after a series of phosphorylation in the cell
Deoxycytidine triphosphate substrate by competing intercalation of DNA double-strand, causes DNA double chain wrong identification, unique so as to play its
Cytotoxicity inhibits growth of tumour cell, promotes Apoptosis (Jordheim LP, Durantel D, Zoulim F, et
al.at Rev Drug Discov,2013,12:447-464).Although dFdC is in Clinical practice, its polarity is larger, cross-film
Ability is poor, is reduced so as to cause vivo biodistribution availability, and half-life period is shorter；Its N4 bit amino is easily lost by dctp deaminase simultaneously
Living (Moysan E, Basttiat G, Benoit JP.Mol Pharm, 2013,10:430-444).Therefore in the N4 positions of dFdC
Amino carries out lipophilicity modification and helps to improve that dFdC is fat-soluble and cross-film ability, also reduces N4 bit aminos by dctp deaminase,
Improve drug vivo biodistribution availability.
The aryl nitrogen mustard drug being clinically used for a long time, such as Chlorambucil (chlorambucil), bendamustine
(bendamustine, Treanda), mainly causes DNA single-stranded and duplex influences the function of DNA by alkanisation crosslinking.
Wherein the bendamustine of Cephalon companies was ratified by U.S. FDA on March 21st, 2008, white for chronic lymphocytic
Blood disease.There is clinical research to show aryl nitrogen mustard drug bendamustine or Chlorambucil and gemcitabine drug combination, it can be bright
Aobvious to promote drug therapy tolerance, collaboration inhibits the growth of malignant tumour, extends the life cycle of cancer patient, and can improve tumour
Cell to the sensibility of chemotherapeutics, for treat recurrence/Refractory Multiple Myeloma and lymthoma (Santoro A,
Mazza R,Pulsoni A,et al.J Clin Oncol.2016,4(27):3293-9；Quaglino P,Maule M,
Prince HM,et al.Ann Oncol.2017,28(10):2517-2525), but such combination therapies lack selection
Property, the toxicity of normal tissue is also very big, and the bioavilability of single drug in itself is not high, these problems are still up for into one
Step is improved.
Reactive oxygen species (ROS, including O in tumor microenvironment2 -, HO and H2O2) level be apparently higher than normal structure, according to
Document report, the H of normal structure2O2Concentration is only at 0.001~0.7 μM or so, and tumor tissues are due to excessive H2O2Generation and
Accumulation, up to 50~100 μM, and can be resistant to the H of 0.1~10mM concentration in external environment2O2(Stone JR.Arch Biochem
Biophys.2004,422,119-124), while ROS levels also will appear raising during the proliferation of tumour cell and transfer.
Can corresponding targeting anti-tumor predrug be designed based on the high-content of ROS in tumor microenvironment.
Based on above research, the present invention utilizes aryl nitrogen mustard such as benzenebutanoic acid nitrogen according to prodrug design principle and principle of hybridization
The N4 bit aminos of mustard, the carboxyl of bendamustine and gemcitabine carry out amidation coupling, at the same gemcitabine 5 ' and/or
Pinacol borate ester is introduced on 3 ' hydroxyl, using pinacol borate ester selectively by the high-caliber ROS of tumour cell
Oxidation is left away, and the characteristics of so as to discharge drug, design has synthesized gemcitabine-aryl nitrogen mustard of target cancer cell high level ROS
Conjugate.Have not yet to see any report to such compound.
Invention content
The present invention is in view of the shortcomings of the prior art, make public for the first time a kind of gemcitabine-virtue of target cancer cell high level ROS
Fragrant mustargen conjugate and its pharmaceutically acceptable salt, preparation method and its medical usage.
Specific technical solution of the present invention is as follows：
Gemcitabine-mustargen the conjugate and its pharmaceutically acceptable salt of a kind of target cancer cell high level ROS, has
Structure shown in general formula I：
In general formula I：
R is representedOr
R1Represent H orR2Represent H or
The preferred embodiment of the present invention, R, R in the structure of the conjugate general formula I1、R2Selected from following combination：
R1=H, R2=H；
OrR2=H；
OrR1=H,
Or
OrR1=H, R2=H；
OrR2=H；
OrR1=H,
Or
Preferred compound number of the present invention and its corresponding structure are as shown in table 1.
1 general formula I preferred compounds of table are numbered and its corresponding structure
Another object of the present invention is to provide the preparation method of compound described in general formula I of the present invention, step includes：
(1) compound 4 is obtained by the reaction with tert-butyl chloro-silicane in the presence of imidazoles in compound 3,
(2) in condensing agent 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (EDCI) and 4- dimethylaminos
In the presence of pyridine (DMAP), compound 4 obtains compound 6 with 5 condensation reaction of compound,
Wherein, R is representedOr
(3) compound 6 obtains general formula compound Ia described in claim 1 under the action of deprotecting regent,
The preferred tetrabutyl ammonium fluoride of deprotection agent (TBAF).
Further, step (4) can also be included after above-mentioned preparation method step (3)：
(4) in the presence of DMAP or n,N-diisopropylethylamine (DIPEA), compound IaWith compound being obtained by the reaction of 2a
Close object Ib、IcAnd Id,
Wherein, R is representedOrR ' is represented
The compound 2a is
Ia、Ib、Ic、IdBelong to compound of Formula I of the present invention.
Preferably, compound 2a can be used following steps and be prepared：To bromobenzene methanol in the [bis- (diphenylphosphines of 1,1'-
Base) ferrocene] palladium chloride catalysis under, compound 2, compound 2 and N, N '-carbonyl is obtained by the reaction with connection boric acid pinacol ester
Compound 2a is obtained by the reaction in diimidazole.
Another object of the present invention is to provide a kind of compound of Formula I of the present invention containing effective dose or it medically may be used
The salt and pharmaceutically acceptable carrier of receiving or the pharmaceutical composition of auxiliary material.
It is a further object of the present invention to provide compound of Formula I application in preparation of anti-tumor drugs of the present invention, especially
It is answering in the antitumor drugs such as treatment acute leukemia, Huppert's disease, liver cancer, lung cancer, gastric cancer and cervical carcinoma are prepared
With.
The compounds of this invention can be combined individually or with one or more kinds of pharmaceutically acceptable carriers and be made
Agent is for administration.For example, solvent, diluent etc., can use oral dosage form, such as tablet, capsule, dispersible powder, particle
Agent etc..The various dosage forms of pharmaceutical composition of the present invention can be prepared according to method well known in pharmaceutical field.These are medicinal
Can contain the active constituent of such as 0.05%~90% weight that is combined with carrier in preparation, more conventional about 15%~60% it
Between weight active constituent.The compounds of this invention dosage can be 0.005~5000mg/kg/ days, also can be according to the serious journey of disease
Degree or the different dosages of dosage form exceed this dosage range.
The compounds of this invention can be with other antitumor drugs such as alkylating agent (such as cyclophosphamide or cis-platinum), antimetabolite
(such as 5 FU 5 fluorouracil or hydroxycarbamide), topoisomerase enzyme inhibitor (such as camptothecine), mitotic inhibitor (such as taxol or length
Spring alkali), DNA inserting agents (such as adriamycin) use in conjunction, in addition it can with radiotherapy use in conjunction.These other it is antitumor
Drug or radiotherapy can simultaneously or in different time be given with the compounds of this invention.These combination therapies can generate collaboration
Effect is so as to help to improve therapeutic effect.
Advantage of the present invention：
The present invention utilizes Chlorambucil, carboxyl and the Ji of bendamustine according to prodrug design principle and principle of hybridization
The N4 bit aminos of his western shore carry out amidation coupling, while pinacol benzene is introduced on 5 ' and/or the 3 ' of gemcitabine hydroxyl
Borate, design have synthesized gemcitabine-aryl nitrogen mustard conjugate of target cancer cell high level ROS.The present invention using frequency that
The characteristics of alcohol borate ester is oxidized to phenol and boric acid by ROS, and chemical bond rupture discharges drug, enables compound of the present invention
It is enough selectively to release gemcitabine-aryl nitrogen mustard conjugate in containing high concentration ROS tumour cells, further pass through
Various esterases or amidase slowly release gemcitabine and aryl nitrogen mustard, play synergistic antitumor effect.The present invention is to Ji Xi
The lipophilic sex modification that his shore carries out, which not only facilitates, improves that gemcitabine is fat-soluble and cross-film ability, independent of nucleoside transporting egg
Enter cell in vain, additionally it is possible to reduce gemcitabine N4 bit aminos by dctp deaminase, improve its vivo biodistribution availability, Er Qieke
The alkanisation that aryl nitrogen mustard causes DNA is generated, influences the function of DNA, realizes the antitumous effect of multiple action, reduces tumour
Cell is to the drug resistance of this kind of drug.
Specific embodiment
In order to which the present invention is furture elucidated, a system is given below；Row embodiment, these embodiments be entirely it is illustrative,
They are only used for specifically describing the present invention, are not construed as limitation of the present invention.
1 4- of embodiment (4- (bis- (2- chloroethyls) amino) phenyl)-N- (1- (two fluoro- 4- hydroxyls of (2R, 4R, 5R) -3,3-
Base -5- (methylol) tetrahydrofuran -2- bases) -2- ketone -1,2- dihydro-pyrimidin -4- bases)-butyramide (I1) preparation
4- amino -1- ((2R, 4R, 5R) -3,3- two fluoro- 4- (tertiary butyl dimethyl Si base) -5- (fert-butyidimethylsilyls
Silica ylmethyl) tetrahydrofuran -2- bases) -1H- pyrimid-2-ones (compound 4) preparation
Gemcitabine (compound 3,1.0g, 3.80mmol) is dissolved in the DMF of 10mL dryings, adds in TBDMS-Cl
(1.15g, 7.64mmol) and 1.03g imidazoles, is stirred at room temperature, and after the reaction was complete through thin-layer chromatography detection, adds in 100ml water, then
Equivalent ethyl acetate is added to extract three times, organic phase is dried over anhydrous sodium sulfate, and is concentrated under reduced pressure to give crude product.Crude product passes through column chromatography
Purify (mobile phase methanol：Dichloromethane=1:25-1:15) 1.64g, yield 88% are obtained.
4- (4- (bis- (2- chloroethyls) amino) phenyl)-N- (1- (two fluoro- 4- (tertiary butyl diformazans of (2R, 4R, 5R) -3,3-
Base siloxy) -5- (tertiary butyl dimethyl Si ylmethyl) tetrahydrofuran -2- bases) -2- ketone -1,2- dihydro-pyrimidin -4- bases)-fourth
The preparation of amide (compound 6a)
By Chlorambucil (compound 5a) (334mg, 1.10mmol), EDCI (384,2.00mmol), DMAP (34mg,
10%) and compound 4 (492mg, 1.00mmol) is dissolved in the anhydrous CH of 10ml2Cl2In, it is stirred overnight at room temperature, depressurizes after reaction
Solvent is steamed, crude product purifies (mobile phase ethyl acetate by column chromatography：Petroleum ether=1:10-1:4) white solid is obtained
666mg, yield 84%.
4- (4- (bis- (2- chloroethyls) amino) phenyl)-N- (1- (two fluoro- 4- hydroxyls -5- (hydroxyl first of (2R, 4R, 5R) -3,3-
Base) tetrahydrofuran -2- bases) -2- ketone -1,2- dihydro-pyrimidin -4- bases)-butyramide (I1) preparation
Previous step product Compound 6a (666mg, 0.84mmol) is dissolved in anhydrous THF, adds in 8.4ml 1M thereto
TBAF tetrahydrofuran solutions, react at room temperature 3-5h, after reaction, decompression steams solvent, adds in 100ml water, ethyl acetate
Extraction three times, organic phase is dried over anhydrous sodium sulfate, and is concentrated under reduced pressure to give crude product.Crude product purifies (mobile phase second by column chromatography
Acetoacetic ester：Petroleum ether=2:1-4:1) (I is obtained1) white solid 410mg, yield 89%.ESI-MS (m/z):549[M+H]+；1H
NMR(DMSO-d6,400MHz):δ 11.01 (s, 1H, NH), 8.25 (d, 1H, J=8.0Hz, C=CH- N), 7.29 (d, 1H, J=
8.0Hz, C=CH- C), 7.03 (d, 4H, J=8.0Hz, Ar-H), 6.66 (d, 4H, J=6.0Hz, Ar-H), 6.35 (s, 1H,
), OH 6.18 (t, 1H, J=8.0Hz, CH), 5.33 (s, 1H, OH), 4.02 (d, 1H, J=8.0Hz, CH), 3.89 (m, 1H,
), CH 3.80 (t, 2H, J=8.0Hz, CH2),3.67(m,8H,CH2),2.44(m,4H,CH2),1.79(m,2H,CH2).
((2R, 3R, 5R) -5- (4- (4- (4- (bis- (2- chloroethyls) amino) phenyl) amide-based small -2- oxos of embodiment 2
Two fluoro- 3- hydroxyl tetrahydrofurans -2- bases of pyrimidine -1 (2H)-base -4,4-) methyl -4- (4,4,5,5- tetramethyl -1,3,2- dioxies
Penta ring -2- bases of boron) carbonic acid benzyl ester (I2), (2R, 3R, 5R) -5- (4- (4- (4- (bis- (2- chloroethyls) amino) phenyl) butyramides
- 1 (2H)-yl of base -2- oxopyrimidins) two fluoro- 2- (methylol) tetrahydrofuran -3- bases of -4,4-) methyl -4- (4,4,5,5- tetramethyls
Penta ring -2- bases of base -1,3,2- dioxies boron) carbonic acid benzyl ester (I3) and ((2R, 3R, 5R) -5- (4- (4- (4- (bis- (2- chloroethyls) ammonia
Base) phenyl) -1 (2H)-yl of amide-based small -2- oxopyrimidins) two fluoro- 3- ((((4- (4,4,5,5- tetramethyls -1,3,2- of -4,4-
Penta ring -2- bases of dioxy boron) benzyl) oxygroup) carboxyl) oxygroup) tetrahydrofuran -2- bases) methyl -4- (4,4,5,5- tetramethyl -1,3,
Penta ring -2- bases of 2- dioxies boron) benzyl) carbonic ester (I4) preparation
The preparation of (4- (penta ring -2- bases of 4,4,5,5- tetramethyl -1,3,2- dioxies boron) phenyl) methanol (compound 2)
Bromobenzene methanol (compound 1,1.0g, 5.35mmol) will be dissolved in Isosorbide-5-Nitrae-dioxane solution of 10mL dryings,
Add in connection boric acid pinacol ester (247mg, 5.88mmol), potassium acetate and pdCl2(dppf), N2Under protective condition, it is heated to 85 DEG C
It is stirred to react.Through thin-layer chromatography detection after completion of the reaction, it removes solvent under reduced pressure, adds in 200ml ethyl acetate, then add equivalent water extraction
It takes three times, organic phase is dried over anhydrous sodium sulfate, and is concentrated under reduced pressure to give crude product.Crude product purifies (mobile phase acetic acid second through column chromatography
Ester：Petroleum ether=1:8-1:4) pale yellow oily liquid 181mg, yield 90%, ESI-MS (m/z) are obtained:235[M+H]+。
4- (penta ring -2- bases of 4,4,5,5- tetramethyl -1,3,2- dioxies boron) benzyl -1H- imidazoles -1- carboxylate (compounds
Preparation 2a)
Compound 2 (660mg, 2.82mmol) is dissolved in the anhydrous CH of 10ml2Cl2In, then add in N, N '-carbonyl dimidazoles
(915mg, 5.64mmol), N2Under protective condition, 1-2h is stirred at room temperature.After reaction, 40ml CH are added2Cl2, with equivalent
1M HCl solutions wash three times, after organic phase is dried over anhydrous sodium sulfate, are concentrated under reduced pressure to obtain white solid 787mg, yield 85%,
ESI-MS(m/z):329[M+H]+。
((2R, 3R, 5R) -5- (4- (4- (4- (bis- (2- chloroethyls) amino) phenyl) amide-based small -2- oxopyrimidins -1
Two fluoro- 3- hydroxyl tetrahydrofurans -2- bases of (2H)-base -4,4-) methyl -4- (penta ring of 4,4,5,5- tetramethyl -1,3,2- dioxies boron -
2- yls) carbonic acid benzyl ester (I2), (2R, 3R, 5R) -5- (4- (4- (4- (bis- (2- chloroethyls) amino) phenyl) amide-based small -2- oxygen
For pyrimidine -1 (2H)-yl) two fluoro- 2- (methylol) tetrahydrofuran -3- bases of -4,4-) methyl -4- (4,4,5,5- tetramethyl -1,3,
Penta ring -2- bases of 2- dioxies boron) carbonic acid benzyl ester (I3) and ((2R, 3R, 5R) -5- (4- (4- (4- (bis- (2- chloroethyls) amino) benzene
Base) -1 (2H)-yl of amide-based small -2- oxopyrimidins) two fluoro- 3- ((((4- (4,4,5,5- tetramethyl -1,3,2- dioxies of -4,4-
Penta ring -2- bases of boron) benzyl) oxygroup) carboxyl) oxygroup) tetrahydrofuran -2- bases) methyl -4- (4,4,5,5- tetramethyls -1,3,2- two
Penta ring -2- bases of oxygen boron) benzyl) carbonic ester (I4) prepare
By compound I1(274mg, 0.50mmol) is dissolved in anhydrous CH2Cl2In, then sequentially add compound 2a (197,
0.60mmol) and DMAP (61mg, 0.50mmol), N2Under protective condition, it is heated to 40 DEG C and is stirred to react.It is detected through thin-layer chromatography
After completion of the reaction, solvent is removed under reduced pressure, crude product purifies (mobile phase methanol through column chromatography：Dichloromethane=1:80-1:50) it detaches
Obtain faint yellow solid (I2、I3And I4), yield is respectively 33%, 27% and 21%.
Wherein compound I2Spectral data is：ESI-MS(m/z):809[M+H]+；1H NMR(DMSO-d6,400MHz):δ
10.99 (s, 1H, NH), 8.00 (d, 1H, J=8.0Hz, C=CH- N), 7.70 (d, 2H, J=8.0Hz, Ar-H), 7.40 (d,
2H, J=8.0Hz, Ar-H), 7.27 (m, 1H, CH), 7.03 (d, 2H, J=8.0Hz, Ar-H), 6.66 (d, 2H, J=8.0Hz,
Ar-H),6.52(m,1H,CH),6.22(m,1H,CH),5.20(s,2H,CH2),4.48(m,2H,CH2),4.23(m,1H,CH),
4.15(m,1H,OH),3.69(m,8H,CH2), 2.46 (t, 2H, J=8.0Hz, CH2), 2.42 (t, 2H, J=8.0Hz, CH2),
1.81(m,2H,CH2),1.27(m,12H,CH3) compounds I3Spectral data is：ESI-MS(m/z):809[M+H]+；1H NMR
(DMSO-d6,400MHz):δ 10.99 (s, 1H, NH), 8.16 (d, 1H, J=8.0Hz, C=CH- N), 7.71 (d, 2H, J=
8.0Hz, Ar-H), 7.42 (d, 2H, J=8.0Hz, Ar-H), 7.30 (m, 1H, CH), 7.03 (d, 2H, J=8.0Hz, Ar-H),
6.67 (d, 2H, J=8.0Hz, Ar-H), 6.31 (m, 1H, CH), 5.33 (m, 1H, CH), 5.27 (m, 2H, CH2),4.29(m,
1H, CH), 3.95 (s, 1H, OH), 3.80 (d, 2H, J=8.0Hz, CH2),3.69(m,8H,CH2), 2.42 (t, J=8.0Hz,
2H,CH2), 1.80 (t, 2H, J=8.0Hz, CH2),1.58(m,2H,CH2),1.28(m,12H,CH3) and compound I4Spectrogram
Data are：1H NMR(DMSO-d6,400MHz):δ 11.02 (s, 1H, NH), 8.05 (d, 1H, J=8.0Hz, C=CH-N),7.69
(m, 4H, Ar-H), 7.39 (d, 4H, J=8.0Hz, Ar-H), 7.29 (m, 1H, CH), 7.03 (d, 2H, J=8.0Hz, Ar-H),
6.66 (d, 2H, J=8.0Hz, Ar-H), 6.33 (m, 1H, CH), 5.44 (s, 1H, CH), 5.26 (m, 1H, CH), 5.20 (m, 4H,
CH2),5.18(m,2H,CH2),4.55(m,4H,CH2),3.69(m,8H,CH2), 2.46 (t, 2H, J=8.0Hz, CH2),2.42
(t, 2H, J=8.0Hz, CH2),1.81(m,2H,CH2),1.27(m,24H,CH2).
3 4- of embodiment (5- (bis- (2- chloroethyls) amino) -1- methyl-1 H- benzos [d] imidazoles -2- bases)-N- (1-
(two fluoro- 4- hydroxyls -5- (methylol) tetrahydrofuran -2- bases of (2R, 4R, 5R) -3,3-) -2- ketone -1,2- dihydro-pyrimidin -4- bases) -
Butyramide (I5) preparation
4- (5- (bis- (2- chloroethyls) amino) -1- methyl-1 H- benzos [d] imidazoles -2- bases)-N- (1- ((2R, 4R, 5R) -
4- ((t-Butyldimethylsilyl) oxygroup) -5- (((t-Butyldimethylsilyl) oxygroup) methyl) -3,3- difluoros tetrahydrofuran -
2- yls) -2- ketone -1,2- dihydro-pyrimidin -4- bases)-butyramide (compound 6b) preparation
By bendamustine hydrochloride (compound 5b) (454mg, 1.10mmol), EDCI (384,2.00mmol), DMAP
(227mg, 50%) and compound 4 (492mg, 1.00mmol) are dissolved in the anhydrous CH of 10ml2Cl2In, 40 DEG C of heating reaction 12h, reaction
After decompression steam solvent, crude product purifies (mobile phase ethyl acetate by column chromatography：Petroleum ether=2:1-4:1) it obtains yellowish
Color solid 656mg, yield 79%.
4- (5- (bis- (2- chloroethyls) amino) -1- methyl-1 H- benzos [d] imidazoles -2- bases)-N- (1- ((2R, 4R, 5R) -
Bis- fluoro- 4- hydroxyls -5- (methylol) tetrahydrofuran -2- bases of 3,3-) -2- ketone -1,2- dihydro-pyrimidin -4- bases)-butyramide (I5)
It prepares
Previous step product Compound 5b (656mg, 0.79mmol) is dissolved in anhydrous THF, adds in 7.9ml 1M thereto
TBAF tetrahydrofuran solutions, react at room temperature 3-5h, after reaction, decompression steams solvent, adds in 100ml water, and solid is precipitated,
Decompression filters, and the vacuum dried case of filter cake is dried to obtain crude product.Crude product purifies (mobile phase methanol by column chromatography：Dichloromethane
=1:30-1:15) (I is obtained5) faint yellow solid, yield 85%, ESI-MS (m/z):603[M+H]+；1H NMR(DMSO-d6,
400MHz):δ 11.12 (s, 1H, NH), 8.24 (d, 1H, J=8.0Hz, C=CH-N), 7.34 (d, 1H, J=8.0Hz, Ar-H),
7.27 (m, 1H, OH), 6.93 (s, 1H, Ar-H), 6.79 (m, 1H, OH), 6.34 (d, 1H, J=8.0Hz, Ar-H), 6.18 (t,
1H, J=8.0Hz, CH), 5.33 (m, 1H, CH), 4.18 (m, 1H, CH), 3.90 (m, 1H, CH), 3.81 (m, 2H, CH2),3.81
(m,8H,CH2),3.68(s,3H,CH3), 2.85 (t, 2H, J=8.0Hz, CH2), 2.58 (t, 2H, J=8.0Hz, CH2),2.05
(m,2H,CH2).
((2R, 3R, 5R) -5- (4- (4- (5- (bis- (2- chloroethyls) amino) -1- methyl-1 H- benzos [d] miaows of embodiment 4
Azoles -2- bases) amide-based small) -2- oxopyrimidins -1 (2H)-yl) two fluoro- 3- hydroxyl tetrahydrofurans -2- bases of -4,4-) methyl -4-
(penta ring -2- bases of 4,4,5,5- tetramethyl -1,3,2- dioxies boron) carbonic acid benzyl ester (I6), (((5- is (double by 4- by 4- by (2R, 3R, 5R) -5-
(2- chloroethyls) amino) -1- methyl-1 H- benzos [d] imidazoles -2- bases) amide-based small) -2- oxopyrimidins -1 (2H)-yl) -4,
4- bis- fluoro- 2- (methylol) tetrahydrofuran -3- bases -4- (penta ring -2- bases of 4,4,5,5- tetramethyl -1,3,2- dioxies boron) carbonic acid benzyl
Ester (I7) and ((2R, 3R, 5R) -5- (4- (4- (4- (bis- -2 bases of (2- chloroethyls) amino -1- methyl-1 H- benzos [d] imidazoles) fourths
- 1 (2H)-yl of amide groups -2- oxopyrimidins) two fluoro- 3- ((((4- (4,4,5,5- tetramethyl -1,3,2- dioxies boron penta of -4,4-
Ring -2- bases) benzyl) oxygroup) carboxyl) oxygroup) tetrahydrofuran -2- bases) methyl -4- (4,4,5,5- tetramethyl -1,3,2- dioxy boron
Penta ring -2- bases) benzyl) carbonic ester (I8) preparation
With reference to compound (I in embodiment 22、I3And I4) preparation method, by (I5) (I in alternative1), with chemical combination
Faint yellow solid (I is made in object 2a reactions6、I7And I8), yield is respectively 22%, 19% and 21%.
Compound I6Spectral data is：ESI-MS(m/z):863[M+H]+.1H NMR(DMSO-d6,400MHz):δ11.15
(s, 1H, NH), 8.16 (d, 1H, J=8.0Hz, CH), 7.71 (d, 2H, J=8.0Hz, Ar-H), 7.42 (d, 2H, J=8.0Hz,
), Ar-H 7.33 (d, 1H, J=8.0Hz, Ar-H), 7.29 (d, 1H, J=8.0Hz, Ar-H), 6.94 (s, 1H, Ar-H), 6.79
(m, 1H, CH), 6.32 (t, 1H, J=8.0Hz, CHCF2),5.33(m,1H,CH),5.28(s,2H,CH2),4.30(m,1H,
CH),3.81(m,2H,CH2),3.71(m,8H,CH2),3.67(s,3H,CH3), 2.85 (t, 2H, J=8.0Hz, CH2),2.59
(d, 2H, J=8.0Hz, CH2),2.05(m,2H,CH2),1.30(s,12H,CH3) compounds I7Spectral data is：ESI-MS
(m/z):863[M+H]+；1H NMR(DMSO-d6,400MHz):δ 11.11 (s, 1H, NH), 8.16 (d, 1H, J=8.0Hz, CH),
7.71 (d, 2H, J=8.0Hz, Ar-H), 7.42 (d, 2H, J=8.0Hz, Ar-H), 7.30-7.33 (m, 2H, CH), 6.95 (s,
1H,Ar-H),6.78(m,1H,CH),6.31(m,1H,CH),5.33(m,1H,CH),5.27(m,2H,CH2),4.29(m,1H,
CH),3.80(m,2H,CH2),3.67-3.70(m,11H,CH2,NCH3), 2.85 (t, 2H, J=8.0Hz, CH2),2.57(t,J
=8.0Hz, 2H, CH2),1.98(m,2H,CH2),1.29(m,12H,CH3) and compound I7Spectral data is：1H NMR
(DMSO-d6,400MHz):δ 11.08 (s, 1H, NH), 8.15 (d, 1H, J=8.0Hz, CH), 7.69 (m, 4H, Ar-H), 7.41
(d, 4H, J=8.0Hz, Ar-H), 7.30 (m, 2H, CH), 6.96 (m, 1H, Ar-H), 6.33 (m, 1H, CH), 5.34 (s, 1H,
CH),5.20-5.26(m,2H,CH2),4.55(m,4H,CH2),3.71(m,8H,CH2),3.67(s,3H,CH3),2.86(t,
2H, J=8.0Hz, CH2), 2.55 (t, 2H, J=8.0Hz, CH2),2.03(m,2H,CH2),1.29(m,24H,CH2).
Embodiment 5 tetramethyl nitrogen azoles indigo plant colorimetric method (MTT) antitumor activity in vitro
Antiproliferative activity of the compounds of this invention to 6 kinds of man―machine systems is routinely had rated using MTT.Mtt assay is wide
It is general to be measured for large-scale screening anti-tumor medicine, cell toxicity test and tumour radiotherapy sensitivity etc., select dFdC as
Positive control drug, Dipyridamole (Dipy) is as nucleoside transporter inhibitor.
Man―machine systems：Cervical cancer cell Hela, stomach cancer cell HGC27, hepatocellular carcinoma H22, lung cell A549, urgency
Property HL-60 cells, multiple myeloma cells H929.
Human normal cell line strain：Normal liver cell LO2.
Experimental method is as follows：It takes in exponential phase of growth one bottle of cell in good condition, adds in 0.25% trypsase and disappear
Change, attached cell is made to come off, be made every milliliter containing 2 × 104~4 × 104The suspension of a cell.Cell suspension inoculation is taken in 96 holes
On plate, per 180 μ L of hole, constant temperature CO is put2It is cultivated 24 hours in incubator.Change liquid, add in Dipyridamole, carboxy-lesterase and by
Try compound I1-I8(compound is diluted after being dissolved with DMSO with PBS, and Test compound concentrations are 2.5 × 10-5Mol/L), per hole
20 μ L are cultivated 72 hours.MTT is added in 96 orifice plates, per 20 μ L of hole, is reacted 4 hours in incubator.Supernatant is sucked, is added in
DMSO per 150 μ L of hole, shakes 5 minutes on plate shaker.In wavelength it is to be measured at 570nm per hole with enzyme-linked immunosorbent assay instrument
Trap calculates cell inhibitory rate.Experimental result is as shown in table 2.
Cell inhibitory rate=(negative control group OD values-tested material group OD values)/negative control group OD value × 100%.
Compound of Formula I of the present invention is tested, medicine under carboxy-lesterase effect by a series of tumour cell antiproliferative activities
Reason is the experimental results showed that (being shown in Table 2), compound of Formula I of the present invention make inhibition of the proliferation with stronger degree of human tumor cells
With, it is significantly 2-3 times stronger than comparison medicine Chlorambucil and bendamustine, wherein most the compounds of this invention it is thin
Cytoactive is close or stronger with positive drug dFdC, and the cell activity of most of the compounds of this invention is similarly comparable to dFdC difference
With the activity of Chlorambucil or bendamustine drug combinations.However, the compounds of this invention I1-I8 is under same concentrations
To the cell toxicant of Human normal hepatocyte LO2 significantly lower than tumour cell, also significantly lower than positive drug dFdC and with
Chlorambucil or bendamustine drug combinations illustrate chemical combination of the present invention to the cytotoxicity of Human normal hepatocyte LO2
Object not only has significant antitumor activity to tumour cell, but also relatively low to normal cell toxicity, thin with certain tumour
Born of the same parents' selectivity is worth further furtheing investigate.
Further, since nucleoside medicine gemcitabine high water solubility, is not easy, through cell membrane, to often rely on nucleoside transporting
Protein carrier enters into the cell, however on drug resistant tumor cell membrane, and nucleoside transporter quantity is reduced, and mutates,
Therefore it hinders drug and enters cell membrane.We are pressed down using Dipyridamole (Dipy) as nucleoside transporter in this experiment
Preparation observes the cell activity influence on gemcitabine and its conjugate.It is found from experimental result, as dFdC, to have combined Dipy same
When be administered, activity is remarkably decreased, and the compounds of this invention is administered simultaneously with Dipy, they still have stronger antitumor work
Property, thus illustrate that the compounds of this invention introduces fat-soluble aryl nitrogen mustard segment, it is fat-soluble to be improved significantly, independent of
Nucleoside transporter carrier cross-film enters cell, plays multiple antitumor action.
2 the compounds of this invention of table is to the inhibiting rate % (25 μM) of Partial tumors cell Proliferation
ND:Is not detected
6 flow cytomery apoptosis rate of embodiment
Stomach cancer cell line HGC27 is selected, and in exponential phase state, adds in digestive juice (0.125% trypsase
+ 0.01%EDTA) digestion, count 2~2.5 × 105A/ml, is made cell suspension, is inoculated in culture plate, puts constant temperature CO2Culture
It is cultivated 24 hours in case.It uses the DMEM medium cultures of 2% serum instead, adds in carboxy-lesterase and various concentration test medicine chemical combination
Object I1-8, continue culture 72 hours.Collect cell, collected by trypsinisation of the attached cell without EDTA, 1000r/min centrifugations
It is secondary (1000rpm centrifuge 5min) to wash cell with cold PBS, after counting, adds about 1 × 10 by 5min5A cell in test tube from
The heart removes supernatant.Suspension cell is in the Binding Buffer of 500 μ L.After adding in 5 μ L Annexin V-FITC mixings, 5 μ are added in
L Propidium Iodide, mixing are protected from light 5~15min.In 1 hour, the observation and inspection of flow cytometer are carried out
It surveys.Excitation wavelength Ex=488nm；Launch wavelength Em=530nm.It manages for every group 3.Cell without drug-treated is negative control.
Apoptotic cell is AnnexinV+And AnnexinV+PI+, and PI+Cell for non-viable non-apoptotic cell, non-dye cell is non-damaging cells.
It is test index to calculate the apoptotic cell in 200 cells.The apoptosis rate of practical apoptosis rate=drug apoptosis rate/negative control group.
Apoptosis rate is detected using flow cytometer, selects reactive compound I1-8To represent, as a result, it has been found that 25
μm ol/L, which has HGC27 cells, remarkably promotes apoptosis of tumor cells, and apoptosis rate can reach 72-91%, and most of inventionization
Close the gemcitabine apoptotic effect that object is better than under same concentration (25 μm of ol/L apoptosis rates are 77%).
Above-mentioned experimental result is preferred compound I in compound of Formula I of the present invention1-I8The pharmacological results, to the present invention
The pharmacological effect for meeting other compounds of general formula I also has directive significance, since compound of Formula I of the present invention has and lucky
His shore of west or the similar chemical constitution of aryl nitrogen mustard and space structure, thus with the same or similar pharmacological effect effect, pass through
Cross above-mentioned preferred compound I1-I8The verification of pharmacological evaluation illustrates that compound of Formula I is respectively provided with different degrees of antitumor activity.
Claims (8)
1. gemcitabine-mustargen the conjugate and its pharmaceutically acceptable salt of a kind of target cancer cell high level ROS, feature
It is with structure shown in general formula I：
In general formula I：
R is representedOr
R1Represent H or
R2Represent H or
2. gemcitabine-mustargen conjugate of target cancer cell high level ROS according to claim 1, it is characterised in that
R, R in the structure of the conjugate general formula I1、R2Selected from following combination：
R1=H, R2=H；
OrR2=H；
OrR1=H,
Or
OrR1=H, R2=H；
OrR2=H；
OrR1=H,
Or
3. a kind of preparation side of gemcitabine-mustargen conjugate of the target cancer cell high level ROS described in claims 1 or 2
Method, it is characterised in that include the following steps：
(1) compound 4 is obtained by the reaction with tert-butyl chloro-silicane in the presence of imidazoles in compound 3,
(2) in the presence of condensing agent 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides and 4-dimethylaminopyridine,
Compound 4 obtains compound 6 with 5 condensation reaction of compound,
Wherein, R is representedOr
(3) compound 6 obtains general formula compound Ia described in claim 1 under the action of deprotecting regent,
4. preparation method as claimed in claim 3, it is characterised in that further include step (4) after step (3)：
(4) in the presence of DMAP or n,N-diisopropylethylamine, compound IaCompound I is obtained by the reaction with compound 2ab、IcWith
Id,
Wherein, R is representedOrR ' is represented
Ia、Ib、Ic、IdBelong to compound of Formula I of the present invention.
The compound 2a is
5. preparation method as claimed in claim 4, it is characterised in that the compound 2a is prepared using following steps：It is right
Bromobenzene methanol reacts under the catalysis of [1,1'- bis- (diphenylphosphino) ferrocene] palladium chloride with connection boric acid pinacol ester
To compound 2, compound 2a is obtained by the reaction in compound 2 and N, N '-carbonyl dimidazoles.
A kind of 6. pharmaceutical composition, it is characterised in that the general formula I as claimed in claim 1 or 2 including treating upper effective dose
Compound or its pharmaceutically acceptable salt and the pharmaceutical composition of acceptable carrier or auxiliary material.
7. gemcitabine-mustargen conjugate of target cancer cell high level ROS as claimed in claim 1 or 2 is preparing anti-swell
Application in tumor medicine.
8. the use as claimed in claim 7, it is characterised in that the tumour for acute leukemia, Huppert's disease, liver cancer,
Lung cancer, gastric cancer or cervical carcinoma.
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| CN110183504A (en) * | 2019-06-13 | 2019-08-30 | 湖南大学 | A kind of gemcitabine pro-drug and its preparation method and application with tumor-targeting |
| CN115028594A (en) * | 2020-06-03 | 2022-09-09 | 吴卫东 | Emotitabine medicinal precursor compound and preparation method and medical application thereof |
| CN115636842A (en) * | 2022-09-05 | 2023-01-24 | 沈阳药科大学 | Preparation method and application of oxidation-sensitive combretastatin derivative |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110183504A (en) * | 2019-06-13 | 2019-08-30 | 湖南大学 | A kind of gemcitabine pro-drug and its preparation method and application with tumor-targeting |
| CN110183504B (en) * | 2019-06-13 | 2023-07-07 | 湖南大学 | Gemcitabine prodrug with tumor targeting function and preparation method and application thereof |
| CN115028594A (en) * | 2020-06-03 | 2022-09-09 | 吴卫东 | Emotitabine medicinal precursor compound and preparation method and medical application thereof |
| CN115636842A (en) * | 2022-09-05 | 2023-01-24 | 沈阳药科大学 | Preparation method and application of oxidation-sensitive combretastatin derivative |
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