CN106632297A - Docetaxel side chain 2'-derived novel taxanes antitumor compound as well as synthesis method and application thereof - Google Patents
Docetaxel side chain 2'-derived novel taxanes antitumor compound as well as synthesis method and application thereof Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
The invention discloses a docetaxel side chain 2'-derived novel taxanes antitumor compound shown as the general structure formula (I) as well as a synthesis method and application thereof. In the formula, X is N or O, R is H or acetyl, and R' is H, nitryl, cyano, methoxyl or a halogen group. The synthesis method takes 10-deacetylbaccatin is used as a raw material; after 7-OH and 10-OH are protected, condensation with phenylisoserine (side chain) protecting 3'-NHBoc and 2'-OH in the presence of condensation agents DCC (Dicyclohexylcarbodiimide) and DMAP (Dimethylaminopyridine) is performed; esterification with substituted phenyl isoxazole carboxylic acid or substituted phenyl oxadiazole methyl carboxylic acid in the presence of the DCC and the DMAP is performed; finally, a protecting group is removed to obtain the compound. The compound disclosed by the invention has relatively high activity on tumor cells.
Description
Technical field
The present invention relates to 2 '-derivative novel taxane anti-tumor compounds of class Docetaxel side chain and its synthesis
Method and application, belong to pharmaceutical sanitary field.
Background technology
Cancer has become the second largest fatal disease of the mankind after cardiovascular and cerebrovascular disease, at the same with the deterioration of environment with
And aging population, this problem can project more.In China, situation also allows of no optimist, and the Chinese tumour issued for 2013 is stepped on
Note is reported in year, nationwide interior pathogenesis of cancer situation very severe, and incidence and mortality is in lasting ascendant trend.Expect
The year two thousand twenty, the annual cancer illness sum of China will be up to 6,600,000, and dead sum will be up to 3,000,000 left stones.Therefore, in global range, resist
Tumour medicine is by with the very big market demand.According to IMS data statistics, surmounted after blood lipid-lowering medicine from 2007, antineoplastic
Thing is always the bellwether of Global Medicine market.
Fact proved, natural products is most potential antineoplastic source.Between past more than 20 years, there is 63%
Antineoplastic directly or indirectly derive from natural products.Important a member in as natural products family, taxol and its
Semi-synthesis product Docetaxel is undoubtedly most successful also most representational antineoplastic.
1966, taxol was extracted from the bark of Ramulus et folium taxi cuspidatae of the Pacific Ocean by Wall and Wani obtain first, and is named
For Taxol.Because of its good antitumor activity and the mechanism of uniqueness, taxol was approved by the fda in the United States for treatment in 1992
Advanced ovarian cancer, is approved for treating metastatic breast cancer again after 2 years.Until current, taxol and Docetaxel by
Confirmation is maximally efficient antineoplastic, is clinically widely used in oophoroma, breast cancer, ED-SCLC and AIDS
Related card ripple agent sarcoma, carcinoma of urinary bladder, prostate cancer, cancer of the esophagus, brain tumor, laryngocarcinoma, cervical carcinoma and carcinoma of endometrium etc. are more
The treatment of type cancer.With going deep into for research, its clinical indication will further expand.
Although taxol and Docetaxel are very important antineoplastics, due to poorly water-soluble and its
The MDR problem of tumour cell self-growth in chemotherapy process（MDR）And limit their extensive utilizations clinically.
In order to solve the problems, such as drug resistance of tumor cell, expand the application clinically of taxol and Docetaxel.Meanwhile, in order to obtain
Selective high activity paclitaxel derivatives, it is necessary to which its structure is transformed.
The content of the invention
It is an object of the invention to provide a kind of raw material be easy to get, the convieniently synthesized, Docetaxel with antitumor activity
Side chain 2 '-derivative novel taxane anti-tumor compounds and its synthetic method.
The present invention's realizes that process is as follows：
General structure（I）Shown compound,
X is N or O；
R is H or acetyl group；
R ' is H, nitro, itrile group, methoxyl group or halogen radical.
General structure（I）The preparation method of shown compound, comprises the following steps：
（1）With natural products 10- deacetylate bar Ka Ting（10-DAB）10-OH acetylations are carried out for raw material, three chloroethenes are then used
Epoxide formyl chloride（TrocCl）Protection 7-OH；
（2）2 '-the OH and 3 '-NHBoc of phenylisoserine are protected with 2,2- dimethoxys acetone or p-tolyl aldehyde；
（3）In the presence of DCC and DMAP,（1）With（2）Product carry out coupling reaction；
（4）Side chain protective group is sloughed in acid medium；
（5）In the presence of dehydrating agent, entered with-the OH of side chain 2 ' using substituted benzene isoxazole carboxylic acid or substituted benzene oxadiazole carboxylic acid
Row esterification；
（6）Slough the hydroxyl protecting group on bar card booth ring.
Specifically, containing the synthetic method of 7-OH and 10-OH bearing taxanes, 10-DAB is protected with protection group first
In 7-OH and 10-OH.
The synthetic route of Docetaxel side chain 2 '-derivative novel taxane 12 is shown below.
The structure of Fang isoxazoles carboxylic acid and (aryl-oxadiazole) carboxylic acid used in the present invention is shown below.
The structure of the typical novel taxane anti-tumor compounds containing Docetaxel skeleton in part is shown below.
According to structure-activity relationship, C13Side chain C2'-OH is significant to the antitumor activity for keeping Docetaxel, takes
In generation, sloughs OH activity and can significantly reduce and even disappears, but it is acylated after will not lose activity because in the cell can be through interior
Source esterase hydrolyzed discharges the Docetaxel of activity.Therefore, on the premise of ensureing that Docetaxel active site is constant, send out
Some are contained the small molecule of Fang isoxazoles or (aryl-oxadiazole) skeleton and are bonded in C by being esterified coupling by a person of good sense2'-OH is obtained
C2'-Fang isoxazoles and C2'-(aryl-oxadiazole) Docetaxel derivatives, in the cell Jing hydrolysis discharges active component.Send out
A person of good sense is contemplated by such synergy, can improve antitumor activity, or improves the quick of multidrug resistance tumor cells strain
Perception.Based on this, inventor's design has synthesized a series of Fang isoxazoles-Docetaxels and (aryl-oxadiazole) Docetaxel
Derivative, and in vitro it is assessed to different tumour cells and the cytotoxicity to mdr cell by MTT methods.
6 are obtained after the selective protection of phenylisoserine methyl ester 5, the imido grpup and hydroxyl in compound 6 is needed before coupling
Protect, following several protection groups can be selected：P-methoxybenzal-dehyde, 2,2- dimethoxy propanes, 1,3- dichloroacetones and
1,1- dichloroacetones etc..
Although 2,2-dimethoxypropane structure is simple, inventor has found the remove-insurance selected during deprotection below
Guard strip part takes off can also Boc parts；1,3- dichloroacetones and 1,1- dichloroacetones then belong to the larger reagent of toxicity；And it is right
Methoxybenzaldehyde raw material is easy to get, cheap, while mild condition during deprotection.Therefore, inventor is selected to methoxybenzene
Formaldehyde can obtain protecting product 7 as protection group with high productivity, and benzene oxazolin carboxylic acid 8, the latter are quantitatively obtained after hydrolysis
In the presence of DCC and DMAP, in 18-52 DEG C and 2（Scheme 1）Dehydrating condensation is carried out, compound 9 is almost quantitatively obtained.
In the presence of TsOH, the P-methoxybenzal-dehyde protection group of side chain in 9 is sloughed, generate compound 10.Next, 10 again with virtue
Isoxazole carboxylic acid is condensed to yield compound 11 in the presence of DCC and DMAP.Finally, 11 protection group is removed with zinc powder reduction
Troc, obtains 2 '-derivative novel taxane antitumoral compounds 12.
Synthesis containing 7-OH and 10- acetylation taxanes is shown below, in the presence of a catalyst, can be with acylating reagent
The 10-OH acylations for optionally making 10-DAB obtain product 13, and yield is almost quantitative.Because catalyst can be with C9And C10's
Two oxygen atom chelatings, make C10- OH is activated, therefore is preferentially acylated.
Then with TrocCl protection 13 7-OH, by steps such as coupling reaction and Deprotections, its process with synthesis
2 '-derivative novel taxane anti-tumor compounds 12（Scheme 2）It is essentially identical, the final product for simply obtaining is 2 '-
Derivative novel taxane anti-tumor compounds 18 rather than 12.
The mentality of designing of the present invention is to keep Docetaxel overall skeleton to include C13(the 2 ' of side chainR,3′S) three-dimensional structure
In the case that type is constant, obtain a series of in the small molecule segment that C2 '-OH positions introduce both biologically actives by esterification
New Taxane derivative, and in vitro it is assessed to different tumour cells by MTT methods（Normal and persister）It is anti-
Proliferation activity, filters out the Taxane derivative with greater activity as drug candidate.
Specific embodiment
The synthesis of the 7,10-diTroc- bar cards booth 2 of embodiment 1
Under the conditions of 63-95 DEG C, by tri-chloroethoxy base dicarbonyl chloride（TrocCl）20.5 mmol are slowly dropped to pyridinium dissolution
10-DAB（10 mmol）In 1, magnetic agitation, TLC（Petroleum ether-AcOEt）Reactant liquor is cooled to into room temperature after monitoring reaction completely
And it is removed under reduced pressure pyridine, residue AcOEt/H2It is neutral to adjust pH value of solution with HCl after O dissolved dilutions.Solution left standstill is layered, point
Go out organic phase, water is extracted with AcOEt, merge organic phase and use H successively2O, saturated common salt water washing, anhydrous MgSO4It is dried, Jing
Removal of solvent under reduced pressure obtains crude product, and Jing column chromatographies obtain 7,10-diTroc- bar cards booth 2, yield：87.4%, m.p. 233.1-
234.2℃。1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 8.1 Hz, 2H), 7.63 (t, J = 7.4
Hz, 1H), 7.50 (t, J = 7.5 Hz, 2H), 6.40 (s, 1H), 5.73 – 5.55 (m, 2H), 5.05
(d, J = 12.0 Hz, 1H), 5.00 (d, J = 9.2 Hz, 1H), 4.82 (dd, J = 9.6, 2H), 4.63
(dd, J = 9.6, 2H), 4.34 (d, J = 8.4 Hz, 1H), 4.17 (d, J = 8.4 Hz, 1H), 4.03
(d, J = 6.8 Hz, 1H), 3.54 – 3.46 (m, 1H), 2.72 – 2.59 (m, 1H), 2.31 (s, 5H),
2.14 (s, 3H), 2.09 – 2.01 (m, 1H), 1.84 (s, 3H), 1.71 (s, 1H), 1.15 (s, 3H),
1.10 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 170.77, 166.96, 153.24, 153.18,
146.52, 133.77, 130.09, 129.22, 128.68, 94.57, 94.40, 83.82, 80.46, 78.68,
77.15, 77.08, 76.60, 76.36, 74.28, 67.83, 60.57, 56.19, 42.75, 38.46, 33.25,
26.68, 22.56, 21.12, 20.18, 15.31, 14.27, 10.64. HRMS(FAB): calcd for
C35H38Cl6O14 (M+NH4 +): 912.0707, found: 912.0709.
The synthesis of the 10-Ac- bar cards booth 13 of embodiment 2
The mol of acetic anhydride 0.2 is added the mmol of 10-DAB 10 and ZnCl dissolved with the mL of anhydrous THF 80220 mmol solution
In, react under room temperature condition, it is added thereto to AcOEt/H after TLC monitoring reactions completely2O simultaneously uses pasty state NaHCO3Adjust pH value of solution be
Alkalescence.Stratification, separates organic phase, and water is extracted with AcOEt, merges organic phase and uses H successively2O, saturated common salt washing
Wash, anhydrous MgSO4It is dried, Jing removal of solvent under reduced pressure obtains crude product, the sterling of 10-Ac- bar cards booth 13 is obtained after recrystallization, is that white is solid
Body, yield：93%.1H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 7.7 Hz, 2H), 7.63 (t, J =
7.3 Hz, 1H), 7.50 (t, J = 7.6 Hz, 2H), 6.34 (s, 1H), 5.64 (d, J = 6.9 Hz,
1H), 5.00 (d, J = 9.1 Hz, 1H), 4.90 (t, J = 7.9 Hz, 1H), 4.48 (dd, J = 10.5,
6.8 Hz, 1H), 4.32 (d, J = 8.4 Hz, 1H), 4.17 (d, J = 8.3 Hz, 1H), 3.89 (d, J =
6.9 Hz, 1H), 2.66 – 2.46 (m, 2H), 2.34 – 2.28 (m, J = 7.1 Hz, 5H), 2.26 (s,
3H), 2.07 (s, 3H), 1.95 – 1.82 (m, 2H), 1.73 (s, 1H), 1.68 (s, 3H), 1.12 (s,
6H).13C NMR (100 MHz, CDCl3) δ 204.19, 171.37, 170.67, 167.06, 146.45, 133.70,
131.79, 130.10, 129.32, 128.65, 84.46, 80.77, 79.08, 76.44, 76.24, 74.92,
72.30, 67.92, 58.69, 46.14, 42.70, 38.61, 35.60, 26.96, 22.59, 20.92, 15.60,
9.44.
The synthesis of the 7-Troc-10-Ac- bar cards booth 14 of embodiment 3
Under the conditions of 50-93 DEG C, by tri-chloroethoxy base dicarbonyl chloride（TrocCl）9.8 mmol are slowly dropped to pyridinium dissolution
Compound 13（9.3 mmol）In, reactant liquor is cooled to room temperature and removes pyridine by magnetic agitation after TLC monitoring reactions completely,
Residue AcOEt/H2It is alkalescent to reconcile pH value of solution with HCl after O dissolved dilutions.Solution left standstill is layered, and separates organic phase, water
Extracted with AcOEt, merge organic phase and use H successively2O, saturated common salt water washing, anhydrous MgSO4It is dried, removes solvent and obtain slightly
Product, Jing column chromatographies obtain 7-Troc-10-Ac- bar cards booth 12, yield 84.2%.m.p.154.8-158.2℃.1H NMR (400
MHz, CDCl3) δ 8.11 (d, J = 8.1 Hz, 2H), 7.63 (t, J = 7.4 Hz, 1H), 7.50 (t, J
= 7.5 Hz, 2H), 6.40 (s, 1H), 5.73 – 5.55 (m, 2H), 5.05 (d, J = 12.0 Hz, 1H),
5.00 (d, J = 9.2 Hz, 1H), 4.89 (dd, J = 13.9, 5.3 Hz, 1H), 4.66 (dd, J =
12.0, 0.9 Hz, 1H), 4.34 (d, J = 8.4 Hz, 1H), 4.17 (d, J = 8.4 Hz, 1H), 4.03
(d, J = 6.8 Hz, 1H), 3.54 – 3.46 (m, 1H), 2.72 – 2.59 (m, 1H), 2.31 (s, 5H),
2.18 (s, 3H), 2.14 (s, 3H), 2.09 – 2.01 (m, 1H), 1.84 (s, 3H), 1.71 (s, 1H),
1.15 (s, 3H), 1.10 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 201.98, 170.77, 169.20,
166.96, 153.24, 145.07, 133.77, 131.60, 130.09, 129.22, 128.68, 94.57, 83.82,
80.46, 78.68, 76.32, 75.92, 74.28, 67.83, 65.87, 56.19, 47.39, 42.75, 38.46,
33.25, 26.68, 22.56, 20.82, 20.18, 15.27, 10.64. HRMS(FAB): calcd for
C34H39Cl3O13 (M+NH4 +): 778.1800, found: 778.1804.
Embodiment 4 (2 'R,3′S)-NThe synthesis of-Boc- phenylisoserine methyl esters 6
CH will be used2Cl2(Boc) of dissolving2The mmol of O 50 are added and are used CH2Cl2/H2(the 2 ' of O dissolvingsR,3′S)-phenylisoserine
In the mmol of methyl esters 50 and the g solution of potassium hydroxide 3.58, reaction under room temperature is carried out, in the completely backward reactant liquor of TLC monitorings reaction
Add H2O, stratification separates organic phase, and water mutually uses CH2Cl2Extraction, merge organic phase and wash with water, anhydrous MgSO4It is dry
It is dry.Solvent afforded crude material is removed, (2 ' are recrystallized to giveR,3′S)-N- Boc- phenylisoserine methyl esters, yield 93.2%.
The synthesis of the Ben oxazolin carboxylate methyl esters compound 7 of embodiment 5
46.4 mmol compounds 6, the mmol of P-methoxybenzal-dehyde 51 and the g of p-methyl benzenesulfonic acid pyridinium 0.1 is molten with toluene
Solution, backflow, after TLC monitoring reactions completely room temperature is cooled to, and is removed solvent and is obtained compound 7.
The synthesis of the Ben oxazolins carboxylic acid 8 of embodiment 6
The MeOH of above-mentioned product 7 is dissolved, dilute NaOH is added, is stirred under room temperature, after TLC monitoring reactions completely MeOH is removed, remained
Excess AcOEt/H2O dissolved dilutions, stratification.AcOEt is added in Xiang Shuixiang, and it is acid to adjust pH with watery hydrochloric acid.It is mixed
Liquid stratification is closed, organic phase is separated, water is extracted with AcOEt, merges organic phase and water washing, anhydrous MgSO4It is dried, removes
Solvent, obtains Ben oxazolins carboxylic acid 8, two step gross production rates 92%, m.p.132-133 DEG C.1H NMR (400 MHz, CDCl3) δ
7.50 – 7.31 (m, 7H), 6.94 (d, J = 8.6 Hz, 2H), 6.41 (s, 1H), 5.42 (s, 1H),
4.64 (d, J = 4.2 Hz, 1H), 3.83 (s, 3H).13C NMR (100 MHz, CDCl3) δ 172.73,
160.44, 151.71, 128.89, 128.33, 128.17, 126.32, 114.00, 92.44, 82.57, 81.14,
63.68, 55.32, 27.82.
The synthesis of the coupled product 9 of embodiment 7
By 11 mmol Ben oxazolins carboxylic acids 8,10 mmol 7,10-diTroc- bar card booths 2,20 mmol DCC and 1 mmol
DMAP CH2Cl2Dissolving, reacts complete to reaction under room temperature.Insoluble matter is leached, filtrate Jing removal of solvent under reduced pressure is obtained being coupled and produced
Thing 9.
Embodiment 8 takes off the synthesis of side chain protected based products 10
Above-mentioned coupled product crude product and the mmol of p-methyl benzenesulfonic acid 10 MeOH are dissolved, is reacted under room temperature, TLC monitorings have been reacted
Entirely.Reactant liquor Jing removal of solvent under reduced pressure must take off side chain protected based products crude product, be purified with column chromatography, obtain white powder product 10.
：Two step gross production rates：92.1%.m.p.（159.5-161.2℃）.1H NMR (400 MHz, CDCl3) δ 8.12
(d, J = 7.5 Hz, 2H), 7.64 (t, J = 7.3 Hz, 1H), 7.52 (t, J = 7.6 Hz, 2H), 7.46
– 7.32 (m, 5H), 6.30 – 6.18 (m, 2H), 5.71 (d, J = 6.8 Hz, 1H), 5.62 – 5.52
(m, 1H), 5.46 (d, J = 8.0 Hz, 1H), 5.34 – 5.23 (m, 1H), 4.97 (d, J = 9.1 Hz,
1H), 4.93 (d, J = 11.8 Hz, 1H), 4.80 (d, J = 1.2 Hz, 2H), 4.69 – 4.57 (m,
2H), 4.35 (d, J = 8.4 Hz, 1H), 4.19 (d, J = 8.4 Hz, 1H), 3.93 (d, J = 6.8 Hz,
1H), 2.71 – 2.58 (m, 1H), 2.41 (s, 3H), 2.34 (s, 2H), 2.13 – 2.03 (m, 1H),
1.97 (s, 4H), 1.87 (s, 3H), 1.72 (d, J = 10.0 Hz, 1H), 1.37 (s, 9H), 1.29 (s,
3H), 1.22 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 200.77, 170.39, 166.90, 155.41,
153.22, 142.56, 133.85, 131.98, 130.19, 128.94, 128.89, 128.76, 128.13,
126.78, 94.19, 83.67, 80.76, 80.29, 79.16, 78.64, 76.38, 74.16, 73.56, 72.26,
56.23, 46.88, 43.15, 35.29, 33.28, 28.21, 26.32, 22.54, 20.97, 14.71, 10.72.
HRMS(FAB): calcd for C49H55Cl6NO18 (M+NH4 +): 1175.1865, found: 1175.1835.
The synthesis of the C2 '-Fang isoxazoles of embodiment 9-Docetaxel coupled product 11
By different 0.11 mmol Fang isoxazole carboxylic acids, 0.1 mmol compounds 10, the 0.2 mmol DCC and 10 mg for replacing
DMAP CH2Cl2Dissolving, reacts about 1 h-4.5 h, TLC under room temperature condition（Petroleum ether-AcOEt）Monitoring reaction.Leach not
Molten thing, filtrate Jing removal of solvent under reduced pressure obtains C2 '-virtue isoxazole-crude product of Docetaxel coupled product 11, not purified direct
For next step reaction.
The synthesis of the C2 ' of embodiment 10-derivative novel taxane anti-tumor compounds 12
The crude product of 0.1 mmol coupled products 11,2 mmol Zn powder and 0.26 mL AcOH AcOEt is dissolved, is reacted under room temperature,
TLC monitoring reactions.Zn powder is leached, filtrate uses saturation NaHCO3Solution adjusts pH for alkalescence.Mixed liquor stratification, separates organic
Phase, water is extracted with AcOEt, is merged organic phase and is washed with water, anhydrous MgSO4It is dried, removes solvent afforded crude material, Jing column chromatographies
Purifying, obtains target product 12.
：Two step gross production rates 79.2%.m.p.（154.6-156.4℃）.1H NMR (400 MHz, CDCl3) δ 8.12
(t, J = 7.5 Hz, 2H), 7.85 (br, s, 1H), 7.61 (d, J = 7.4 Hz, 2H), 7.52 (br, s,
5H), 7.46 – 7.37 (m, 5H), 7.35 (br, s, 1H), 6.47 – 6.14 (m, 1H), 5.70 (t, J =
7.5 Hz, 1H), 5.65 – 5.48 (m, 2H), 5.25 (d, J = 9.6 Hz, 1H), 5.07 – 4.89 (m,
1H), 4.38 – 4.18 (m, 4H), 3.94 (dd, J = 18.3, 6.8 Hz, 1H), 2.67 – 2.54 (m,
1H), 2.49 (s, 1H), 2.39 (s, 2H), 2.27 (s, 1H), 2.00 (s, 3H), 1.86 (s, 2H),
1.77 (s, 3H), 1.36 (s, 9H), 1.25 (s, 6H), 1.14 (s, 3H). 13C NMR (100 MHz,
CDCl3) δ 211.41, 170.32, 169.71, 167.15, 167.01, 163.18, 159.33, 155.68,
155.38, 138.90, 138.45, 135.83, 133.69, 130.92, 130.80, 130.18, 129.19,
129.09, 128.83, 128.72, 128.05, 127.60, 126.92, 126.76, 126.55, 108.95,
84.20, 81.07, 78.92, 78.80, 76.01, 75.02, 74.83, 74.51, 72.53, 71.93, 65.59,
57.63, 49.25, 46.45, 43.10, 36.93, 35.75, 33.89, 30.57, 28.17, 26.46, 26.36,
25.60, 24.91, 22.69, 22.57, 20.91, 19.19, 14.29, 13.73, 9.91. HRMS(FAB):
calcd for C53H58N2O16 (M+H+): 979.3865, found: 979.3847.
The extracorporeal anti-tumor cell-proliferation activity of embodiment 11 is evaluated
Inventor adopts different tumor cell line Hela（Cervical cancer cell）、A549（Lung carcinoma cell）、A2780（Oophoroma is thin
Born of the same parents）、MCF-7（Breast cancer cell）And 6 kinds of cell lines such as multidrug resistance tumor cells strain A2780-MDR and MCF-7-MDR, with
Docetaxel（Docetaxel）As positive control, 16 new aryl isoxazole-polyenoid Japanese yews are evaluated by MTT methods
Antiproliferative activity of the 01 derivatives to different tumour cells.
For A549 cells, compound 12f, 12g, 18b, 18d and 18f show the suppression similar to Docetaxel and live
Property.For A2780 cells, compound 12d, 12h, 18a, 18b, 18d, 18e, 18g and 18h show preferable inhibitory activity,
Wherein the inhibitory activity of 12d, 18b and 18d is stronger than Docetaxel 2 times.For MCF-7 cells, compound 12c, 12d, 12f,
12g, 18a, 18b, 18d, 18g and 18h show the activity similar to Docetaxel.
From horizontal analysis, compound 18b shows preferable inhibitory activity to Hela, A549, A2780 and MCF-7, its
In it is stronger than Docetaxel to the inhibitory activity of Hela cells 3 times.Although compound 18c does not have to A549, A2780 and MCF-7
Preferable inhibitory activity is shown, but the ability of its Selective depression Hela cells is stronger than Docetaxel 4 times.Compound
18g shows preferable activity in addition to performing poor to A549 to Hela, A2780 and MCF-7.It should be noted that changing
Compound 18h shows the ability of selective preferential suppression Hela cells, and its activity is stronger than Docetaxel 5 times.
See on the whole, C10The inhibitory activity of compound that position is acetylation is better than what is be not acetylation, this 18a,
18b, 18c, 18g and 18h are to being especially apparent for showing in the inhibitory activity of Hela cells.This explanation C10Acetylation is to a certain degree
On can increase the inhibitory activity of these compound on tumor cell.
What is more important, all these compounds improve in various degree two cells of resistant tumors A2780-MDR
With sensitiveness of the MCF-7-MDR to Docetaxel.For A2780-MDR cells, compound 12c, 12d, 12e, 12g and
12d performances are preferable, and wherein the activity of compound 12g is stronger than Docetaxel 15 times.For MCF-7-MDR, compound 18f and
The inhibitory activity of 18h is stronger than Docetaxel 10 times.
According to result above, inventor thinks the Jing hydrolysis in the cell of C2 '-Fang isoxazoles-Docetaxel derivative
Active component is discharged, two parts play a role jointly, make antitumor activity increase.As for being therebetween separate
Or mutual collaboration to play a role also need and further study.
Claims (2)
1. general structure（I）Shown compound,
X is N or O；
R is H or acetyl group；
R ' is H, nitro, itrile group, methoxyl group or halogen radical.
2. the preparation method of the compound described in claim 1, it is characterised in that comprise the following steps：
Or
（1）10-OH acetylations are carried out as raw material with natural products 10- deacetylate bar Ka Ting, then with tri-chloroethoxy base formyl
Chlorine protects 7-OH；
（2）2 '-the OH and 3 '-NHBoc of phenylisoserine are protected with 2,2- dimethoxys acetone or p-tolyl aldehyde；
（3）In the presence of DCC and DMAP,（1）With（2）Product carry out coupling reaction；
（4）Side chain protective group is sloughed in acid medium；
（5）In the presence of dehydrating agent, entered with-the OH of side chain 2 ' using substituted benzene isoxazole carboxylic acid or substituted benzene oxadiazole carboxylic acid
Row esterification；
（6）Slough the hydroxyl protecting group on bar card booth ring.
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