CN106632296A - Novel taxane anti-tumor compound as well as synthesis method and application thereof - Google Patents
Novel taxane anti-tumor compound as well as synthesis method and application thereof Download PDFInfo
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Abstract
The invention discloses a novel taxane anti-tumor compound shown in a structural formula (I). 10-DAB (10-deacetylbaccatin) is adopted as a raw material, and is condensed with phenylisoserine (side chain) with protected 3'-NH2 and 2'-OH in the presence of condensing agents DCC and DMAP after 7-OH and 10-OH are protected, the side chain and a protecting group on a baccatin ring are simultaneously removed in the presence of zinc powder, and coupling is performed with substituted phenylisoxazole in an alkaline medium to obtain a target product. The compound has relatively high anti-tumor activity. (The structural formula (I) is shown in the description.).
Description
Technical field
The present invention relates to novel taxane antitumoral compounds and its synthesis derived from the new-N of paclitaxel lateral chain 3 ' of a class
Method and antitumor activity application, belong to pharmaceutical sanitary field.
Technical background
Cancer has become the second largest fatal disease of the mankind after cardiovascular and cerebrovascular disease, meanwhile, with the deterioration of environment
And aging population, this problem can project more.The China's tumour registration annual report issued for 2013 claims, nationwide interior cancer
Disease morbidity situation very severe, incidence and mortality is in lasting ascendant trend.The year two thousand twenty is expected, the annual cancer of China is suffered from
Sick sum is up to 6,600,000, and dead sum will be up to 3,000,000 or so.Therefore, in the world antineoplastic have it is very big
The market demand.According to IMS data statistics, surmounted after blood lipid-lowering medicine from 2007, antineoplastic is always Global Medicine market
Bellwether.
Fact proved, natural products is most potential antineoplastic source.Between past more than 20 years, there is 63%
Antineoplastic it is direct or indirect from natural products.Important a member in as natural products family, taxol and
It is also most representational antineoplastic that its semi-synthesis product Docetaxel and Cabazitaxel are undoubtedly most successful.
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 action of uniqueness, taxol was approved by the fda in the United States in 1992
Treatment advanced ovarian cancer, is approved for treating metastatic breast cancer again after 2 years.Until current, taxol and Docetaxel
It is maximally efficient antineoplastic to have been found to, be 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
Deng the treatment of polytype cancer.With going deep into for research, its clinical indication will further expand.
In June, 2010, the taxane Cabazitaxel of U.S. FDA approval is the clinic use of currently the only treatment prostate cancer
Medicine.Chemically analyze in structure, Cabazitaxel is with the unique difference of Docetaxel, the C on the latter's Ba Ka booth rings7And C10Even
Free hydroxyl is connect, and Cabazitaxel is then methoxyl group.Only little difference in structure but result in different purposes clinically.
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 is easy to get, convieniently synthesized, the class taxane with antitumor activity
Derivative and preparation method thereof.
The present invention's realizes that process is as follows：
General structure（I）Shown compound,
R is H or acetyl group；
R ' is selected from H ,-CH3、-NO2、-CN、CH3O-, halogen radical.
Above-claimed cpd is preferably：
。
The preparation method of above-claimed cpd, comprises the following steps：
（1）With natural products 10- deacetylate bar Ka Ting（10-DAB）For raw material, with tri-chloroethoxy base formyl chloride（TrocCl）Together
When protect 7-OH and 10-OH, or first make 10-OH acetylations, then protect 7-OH with TrocCl；
（2）- the OH of side chain 2 ' and 3 '-NH is protected with trichloroacetaldehyde2, or with P-methoxybenzal-dehyde protection 2 '-OH and 3 '-
NHBoc；
（3）In the presence of DCC and DMAP, step（1）With（2）Product carry out coupling reaction；
（4）Slough the protection group on side chain and Ba Ka booth rings simultaneously in the presence of zinc powder；
（5）In alkaline medium and in the presence of DMAP, substituted benzene isoxazole carboxylic acid chloride and step（4）Product reaction obtain
General structure（I）Shown compound.
Specifically, the synthetic route of 7,10-diTroc bars Ka Ting and 10-Ac-7-Troc bar Ka Ting is such as（Formula 1）With（Formula
2）It is shown.
The synthetic route of novel taxane is as shown in method 1 derived from the-N of paclitaxel lateral chain 3 '.First with the different silk ammonia of phenyl
Sour methyl esters 4 is that raw material obtains Ben oxazolins carboxylate methyl ester 5 with the reaction of protection group trichloroacetaldehyde, with 7,10- after the latter's hydrolysis
DiTroc bar cards booth 1 or 7-Troc-10-Ac bar cards booth 3 are coupled and generate 7, and the reduction in the presence of zinc powder removes side chain and bar simultaneously
Deprotection on card booth ring, then in the presence of alkaline medium catalyst neutralisation with phenyl（Or substituted-phenyl）Isoxazole formyl
Chlorine reaction finally gives paclitaxel lateral chain 3 '-derivative novel taxane [1].
Method 1：
The phenyl that the present invention is used（Or substituted-phenyl）The structure of isoxazole formyl chloride is shown below.
Note：The synthesis of taxane derived from the-N of paclitaxel lateral chain 3 ' in method 1, if using 7-Troc-10-Ac- from 6 → 7
When bar card booth 3 replaces 7,10-diToc- bar card booths 1, then final product is：
The advantage of method 1 is that route is short, it is easy to operated, but the step of 7 → 8 in conversion ratio it is low, it is pure that product 8 also needs to column chromatography
Change.To solve the above problems, inventor has invented Article 2 synthetic route（Method 2）.Although ratio method single step reaction more than 1,
Reaction gross production rate is higher and more easy to operate, also allows for amplifying production.
Method 2：
Method 2 is that protection group is different from the main distinction of method 1, and the former makees protection group using trichloroacetaldehyde, and the latter is to methoxy
Benzaldehyde.Therefore, first with (Boc)2The amino of O selective protection phenylisoserines（4→9）, then again with to methoxy
Benzaldehyde protects-NHBoc and-OH.
The present invention is keeping taxol overall skeleton including C13(the 2 ' of side chainR,3′S) in the case that spatial configuration is constant,
By esterification in C-13- N the positions of side chain 3 ' introduce the small molecule isoxazole fragment of biologically active and obtain a series of new taxanes
Derivative, and in vitro it is assessed to different tumour cells by MTT methods（Normal and persister）Antiproliferative activity, sieve
The Taxane derivative with greater activity is selected as drug candidate.
Specific embodiment
The synthesis of the 7,10-diTroc bar cards booth 1 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, reactant liquor is cooled to room temperature and pyrrole is removed under reduced pressure by magnetic agitation after TLC monitoring reactions completely
Pyridine, residue AcOEt/H2It is neutral to adjust 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, Jing is removed under reduced pressure molten
Agent obtains crude product, and Jing column chromatographies obtain 7,10-diTroc- bar cards booth 2, yield：233.1-234.2 DEG C of 87.4%, m.p..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 2 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 3 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
10-Ac bar cards booth 2（9.3 mmol）In, reactant liquor is cooled to room temperature and removes pyrrole by magnetic agitation after TLC monitoring reactions completely
Pyridine, 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 is extracted with AcOEt, is merged organic phase and is used H successively2O, saturated common salt water washing, anhydrous MgSO4It is dried, removes solvent
Crude product is obtained, Jing column chromatographies obtain 7-Troc-10-Ac bar cards booth 3, 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 9
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 9, yield 93.2%.
The synthesis of the Ben oxazolins carboxylate methyl ester 10 of embodiment 5
46.4 mmol compounds 9, 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 Ben oxazolins carboxylate methyl ester 10.
The synthesis of the Ben oxazolins carboxylic acid 11 of embodiment 6
The MeOH of above-mentioned product 10 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 11, 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 Ben oxazolin carboxylic acid 7,10-diTroc- bar card booths ester 12 of embodiment 7
By 5.5 mmol Ben oxazolins carboxylic acids 11,5 mmol 7,10-diTroc- bar card booths 1,10 mmol DCC and 0.5
The appropriate CH of mmol DMAP2Cl2Dissolving, reacts under room temperature condition, and TLC monitoring reactions are complete.Reaction leaches insoluble matter after terminating,
Filtrate Jing removal of solvent under reduced pressure obtains coupled product 12, yield：95.4%.m.p.151.9-154.2℃.1H NMR (400
MHz, CDCl3) δ 8.06 (d, J = 8.0 Hz, 2H), 7.65 (t, J = 7.4 Hz, 1H), 7.56 – 7.37
(m, 9H), 6.95 (d, J = 8.2 Hz, 2H), 6.64 (s, 1H), 6.38 (t, J = 8.7 Hz, 1H),
6.29 (s, 1H), 5.71 (d, J = 7.0 Hz, 1H), 5.60 (dd, J = 10.7, 7.1 Hz, 1H), 5.52
(d, J = 3.3 Hz, 1H), 5.04 – 4.90 (m, 3H), 4.81 (s, 2H), 4.77 – 4.61 (m, 3H),
4.31 (d, J = 8.5 Hz, 1H), 4.16 (d, J = 8.6 Hz, 1H), 3.95 (d, J = 6.9 Hz, 1H),
3.86 (s, 3H), 3.50 (q, J = 7.0 Hz, 1H), 2.69 – 2.59 (m, 1H), 2.38 – 2.21 (m,
2H), 2.13 (s, 3H), 2.11 – 2.04 (m, 1H), 1.98 (s, 3H), 1.87 (s, 3H), 1.79 (s,
1H), 1.32 (s, 3H), 1.23 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 200.66, 170.22,
166.88, 160.38, 153.22, 152.52, 142.04, 138.21, 133.94, 132.35, 130.07,
129.11, 128.93, 128.73, 128.55, 127.29, 113.93, 94.19, 91.78, 83.68, 80.50,
79.04, 78.91, 76.37, 75.21, 74.20, 71.55, 65.86, 64.12, 56.20, 55.36, 46.88,
43.17, 35.43, 33.24, 26.36, 21.80, 21.01, 15.29, 14.92, 10.74. HRMS(FAB):
calcd for C55H54Cl9NO19 (M+NH4 +): 1369.0772, found: 1369.0784。
The synthesis of the phenylisoserine 10- deacetylate bar card booths ester 13 of embodiment 8
4.8 mmol coupled products 12, the mmol of Zn powder 143 and the mL of AcOH 29 mL of AcOEt 70 are dissolved, under room temperature condition
Reaction, TLC monitoring reaction ends.Zn powder is leached, filtrate uses saturation NaHCO3Solution is adjusted to alkalescent.Mixed liquor stands and divides
Layer, separates organic phase, and in organic phase H is added2O and with alkene HCl adjust mixed liquor be faintly acid.Mixed liquor stratification, separates
Water phase is simultaneously fully washed to organic impurities is not contained in water phase with ether（TLC is monitored）.In Xiang Shuixiang add AcOEt and with satisfy
And NaHCO3Solution is adjusted to alkalescent.Mixed liquor stratification, separates organic phase, and water is extracted with AcOEt, merges organic phase
And with saturated common salt water washing, anhydrous MgSO4It is dried, Jing removal of solvent under reduced pressure obtains coupling compound 13, is white powder, produces
Rate：93.5%.m.p.（166.2-167.6℃）.1H NMR (400 MHz, DMSO) δ 7.95 (d, J = 7.1 Hz,
2H), 7.73 (t, J = 7.4 Hz, 1H), 7.65 (t, J = 7.5 Hz, 2H), 7.42 (d, J = 4.3 Hz,
4H), 7.28 – 7.19 (m, 1H), 5.85 (t, J = 8.7 Hz, 1H), 5.40 (d, J = 7.2 Hz, 1H),
5.09 (s, 1H), 5.04 (d, J = 7.1 Hz, 1H), 4.97 (s, 1H), 4.89 (d, J = 10.0 Hz,
1H), 4.53 (s, 1H), 4.22 (d, J = 7.9 Hz, 1H), 4.16 (d, J = 7.9 Hz, 1H), 4.10 –
3.96 (m, 3H), 3.63 (d, J = 7.2 Hz, 1H), 2.33 – 2.20 (m, 1H), 2.11 (s, 3H),
1.74 (s, 3H), 1.69 – 1.62 (m, 1H), 1.51 (s, 3H), 1.01 (s, 3H), 0.97 (s, 3H).13C NMR (100 MHz, DMSO) δ 214.55, 177.74, 174.90, 170.41, 141.99, 141.07,
138.65, 135.24, 134.72, 133.89, 133.53, 133.09, 132.81, 88.93, 85.48, 82.06,
80.63, 80.37, 79.95, 78.97, 75.98, 75.04, 63.33, 62.18, 51.14, 48.09, 41.66,
40.19, 31.73, 27.64, 26.02, 18.94, 15.01.HRMS(FAB):calcd for C38H45NO12(M+H+)
708.3015, found708.3005。
The synthesis of taxane [1]-A derived from the paclitaxel lateral chain C3 '-N of embodiment 9
By 0.1 mmol 3- (2 '-cyano-phenyl) isoxazole -5- formyl chlorides, 0.1 mmol coupling compounds 13 and DMAP 10
Mg is with appropriate pyridinium dissolution and reacts about 1-5 h at room temperature（TCL monitoring reactions）.After reaction terminates, reactant liquor CH2Cl2
Dilute and successively with dilute HCl, H2O and saturated common salt water washing, anhydrous MgSO4It is dried, removal of solvent under reduced pressure obtains crude product, Jing posts
Chromatography obtains C3 '-N- Fang isoxazole taxol [1]-A sterlings, is white solid, yield 74.2%, yield 74.2%.m.p.
202-203.1℃。1H NMR (500 MHz, CDCl3) δ 8.16 (d, J = 7.2 Hz, 2H), 7.89 – 7.79
(m, 3H), 7.71 (td, J = 7.8, 1.2 Hz, 1H), 7.67 – 7.59 (m, 2H), 7.57 – 7.51 (m,
4H), 7.45 (t, J = 7.6 Hz, 2H), 7.39 (d, J = 7.3 Hz, 1H), 7.36 (s, 1H), 6.31
(t, J = 8.5 Hz, 1H), 5.83 (dd, J = 9.2, 2.5 Hz, 1H), 5.70 (d, J = 7.1 Hz,
1H), 5.25 (s, 1H), 4.97 (d, J = 9.4 Hz, 1H), 4.83 (d, J = 2.7 Hz, 1H), 4.33
(d, J = 8.5 Hz, 1H), 4.29 – 4.22 (m, 2H), 3.93 (d, J = 7.0 Hz, 1H), 3.50 (s,
2H), 2.64 – 2.53 (m, 1H), 2.42 (s, 3H), 2.37 – 2.29 (m, 2H), 2.27 – 2.22 (m,
1H), 2.09 (br, s, 1H), 1.91 (d, J = 13.9 Hz, 1H), 1.85 (s, 3H), 1.79 (s, 3H),
1.23 (s, 3H), 1.14 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 211.15, 171.94, 170.70,
166.85, 163.68, 161.05, 155.07, 137.91, 137.25, 136.29, 134.32, 133.81,
133.39, 130.91, 130.65, 130.21, 129.55, 129.32, 129.05, 128.72, 128.56,
127.11, 117.45, 110.97, 107.24, 84.26, 81.32, 78.66, 74.82, 74.53, 73.45,
72.30, 71.81, 57.72, 54.84, 50.82, 46.53, 43.05, 36.91, 35.91, 26.58, 22.61,
20.57, 14.47, 9.94. HRMS (FAB): calcd for C49H49N3O14 (M+Na+): 926.3107, found:
926.3103。
The extracorporeal anti-tumor cell proliferation activity rating of embodiment 10
Inventor have selected the typical compound of following 5 kinds of structures in taxane derived from the-N of paclitaxel lateral chain 3 ' for having synthesized
[1]-A, [1]-B, [1]-C, [1]-D and [1]-E carry out the test of extracorporeal anti-tumor cell proliferation activity.
Using different tumor cell line Hela（Cervical cancer cell）、SK-OV-3（Ovarian cancer cell）、A549（Lung cancer is thin
Born of the same parents）、A2780（Ovarian cancer cell）、MCF-7（Breast cancer cell）And multidrug resistance tumor cells strain A2780-MDR and MCF-
7 kinds of cell lines such as 7-MDR, with Docetaxel（docetaxel）As positive control, 5 new virtues are evaluated by MTT methods
Isoxazole-antiproliferative activity of the Docetaxel derivative to different tumour cells.Tumor cell line is in test-compound
Culture 72h, each sample concentration sets three repetitions, to reduce error.Acquired results are as shown in table 1.
As can be seen from the table, these compounds show similar to Docetaxel or preferable Selective depression
The ability of tumor cell proliferation.From vertical analysis, for Hela cells, except [1]-D, remaining 4 compound all show compared with
Good activity, wherein the rejection ability of [1]-B and [1]-E is stronger than Docetaxel 2 times.For SK-OV-3 cells, 5 chemical combination
Thing all shows preferable activity, wherein the rejection ability of [1]-E is most strong, it is stronger than Docetaxel 2.5 times.It is thin for A549
Born of the same parents, 5 compounds show the activity similar to Docetaxel.For A2780 cells, all 5 compounds are all showed
Go out outstanding activity, wherein the rejection ability of [1]-A and [1]-E is stronger than Docetaxel 4 times.For MCF-7 cells, [1]-B
Show preferable activity.
From horizontal analysis, [1]-A shows the ability for preferentially suppressing A2780 cells to breed.[1]-B and [1]-E is to all
Tumour cell shows preferable rejection ability.[1]-C and [1]-D is several better than other to the rejection ability of A2780 cells
Cell.Importantly, in C3'-N positions introduce fragrant isoxazole skeleton and not only increase Docetaxel to normal tumour cell
Rejection ability, and also have performance well to cells of resistant tumors.These compounds inhibit in various degree A2780-MDR
With the propagation of MCF-7-MDR tumour cells.
Claims (3)
1. general structure（I）Shown compound,
R is H or acetyl group；
R ' is selected from H ,-CH3、-NO2、-CN、CH3O-, halogen radical.
2. compound according to claim 1, it is characterised in that compound is：
。
3. the preparation method of compound described in claim 1, it is characterised in that comprise the following steps：
（1）With natural products 10- deacetylate bar Ka Ting（10-DAB）For raw material, with tri-chloroethoxy base formyl chloride（TrocCl）Together
When protect 7-OH and 10-OH, or first make 10-OH acetylations, then protect 7-OH with TrocCl；
（2）- the OH of side chain 2 ' and 3 '-NH is protected with trichloroacetaldehyde2, or with P-methoxybenzal-dehyde protection 2 '-OH and 3 '-
NHBoc；
（3）In the presence of DCC and DMAP, step（1）With（2）Product carry out coupling reaction；
（4）Slough the protection group on side chain and Ba Ka booth rings simultaneously in the presence of zinc powder；
（5）In alkaline medium and in the presence of DMAP, substituted benzene isoxazole carboxylic acid chloride and step（4）Product reaction obtain
General structure（I）Shown compound.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999037631A1 (en) * | 1998-01-26 | 1999-07-29 | Hanmi Pharmaceutical Co., Ltd. | Novel taxaneterpine compounds |
| CN1491946A (en) * | 2001-08-06 | 2004-04-28 | 佛罗里达州立大学研究基金有限公司 | C 10 ester substituted taxadane |
| CN1491947A (en) * | 2001-08-06 | 2004-04-28 | 佛罗里达州立大学研究基金有限公司 | C10 ester carbonate substituted taxadane |
-
2016
- 2016-12-28 CN CN201611232072.4A patent/CN106632296A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999037631A1 (en) * | 1998-01-26 | 1999-07-29 | Hanmi Pharmaceutical Co., Ltd. | Novel taxaneterpine compounds |
| CN1491946A (en) * | 2001-08-06 | 2004-04-28 | 佛罗里达州立大学研究基金有限公司 | C 10 ester substituted taxadane |
| CN1491947A (en) * | 2001-08-06 | 2004-04-28 | 佛罗里达州立大学研究基金有限公司 | C10 ester carbonate substituted taxadane |
Non-Patent Citations (2)
| Title |
|---|
| JAE HO HEO，等: "Development of new efficient synthetic methods for docetaxel", 《BULL. KOREAN CHEM. SOC.》 * |
| 陈明: "新型紫杉烷类衍生物的设计、合成及抗肿瘤活性研究", 《第四军医大学博士学位论文》 * |
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