CN102816197B - New pyrimidopyrimidine nucleoside analogue, its preparation method, supermolecular structure formed by the same and application thereof - Google Patents
New pyrimidopyrimidine nucleoside analogue, its preparation method, supermolecular structure formed by the same and application thereof Download PDFInfo
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Abstract
Belonging to the field of pharmaceutical chemistry, the invention relates to a new pyrimidopyrimidine nucleoside analogue and its preparation method, especially to a nucleoside analogue shown in formula I, its preparation method and application in anti-tumor, anti-virus and other aspects. The invention also provides application of the compound, its salts and the formed nanostructure in drug carriers, regenerative medicine, catalysis and other aspects.
Description
Technical field
The present invention relates to a kind of new pyrimido-pyrimidine nucleoside analog, preparation method, the nanostructure of this type of compound formation carried at medicine, application in regenerative medicine and catalysis etc.
Background technology
DNA and RNA molecule are in field of nanometer technology, because it has good biological function, nanoscale, biocompatibility, biological degradability, molecule distinguishability, Heat stability is good and the characteristic such as length is controlled, be proved to be the easiest cutting and broad-spectrum general purpose material.Scientist has successfully used DNA and RNA to construct various mirable nanostructure, such as regular grid, paper folding, supramolecular aggregation or even three-dimensional structure.In addition, the basic composition unit dezyribonucleoside of DNA and RNA and ribonucleoside are also used to build supramolecular structure miscellaneous.Except purine and the pyrimidine nucleoside of classics, the nucleosides of structural modification is also widely used in building difform supramolecular structure.In order to find raw better nano material, we have designed and synthesized a series of pyrimido-pyrimidine nucleoside compound with self-assembly ability first, wish that this compounds can provide new approach for the drug delivery system of development of new, uncommon its has new application as timbering material in regenerative medicine and catalysis etc. simultaneously.
Summary of the invention
The object of the invention is to be provided in the new nucleoside analog that base or sugar moieties carry out modifying.To each group of the general formula (I) of following definitions be illustrated in greater detail below:
Wherein A is selected from O, S, CH
2; R
2, R
2 ', R
3, and R
3 'independently be selected from H, F, OH, NH
2, SH, CN, N
3and R, wherein R is low alkyl group, low-grade alkenyl, alkynyl of low-grade chain or lower acyl, and optional containing at least one heteroatoms; R
4for H, OH, NH
2, SH, CN, N
3, and R, wherein R is low alkyl group, low-grade alkenyl, alkynyl of low-grade chain or lower acyl, and optional containing at least one heteroatoms; R
5for H, OH, OR
6, SH, SR
7, R
8, OP (O) (OH)
2, OP (O) (OR ＂)
2, SP (O) (OH)
2, SP (O) (OR ＂)
2wherein R
6, R
7, R
8, R ＂ is functionalization group; And B is for being selected from formula (II):
Wherein X, Y, Z, U are independently selected from H, halogen, SH, SR, NH
2, NHR, NHC (O) OR, OH or OR, wherein R is low alkyl group, lower acyl.
Wherein said low alkyl group, low-grade alkenyl, alkynyl of low-grade chain or lower acyl refer to:
Low alkyl group comprises: the alkyl within the C18 such as methyl, ethyl, propyl group, sec.-propyl, butyl.
Light alkene comprises: the alkene within the C18 such as ethene, propylene.
Low-grade alkynyl comprises: the alkynes within the C18 such as acetylene, propine.
Lower acyl comprises: the acyl group within the C18 such as ethanoyl.
Described heteroatoms refers to: O, S, N
Described functionalization group refers to: as fluorophor (tonka bean camphor, fluorine boron are glimmering).
It should be noted that above-mentioned three substituting groups can be R, when these three substituting groups are all R, substituting group can not be identical simultaneously.
Specifically, described pyrimido-pyrimidine nucleoside analog is:
The object of the invention is also the preparation method providing above-mentioned class nucleosides;
The object of the invention is also to provide the above-mentioned nucleoside compound being obtained numbering 1-6 by following synthetic method;
The object of the invention is also to provide the supramolecular structure be made up of above-mentioned compounds, the nanometer rod formed as nanotube, nanotube and nano flower;
The object of the invention be also to provide this type of nanostructure medicament carrier system, as support in regenerative medicine and the application in catalysis etc.;
Accompanying drawing explanation
Fig. 1: the flower-shaped and tubular nanostructures that pyrimido-pyrimidine nucleoside analog is formed in aqueous, is wherein respectively the supramolecular structure that nucleosides 1-6 is formed in aqueous.
Fig. 2: medicine parcel SEM comparison diagram, is wherein respectively the medicine parcel comparison diagram of nucleosides 2 and 6.
Fig. 3: medicine parcel UV comparison diagram, is wherein respectively the medicine parcel comparison diagram of nucleosides 2 and 6.
Embodiment
Following embodiment will illustrate in greater detail the present invention, instead of limit its scope in all senses
Embodiment one: 4,7-diaminostilbene-(D-RIBOSE)-5-methoxy-pyrimidine also [4,5-d] pyrimidine-2,5 (1H, 2H)-diketone (compound 1)
By 4,7-diaminostilbene-(2 ', 3 '-O-isopropylidene-D-RIBOSE)-5-methoxy-pyrimidine also [4,5-d] pyrimidine-2 (1H)-one 3.8g (purchase, 10mmol) be dissolved in acetone, add 4.5g sodium iodide and 3.3g (30mmol) tetramethyl-chlorosilane, stirring at room temperature 20 hours.Consider react the precipitation generated, wash with acetonitrile (30ml*3) and acetone (30ml*3).Then the yellow mercury oxide obtained is added 30ml trifluoracetic acid under condition of ice bath, stir after 20 minutes, pressure reducing and steaming trifluoracetic acid.Products therefrom steams altogether with ethanol repeatedly, to remove residual acid.Finally the product heats obtained is dissolved in water, leave standstill some hours, pure white solid product 4 can be obtained, 7-diaminostilbene-(D-RIBOSE)-5-methoxy-pyrimidine also [4,5-d] pyrimidine-2,5 (1H, 2H)-diketone (3g, 91% productive rate).
λmax(MeOH)/nm(ε/dm
3mol
-1cm
-1):228(2359),283(1216).δ
H(400MHz；d
6-DMSO):3.41-3.45(1H,m,4’H),3.59-3.65(2H,t,5’CH
2),4.19(1H,s,3’H),4.54-4.56(1H,d,J＝8.0Hz,3’OH),4.68(1H,s,2’OH),4.80-4.81(1H,bd,J＝2.0Hz,2’H),5.02(1H,s,5’OH),6.47(1H,s,1’H),7.57-8.25(4H,m,NH
2×2),11.72(1H,br,NH).HRMS(ESI-)m/z:Calc.for C
11H
14N
6O
6:325.0896[M-H]
-.Found325.0891[M-H]
-
Embodiment two: preparation 5-amino-8-(2,3,5-, tri--oxygen-benzoyl base-D-RIBOSE) Kui Linpyrimido quinoline [4,5-d] pyrimidine-2,4 (3H, 8H)-diketone
600mg base (3.3mmol) is added in 30mL hexamethyldisilane amine (HMDS), at 140 DEG C, stirs about 2-3 minute, add trimethylchlorosilane (TMSCl) subsequently.React 18 hours under reflux state.Then, remove remaining HMDS, obtain silylated base.Use it for next step glycosylation immediately.Add in the reactor containing compound by anhydrous for 20ml 1,2-ethylene dichloride, stirring at normal temperature is dissolved, and is added in above-mentioned reactor by the 630mg 3,5-bis--O-benzoyl-β-D-RIBOSE (purchase) being dissolved in 20ml anhydrous acetonitrile subsequently.550 μ L (mmol) tin tetrachloride add in said mixture as catalyzer.Until 3,5-bis--O-benzoyl-β-D-RIBOSE disappears.Add the saturated NaHCO of 40ml
3the aqueous solution is used for termination reaction.Add dichloromethane extraction organic phase (40 × 3), merge organic phase and use anhydrous sodium sulfate drying, last vacuum rotary steam.Revolving the product after steaming uses column chromatography to be separated; silicagel column 4 × 8cm; the ribonucleoside into white powder is obtained: 5-amino-8-(2 after vacuum-drying; 3; 5-tri--oxygen-benzoyl base-D-RIBOSE) Kui Linpyrimido quinoline [4; 5-d] pyrimidine-2,4 (3H, 8H)-diketone 940mg (45%).λmax(MeOH)/nm(ε/dm3mol-1cm-1):225(95658),251(27263),273(15395),278(14355)；1H-NMR(DMSO-d6,600MHz):δ4.73～4.75(2H,t,J＝6Hz,5’-H2),4.82～4.84(1H,t,J＝6Hz,4’-H),6.12～6.13(1H,d,J＝6Hz,3’-H),6.17-6.20(1H,t,J1＝12Hz,J2＝6Hz,2’-H),6.51(1H,s,1’-H),7.40～7.99(15H,m,H-arom),8.66(1H,s,CH),9.07(1H,s,NHα)9.14(1H,s,NHβ),10.87(1H,s,NH).13C NMR(600MHz；DMSO-d6)δ64.41,71.12,74.68,80.25,87.59,129.00,129.05,129.13,129.20,129.62,129.73,129.78,129.89,133.98,134.27,134.37,153.06,156.72,157.70,162.03,164.99,165.13,165.31。
Embodiment three: preparation 5-amino-8-(D-RIBOSE) Kui Linpyrimido quinoline [4,5-d] pyrimidine-2,4 (3H, 8H)-diketone (compound 2)
By the 5-amino-8-(2 that 80mg prepares via embodiment one, 3, 5-tri--oxygen-benzoyl base-D-RIBOSE) Kui Linpyrimido quinoline [4, 5-d] pyrimidine-2, 4 (3H, 8H)-diketone (0.13mmol), be dissolved in 10ml 0.5M NaOMe/MeOH, reactant becomes jelly from the state of being suspended, after being cooled to room temperature, with the Glacial acetic acid neutralization after dilution, filter, with methanol wash column three times, pale yellow powder 5-amino-8-(D-RIBOSE) Kui Linpyrimido quinoline [4 is obtained after vacuum-drying, 5-d] pyrimidine-2, 4 (3H, 8H)-diketone (32mg, 80%).λmax(MeOH)/nm(ε/dm3mol-1cm-1)251(25943),277(5681)；1H-NMR(DMSO-d6,600MHz):δ3.60～3.80(2H,m,5’-H2),3.94～3.97(1H,m,4’-H),4.08～4.17(2H,m,3’-H,2’-H),5.08～5.09(1H,d,J＝6Hz,5’-OH),5.27～5.29(1H,t,J＝6Hz,3’-OH),5.55～5.56(1H,d,J＝6Hz,2’-OH),6.17～6.18(1H,d,J＝6Hz,1’-H),8.88(1H,s,CH),8.92(1H,s,NHα)8.98(1H,s,NHβ),10.77(1H,s,NH).13C NMR(600MHz；DMSO-d6)δ60.04,69.04,74.98,85.06,87.44,90.26,151.88,157.00,158.18,162.00,165.44。
Embodiment four: 4,6-dichloro pyrimidine-5 formoxime
1.8g 4,6-dichloro pyrimidine-5 formaldehyde (purchase) is dissolved in 20ml glacial acetic acid, then instills 40ml oxammonium hydrochloride ethanolic soln (1.4g), normal-temperature reaction 15 hours.After solution is spin-dried for, use saturated NaHCO
3with washing organic phase, finally use anhydrous sodium sulfate drying organic phase, be spin-dried for and obtain white product 4,6-dichloro pyrimidine-5 formoxime (1.8g, 84% productive rate).1H NMR(400MHz；DMSO-d6):δ＝8.19(s,1H),8.91(s,1H),12.27(s,1H).13C NMR(600MHz；DMSO-d6)δ＝113.63,142.03,149.50,154.25.Anal.Calcd for C5H3Cl2N3O:C,31.28；H,1.57；N,21.89.Found C,31.44；H,1.46；N,22.17.
Embodiment five: 4-(5 '-O ethanoyl-2 ', 3 '-O-isopropylidene-β-D ribofuranose) amine-5 cyano group-6-chloropyrimide
By chloro-for 1.7g compound 4,6-bis-5 cyanopyrimidines (purchase), be dissolved in 50ml dry tetrahydrofuran (THF).Add 7.2g 2,3-O-isopropylidene-D-furans osamine tosilate (purchase) successively, 1.7g NaHCO
3, 3.4ml ipr
2etN (DIPEA is bought).Mixing solutions to 60 DEG C, continues reaction 60 minutes at room temperature reaction 10 minutes post-heating.After cooling, with 50ml methylene dichloride (DCM) lysate again.Product uses water and dilute hydrochloric acid (0.1N) to wash twice, anhydrous sodium sulfate drying more respectively, is spin-dried for and obtains crude product 4d.Not purified 4d is dissolved in 50ml DCM, adds 2.6ml ipr2EtN, 1.4ml diacetyl oxide, 12.2mgDMAP (DMAP, lower same).React after about 10 minutes, add 1ml dilute hydrochloric acid and stop.The solution DCM obtained is diluted to 150ml, then uses dilute hydrochloric acid and washing, anhydrous sodium sulfate drying, is spin-dried for obtain spumescence product crude product.Column chromatography for separation (eluent: DCM, Rf=0.9) obtains colourless product 4-(5 '-O ethanoyl-2 ', 3 '-O-isopropylidene-β-D ribofuranose) amine-5 cyano group-6-chloropyrimide (2.1g, 58% productive rate).1H NMR(400MHz；DMSO-d6)δ＝1.295(s,3H),1.462(s,3H),2.021(s,3H),4.125-4.185(m,3H)4.753-4.775(m,1H)4.998-5.019(m,1H),5.861-5.885(m,1H),8.619(s,1H),8.996-9.015(d,1H,)；13C NMR(600MHz；DMSO-d6)δ＝21.06,25.56,27.21,64.48,81.80,83.13,83.84,87.91,113.20,159.97,162.23,170.57.HR-MS(ESI+):calcd for C15H17ClN4O5:368.0877Found:369.0973[M+H]。
Embodiment six: 4-amino-1-(2 ', 3 '-O-isopropylidene-β-D ribofuranose)-5-methoxy pyrimidine also [4,5-d] pyrimidine-2 (1H)-one
The 4-that prepared via embodiment 4 by 3.7g (5 '-O ethanoyl-2 ', 3 '-O-isopropylidene-β-D ribofuranose) amine-5 cyano group-6-chloropyrimide is dissolved in the dry DCM of 100ml, adds 6.5ml ipr under condition of ice bath
2etN (DIPEA is bought).After stirring for some time, be added dropwise to 5.2ml CCI (N-(chloroformyl) isocyanic ester is bought).After CCI adds completely, add 5ml HCl (0.1N) termination reaction afterwards, after filtering-depositing, filtrate water is washed twice, anhydrous sodium sulfate drying, be spin-dried for and obtain adding urea product crude product.By the reaction in 50ml sodium methylate (0.15N) of this crude product, namely obtain into ring product.The mixture of gained obtains white product 4-amino-1-(2 ' through column chromatography for separation, 3 '-O-isopropylidene-β-D ribofuranose)-5-methoxy pyrimidine also [4,5-d] pyrimidine-2 (1H)-one (1.1g, 30% productive rate).1H NMR(400MHz；DMSO-d6)δ＝1.280(s,3H),1.492(s,3H),3.474-3.33(m,1H),3.579-3.636(m,1H),3.956-3.997(m,1H),4.104(s,3H),4.720-4.749(t,1H),4.871-4.898(t,1H),5.197-5.217(m,1H),6.852(s,1H),7.818(s,1H),8.521(s,1H),8.716,8.729(s,1H)；13C NMR(600MHz；DMSO-d6)δ＝25.74,27.68,55.84,62.68,82.67,84.53,88.21,112.96,154.09,159.42,160.12,161.10,166.85.HR-MS(ESI-):calcdfor[C15H19N5O6]:365.1335Found:364.0982[M-H]。
Embodiment seven: 4-amino-1-(β-D ribofuranose) Kui Linpyrimido quinoline [4,5-d] pyrimidine-2,5 (1H, 6H)-diketone (compound 3)
Compound 4-amino-1-(2 ', 3 '-O-isopropylidene-β-D the ribofuranose)-5-methoxy pyrimidine prepared via embodiment 4 by 3.6g also [4,5-d] pyrimidine-2 (1H)-one is dissolved in 30ml acetone.Add 4.5g sodium iodide and 3.3gTMSi-Cl (trimethylchlorosilane is bought), stirring at room temperature 20 hours.Filter react the precipitation generated, precipitation 30ml acetonitrile is washed 3 times, and 30ml acetone washes 3 times.Afterwards gained yellow mercury oxide (3.3g, 94% productive rate) is added 30ml trifluoracetic acid (containing 10% water) under condition of ice bath.Stir after 20 minutes, pressure reducing and steaming trifluoracetic acid.Products therefrom steams altogether with ethanol repeatedly, to remove residual acid.Finally by soluble in water for the product heats obtained, after room temperature leaves standstill some hours, pure white solid product precipitation 4-amino-1-(β-D ribofuranose) Kui Linpyrimido quinoline [4 can be obtained, 5-d] pyrimidine-2,5 (1H, 6H)-diketone (2.66g, 91% productive rate) 1H NMR (400MHz; DMSO-d6) δ=3.45 (br, 1H); (3.608-3.699 m, 2H); (4.196 s, 1H); (4.561 s, 1H); (4.636 s, 1H); (4.838 s, 1H); (5.042 s, 1H); (6.512 s, 1H); (8.221-8.304 t, 1H); (8.400-8.419 d, 2H); 13.150 (br, 1H) .HR-MS (ESI-): calcd for [C11H13N5O6]: 311.0866Found 310.0782 [M-H].
Embodiment eight: 5-amino-8-(2-deoxy-D-ribofuranose) Kui Linpyrimido quinoline [4,5-d] pyrimidine-2,4. (3H, 8H)-diketone (compound 5)
Product 4-aminopyrimidine also [4 is utilized according to the method that embodiment two is similar, 5-d] pyrimidine-5,7 (6H, 8H)-diketone (synthesizing by document 1) obtains 5-amino-8-(2-deoxy-D-ribofuranose) Kui Linpyrimido quinoline [4,5-d] pyrimidine-2,4. (3H, 8H)-diketone.λmax(MeOH)/nm(ε/dm3mol-1cm-1),251(28571),277(6158)；1H-NMR(DMSO-d6,600MHz):δ2.18～2.22(1H,m,2’-Hα),2.35-2.39(1H,m,2’-Hβ),3.59～3.61(1H,d,J＝12Hz,5’-Hα),3.67-3.69(1H,d,J＝12Hz,5’-Hβ),3.89～3.91(1H,t,J＝6HZ,4’-H),4.27(1H,s,3’-H),5.20(1H,s,5’-OH),5.34(1H,s,3’-OH),6.41～6.43(1H,t,J＝6Hz,1’-H),8.77(1H,s,CH),8.89～8.93(2H,2s,NH2),10.76(1H,s,NH).13C NMR(600MHz；DMSO-d6).13C NMR(600MHz；DMSO-d6)δ41.60,60.95,69.99,86.75,87.46,88.59,151.39,157.11,157.78,162.07,165.43。
Embodiment nine: 5-amino-1-(2-deoxy-D-ribofuranose) Kui Linpyrimido quinoline [4,5-d] pyrimidine-2,4. (1H, 3H)-diketone (compound six)
Product 4-aminopyrimidine also [4 is utilized according to the method that embodiment two is similar, 5-d] pyrimidine-5, 7 (6H, 8H)-diketone (synthesizing by document 1) obtains 5-amino-1-(2-deoxy-D-ribofuranose) Kui Linpyrimido quinoline [4, 5-d] pyrimidine-2, 4. (1H, 3H)-diketone .1H NMR (400MHz, d6-DMSO) δ (ppm): 2.31-2.38 (1H, m, 2 '-CH), 2.51-2.63 (1H, m, 2 '-CH), 3.36-3.60 (2H, m, 5 '-CH2), 4.07-4.14 (2H, m, 3 '-CH and 4 '-CH), 4.61-4.63 (1H, t, J=5.2Hz, 5 '-OH), 5.16-5.18 (1H, d, J=2.4Hz, 3 '-OH), 6.48-6.50 (1H, t, J=7.6Hz, 1 '-CH), 8.22-8.23 (2H, d, J=5.2Hz,-NH2), 8.25 (1H, s, 7-CH), 11.89-11.90 (1H, d, J=2.4Hz,-NH), 13C NMR (100MHz, d6-DMSO) δ (ppm): 36.39,61.81,70.89,81.45,86.06,89.56,150.26,157.68,161.95,162.66,163.56, UV (H2O): λ max (ε): 227 (10000), 289 (1559), HRMS (ESI) calcd for (M+Na+)/z:318.0815, found:318.0807.
Embodiment ten: 5-amino-1-(D-RIBOSE) Kui Linpyrimido quinoline [4,5-d] pyrimidine-2,4 (1H, 3H)-diketone (compound 4)
Product 4-aminopyrimidine also [4 is utilized according to the method that embodiment two is similar, 5-d] pyrimidine-5,7 (6H, 8H)-diketone (synthesizing by document 1) obtains 5-amino-1-(D-RIBOSE) Kui Linpyrimido quinoline [4,5-d] pyrimidine-2,4 (1H, 3H)-diketone.1H NMR(600MHz,d6-DMSO)δ(ppm):3.18(1H,s,3’-CH),3.44-3.47(1H,m,4’-CH),3.61-3.72(4H,m,5’-CH2,2’-CH and 5’-OH),4.17(1H,t,J＝6Hz,3’-OH),4.52-4.54(1H,q,J＝3.6Hz,2’-OH),6.17(1H,d,J＝3.6Hz,1’-CH),7.79-8.19(2H,m,-NH2),8.14(1H,s,7-CH)；13C NMR(150MHz,d6-DMSO)δ(ppm):22.83,48.09,62.90,70.73,71.58,84.86,89.87,161.77,163.18,173.30；UV(H2O):λmax(ε):227(10412)；289(1777)；HRMS(ESI)calcd for(M+Na+)/z:334.0764,found:334.0766.
Embodiment 11: this type of nucleoside compound all forms good nanostructure by self-assembly in aqueous, take nucleosides 1-60.2mg in said structure figure respectively soluble in water, then be heated to boiling, at room temperature leave standstill 48h, scanning electron microscope, transmission electron microscope results are as shown in Figure 1.
Embodiment 12: these nanostructures all may be used for packaging medicine.
Weigh Compound 2 and 6 is (shown in structure iron as in the previous respectively, other other compounds and this two compounds are the same all have two-sided base structure and can self aggregation in water, preliminary scanning electron microscope is to show that this type of nucleoside compound all can form similar supramolecular structure.0.2mg as shown in figure), heats soluble in water, then leaves standstill 24h, adds 1mg Honokiol respectively, then places room temperature 2 days, and before and after scanning electron microscope medicine parcel, result as shown in Figure 2, and before and after packaging medicine, UV comparison diagram as shown in Figure 3.
And by MTT cytotoxicity experiment, confirm that the IC50 of this type of nucleoside compound is all greater than 3000umol, show that bio-toxicity is very low, may be used in body.(do not need to describe experimental program in detail, adopt the mode of citing document to get final product document 2), meanwhile, utilize the drug loading of NMR drugs, show that the drug loading of compound 2,6 reaches 40% (see table 1).
Table 1: the drug loading research of medicine
| Bag medicine ratio | 5:1 | 5:3 | 5:5 | 5:7 |
| Integration before bag medicine | 0.3 | 1.0 | 2.5 | 4.5 |
| Integration after bag medicine | 0.2 | 0.6 | 1.5 | 2.65 |
| Drug loading | 33.3％ | 40％ | 40％ | 41％ |
Above-mentioned experiment tentatively shows that this type of nucleoside compound has good medicine parcel ability, and toxicity is lower, therefore have good application prospect as novel medicine loading system, this compounds also has larger application potential in regenerative medicine, catalysis etc. simultaneously.
Document:
1 Y.Tominaga,S.Ohno,S.Kohra,H.Fujito,H.Mazurae,J.Heterocycl.Chem.1991,28,1039-1042.
2 Geise Ribeiro et al.Polyhedron，2008,27，1131-1137.
Claims (3)
1. a pyrimido-pyrimidine nucleoside analog, is characterized in that having following structure:
2. the supramolecular structure be made up of pyrimido-pyrimidine nucleoside analog according to claim 1, described supramolecular structure is: the nanometer rod that nanotube, nanotube are formed and nano flower.
3. the application of supramolecular structure according to claim 2 in medicament carrier system.
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| SG11201602595TA (en) | 2013-10-11 | 2016-04-28 | Alios Biopharma Inc | Substituted nucleosides, nucleotides and analogs thereof |
| CN105131066B (en) * | 2015-07-31 | 2018-08-03 | 四川大学 | A kind of pyrimidine derivatives and preparation method thereof and purposes |
| CN113842936B (en) * | 2021-10-22 | 2023-06-23 | 四川大学华西医院 | Platinum-based monoatomic electrocatalytic material and preparation method and application thereof |
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| WO2002003997A1 (en) * | 2000-07-06 | 2002-01-17 | Ribapharm Inc. | Pyrido[2,3-d]pyrimidine and pyrimido[4,5-d]pyrimidine nucleosides |
| CN1601383A (en) * | 2003-06-05 | 2005-03-30 | 韩国科学技术院 | Method for fabricating a carbon nanotube chip and a biochip using the self-assembly of super molecules and staining of metal compound |
| CN102516339A (en) * | 2010-10-21 | 2012-06-27 | 四川大学华西医院 | Pyrimidopyrimidine compound, nucleoside analog derivative thereof, preparation method thereof and use thereof |
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Patent Citations (3)
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| WO2002003997A1 (en) * | 2000-07-06 | 2002-01-17 | Ribapharm Inc. | Pyrido[2,3-d]pyrimidine and pyrimido[4,5-d]pyrimidine nucleosides |
| CN1601383A (en) * | 2003-06-05 | 2005-03-30 | 韩国科学技术院 | Method for fabricating a carbon nanotube chip and a biochip using the self-assembly of super molecules and staining of metal compound |
| CN102516339A (en) * | 2010-10-21 | 2012-06-27 | 四川大学华西医院 | Pyrimidopyrimidine compound, nucleoside analog derivative thereof, preparation method thereof and use thereof |
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| Janus-type AT nucleosides: synthesis, solid and solution state structures;Mei-Ying Pan，等;《Organic & Biomolecular Chemistry》;20110518;第9卷;第5692-5702页 * |
| Synthesis of Janus type nucleoside analogues and their preliminary bioactivity;Hao-Zhe Yang，等;《Organic & Biomolecular Chemistry》;20101115;第9卷;第1516-1522页 * |
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