CN104098627B - Seleno derivative of N-trifluoroacetyl epidaunorubicin as well as preparation method and application thereof - Google Patents
Seleno derivative of N-trifluoroacetyl epidaunorubicin as well as preparation method and application thereof Download PDFInfo
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- CN104098627B CN104098627B CN201410373128.2A CN201410373128A CN104098627B CN 104098627 B CN104098627 B CN 104098627B CN 201410373128 A CN201410373128 A CN 201410373128A CN 104098627 B CN104098627 B CN 104098627B
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- Prior art keywords
- epidnr
- seleno
- tfa
- trifluoroacetyl
- epidaunorubicin
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- 238000002360 preparation method Methods 0.000 title claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 27
- 239000003814 drug Substances 0.000 claims abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims abstract description 10
- 201000011510 cancer Diseases 0.000 claims abstract description 8
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims abstract description 7
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 17
- 241001597008 Nomeidae Species 0.000 claims description 17
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 claims description 8
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 claims description 7
- -1 Dichloromethane Alkane Chemical class 0.000 claims description 7
- 229960000975 daunorubicin Drugs 0.000 claims description 7
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 claims description 7
- 238000003756 stirring Methods 0.000 claims description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 6
- 239000000376 reactant Substances 0.000 claims description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 4
- 238000004440 column chromatography Methods 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 3
- 238000005352 clarification Methods 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000010410 layer Substances 0.000 claims description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical group CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 239000012044 organic layer Substances 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- 238000006482 condensation reaction Methods 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 239000007787 solid Substances 0.000 claims description 2
- 150000001721 carbon Chemical class 0.000 claims 1
- 239000012295 chemical reaction liquid Substances 0.000 claims 1
- 150000002431 hydrogen Chemical class 0.000 claims 1
- 238000005406 washing Methods 0.000 claims 1
- 230000000259 anti-tumor effect Effects 0.000 abstract description 4
- 150000003343 selenium compounds Chemical class 0.000 abstract description 3
- 239000002246 antineoplastic agent Substances 0.000 abstract description 2
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 2
- 125000001424 substituent group Chemical group 0.000 abstract description 2
- STQGQHZAVUOBTE-RPDDNNBZSA-N (7s,9s)-9-acetyl-7-[(2r,4s,5r,6s)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 STQGQHZAVUOBTE-RPDDNNBZSA-N 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 238000012216 screening Methods 0.000 abstract 1
- 238000001308 synthesis method Methods 0.000 abstract 1
- 230000003407 synthetizing effect Effects 0.000 abstract 1
- 239000011669 selenium Substances 0.000 description 14
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 description 8
- 229910052711 selenium Inorganic materials 0.000 description 8
- 150000001454 anthracenes Chemical class 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 206010048610 Cardiotoxicity Diseases 0.000 description 3
- 231100000259 cardiotoxicity Toxicity 0.000 description 3
- 230000007681 cardiovascular toxicity Effects 0.000 description 3
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Substances ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 3
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 238000011275 oncology therapy Methods 0.000 description 3
- 230000001093 anti-cancer Effects 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- 239000011573 trace mineral Substances 0.000 description 2
- 235000013619 trace mineral Nutrition 0.000 description 2
- NWXMGUDVXFXRIG-WESIUVDSSA-N (4s,4as,5as,6s,12ar)-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4,4a,5,5a-tetrahydrotetracene-2-carboxamide Chemical compound C1=CC=C2[C@](O)(C)[C@H]3C[C@H]4[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]4(O)C(=O)C3=C(O)C2=C1O NWXMGUDVXFXRIG-WESIUVDSSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 description 1
- 206010000830 Acute leukaemia Diseases 0.000 description 1
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 1
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 1
- LJZPVWKMAYDYAS-UHFFFAOYSA-N Aklavine Natural products C12=C(O)C=3C(=O)C4=C(O)C=CC=C4C(=O)C=3C=C2C(C(=O)OC)C(CC)(O)CC1OC1CC(N(C)C)C(O)C(C)O1 LJZPVWKMAYDYAS-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 229930195573 Amycin Natural products 0.000 description 1
- 0 CC(C(*c1c(C)cccc1)C(C1)NC(C(F)(F)F)=O)OC1[C@@](C[C@@](Cc1c(c(C(c2c3c(OC)ccc2)=O)c2C3=O)O)(C(C)=O)O)c1c2O Chemical compound CC(C(*c1c(C)cccc1)C(C1)NC(C(F)(F)F)=O)OC1[C@@](C[C@@](Cc1c(c(C(c2c3c(OC)ccc2)=O)c2C3=O)O)(C(C)=O)O)c1c2O 0.000 description 1
- UVEUBVOCNZYAQP-ANKYOSCQSA-N CC(C(C(C1)NC(C(F)(F)F)=O)O)OC1[C@@H](C[C@@](Cc1c(c(C(c2cccc(OC)c22)=O)c3C2=O)O)(C(C)=O)F)c1c3O Chemical compound CC(C(C(C1)NC(C(F)(F)F)=O)O)OC1[C@@H](C[C@@](Cc1c(c(C(c2cccc(OC)c22)=O)c3C2=O)O)(C(C)=O)F)c1c3O UVEUBVOCNZYAQP-ANKYOSCQSA-N 0.000 description 1
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 description 1
- 208000035126 Facies Diseases 0.000 description 1
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- LJZPVWKMAYDYAS-QKKPTTNWSA-N aclacinomycin T Chemical compound O([C@H]1C[C@]([C@@H](C2=CC=3C(=O)C4=CC=CC(O)=C4C(=O)C=3C(O)=C21)C(=O)OC)(O)CC)[C@H]1C[C@H](N(C)C)[C@H](O)[C@H](C)O1 LJZPVWKMAYDYAS-QKKPTTNWSA-N 0.000 description 1
- 125000005577 anthracene group Chemical group 0.000 description 1
- 239000003005 anticarcinogenic agent Substances 0.000 description 1
- 239000003972 antineoplastic antibiotic Substances 0.000 description 1
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 1
- MVPPADPHJFYWMZ-IDEBNGHGSA-N chlorobenzene Chemical group Cl[13C]1=[13CH][13CH]=[13CH][13CH]=[13CH]1 MVPPADPHJFYWMZ-IDEBNGHGSA-N 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229960001904 epirubicin Drugs 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229960002668 sodium chloride Drugs 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a seleno derivative of N-trifluoroacetyl epidaunorubicin, and adopts the structure of a general formula I (shown in the Specification). According to the invention, through the reaction of epidaunorubicin and trifluoroacetyl, an N-trifluoroacetyl epidaunorubicin is generated for reacting with a corresponding substituted seleno acetic acid so as to generate the N-trifluoroacetyl epidaunorubicin seleno derivative, wherein a substituent group being a seleno compound, is introduced through N-trifluoroacetyl epidaunorubicin 4' isotope for synthetizing the N- trifluoroacetyl epidaunorubicin seleno derivative in the hope of screening out anti-cancer drugs good in antitumor activity. The synthesis method provided by the invention is simple and scientific, and facilitates industrial production; the N-trifluoroacetyl epidaunorubicin seleno derivative can be used for the treatment of malignant tumors in the field of medicine.
Description
Technical field
The present invention relates to pharmaceutical technology field, more particularly to a kind of seleno of cancer therapy drug N-TFA EPIDNR
Derivant, its preparation method and antitumor application thereof.
Background technology
Anthracene nucleus antineoplastic antibiotic is the medicine being clinically most widely used at present, such as daunorubicin, amycin, she
Up to than star, aklavine etc..In these medicines some be it is natural, some be by semi-synthetic or complete synthesis obtain.But anthracene
Ring class medicine generally has cardiac toxicity, and this point limits the extensive and life-time service of anthracene nucleus medicament.Therefore people pass through
Various methods obtain such compound, it is therefore an objective to be found that active anticancer is good, small toxicity medicine.At present people by synthesis,
Semi-synthetic or natural such compound for obtaining alreadys exceed more than 2000.
Daunorubicin IV is first antitumor drug for developing and being applied to clinic in such compound, and it is mainly used in
Treatment acute leukemia, acute lymphoblastic leukemia etc..But daunorubicin has larger cardiac toxicity, as this point is limited
Its extensive application has been made, this medicine has clinically seldom been used now.
EPIDNR II and daunorubicin IV have difference in structure, only on the configuration of 4 ' hydroxyls, daunorubicin is α
Configuration, and EPIDNR is beta comfiguration.
EPIDNR is the product obtained by genetic engineering improvement, although which is not directly used in clinic as medicine
Use, but EPIDNR is the precursor of clinically widely used epirubicin.Therefore, structure is carried out to EPIDNR
Modification, to find the good new cancer therapy drug of activity also very important meaning.
Selenium is the indispensable important trace element of human body, be experimental results demonstrate, scarce selenium can with cause cancer, meanwhile, selenium
Ability with cancer-resisting.Therefore, selenium element is introduced in EPIDNR medicine, this is synthesis EPIDNR derivant
A good thinking.
The content of the invention
The present invention has the problem of cardiac toxicity for cancer therapy drug EPIDNR of the prior art, and which is tied
Structure transform, introduce seleno compound, synthesize a class N-TFA EPIDNR derivant, field of medicaments research with
Using having very important significance.
The technical purpose of the present invention is achieved through the following technical solutions：
The seleno derivant of one class N-TFA EPIDNR, the structure with formula I：
Wherein R is selected from group X1、X2、X3And X4In one kind,
Another technical purpose of the present invention is the system of the seleno derivant for providing the N-TFA EPIDNR
Preparation Method, comprises the following steps：
(1) EPIDNR II generates N-TFA EPIDNR III with trifluoroacetic acid anhydride reactant,
(2) N-TFA EPIDNR III generates the N- trifluoros with corresponding replacement seleno acetic acid condensation reaction
The seleno derivative I of acetyl EPIDNR；
Corresponding replacement seleno acetic acid is selected from And n-Bu-SeCH2One kind in COOH.
Further, the actual conditions of step (1) is：EPIDNR II is suspended in ethyl acetate, is protected in nitrogen
Under shield, trifluoro-acetic anhydride, solution is added to become clarification, this solution is washed with saturated sodium bicarbonate solution, ethyl acetate is separated
Layer, adds the methanol solution of NaOH, stirring at normal temperature reaction, reactant liquor to be washed with saturated sodium-chloride water solution, taken in this solution
Organic layer anhydrous sodium sulfate drying, obtains trifluoroacetyl EPIDNR III.
Further, the actual conditions of step (2) is：Trifluoroacetyl EPIDNR III dichloromethane is dissolved, plus
Enter corresponding replacement seleno acetic acid, DCC and DMAP, stirring at normal temperature reaction, reactant liquor sucking filtration remove insoluble solid, Jing column chromatographies
Separate, obtain the seleno derivative I of the N-TFA EPIDNR.
Further, the eluant of the column chromatography is normal hexane:Dichloromethane:Acetone=3:3:1 mixed liquor.
Further, the time of the stirring at normal temperature reaction is 8-12h.
Another technical purpose of the present invention is the seleno derivant for providing the N-TFA EPIDNR in system
Purposes in standby treatment malignant tumor medicine.
The present invention's has advantages below compared with prior art：
(1) EPIDNR is carried out structure of modification by the present invention, synthesizes N-TFA EPIDNR, and in its 4 ' position
Substituent group is introduced, synthesizes N-TFA EPIDNR derivant, it would be desirable to therefrom filter out the good anticarcinogen of active anticancer
Thing；
(2) the introduced group of the present invention is seleno compound, selenium be it is important in human body be trace element, human body lacks selenium meeting
Cause cancer, meanwhile, the selenium also function with cancer-resisting, therefore, selenium is incorporated in N-TFA EPIDNR, is closed
Into N-TFA EPIDNR seleno derivant, it is desirable to which such compound has preferable anti-tumor activity；
(3) synthetic method of N-TFA EPIDNR seleno derivant of the present invention is simple, science, is easy to industrialization
Production；
(4) N-TFA EPIDNR seleno derivant of the present invention can be used for controlling for malignant tumor in field of medicaments
Treat.
Specific embodiment
Following non-limiting examples can make one of ordinary skill in the art be more fully understood the present invention, but not with
Any mode limits the present invention.
Example 1 below～4 synthesize N-TFA EPIDNR seleno derivant using following steps：
(1) synthesis of trifluoroacetic acid EPIDNR：1.007g (1.77mmol) EPIDNR II is suspended in into acetic acid
In ethyl ester (20mL), under nitrogen protection, trifluoro-acetic anhydride 1mL, solution is added to become clarification.By this solution unsaturated carbonate hydrogen
Sodium solution is washed to solution in alkalescence, separates ethyl acetate layer, adds NaOH's (106mg, 2.65mmol) in this solution
Methanol (5mL) solution, stirring at normal temperature 1 hour, TLC detection substrates point disappear.Reactant liquor is washed with saturated sodium-chloride water solution
Twice, organic layer anhydrous sodium sulfate drying, decompression obtain trifluoroacetyl EPIDNR (III) 1.1g except solvent, and yield is
100%.Fusing point：154-155 DEG C.
(2) 4 ' seleno derivative I of N-TFA EPIDNR synthesis：By trifluoroacetyl EPIDNR (III)
97mg (0.16mmol), is dissolved with 15mL dichloromethane, adds the corresponding seleno acetic acid of 0.16mmol, 46mg (0.223mmol)
DCC and 10mg DMAP, stirring at normal temperature 8-12 hour, TLC detection reactions are complete.Reactant liquor uses saturated ammonium chloride and saturation respectively
Sodium-chloride water solution is washed, and organic faciess anhydrous sodium sulfate drying, residual liquid are normal hexane with silica gel H chromatograph post separation, eluant:
Dichloromethane:Acetone=3:3:1.
Each reaction equation and each product are characterized as below：
Embodiment 1
4 '-adjacent chlorobenzene seleno -4 '-'-deoxy-n-trifluoroacetyl EPIDNR of acetoxyl group：
Yield：78%, fusing point：128-130℃.IR(cm-1)：3600-3200 (NH, OH), 1738 (C=O), 1717 (C=
O), 1626,1577 (anthracene nucleus C=O), 1457,1419,1258,1204.1H-NMR(δppm)：(14.00 1H, s, OH), 13.29
(1H, s, OH), 8.03 (1H, d, J=7.6Hz, ArH), 7.78 (1H, t, J=8.1Hz, ArH), 7.52 (1H, m, Ar ' H),
7.39 (2H, m, ArH+Ar ' H), 7.21 (2H, m, Ar ' H), 6.61 (1H, d, J=7.8Hz, H-1 '), 5.49 (1H, d, J=
3.3Hz, H-7), 5.26 (1H, s, H-4 '), 4.57 (1H, t, J=9.9Hz, H-3 '), 4.26 (1H, s, OH-9), 4.10 (2H,
M, NH+H-5 '), 4.08 (3H, s, OCH3), 3.61 (1H, d, J=12.8Hz, H-Se), 3.58 (1H, d, J=12.8Hz, H-
Se), 3.26 (1H, d, J=18.8Hz, H-10e), 2.93 (1H, d, J=18.8Hz, H-10a), 2.44 (3H, s, CH3), 2.31
(1H, m, H-8e), 2.17 (1H, m, H-8a), 1.72 (2H, m, H-2 '), 1.22 (3H, d, J=6.2Hz, CH3).MS(FAB)：
855.3(M+), 398.2.
Embodiment 2
4 '-to -4 '-'-deoxy-n-trifluoroacetyl EPIDNR of chlorobenzene seleno acetoxyl group：
Yield：95%, fusing point：100-102 DEG C.IR(cm-1)：3473, (NH), 3328 (OH), 1733 (C=O), 1717
(C=O), 1636 (C=O), 1623,1577 (anthracene nucleus C=O), 1559,1474,1418,1285,1265,1208,1161,
1119,1089.1H-NMR(δppm)：14.00 (1H, s, OH), 13.26 (1H, s, OH), 8.02 (1H, d, J=7.6Hz, ArH),
7.78 (1H, t, J=8.4Hz, ArH), 7.48 (1H, d, J=8.4Hz, Ar ' H), 7.39 (1H, d, J=8.4Hz, ArH), 7.28
(2H, 2H, J=8.4Hz, Ar ' H), 6.68 (1H, d, J=7.7Hz, H-1 '), 5.49 (1H, d, J=2.9Hz, H-7), 5.27
(1H, s, H-4 '), 4.60 (1H, t, J=9.9Hz, H-3 '), 4.26 (1H, s, 9-OH), 4.21 (1H, m, NH), 4.12 (1H, m,
H-5 '), 4.08 (3H, s, OCH3), 3.50 (1H, d, J=12.5Hz, H-Se), 3.44 (1H, d, J=12.5Hz, H-Se),
3.26 (1H, d, J=18.7Hz, H-10e), 2.93 (1H, dd, J=18.7,3.8Hz, H-10a), 2.43 (3H, s, CH3),
2.28 (1H, d, J=14.8Hz, H-8e), 2.15 (1H, dd, J=14.8,4.1Hz, H-8a), 1.91 (1H, m, H-2 '), 1.81
(1H, m, H-2 '), 1.22 (3H, d, J=6.5Hz, CH3)。13C-NMR(δppm)：212.9 (C-13), 187.2 (C-12),
186.8 (C-5), 172.0 (COO), 171.9 (CONH), 161.2 (C-4), 156.8 (CF3), 156.4 (C-6), 155.9 (C-
11), 135.9 (C), 135.9 (C-6a), 135.6 (C-10a), 134.8 (2 × CH), 134.5 (C-2), 133.8 (C-12a),
129.7 (2 × CH), 127.3 (C), 121.1 (C-4a), 120.1 (C-3), 118.7 (C-1), 111.8 (C-5a), 111.6 (C-
11a), 99.9 (C-1 '), 76.8 (C-7), 75.6 (C-4 '), 70.7 (C-5 '), 67.1 (C-3 '), 56.8 (OCH3), 48.2
(CH2), 35.9 (C-9), 34.2 (C-10), 33.6 (C-8), 27.2 (C-2 '), 25.0 (C-14), 17.7 (C-6 ').
Embodiment 3
- 4 '-'-deoxy-n-trifluoroacetyl EPIDNR of 4 '-α-naphthalene seleno acetoxyl group：
Yield：97%, fusing point：120-123℃.IR(cm-1)：3600-3200 (OH, NH), 1718 (C=O), 1618,
1578 (anthracene nucleus C=O), 1413,1284,1263,1208,1162,1121,1031.1H-NMR(δppm)：13.99 (1H, s,
OH), 13.25 (1H, s, OH), 8.31 (1H, d, J=8.4Hz, Ar ' H), 8.00 (1H, d, J=7.6Hz, ArH), 7.84 (3H,
D, J=8.5Hz, Ar ' H), 7.77 (1H, t, H=8.1Hz, ArH), 7.58 (1H, t, J=7.2Hz, Ar ' H), 7.52 (1H, t, J
=7.4Hz, Ar ' H), 7.39 (2H, m, ArH+Ar ' H), 6.74 (1H, d, J=7.8Hz, H-1 '), 5.46 (1H, d, J=
3.4Hz, H-7), 5.23 (1H, d, J=1.7Hz, H-4 '), 4.55 (1H, t, J=9.9Hz, H-3 '), 4.26 (1H, s, OH-9),
4.15 (1H, m, H-5 '), 4.06 (4H, m, OCH3+ NH), 3.56 (1H, d, J=12.3Hz, H-Se), 3.48 (1H, d, J=
12.3Hz, H-Se), 3.24 (1H, dd, J=18.7,1.0Hz, H-10e), 2.89 (1H, d, J=18.7Hz, H-10a), 2.42
(3H, s, CH3), 2.29 (1H, d, J=14.9Hz, H-8e), 2.14 (1H, dd, J=14.9,4.2Hz, H-8a), 1.68 (2H,
M, H-2 '), 1.14 (3H, d, J=6.2Hz, CH3).MS(FAB)：871.5(M+), 398.2.
Embodiment 4
- 4 '-'-deoxy-n-trifluoroacetyl EPIDNR of 4 '-normal-butyl seleno acetoxyl group：
Yield：94%, fusing point：183-186℃.IR(cm-1)：3600-3200 (OH, NH), 1738 (C=O), 1710 (C=
O), 1618,1578 (anthracene nucleus C=O), 1413,1285,1209,1165,1120,1031.1H-NMR(δppm)：14.00 (1H, s,
OH), 13.27 (1H, s, OH), 8.03 (1H, d, J=7.6Hz, ArH), 7.78 (1H, t, J=8.1Hz, ArH), 7.39 (1H, d,
J=8.4Hz, ArH), 6.66 (1H, d, J=7.8Hz, H-1 '), 5.51 (1H, d, J=3.4Hz, H-7), 5.28 (1H, d, J=
1.8Hz, H-4 '), 4.61 (1H, t, J=9.9Hz, H-3 '), 4.29 (1H, s, OH-9), 4.17 (2H, m, NH+H-5 '), 4.08
(3H, s, OCH3), 3.24 (1H, d, J=18.7Hz, H-10e), 3.14 (2H, s, CH2), 2.93 (1H, d, J=18.7Hz, H-
10a), 2.73 (2H, t, J=7.5Hz, CH2), 2.44 (3H, s, CH3), 2.34 (1H, m, H-8e), 2.17 (1H, dd, J=
14.8,4.7Hz, H-8a), 1.71 (2H, m, H-2 '), 1.66 (2H, m, CH2), 1.39 (2H, m, CH2), 1.31 (3H, d, J=
6.2Hz, CH3), 0.93 (3H, t, J=7.3Hz, CH3).MS(FAB)：801.8(M+), 398.
Application examples
Using general MTT methods, the 4 ' seleno of N-TFA EPIDNR for choosing the preparation of embodiment 1,3 and 4 spreads out
Biology carries out evaluated biological activity to human leukemia HL-60, and is contrasted with daunorubicin, as a result as shown in table 1：
Biological activity test result shows that all there is to human leukemia HL-60 these three compounds preferable antitumor to live
Property, practical application can be met.
The present invention is not limited to the preparation of the N-TFA EPIDNR seleno derivant described in above-described embodiment
Method and purposes, the change of seleno classes of compounds, the change of reaction condition are within protection scope of the present invention.
Finally it should be noted that：Various embodiments above only to illustrate technical scheme, rather than a limitation；To the greatest extent
Pipe has been described in detail to the present invention with reference to foregoing embodiments, it will be understood by those within the art that：Its according to
So the technical scheme described in foregoing embodiments can be modified, or which part or all technical characteristic are entered
Row equivalent；And these modifications or replacement, do not make the essence of appropriate technical solution depart from various embodiments of the present invention technology
The scope of scheme.
Claims (6)
1. the seleno derivant of a class N-TFA EPIDNR, it is characterised in that the derivant has the knot of formula I
Structure：
Wherein R is selected from group X1、X3In one kind,
2. the preparation method of the seleno derivant of the N-TFA EPIDNR described in claim 1, comprises the following steps：
(1) EPIDNR II generates N-TFA EPIDNR III with trifluoroacetic acid anhydride reactant,
(2) N-TFA EPIDNR III generates the N-TFA with corresponding replacement seleno acetic acid condensation reaction
The seleno derivative I of EPIDNR；
Corresponding replacement seleno acetic acid is selected fromIn one
Kind.
3. preparation method according to claim 2, it is characterised in that the actual conditions of step (1) is：By EPIDNR
II is suspended in ethyl acetate, under nitrogen protection, adds trifluoro-acetic anhydride, and solution becomes clarification, by this solution saturated carbon
Sour hydrogen sodium solution washing, separates ethyl acetate layer, and the methanol solution of NaOH, stirring at normal temperature reaction, reaction are added in this solution
Liquid is washed with saturated sodium-chloride water solution, takes organic layer anhydrous sodium sulfate drying, obtains trifluoroacetyl EPIDNR III.
4. preparation method according to claim 2, it is characterised in that the actual conditions of step (2) is：By trifluoroacetyl table
Daunorubicin III dichloromethane dissolves, and adds corresponding replacement seleno acetic acid, DCC and DMAP, stirring at normal temperature reaction, reaction
Liquid sucking filtration removes insoluble solid, and Jing column chromatography for separation obtains the seleno derivative I of the N-TFA EPIDNR.
5. preparation method according to claim 4, it is characterised in that the eluant of the column chromatography is normal hexane：Dichloromethane
Alkane：Acetone=3：3：1 mixed liquor.
6. the seleno derivant of the N-TFA EPIDNR described in claim 1 is in treatment malignant tumor medicine is prepared
Purposes.
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