CN104098627A - 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 PDF

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CN104098627A
CN104098627A CN201410373128.2A CN201410373128A CN104098627A CN 104098627 A CN104098627 A CN 104098627A CN 201410373128 A CN201410373128 A CN 201410373128A CN 104098627 A CN104098627 A CN 104098627A
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epidnr
seleno
tfa
trifluoroacetyl
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CN104098627B (en
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张殊佳
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Dalian University
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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

Seleno derivative, its preparation method and the application of one class N-TFA EPIDNR
Technical field
The present invention relates to medical technical field, relate in particular to a kind of seleno derivative of cancer therapy drug N-TFA EPIDNR, its preparation method and antitumor application.
Background technology
Anthracene nucleus antineoplastic antibiotic is the medicine being most widely used clinically at present, as daunorubicin, Zorubicin, idarubicin, aclacinomycin etc.In these medicines some be natural, some is by semi-synthetic or complete synthesis obtaining.But anthracene nucleus medicament generally has cardiac toxic, this point has limited the extensive and life-time service of anthracene nucleus medicament.Therefore people obtain this compounds by the whole bag of tricks, and object is to find the medicine that antitumour activity is good, toxicity is little.People have surpassed more than 2000 by synthetic, semi-synthetic or natural this compounds obtaining at present.
Daunorubicin IV is first exploitation be applied to clinical antitumor drug in this compounds, and it is mainly used in treating acute leukemia, acute lymphoblastic leukemia etc.But daunorubicin has larger cardiac toxic, because this point has limited its widespread use, seldom used clinically now this medicine.
EPIDNR II and daunorubicin IV structurally, only have on the configuration of 4 ' hydroxyl and have difference, and daunorubicin is α configuration, and EPIDNR is beta comfiguration.
EPIDNR is to improve by genetically engineered the product obtaining, although that it is not directly used in is clinical in drug use, EPIDNR is the precursor of widely used pidorubicin clinically.Therefore, EPIDNR is carried out to structural modification, to find also very important meaning of active good new cancer therapy drug.
Selenium is the indispensable important trace element of human body, experimental results demonstrate, scarce selenium can cause cancer, and meanwhile, selenium has the ability of cancer-resisting.Therefore, introduce selenium element in EPIDNR medicine, this is a good thinking of synthetic table daunorubicin derivative.
Summary of the invention
The present invention is directed to the problem that cancer therapy drug EPIDNR of the prior art has cardiac toxic, it is carried out to structure of modification, introduce seleno compound, the derivative of a synthetic class N-TFA EPIDNR, has very important significance in research and the application of field of medicaments.
Technical purpose of the present invention is achieved through the following technical solutions:
The seleno derivative of one class N-TFA EPIDNR, has the structure of formula I:
Wherein R is selected from radicals X 1, X 2, X 3and X 4in a kind of,
Another technical purpose of the present invention is to provide the preparation method of the seleno derivative of described N-TFA EPIDNR, comprises the following steps:
(1) EPIDNR II and trifluoroacetic acid anhydride reactant generate N-TFA EPIDNR III,
(2) N-TFA EPIDNR III and the condensation reaction of corresponding replacement seleno acetic acid generate the seleno derivative I of described N-TFA EPIDNR;
Corresponding replacement seleno acetic acid is selected from and n-Bu-SeCH 2a kind of in COOH.
Further; the actual conditions of step (1) is: EPIDNR II is suspended in ethyl acetate, under nitrogen protection, adds trifluoro-acetic anhydride; the solution clarification that becomes; this solution is washed with saturated sodium bicarbonate solution, separate ethyl acetate layer, to the methanol solution that adds NaOH in this solution; stirring at normal temperature reaction; reaction solution washs with saturated sodium-chloride water solution, gets organic layer anhydrous sodium sulfate drying, obtains trifluoroacetyl EPIDNR III.
Further, the actual conditions of step (2) is: trifluoroacetyl EPIDNR III is dissolved with methylene dichloride, add corresponding replacement seleno acetic acid, DCC and DMAP, stirring at normal temperature reaction, reaction solution suction filtration is removed insoluble solid, through column chromatography for separation, obtain the seleno derivative I of described N-TFA EPIDNR.
Further, the eluent of described column chromatography is normal hexane: the mixed solution of methylene dichloride: acetone=3:3:1.
Further, the time of described stirring at normal temperature reaction is 8-12h.
A technical purpose more of the present invention is to provide the seleno derivative of described N-TFA EPIDNR to treat the purposes in malignant tumor medicine in preparation.
Of the present inventionly have the following advantages compared with prior art:
(1) the present invention carries out structure of modification by EPIDNR, synthetic N-TFA EPIDNR, and introduce substituting group in its 4 ' position, and synthetic N-TFA EPIDNR derivative, hope can therefrom filter out the cancer therapy drug that antitumour activity is good;
(2) group that the present invention introduces is seleno compound, selenium be in human body important be trace element, human body lacks selenium meeting cause cancer, simultaneously, selenium also has the function of cancer-resisting, therefore, selenium is incorporated in N-TFA EPIDNR, synthetic N-TFA EPIDNR seleno derivative, wishes that this compounds has good anti-tumor activity;
(3) simple, the science of the synthetic method of N-TFA EPIDNR seleno derivative of the present invention, is convenient to suitability for industrialized production;
(4) N-TFA EPIDNR seleno derivative of the present invention can be for the treatment of field of medicaments malignant tumour.
Embodiment
Following non-limiting example can make the present invention of those of ordinary skill in the art's comprehend, but does not limit the present invention in any way.
Following examples 1～4 all adopt following steps to synthesize N-TFA EPIDNR seleno derivative:
(1) trifluoroacetic acid EPIDNR is synthetic: 1.007g (1.77mmol) EPIDNR II is suspended in ethyl acetate (20mL), under nitrogen protection, adds trifluoro-acetic anhydride 1mL, the solution clarification that becomes.This solution is washed to solution and is weakly alkaline with saturated sodium bicarbonate solution, separate ethyl acetate layer, to methyl alcohol (5mL) solution that adds NaOH (106mg, 2.65mmol) in this solution, stirring at normal temperature 1 hour, TLC detection substrate point disappears.By reaction solution saturated sodium-chloride water solution washed twice, organic layer anhydrous sodium sulfate drying, decompression desolventizes, and obtains trifluoroacetyl EPIDNR (III) 1.1g, and productive rate is 100%.Fusing point: 154-155 ℃.
(2) N-TFA EPIDNR 4 ' seleno derivative I is synthetic: by trifluoroacetyl EPIDNR (III) 97mg (0.16mmol), with 15mL methylene dichloride, dissolve, add the corresponding seleno acetic acid of 0.16mmol, 46mg (0.223mmol) DCC and 10mg DMAP, stirring at normal temperature 8-12 hour, TLC detection reaction is complete.Reaction solution washs with saturated ammonium chloride and saturated sodium-chloride water solution respectively, organic phase anhydrous sodium sulfate drying, and raffinate is separated with silica gel H chromatographic column, and eluent is normal hexane: methylene dichloride: acetone=3:3:1.
The sign of each reaction formula and each product is as follows:
Embodiment 1
4 '-adjacent chlorobenzene seleno acetoxyl group-4 '-'-deoxy-n-trifluoroacetyl EPIDNR:
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，OCH 3)，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，CH 3)，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，CH 3)。MS(FAB)：855.3(M +)，398.2。
Embodiment 2
4 '-to chlorobenzene seleno acetoxyl group-4 '-'-deoxy-n-trifluoroacetyl EPIDNR:
Yield: 95%, fusing point: 100-102 ℃.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，OCH 3)，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，CH 3)，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，CH 3)。 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(CF 3)，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(CH 2)，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 '-α-naphthalene seleno acetoxyl group-4 '-'-deoxy-n-trifluoroacetyl EPIDNR:
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，OCH 3+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，CH 3)，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，CH 3)。MS(FAB)：871.5(M +)，398.2。
Embodiment 4
4 '-normal-butyl seleno acetoxyl group-4 '-'-deoxy-n-trifluoroacetyl EPIDNR:
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，OCH 3)，3.24(1H，d，J＝18.7Hz，H-10e)，3.14(2H，s，CH 2)，2.93(1H，d，J＝18.7Hz，H-10a)，2.73(2H，t，J＝7.5Hz，CH 2)，2.44(3H，s，CH 3)，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，CH 2)，1.39(2H，m，CH 2)，1.31(3H，d，J＝6.2Hz，CH 3)，0.93(3H，t，J＝7.3Hz，CH 3)。MS(FAB)：801.8(M +)，398。
Application examples
Adopt general MTT method, N-TFA EPIDNR 4 ' seleno derivative of choosing embodiment 1,3 and 4 preparations carries out evaluated biological activity to human leukemia HL-60, and contrasts with daunorubicin, and result is as shown in table 1:
Biological activity test result shows, these three compounds all have good anti-tumor activity to human leukemia HL-60, can meet practical application.
The present invention is not limited to the Preparation method and use of the N-TFA EPIDNR seleno derivative that above-described embodiment records, and the change of seleno classes of compounds, the change of reaction conditions are all within protection scope of the present invention.
Finally it should be noted that: each embodiment, only in order to technical scheme of the present invention to be described, is not intended to limit above; Although the present invention is had been described in detail with reference to aforementioned each embodiment, those of ordinary skill in the art is to be understood that: its technical scheme that still can record aforementioned each embodiment is modified, or some or all of technical characterictic is wherein equal to replacement; And these modifications or replacement do not make the essence of appropriate technical solution depart from the scope of various embodiments of the present invention technical scheme.

Claims (6)

1. the seleno derivative of a class N-TFA EPIDNR, is characterized in that described derivative has the structure of formula I:
Wherein R is selected from radicals X 1, X 2, X 3and X 4in a kind of,
2. the preparation method of the seleno derivative of N-TFA EPIDNR claimed in claim 1, comprises the following steps:
(1) EPIDNR II and trifluoroacetic acid anhydride reactant generate N-TFA EPIDNR III,
(2) N-TFA EPIDNR III and the condensation reaction of corresponding replacement seleno acetic acid generate the seleno derivative I of described N-TFA EPIDNR;
Corresponding replacement seleno acetic acid is selected from and n-Bu-SeCH 2a kind of in COOH.
3. preparation method according to claim 2; the actual conditions that it is characterized in that step (1) is: EPIDNR II is suspended in ethyl acetate; under nitrogen protection; add trifluoro-acetic anhydride; the solution clarification that becomes; this solution is washed with saturated sodium bicarbonate solution; separate ethyl acetate layer; to the methanol solution that adds NaOH in this solution; stirring at normal temperature reaction; reaction solution washs with saturated sodium-chloride water solution, gets organic layer anhydrous sodium sulfate drying, obtains trifluoroacetyl EPIDNR III.
4. preparation method according to claim 2, the actual conditions that it is characterized in that step (2) is: trifluoroacetyl EPIDNR III is dissolved with methylene dichloride, add corresponding replacement seleno acetic acid, DCC and DMAP, stirring at normal temperature reaction, reaction solution suction filtration is removed insoluble solid, through column chromatography for separation, obtain the seleno derivative I of described N-TFA EPIDNR.
5. preparation method according to claim 4, the eluent that it is characterized in that described column chromatography is normal hexane: the mixed solution of methylene dichloride: acetone=3:3:1.
6. the seleno derivative of N-TFA EPIDNR claimed in claim 1 is treated the purposes in malignant tumor medicine in preparation.
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