CN102234506B - Purpose of 1,8-naphthalimide derivatives - Google Patents

Purpose of 1,8-naphthalimide derivatives Download PDF

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CN102234506B
CN102234506B CN2010101558905A CN201010155890A CN102234506B CN 102234506 B CN102234506 B CN 102234506B CN 2010101558905 A CN2010101558905 A CN 2010101558905A CN 201010155890 A CN201010155890 A CN 201010155890A CN 102234506 B CN102234506 B CN 102234506B
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acetyltransferase
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徐玉芳
崔雷
钱旭红
朱维平
鈡烨
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East China University of Science and Technology
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Abstract

The invention relates to a purpose of 1,8-naphthalimide derivatives. 3-amino-1,8-naphthalimide derivatives are N-alkyl or substituted alkyl. A 3-amino-1,8-naphthalimide compound can be used as a fluorescence probe for detecting activity of N-acetyltransferase2. According to the invention, a base is established for treating tumour in a customized administration mode.

Description

The purposes of 1,8-naphthalimide analog derivative
Technical field
The present invention relates to a kind ofly 1, the purposes of 8-naphthalimide analog derivative, specifically, relate to a kind of 3-amino-1, the purposes of 8-naphthalimide analog derivative.
Background technology
N-acetyltransferase 2 (N-acetyltransferase2; NAT.) be a kind of important phase II metabolic enzyme in human body; being mainly the catalysis acetyl group transfers on its effect substrate aromatic amine and heterocyclic amine material from acetyl-CoA, plays an important role in the metabolic process of human body to the activation of aromatic amine carcinogenic substance and/or deactivation and some drugs.
But the genetic polymorphism of NAT. and tissue specific expression, add the interaction between environmental factors and NAT. gene, jointly caused the greatest differences of the NAT. activity of different crowd, thereby the clinical administration amount has been proposed huge challenge.Thereby pass through simple and the activity individual NAT. of effective means mensuration, thus determine suitable dosage, this has great importance to improving the tumour patient healing and reducing the side effect aspect.
At present, mainly to determine that by the meta-bolites (as sulfonamides compound) that HPLC detects known compound enzyme lives for detection of the method for the activity of N-acetyltransferase 2, perhaps use radioelement, fluorophor labeling polypeptide chain, by polymerase chain reaction (PCR), the gene type of Different Individual is detected (Clin.Chem., 2004.50 (7): p.1264-6; Analytical Biochemistry 1985,145,367-75).The main drawback of these methods is length consuming time, trivial operations.Therefore study easy, efficient N-acetyltransferase 2 probes efficiently that reach very important meaning is arranged.
Summary of the invention
Existing known aromatic amine compounds can produce corresponding amides (a.T.B.Felder under N-acetyltransferase 2 (NAT.) effect, M.A.McLean, M.L.Vestal, K.Lu, D.Farquhar, S.S.Legha, R.Shah and R.A.Newman, Drug Metab.Dispos., 1987,15,773; B.M.F.Brana and A.Ramos, Curr.Med.Chem.Anticancer Agents, 2001,1,237.)., if the gained amides possesses fluorescence and has higher fluorescence quantum yield, can be used for can reaching nmole rank (10nM) to detection and its detectability of N-acetyltransferase 2.Accordingly; the present inventor finds after a large amount of screening compounds: have a kind of N-to replace; 3-amino-1,8-naphthoyl imide compounds (wherein the substituting group on N is: alkyl or substituted alkyl) has high sensitivity and capability of fast response to N-acetyltransferase 2.
Spectrum test shows: this kind N-replaces; 3-amino-1; the 8-naphthoyl imide compounds is under N-acetyltransferase 2 (buffer solution system of pH=7.4) effect; after excitation with certain wavelength; there will be the product after obvious emission peak and acetylize that higher fluorescence quantum yield is arranged, to the detectability of N-acetyltransferase 2, can reach the nmole rank.
Bioassay shows: this kind N-replaces; 3-amino-1; the 8-naphthoyl imide compounds has higher specificity, high sensitivity and the ability of response fast to N-acetyltransferase 2, can be to supply a model basis and according to the activity of N-acetyltransferase 2 in different patient bodies, determine that different dosages judges foundation of phase II metabolic in the body of aromatic amine and hydrazine class compound.
The said amino of 3-for detection of N-acetyltransferase 2 activity-1 of the present invention, 8-naphthalimide analog derivative has structure shown in formula I:
Figure RE-GSA00000094935200021
In formula I: R 1For C 1～C 6The C of alkyl or replacement 1～C 6Alkyl;
The C of said replacement 1～C 6The substituting group of alkyl is selected from: hydroxyl, alkoxyl group or R 2NR 3In a kind of, two or more, R wherein 2And R 3Be selected from respectively H or C 1～C 6A kind of in alkyl.
In preferred technical scheme of the present invention, R 1For C 1～C 4The C of alkyl or replacement 1～C 4Alkyl;
The C of said replacement wherein 1～C 4The substituting group of alkyl is selected from: hydroxyl, C 1～C 3Alkoxyl group or R 2NR 3In a kind of, two or more, R 2And R 3Be selected from respectively H or C 1～C 3A kind of in alkyl.
In a further preferred technical solution of the present invention, R 1For C 4The C of alkyl or replacement 1～C 3Alkyl;
The C of said replacement wherein 1～C 3The substituting group of alkyl is selected from: hydroxyl, CH 3NCH 3Or C 1～C 2A kind of in alkoxyl group, two or more.
Best R 1For normal-butyl [CH 2(CH 2) 2CH 3], Or
Figure RE-GSA00000094935200023
Description of drawings
Fig. 1 is the Absorption and emission spectra figure of compound shown in formula Ia in the Tris-HCl (containing 1%DMSO) of pH=7.4 damping fluid;
Wherein: (a) be the abosrption spectrogram of compound in Tris-HCl (containing 1%DMSO) damping fluid shown in formula Ia;
(b) be the utilizing emitted light spectrogram of compound in Tris-HCl (containing 1%DMSO) damping fluid shown in formula Ia.
(b-1) be the graph of a relation of the intensity of fluorescence emission spectrum and its concentration of Compound I a.
Fig. 2 is the Absorption and emission spectra figure of Compound I a-1 in the Tris-HCl (containing 1%DMSO) of pH=7.4 damping fluid;
Wherein: (a) be the abosrption spectrogram of Compound I a-1 in Tris-HCl (containing 1%DMSO) damping fluid;
(b) be the utilizing emitted light spectrogram of Compound I a-1 in Tris-HCl (containing 1%DMSO) damping fluid;
(b-1) graph of a relation of the intensity of the fluorescence emission spectrum of Compound I a-1 and its concentration.
Fig. 3 be compound shown in formula Ia in the Tris-HCl (containing 1%DMSO) of pH=7.4 damping fluid by the fluorescence spectrum figure of N-acetyltransferase 2 catalysis.
Wherein: (a) concentration for compound shown in formula Ia is 10 μ M, and the concentration of acetyl-CoA is 50 μ M, and the concentration of N-acetyltransferase 2 is 5 μ g/mL, and illustration (figure a-1) is the dependence graph of catalysis time and fluorescence intensity under condition for this reason;
(b) concentration for compound shown in formula Ia is 10 μ M, and the concentration of acetyl-CoA is 50 μ M, and the concentration of N-acetyltransferase 2 is 2.5 μ g/mL, and illustration (figure b-1) is the dependence graph of catalysis time and fluorescence intensity under condition for this reason;
(c) concentration for compound shown in formula Ia is 10 μ M, and the concentration of acetyl-CoA is 50 μ M, and the concentration of N-acetyltransferase 2 is 1.25 μ g/mL, and illustration (figure c-1) is the dependence graph of catalysis time and fluorescence intensity under condition for this reason;
(d) concentration for compound shown in formula Ia is 10 μ M, and the concentration of acetyl-CoA is 50 μ M, and the concentration of N-acetyltransferase 2 is 1 μ g/mL, and illustration (figure d-1) is the dependence graph of catalysis time and fluorescence intensity under condition for this reason;
(e) graph of a relation of the fluorescence intensity of compound shown in different concns N-acetyltransferase 2 and formula Ia.
Fig. 4. the metabolism fluorescence imaging figure for compound shown in formula Ia in the HepG2 cell.
Wherein: (a) represent that compound shown in formula Ia adds the picture under light field after HepG2 cell 45min; (b) represent that compound shown in formula I a adds the picture that gathers at the 535-600nm wave band after HepG2 cell 45min; (c) represent that compound shown in formula Ia adds the picture that gathers at the 430-495nm wave band after HepG2 cell 45min; (d) represent that compound shown in formula Ia adds the picture under light field under HepG2 cell 90min; (e) represent that compound shown in formula Ia adds the picture that gathers at the 535-600nm wave band after HepG2 cell 90min; (f) represent that compound shown in formula Ia adds the picture that gathers at the 430-495nm wave band after HepG2 cell 90min; (g) representative adds the picture under light field after HepG2 cell 90min without any compound; (h) representative adds the picture that gathers at the 535-600nm wave band after HepG2 cell 90min without any compound; (i) representative adds the picture that gathers at the 430-495nm wave band after HepG2 cell 90min without any compound.
Embodiment
Fig. 5 is 460nm and the 580nm fluorescence intensity ratio that compound shown in formula Ia adds HepG2 cell front and back
Wherein Gr represents the average cell fluorescence intensity of the picture that the 535-600nm wave band gathers; Bl represents the average cell fluorescence intensity of the picture that the 430-495nm wave band gathers; Ra represents the average cell fluorescence intensity of the picture that the 430-495nm wave band gathers and the average cell fluorescence intensity ratio of the picture that the 535-600nm wave band gathers.All numerical value are by ImageJ computed in software gained.
It is a kind of that to prepare 3-of the present invention amino-1, the method for 8-naphthalimide analog derivative, and its syntheti c route is as follows:
Key step is: 3-amino-1,8-naphthalene acid anhydride (compound shown in the formula II), aminated compounds (R 1-NH 2) and organic solvent (as ethanol and/or N, N-dimethyl-ethylenediamine etc.) reacted 2 hours～8 hours under reflux state, successively through steam except after organic solvent, filtration and column chromatography target compound (compound shown in the formula I).
Wherein: 3-amino-1,8-naphthalene acid anhydride are by 3-nitro-1, and the reduction of 8-naphthalene acid anhydride is [as adopting the inferior tin (SnCl of chlorine 2)/hydrochloric acid reduction etc.] make (Bioorganic ﹠amp; Medicinal Chemistry Letters, 15 (7), 1769-1772; 2005)
The present invention is further elaborated below by embodiment, and its purpose only is better to understand content of the present invention.Therefore, protection scope of the present invention is not limited by the cases cited.
Embodiment 1
Figure DEST_PATH_GSB00000217432700022
In 50ml single port flask, add successively 0.5g (3mmol) 3-amino-1,8-naphthalene acid anhydride, 0.3mL (2.9mmol) N; N-dimethyl-ethylenediamine and 25ml ethanol, under argon shield, alcohol reflux; TLC follows the tracks of reaction, until react completely, approximately 1 hour reaction times.The reduced vacuum rotary evaporation, except desolventizing, obtains the red-brown solid.Separate (developping agent (v/v): CH with silica gel column chromatography 2Cl 2: CH 3OH=20: 1), collect the material of yellow hyperfluorescenceZeng Yongminggaoyingguang bands of a spectrum, rotary evaporation falls solvent and obtains the solid head product, then with ethyl alcohol recrystallization, obtains the glassy yellow solid.Productive rate is 75%, fusing point:＞300 ℃.
1H-NMR(D 6-DMSO)：δ＝2.30(6H，s，N(CH 3) 2)，2.49(2H，t，J＝7.2Hz，CH 2CH 2N(CH 3) 2)，4.07(2H，s，-NH 2)，4.25(2H，t，J＝7.2Hz，CH 2CH 2N(CH 3) 2)，7.22(1H，d，J＝2.1Hz，)，7.53(1H，t，J＝7.8Hz)，7.85(1H，d，J＝2.1Hz)，7.94(1H，d，J＝7.8Hz)，8.24(1H，d，J＝7.8Hz).
13C-NMR(D 6-DMSO)：δ＝37.4，45.3，56.4，111.6，120.4，121.6，121.6，122.4，125.3，126.8，131.4，133.4，147.8，163.4 and 163.4.EI-MS：58(100)；71(31)and 283(6).ESI-MS(+)：239(15)and 284(M+H，10)。
Embodiment 2
Figure RE-GSA00000094935200051
In 50ml single port flask, add successively 0.5g (3mmol) 3-amino-1,8-naphthalene acid anhydride, 640mg (2.9mmol) n-Butyl Amine 99 and 25ml ethanol, under argon shield, alcohol reflux, TLC follows the tracks of reaction, until react completely, approximately 1 hour reaction times.The reduced vacuum rotary evaporation, except desolventizing, obtains the red-brown solid.Separate (developping agent (v/v): CH with silica gel column chromatography 2Cl 2: CH 3OH=80: 1), collect the material of yellow hyperfluorescenceZeng Yongminggaoyingguang bands of a spectrum, rotary evaporation falls solvent and obtains the solid head product, then with ethyl alcohol recrystallization, obtains the glassy yellow solid.Productive rate is 80%, fusing point:＞300 ℃.
Embodiment 3
Figure RE-GSA00000094935200052
In 50ml single port flask, add successively 0.2g (0.94mmol) 3-amino-1,8-naphthalene acid anhydride, 0.125mL (1.25mmol) 2-(2-monoethanolamine) ethanol and 25ml ethanol; under argon shield, alcohol reflux, TLC follows the tracks of reaction; until react completely, the reaction times is 1h approximately.The reduced vacuum rotary evaporation, except desolventizing, obtains the red-brown solid.Separate (developping agent: CH with silica gel column chromatography 2Cl 2: CH 3OH=80: 1), collect the material of yellow hyperfluorescenceZeng Yongminggaoyingguang bands of a spectrum, rotary evaporation falls solvent and obtains the solid head product, then with ethyl alcohol recrystallization, obtains the glassy yellow solid.Productive rate is 80%, fusing point:＞300 ℃.
1H NMR(400MHz，DMSO-d 6)δ8.62(d，1H，J＝8.0Hz)，8.43(d，1H，J＝8.0Hz)，8.19(d，1H，J＝8.4Hz)，7.65(t，1H，J＝8.1Hz)，7.448(s，2H)，6.84(d，1H，J＝8.4Hz)，4.58(s-br，1)，4.21(t，2H，J＝6.0Hz)，3.57(s，2H，J＝6.0Hz)，3.45(m，4H).
13C-NMR(100MHz，DMSO-d 6)δ：164.3，163.4，153.3，134.5，131.6，132.0，129.9，124.4，122.1，179.8，108.6，107.8，72.3，67.5，60.6，38.8。
Embodiment 4
The spectrum property test of compound:
1) mensuration of ultraviolet and fluorescence spectrum
After vacuum-drying, accurate weighing sample on balance (being accurate to 0.0001 gram),, with dimethyl sulfoxide (DMSO) (DMSO) constant volume, be made into 10 with compound shown in formula Ia, formula Ib and formula Ic -3The solution of M and constant volume are in the 10mL volumetric flask, and as mother liquor, Compound I a, compounds ib and the Compound I c solution of preparation different concns are used for the test of absorption spectrum and excitation-emission spectrum.
2) mensuration of fluorescence quantum yield
The relative fluorescence quantum yield Φ of compound shown in formula Ia, formula Ib and formula Ic sThe quinoline sulfate (Φ with 0.5mol ref=0.55) solution is with reference to recording, and result is got the mean value of measuring three times, by (1) formula, calculates:
Φ s＝Φ ref.A ref.F s/(F ref.A s) (1)
In formula: Φ s, Φ refThe fluorescence quantum yield that represents respectively testing sample and standard substance; A s, A refRepresent respectively testing sample and the standard substance radiative absorbancy to this excitation wavelength; F s, F refThe integration fluorescence intensity that represents respectively testing sample and standard substance.
Concrete outcome sees that Fig. 1 (is the Absorption and emission spectra figure of compound in the Tris-HCl (containing 1%DMSO) of pH=7.4 damping fluid shown in formula I a, shown in formula Ib and formula Ic, the collection of illustrative plates of compound is similar, unlisted) and in Table 1 (shown in formula Ia, formula Ib and formula Ic, compound is at the spectroscopic data of Tris-HCl (containing 1%DMSO) damping fluid).
Table 1
Figure RE-GSA00000094935200061
By in Fig. 1 (b-1) as can be known: the intensity of the fluorescence emission spectrum of Compound I a and concentration have extraordinary linear light relation.
Embodiment 5
Respectively " meta-bolites " of compound shown in synthesis type Ia, formula Ib and formula Ic, as follow these steps to make " meta-bolites " of compound as shown in formula Ia.
The mixing solutions (its volume ratio is 1: 1) that adds successively compound shown in the formula Ia of 283mg (10mmol) and 4mL pyridine and diacetyl oxide in 25ml single port flask.After stirring 24 hours under room temperature (20 ℃～25 ℃) condition, when TLC point plate is followed the tracks of, raw material reaction is complete.The reduced vacuum rotary evaporation except desolventizing, obtains yellow oily liquid, this oily liquids is dissolved in about 50mL chloroform, and, with the water washing organic phase of 2 * 50mL, collects organic phase and also use the anhydrous sodium sulphate dried overnight.The chloroform rotary evaporation that reduces pressure is removed with re-crystallizing in ethyl acetate and can be obtained 2.76g lark solid, and productive rate is 85%.
1HNMR(CDCl3)：δ＝2.27(3H，s，)，2.53(6H，s，)，2.92(2H，t，J＝6.0Hz)，4.38(2H，t，J＝6.0Hz，)，7.65(1H，t，J＝8.0Hz)，7.90(1H，d，J＝8.0Hz)，7.94(1H，s)，8.35(1H，d，J＝7.8Hz)，8.54(1H，s)，8.59(1H，s). 13C NMR(CDCl 3)：δ＝24.7，37.7，46.1，58.3，120.9，121.9，122.6，122.8，124.2，127.4，129.5，132.1，133.7，136.8，163.5，164.4and 169.2.EI-MS：58(100)；71(69)；140(8)；169(7)；212(8)and 325(10).ESI-MS(+)：281(13)and 326(M+H，100)。
Because reactant and product are known substance, therefore those skilled in the art's instruction as stated above can make the meta-bolites of other compound.The structure of said " meta-bolites " is as shown in formula III:
Figure RE-GSA00000094935200071
In formula III, work as R 1During for normal-butyl, note by abridging as Compound I a-1; Work as R 1For The time, note by abridging as compounds ib-1; Work as R 1For
Figure RE-GSA00000094935200073
The time, note by abridging as Compound I c-1;
Compound I a-1, compounds ib-1 and Compound I c-1 are surveyed its ultraviolet (absorption) and fluorescence (emission) wavelength and fluorescence quantum yield by the described method of embodiment 4, and concrete outcome sees that (Fig. 2 is the Absorption and emission spectra figure of Compound I a-1 in the Tris-HCl (containing 1%DMSO) of pH=7.4 damping fluid to Fig. 2; Shown in formula Ib-1 and formula Ic-1, the collection of illustrative plates of compound is similar, unlisted) and table 2.
Table 2
Figure RE-GSA00000094935200074
Intensity and concentration by the fluorescence emission spectrum of the enzymes metabolism product that can find out Compound I a in Fig. 2 (b-1) have extraordinary linear light relation.By the fluorescence intensity ratio that can infer Compound I a and its meta-bolites in Fig. 1 (b) and Fig. 2 (b) and its concentration, good linear relationship is arranged, therefore can by fluorescence intensity indirectly two kinds of compounds of deduction place concentration so that can infer that enzyme lives.
Embodiment 6
The mensuration of compound shown in formula Ia, formula Ib and formula Ic to the response of N-acetyltransferase 2:
in the micro-fluorescence cuvette of 40 μ L, we select the concentration 50 μ M of acetyl-CoA (available from Sigma company), in the Tris-HCl damping fluid (containing 1%DMSO) of pH=7.5, adjusting adds N-acetyltransferase 2 (available from Sigma company), make its ultimate density be respectively 5 μ g/mL, 2.5 μ g/mL, 1.25 μ g/mL, 1 μ g/mL, add compound mother liquor shown in the formula Ia of 1 μ L after the N-acetyltransferase 2 solution 100 μ L that prepare each group concentration, make the concentration of compound shown in the formula Ia that adds reach 10 μ M and put into rapidly fluorophotometer and measured the fluorescence intensity variation every 30 seconds.We have measured the fluorescence response of Ia to the N-acetyltransferase 2 under four groups of different concns, the results are shown in accompanying drawing 3.
Can find out that by Fig. 3 (a) compound shown in formula Ia is very fast to the response speed of N-acetyltransferase 2, the fluorescence intensity at the 580nm place when the fluorescence intensity at 410nm place obviously strengthens reduces.Can find out from above-mentioned test result, compound shown in formula Ia can be used as the proportionality fluorescent probe of N-acetyltransferase 2.Dotted line represents the curve (R=0.9978) after match in Fig. 3 (e), has shown good linear relationship, illustrates that the concentration of enzyme and fluorescence intensity have had relation since good linearity.
Also obtained similar result in the test result to compound shown in formula Ib and formula Ic.Fluorescence intensity at the 566nm place reduces when the fluorescence intensity at 455nm place obviously strengthens in compound thing shown in formula Ib.Can find out from above-mentioned test result, compound shown in formula Ib can be used as the proportionality fluorescent probe of N-acetyltransferase 2.Fluorescence intensity at the 570nm place reduces when the fluorescence intensity at 460nm place obviously strengthens in compound thing shown in formula Ic.Can find out from above-mentioned test result, compound shown in formula Ic can be used as the proportionality fluorescent probe of N-acetyltransferase 2.
Embodiment 7
The mensuration [viable cell (HepG2) body in] of compound shown in formula Ia, formula Ib and formula Ic to the response of N-acetyltransferase 2:
HepG2 cell (Chinese Academy of Sciences's cell bank) is cultivated in 6 orifice plates, substratum adopts DEME (to contain 10% foetal calf serum, phenol red reagent, 4.5g/L D-Glucose, GlutaMax-1), after cell is paved with, draw supernatant liquor, and, with PBS damping fluid washing three times, then add compound shown in formula Ia, making its ultimate density is that the content of 10 μ M and DMSO is 5.0 (V/V).Subsequently 6 orifice plates are transferred in cell culture incubator (37 ℃, 5%CO 2), respectively take out culture plate when 45 minutes and 90 minutes,, with PBS damping fluid washed twice, remove compound shown in the formula Ia in nutrient solution.Add again PBS damping fluid (pH=7.5,1%DMSO) be placed in Leica DMIRB fluorescent microscope (being furnished with COHU high performance CCD camera lens), gather respectively the green fluorescence (time shutter 800ms) at 430-495nm blue-fluorescence (time shutter 3000ms) and 535-600nm place, the results are shown in Figure 4 and Fig. 5.
As shown in Figure 4: the accumulation number of photons at 430-495nm place blue-fluorescence strengthens along with administration timing of drug, and the accumulation number of photons of opposite green fluorescence (the same) at the 535-600nm place but weakens (with the conclusion of embodiment 6, conforming to) along with the increase of time.
Also obtained similar result in the test result to compound shown in formula Ib and formula Ic.Fluorescence intensity at the 535-600nm place reduces when the fluorescence intensity at 430-495nm place obviously strengthens in compound thing shown in formula Ib.Can find out from above-mentioned test result, compound shown in formula Ib can be used as the viable cell proportionality fluorescent probe of N-acetyltransferase 2.Fluorescence intensity at the 535-600nm place reduces when the fluorescence intensity at 430-495nm place obviously strengthens in compound thing shown in formula Ic.Can find out from above-mentioned test result, compound shown in formula Ic can be used as the viable cell proportionality fluorescent probe of N-acetyltransferase 2.

Claims (5)

1. compound shown in a formula I is as the application of the fluorescent probe that detects N-acetyltransferase 2 activity:
In formula I: R 1For C 1～C 6The C of alkyl or replacement 1～C 6Alkyl;
The C of said replacement 1～C 6The substituting group of alkyl is selected from: hydroxyl, alkoxyl group or R 2NR 3In a kind of, two or more, R wherein 2And R 3Be selected from respectively H or C 1～C 6A kind of in alkyl.
2. application as claimed in claim 1, is characterized in that, wherein R 1For C 1～C 4The C of alkyl or replacement 1～C 4Alkyl;
The C of said replacement 1～C 4The substituting group of alkyl is selected from: hydroxyl, C 1～C 3Alkoxyl group or R 2NR 3In a kind of, two or more, R 2And R 3Be selected from respectively H or C 1～C 3A kind of in alkyl.
3. application as claimed in claim 2, is characterized in that, wherein R 1For C 4The C of alkyl or replacement 1～C 3Alkyl;
The C of said replacement 1～C 3The substituting group of alkyl is selected from: hydroxyl, CH 3NCH 3Or C 1～C 2A kind of in alkoxyl group, two or more.
4. application as claimed in claim 3, is characterized in that, wherein R 1For normal-butyl or
Figure FSB00001119674800012
5. compound shown in a formula Ic is as the application of the fluorescent probe that detects N-acetyltransferase 2 activity,
Figure FSB00001119674800013
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PHARMACOGENETICS OF ANTICANCER AGENTS: LESSONS FROM AMONAFIDE;FEDERICO INNOCENTI等;《DRUG METABOLISM AND DISPOSITION》;20010401;第29卷(第4期);全文 *

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