CN103463119B - Sir2 inhibitor - Google Patents

Sir2 inhibitor Download PDF

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CN103463119B
CN103463119B CN201310363980.7A CN201310363980A CN103463119B CN 103463119 B CN103463119 B CN 103463119B CN 201310363980 A CN201310363980 A CN 201310363980A CN 103463119 B CN103463119 B CN 103463119B
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sir2
nmr
inhibitor
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ppm
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CN103463119A (en
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侯淑华
刘玉静
任冬梅
汤立军
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Bohai University
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Bohai University
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Abstract

A kind of Sir2 inhibitor, structural formula is as follows: ; Wherein, R is or , R 1for the one in aromatic amine, saturated or unsaturated alkyl, hydroxyl, amido , R 2for the one in aromatic radical, saturated or unsaturated alkyl, hydroxyl, amino.This compound is Sir2 inhibitor, can grow by anticancer, can be applied to the medicine of the preparation treatment mankind and other mammiferous cancer.

Description

Sir2 inhibitor
Technical field
The present invention relates to a kind of Sir2 inhibitor.
Background technology
Sir2(Silent information regulator) be a kind of NAD +the histon deacetylase (HDAC) of (nicotinamide adenine dinucleotide) dependent form, take part in the regulation and control of many vital movements, comprises DNA reparation, gene silencing and cell survival etc.Sir2 is at NAD +under existence, the acetyl group on histone is taken off, generates nicotine and 2-acetyl group-ADP(adenosine diphosphate (ADP)) or 3-acetyl group-ADP.The overexpression of Sir2 reduces antioncogene p53 activity, suppress Sir2 activity can contain the diffusion of cancerous cell simultaneously, also there are some researches show and suppress Sir2 activity to alleviate Parkinson disease, therefore it is very important for suppressing the activity of Sir2 to be considered in the advancing of disease preventing cancer and Parkinson disease, diabetes etc., needs to develop new Sir2 inhibitor.
At present, the IC of Sir2 inhibitor 50mostly in a μM rank, inhibition is not good, if nicotine is to the IC of Sirt2 50be 100 μMs, 4-Chromanone derivant is to the IC of Sirt2 50be 1.5 ~ 10 μMs, need effectively and more potent Sir2 inhibitor provides the treatment of cancer and Parkinson disease.
Summary of the invention
The technical problem to be solved in the present invention is to provide the good Sir2 inhibitor of a kind of inhibition, can effectively and more potent Therapeutic cancer.
Technical solution of the present invention is:
A kind of Sir2 inhibitor, has following structural formula:
；
Wherein, R is or , R 1for the one in aromatic amine, saturated or unsaturated alkyl, hydroxyl, amido, R 2for the one in aromatic radical, saturated or unsaturated alkyl, hydroxyl, amino.
Described Sir2 inhibitor, its structural formula is as follows:
In one.
Described Sir2 inhibitor, its structural formula is as follows:
In one.
As mentioned above, the compound that the present invention relates to is Sir2 inhibitor, can grow by anticancer, therefore, can be applied to the medicine of the preparation treatment mankind and other mammiferous cancer.
Accompanying drawing explanation
Fig. 1 is the present invention's (corresponding embodiment 5) Sir2 inhibitor 1h NMR spectrogram;
Fig. 2 is the present invention's (corresponding embodiment 5) Sir2 inhibitor 13c NMR spectrogram;
Fig. 3 is the present invention's (corresponding embodiment 5) Sir2 inhibitor 31p NMR spectrogram;
Fig. 4 is the present invention's (corresponding embodiment 6) Sir2 inhibitor 1h NMR spectrogram;
Fig. 5 is the present invention's (corresponding embodiment 6) Sir2 inhibitor 13c NMR spectrogram;
Fig. 6 is the present invention's (corresponding embodiment 6) Sir2 inhibitor 31p NMR spectrogram;
Fig. 7 is the present invention's (corresponding embodiment 7) Sir2 inhibitor 1h NMR spectrogram;
Fig. 8 is the present invention's (corresponding embodiment 7) Sir2 inhibitor 13c NMR spectrogram;
Fig. 9 is the present invention's (corresponding embodiment 7) Sir2 inhibitor 31p NMR spectrogram;
Figure 10 is the present invention's (corresponding embodiment 8) Sir2 inhibitor 1h NMR spectrogram;
Figure 11 is the present invention's (corresponding embodiment 8) Sir2 inhibitor 13c NMR spectrogram;
Figure 12 is the present invention's (corresponding embodiment 8) Sir2 inhibitor 31p NMR spectrogram;
Figure 13 is the present invention's (corresponding embodiment 9) Sir2 inhibitor 1h NMR spectrogram;
Figure 14 is the present invention's (corresponding embodiment 9Sir2 inhibitor 13c NMR spectrogram;
Figure 15 is the present invention's (corresponding embodiment 9) Sir2 inhibitor 31p NMR spectrogram;
Figure 16 is the present invention's (corresponding embodiment 10) Sir2 inhibitor 1h NMR spectrogram;
Figure 17 is the present invention's (corresponding embodiment 10) Sir2 inhibitor 13c NMR spectrogram;
Figure 18 is the present invention's (corresponding embodiment 10) Sir2 inhibitor 31p NMR spectrogram.
Detailed description of the invention
Embodiment 1
By lyophilizing Carba-NMN structural formula be (89 mg, 0.25 mmol) is suspended in 5 ml and heavily steams in dimethyl sulfoxide (DMSO) and 1 ml DMF (DMF), and ultrasonic, stirring makes it to dissolve.Add Methylimidazole. (415 μ l, 5.2 mmol), 2,2 two sulfur two pyridines ((PyS) 2) (286 mg, 0.93 mmol) is dissolved in 0.8 ml DMF, triphenyl phosphorus (PPh 3) (341mg, 1.3 mmol) be dissolved in 0.8 ml DMF, join successively in reaction system, stirring at room temperature 15 min, adds phosphate monoester 6-phenyl adenine mononucleotide (555 mg, 0.7 mmol are dissolved in 1.5ml DMF), stirring at room temperature 9 h; Be transferred in 50 ml centrifuge tubes and add 30 ml 0.2 M NaI acetone solns, have precipitation to produce, centrifugal, precipitation adds 8 ml water dissolutioies, uses 15ml CH 2cl 2extract 3 times, concentrated aqueous phase, adjust pH to be 2, (2 M NaCl 1000 ml wash upper DEAE-agarose column, rear 10 mM NH 4cOOH washes 1000 ml, and rear use 1000 ml washes), first wash with water, then use 10 mM NH 4hCO 3wash post, concentrated have uv absorption part; Again (2 M NaCl 1000 ml wash, rear 10 mM NH to go up DEAE post 4hCO 3wash 1000 ml), there is absorption portion at concentrated 254 nm places, obtain target product, productive rate 37.7%. 1H NMR (D 2O, 400 MHz) δ(ppm) 9.09 (s, 1H), 8.92 (d, J = 6.0 Hz, 1H), 8.64 (d, J = 8.0 Hz, 1H), 8.29 (s, 1H)，8.00 (s, 1H)，7.99 (dd, J = 6.0 Hz, 8.0 Hz, 1H ), 7.32 (m, 5H)，5.89 (d, J = 5. Hz, 1H), 5.85 (d, J = 5.2 Hz, 1H), 4.38 (dd, J = 5.6Hz, 9.4 Hz, 1H), 4.16 (m, 7H), 3.99 (m, 1H), 2.60 (ddd, J = 9.4 Hz, 9.4 Hz, 13.3 Hz, 1H), 2.32 (m, 1H), 2.05 (m, 1H)； 13C NMR (D 2O, 100.6 MHz) 164.9, 152.2, 152.0, 148.8, 145.7, 142.2, 139.8, 139.7, 137.1, 133.5, 129.1, 128.5, 125.0, 122.1, 119.2, 87.0 (d, J = 8.1 Hz), 86.7, 83.8 (d, J = 8.2 Hz), 77.5, 73.9, 70.5, 70.3, 65.3 (d, J = 1.8 Hz), 64.8, 43.1 (d, J = 8.0 Hz), 28.5； 31P NMR (D 2O, 162 MHz) δ(ppm) -10.8 (d, J = 19.4 Hz), -11.2 (d, J = 19.4 Hz); HRMS (ESI) calcd for (C 27H 34N 8O 14P 2) -requires m/z 754.5788, found m/z 754.5786.。
Sir2 inhibit activities IC 50measure:
The ability of Sirt2 is suppressed with the Sirt2 Fluorimetric Drug Discovery Kit-BML-AK556 kits compound purchased from Enzo Life Science company.In brief, when presence or absence inhibitor, by Fluor de Lys ?substrate (a kind of acetylation substrate) with there is deacetylase Sirt2 and NAD +hatch together.The deacetylated substrate that makes of substrate is to Fluor de Lys ?developer II developing agent is responsive thus produce fluorescence.Therefore, by substrate and Sirt2 and NAD +hatch together and cause fluorescence signal to strengthen, and when there is Sirt2 inhibitor signal weakening.Data representation is the percentage ratio accounting for the contrast recorded when there is not inhibitor, and all samples wants subtracting background signal, as follows:
% activity=((Si-B)/(So-B)) × 100
Wherein, Si is signal when there is substrate, enzyme and inhibitor, and So is signal when there is substrate, enzyme and carrier, and inhibitor is wherein dissolved, and the background signal recorded when B is and there is not enzyme.
In inhibitor test kit, buffering is made into different concentration, then gets 10 μ l respectively and is added in 96 hole blanks, add 15 μ l SIRT2(0.3 U/ μ l respectively), 15 μ l acetylation substrates, 10 μ l NAD +(1 mM) mix homogeneously, 37 ° of C react 1 h, then in every hole, adding 50 μ l Developer II solution, (38 μ l cushion, 2 μ l nicotine, 10 μ l Developer II), react 45 min under mix homogeneously room temperature, then at spectrofluorophotometer reading, excitation wavelength is 365 nm, and emission wavelength is 460 nm.Namely cushioning with without inhibitor replaces inhibitor solution for blank.Inhibitor concentration records 9 points (1500 μMs, 1000 μMs, 100 μMs, 10 μMs, 1 μM, 0.1 μM, 0.01 μM, 0.001 μM, 0.0001 μM), and each point in triplicate, records IC 50be 120 nM.
Carbazole alkaloid is tested
Results grow the corresponding cancerous cell (Hela) in logarithmic (log) phase and are inoculated in 96 hole tissue culturing plates with 1000 cells/well (final volume is 200 μ l).Growth of Cells processed cell 48 hours with compound (ultimate density is 20 μMs) after 24 hours.And then flat board is hatched 72 hours, afterwards according to Skehan 1990 J Natl Canc Inst82,1107-1112 carries out Sulforhodamine B (SRB) cell survival assay.
The suppression percent of the contrast that data representation records when being and there is not inhibitor, as follows:
% suppression=100-((S i/ S o) × 100)
Wherein, S isignal when there is inhibitor, S oit is signal when there is without inhibitor.
Determine IC 50adopt Graphpad Prism software during value, the result of 8 data points is fitted to the S shape dose-effect curve equation (logarithm of % activity and compound concentration) with variable slope, then determines IC by nonlinear regression analysis 50value.Record IC 50be 300 nM.
Embodiment 2
Replace 6-morpholine adenine mononucleotide with 6-phenyl adenine mononucleotide, the other the same as in Example 1, the productive rate of obtained target product is 22.9%. 1H NMR (D 2O, 400 MHz) δ(ppm) 9.36 (s, 1H), 9.12 (d, J = 6.0 Hz, 1H), 8.63 (d, J = 7.1 Hz, 1H), 8.16 (s, 1H)，8.01 (dd, J = 6.0 Hz, 7.1 Hz, 1H ), 7.93 (s, 1H)，5.83 (m, 2H), 4.3~4.0 (m, 9H), 3.91 (bs, 4H), 3.68 (bs, 4H), 2.60 (ddd, J = 9.4 Hz, 9.4 Hz, 13.3 Hz, 1H), 2.32 (m, 1H), 2.05 (m, 1H); 13C NMR (D 2O, 100.6 MHz) 165.1, 153.2, 151.8, 149.7, 145.6, 142.3, 139.9, 139.1, 133.6, 128.6, 118.9, 87.0 (d, J = 8.5 Hz), 86.5, 83.6 (d, J = 8.3 Hz), 77.5, 73.8, 70.6, 70.2, 66.3, 65.3 (d, J = 4.8 Hz), 64.8 (d, J = 4.1 Hz), 45.643.1 (d, J = 8.0 Hz), 28.8; 31P NMR (D 2O, 162 MHz) δ(ppm) -11.0 (d, J = 19.4 Hz), -11.3 (d, J = 19.4 Hz); HRMS (ESI) calcd for (C 25H 32N 7O 15P 2) -requires m/z 748.5726, found m/z 748.5732.
Sir2 inhibit activities IC 50assay method is with embodiment 1; Difference from Example 1 is, gained IC 50be 50 nM.Carbazole alkaloid test determination method is with embodiment 1; Record IC 50be 90 nM.
Embodiment 3
With embodiment 1 method; Difference from Example 1 is, phosphate monoester used is 6-imidazoles adenine mononucleotide, and productive rate is 34.9%. 1H NMR (D 2O, 400 MHz) δ(ppm) 9.20 (s, 1H), 9.04 (d, J = 4.0 Hz, 1H), 8.72 (d, J = 8.0 Hz, 1H), 8.66 (br, 2H)，8.59 (s, 1H)，8.04 (dd, J = 4.0 Hz, 8.0 Hz, 1H ), 7.97 (s, 1H), 7.1 (s, 1H), 6.11 (d, J = 5.3 Hz, 1H), 5.9 (d, J = 5.2 Hz, 1H), 4.41 (m, 3H), 4.36 (m, 1H), 4.29 (m, 3H), 4.16 (m, 2H), 3.99 (m, 1H), 2.60 (ddd, J = 9.4 Hz, 9.4 Hz, 13.3 Hz, 1H), 2.32 (m, 1H); 13C NMR (D 2O, 100.6 MHz) 164.8, 152.6, 151.7, 145.7, 144.4, 143.9, 142.5, 139.6, 136.9, 133.5, 129.4, 128.4, 121.4, 117.1, 87.5, 86.8 (d, J = 5.7 Hz), 83.7 (d, J = 6.0 Hz), 77.4, 74.2, 70.4, 70.2, 65.2, 64.8, 43.1 (d, J = 8.0 Hz), 28.8; 31P NMR (D 2O, 162 MHz) δ(ppm) -10.9 (d, J = 17.8 Hz), -11.2 (d, J = 17.8 Hz); HRMS (ESI) calcd for (C 24H 27N 8O 14P 2) -requires m/z 729.5295, found m/z 729.5222.
Sir2 inhibit activities IC 50assay method is with embodiment 1; Difference from Example 1 is, gained IC 50be 280 nM.Carbazole alkaloid test determination method is with embodiment 1; Record IC 50be 620 nM.
Embodiment 4
With embodiment 1 method; Difference from Example 1 is, phosphate monoester used is 6-dibutyl amine adenine mononucleotide, and productive rate is 24.4%. 1H NMR (D 2O, 400 MHz) δ(ppm) 9.15 (s, 1H), 8.96 (d, J = 5.0 Hz, 1H), 8.68 (d, J = 7.9 Hz, 1H), 8.13 (s, 1H), 8.05 (dd, J = 5.0 Hz, 7.9 Hz, 1H ), 7.83 (s, 1H), 5.84 (d, J = 4.3 Hz, 1H), 5.82 (d, J = 5.8 Hz, 1H), 4.55 (m, 1H), 4.50 (m, 4H), 4.19 (m, 4H), 3.99 (m, 1H), 3.46 (m, 4H), 2.60 (ddd, J = 9.4 Hz, 9.4 Hz, 13.3 Hz, 1H), 2.32 (m, 1H), 1.30 (bs 4H), 1.08 (bs, 4H), 0.67 (bs, 6H); 13C NMR (D 2O, 100.6 MHz) 165.0, 153.5, 152.1, 149.5, 145.8, 142.3, 139.8, 137.4, 133.8, 128.7, 118.6, 87.1 (d, J = 5.9 Hz), 86.6, 83.4 (d, J = 5.7 Hz), 77.6, 73.9, 70.6, 70.2, 65.4, 64.9, 48.7, 43.2, 29.8, 28.5, 19.5, 13.4; 31P NMR (D 2O, 162 MHz) δ(ppm) -10.9 (d, J = 17.8 Hz), -11.2 (d, J = 17.8 Hz); HRMS (ESI) calcd for (C 29H 46N 8O 14P 2) -requires m/z 790.6954, found m/z 790.6965.
Sir2 inhibit activities IC 50assay method is with embodiment 1; Difference from Example 1 is, gained IC 50be 750 nM.Carbazole alkaloid test determination method is with embodiment 1; Record IC 50be 950 nM.
Embodiment 5
With embodiment 1 method; Difference from Example 1 is, phosphate monoester used is 5-phosphoric acid-1-N-(4 '-(4 ' '-methoxybenzene))-[1 ', 2 ', 3 ']-triazole-β-D-RIBOSE, productive rate is 38.2%. 1h NMR (D 2o, 400 MHz) δ (ppm) 9.05 (s, 1H), 8.83 (d, j=6.2 Hz, 1H), 8.60 (d, j=8.2 Hz, 1H), 8.26 (s, 1H), 7.92 (dd, j=6.2 Hz, 8.2 Hz, 1H), 7.40 (d, j=8.6 Hz, 2H), 6.75 (d, j=8.6 Hz, 2H), 5.99 (d, j=4.8 Hz, 1H), 4.80 (ddd, j=8.7 Hz, 8.7 Hz, 8.7 Hz, 1H), 4.57 (dd, j=4.8 Hz, 4.8 Hz, 1H), 4.41 (dd, j=4.8 Hz, 4.8 Hz, 1H), 4.29 (m, 1H), 4.21 (m, 2H), 4.10 (m, 1H), 3.99 (m, 2H), 3.87 (m, 1H), 3.66 (s, 3H), 2.35 (ddd j=8.7 Hz, 8.7 Hz, 13.2 Hz, 1H), 2.20 (m, 1H), 1.84 (m, 1H) (as shown in Figure 1); 13c NMR (D 2o, 100.6 MHz) δ (ppm) 164.6,159.0,147.2,144.9,144.6,142.4,133.4,128.4,126.9,121.7,119.3,114.4,92.1,84.0 (d, j=7.6 Hz), 76.9,75.5,74.9,71.8,70.3,66.5,65.3,55.3,43.0 (d, j=8.2 Hz), 28.5(is as shown in Figure 2); 31p NMR (D 2o, 162 MHz) δ (ppm)-10.6 (d, j=18.6 Hz) ,-11.0 (d, j=19.1 Hz) (as shown in Figure 3); HRMS (ESI) calcd for (C 26h 32n 5o 14p 2) -requires m/z 700.1426, found m/z 700.1448.
Sir2 inhibit activities IC 50assay method is with embodiment 1; Difference from Example 1 is, gained IC 50be 800 nM.Carbazole alkaloid test determination method is with embodiment 1; Record IC 50it is 1.5 μMs.
Embodiment 6
With embodiment 1 method; Difference from Example 1 is, phosphate monoester used is 5-phosphoric acid-1-N-(4 '-(2 ' '-trifluoromethylbenzene))-[1 ', 2 ', 3 ']-triazole-β-D-RIBOSE, productive rate is 21.5%. 1h NMR (D 2o, 400 MHz) δ (ppm) 9.23 (s, 1H), 9.01 (d, j=6.2 Hz, 1H), 8.72 (d, j=8.2 Hz, 1H), 8.25 (s, 1H), 8.06 (dd, j=6.2 Hz, 8.2Hz, 1H), 7.71 (d, j=7.8 Hz, 1H), 7.58 (m, 1H), 7.50 (m, 1H), 6.05 (d, j=4.8 Hz, 1H), 4.95 (ddd, j=8.7 Hz, 8.7 Hz, 8.7 Hz, 1H), 4.64 (dd, j=4.9 Hz, 4.8 Hz, 1H), 4.43 (dd, j=4.8 Hz, 4.8 Hz, 1H), 4.35 (m, 2H), 4.13 (m, 3H), 4.02 (m, 1H), 3.89 (m, 1H), 2.50 (ddd, j=8.7 Hz, 8.7 Hz, 13.2 Hz, 1H), 2.27 (m, 1H), 2.06 (m, 1H) (as shown in Figure 4); 13c NMR (D 2o, 100.6 MHz) δ (ppm) 165.2,145.5,144.9,142.7,133.8,132.4,131.9,129.4,128.6,127.6,126.5,126.4,125.1,123.3,92.1,84.2 (d, j=8.7 Hz), 77.1,75.8,74.9,72.1,70.4,66.6,65.5,42.9 (d, j=8.3 Hz), 28.6(is as shown in Figure 5); 31p NMR (D 2o, 162 MHz) δ (ppm)-10.6 (d, j=19.3 Hz) ,-10.9 (d, j=19.3 Hz) (as shown in Figure 6); HRMS (ESI) calcd for (C 26h 29f 3n 5o 13p 2) -requires m/z 738.1195, found m/z 738.1198.
Sir2 inhibit activities IC 50assay method is with embodiment 1; Difference from Example 1 is, gained IC 50be 30 nM.Carbazole alkaloid test determination method is with embodiment 1; Record IC 50be 100 nM.
Embodiment 7
With embodiment 1 method; Difference from Example 1 is, phosphate monoester used is 5-phosphoric acid-1-N-(4 '-(2 ' '-fluorobenzene))-[1 ', 2 ', 3 ']-triazole-β-D-RIBOSE, productive rate is 32.6%. 1h NMR (D 2o, 400 MHz) δ (ppm) 9.14 (s, 1H), 8.93 (d, j=5.8 Hz, 1H), 8.65 (d, j=8.1 Hz, 1H), 8.39 (d, j=2.6 Hz, 1H), 7.99 (dd, j=5.8 Hz, 8.1 Hz, 1H), 7.80 (m, 1H), 7.34 (m, 1H), 7.20 (m, 2H), 6.04 (d, j=4.8 Hz, 1H), 4.87 (ddd, j=9.0 Hz, 9.0 Hz and 9.0 Hz, 1H), 4.65 (dd, j=4.8 Hz, 4.8 Hz, 1H), 4.43 (dd, j=4.8 Hz, 4.8 Hz, 1H), 4.32 (m, 2H), 4.14 (m, 1H), 4.13 (m, 1H), 4.09 (m, 2H), 3.91 (m, 1H), 2.50 (ddd, j=9.0 Hz, 9.0 Hz, 13.2 Hz, 1H), 2.26 (m, 1H), 2.04 (m, 1H) (as shown in Figure 7); 13c NMR (D 2o, 100.6 MHz) δ (ppm) 164.8,159.9 (d, j=248.4 Hz), 145.2,144.7,142.6,141.3,133.6,130.6 (d, j=8.3 Hz), 128.6,127.3,124.9,122.9 (d, j=10.7 Hz), 116.7 (d, j=13.1 Hz), 116.2 (d, j=20.9 Hz), 92.0,84.2 (d, j=8.4 Hz), 77.0,75.7,74.7,72.0,70.5,66.6,65.6,42.9 (d, j=8.3 Hz), 28.6(is as shown in Figure 8); 31p NMR (D 2o, 162 MHz) δ (ppm)-10.6 (d, j=17.7 Hz) ,-10.9 (d, j=17.7 Hz) (as shown in Figure 9); HRMS (ESI) calcd for (C 25h 29fN 6o 13p 2) -requires m/z 688.1227, found m/z 688.1225.
Sir2 inhibit activities IC 50assay method is with embodiment 1; Difference from Example 1 is, gained IC 50it is 2 μMs.Carbazole alkaloid test determination method is with embodiment 1; Record IC 50it is 4.5 μMs.
Embodiment 8
With embodiment 1 method; Difference from Example 1 is, phosphate monoester used is 5-phosphoric acid-1-N-(4 '-(2 ' '-aminobenzene))-[1 ', 2 ', 3 ']-triazole-β-D-RIBOSE, productive rate is 19.7%. 1h NMR (D 2o, 400 MHz) δ (ppm) 9.14 (s, 1H), 8.89 (d, j=6.0 Hz, 1H), 8.65 (d, j=7.9 Hz, 1H), 8.40 (s, 1H), 7.96 (dd, j=6.0 Hz, 7.9 Hz, 1H), 7.36 (d, j=7.7 Hz, 1H), 7.11 (dd, j=7.7 Hz, 7.7 Hz, 1H), 6.80 (m, 2H), 6.07 (d, j=4.8 Hz, 1H), 4.80 (ddd, j=9.4 Hz, 9.4 Hz, 9.4 Hz, 1H), 4.65 (dd, j=4.8 Hz, 4.8 Hz, 1H), 4.44 (dd, j=4.8 Hz, 4.8 Hz, 1H), 4.31 (m, 1H), 4.28 (m, 1H), 4.17 (m, 2H), 4.00 (m, 2H), 3.97 (m, 2H), 3.87 (m, 1H), 2.58 (ddd j=9.4 Hz, 9.4 Hz, 13.2 Hz, 1H), 2.32 (m, 1H), 2.02 (m, 1H) (as shown in Figure 10); 13c NMR (D 2o, 100.6 MHz) δ (ppm) 165.0,146.9,145.1,144.7,143.6,142.5,133.5,129.9,119.3,117.8,114.5,92.2,84.3 (d, j=7.9 Hz), 77.0,75.7,75.0,72.0,70.4,66.6,65.4,43.0 (d, j=7.8 Hz), 28.5(is as shown in figure 11); 31p NMR (D 2o, 162 MHz) δ (ppm)-10.6 (d, j=20.1 Hz) ,-11.0 (d, j=20.1Hz) (as shown in figure 12); HRMS (ESI) calcd for (C 25h 35n 7o 13p 2) -requires m/z 685.1430, found m/z 685.1439.
Sir2 inhibit activities IC 50assay method is with embodiment 1; Difference from Example 1 is, gained IC 50it is 1 μM.Carbazole alkaloid test determination method is with embodiment 1; Record IC 50it is 2.5 μMs.
Embodiment 9
With embodiment 1 method; Difference from Example 1 is, phosphate monoester used is 5-phosphoric acid-1-N-(4 '-naphthyl)-[1 ', 2 ', 3 ']-triazole-β-D-RIBOSE, productive rate is 38.6%. 1h NMR (D 2o, 400 MHz) δ (ppm) 8.94 (s, 1H), 8.71 (d, j=6.0 Hz, 1H), 8.50 (s, 1H), 8.34 (d, j=8.9 Hz, 1H), 7.99 (m, 1H), 7.82 (m, 2H), 7.74 (m, 1H), 7.57 (m, 1H), 7.45 (m, 3H), 6.15 (d, j=4.9 Hz, 1H), 4.74 (ddd, j=8.7 Hz, 8.7 Hz, 8.7 Hz, 1H), 4.65 (dd, j=4.9 Hz, 4.9 Hz, 1H), 4.48 (dd, j=4.9 Hz, 4.9 Hz, 1H); 4.35 (m, 1H), 4.19 (m; 1H), 4.12 (m, 2H); 3.95 (m, 2H), 3.80 (m; 1H), 2.22 (m, 2H); 1.86 (m, 1H) (as shown in figure 13); 13c NMR (D 2o, 100.6 MHz) δ (ppm) 164.5,146.4,144.8,144.2,142.0,133.2,132.9,129.8,129.4,128.5,128.0,127.6,127.2,126.5,126.1,125.6,124.6,122.9,92.2,84.3 (d j=9.2 Hz), 76.9,75.4,75.0,71.8,70.6,66.5,65.5,43.0 (d, j=7.9Hz), 28.1(as shown in figure 14); 31p NMR (D 2o, 162 MHz) δ (ppm)-11.4 (d, j=20.4 Hz) ,-11.7 (d, j=20.4 Hz) (as shown in figure 15); HRMS (ESI) calcd for (C 29h 32n 5o 13p 2) -requires m/z 720.1477, found m/z 720.1459.
Sir2 inhibit activities IC 50assay method is with embodiment 1; Difference from Example 1 is, gained IC 50it is 0.2 μM.Carbazole alkaloid test determination method is with embodiment 1; Record IC 50it is 0.8 μM.
Embodiment 10
With embodiment 1 method; Difference from Example 1 is, phosphate monoester 5-flurocytosine mononucleotide used, productive rate is 36.0%. 1h NMR (D 2o, 400 MHz) δ (ppm) 9.26 (s, 1H), 9.04 (d, j=6.2 Hz, 1H), 8.82 (d, j=8.1 Hz, 1H), 8.13 (dd, j=6.2 Hz, 8.1 Hz, 1H), 7.86 (d, j=6.4 Hz, 1H), 5.71 (d, j=3.9 Hz, 1H), 4.97 (ddd, j=9.4 Hz, 9.4 Hz, 9.4 Hz, 1H), 4.38 (dd, j=5.6Hz, 9.4 Hz, 1H), 4.16 (m, 7H), 3.99 (m, 1H), 2.60 (ddd, j=9.4 Hz, 9.4 Hz, 13.3 Hz, 1H), 2.32 (m, 1H), 2.05 (m, 1H) (as shown in figure 16); 13c NMR (D 2o, 100.6 MHz) δ (ppm) 165.4,158.2 (d, j=14.9 Hz), 155.6,145.5,145.0,142.9,138.6 (d, j=243.4 Hz), 133.9,128.7,125.7 (d, j=32.9 Hz), 89.6,82.6 (d, j=8.5 Hz), 76.8,75.7,74.1,71.9,69.1,66.6,64.7,43.1 (d, j=8.0 Hz), 28.8(is as shown in figure 17); 31p NMR (D 2o, 162 MHz) δ (ppm)-10.6 (d, j=19.4 Hz) ,-11.0 (d, j=19.4 Hz) (as shown in figure 18); 19f NMR (D 2o, 376.5 MHz) δ-161.7; HRMS (ESI) calcd for (C 21h 27fN 5o 14p 2) -requires m/z 654.1019, found m/z 654.1009.
Sir2 inhibit activities IC 50assay method is with embodiment 1; Difference from Example 1 is, gained IC 50it is 2 μMs.Carbazole alkaloid test determination method is with embodiment 1; Record IC 50it is 4.5 μMs.

Claims (3)

1. a Sir2 inhibitor, is characterized in that:
Structural formula is as follows:
In one.
2. a Sir2 inhibitor, is characterized in that:
In one.
3. a Sir2 inhibitor, is characterized in that:
Structural formula is as follows:
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