CN107629061A - A kind of fluoro (±) PenibrugiueramineA and its synthesis and the application as antibacterials - Google Patents
A kind of fluoro (±) PenibrugiueramineA and its synthesis and the application as antibacterials Download PDFInfo
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Abstract
A kind of application the invention discloses fluoro (±) Penibrugiueramine A and its synthetic method and as antibacterials, its synthetic method is with (2S, 4R/4S) 4 fluoro proline tert-butyl esters are that initiation material passes through condensation, intramolecular aldol reactions, hydrolysis and reduction reaction successively with olefin(e) acid compound, obtain fluoro (±) Penibrugiueramine A；The synthetic method is simple to operate, reaction condition is gentle, cost is low, accessory substance is few, high income, and obtained fluoro () Penibrugiueramine A have better inhibition effect to staphylococcus aureus and Escherichia coli isoreactivity, antibacterial medicines application can be used as.
Description
Technical field
The present invention relates to a kind of antibacterials, more particularly to a kind of fluoro (±)-Penibrugiueramine A and its conjunction
Application into method and as antibacterials, belongs to technical field of medicine synthesis.
Background technology
At present, in the numerous marketed drug in the whole world, Drugs Containing Fluorine alreadys exceed 160, in medicinal chemistry arts, Xiang You
It is the new cancer therapy drug of exploitation, antiviral drugs, anti-inflammation drugs, medicine for central nervous system etc. that fluorine atom is introduced in machine molecule
Important directions.The characteristics of having small volume and high electronegativity due to fluorine atom, it can be to Special Influence caused by molecule.Small size
Fluorine atom be typically considered the non-classical bioisostere of hydrogen atom, biological target has to the molecule being slightly fluorinated
Have and identified with its parent drug identical, and by the regulation of electronics, make the Interaction enhanced between prodrugs.
(-)-Penibruguieramine A are a kind of natural ocean pyrrolizidine alkaloidses, its molecular structure
Have very much particularity, possess a double pyrrole ring, each occur a hydroxyl on C1 and C8, while seven carbon are also carried on C1
Hydrocarbyl side chain.The absolute configuration of the natural products by Guo and its colleague separated first from Chinese mangrove bruguiera and identify Lai,
It is Bruguiera conjugata endogenetic fungus Penicillium sp.GD6 (Penicillium) effective active composition, and crude extract, which is shown, to be had
The biological action of certain anti-Staphylococcus aureus, therefore the bio-mimetic syntheses to it are significant.2015, Kim etc.
People is using chiral memory tactics P.A fully synthetic first, but its product yield is low, do not carry out relevant biological activity survey to it
It is fixed.
The content of the invention
The defects of existing for prior art, of the invention first purpose be to provide it is a kind of to Staphylococcus aureus
Bacterium and E. coli Activity are respectively provided with fluoro (±)-Penibrugiueramine A compounds of better inhibition effect.
Another object of the present invention be to provide a kind of flow is short, step is simple, the synthesizing fluoro (±) of low cost-
Penibrugiueramine A method.
Third object of the present invention is to be to provide fluoro (±)-Penibrugiueramine A compounds as suppression
The application of bacterium medicine, better inhibition effect is respectively provided with to staphylococcus aureus and E. coli Activity, particularly (6S) -6- fluorine
P.A is better than to the inhibitory action of staphylococcus aureus activity for Penibruguieramine A, and (6R) -6- fluoro
Penibruguieramine A are better than P.A to the inhibitory action of E. coli Activity.
In order to realize above-mentioned technical purpose, the invention provides a kind of fluoro (±)-Penibrugiueramine A, tool
There is the structure of formula 1：
Wherein, F substituents are R configurations or S configurations.
Present invention also offers a kind of fluoro (±)-Penibrugiueramine A preparation method, it includes following step
Suddenly：
1) (2S, 4R) -4- fluoro proline tert-butyl ester or (2S, 4S) -4- fluoro proline tert-butyl ester and the diluted acid chemical combination of formula 2
Thing carries out condensation reaction and obtains the intermediate of formula 3；
2) intermediate of formula 3 carries out intramolecular aldol reactions, obtains the intermediate of formula 4；
3) intermediate of formula 4 is hydrolyzed and reduction reaction, obtains fluoro (±)-Penibrugiueramine A；
Wherein, F substituents are R configurations or S configurations.
Preferable scheme, in step 1), (2S, 4R) -4- fluoro proline tert-butyl ester or (2S, 4S) -4- fluoro proline
The tert-butyl ester under condensing agent effect, reacts 18~30h at room temperature with the diluted acid compound of formula 2.Preferred scheme, step 1) will
Diluted acid compound is dissolved in organic solvent, adds condensing agent, and (2S, 4R) -4- fluoro proline tert-butyl esters are added after stirring 10min
Or (2S, 4S) -4- fluoro proline tert-butyl esters, in room temperature reaction 20min, DIPEA is added, continues to react 24h, treats that raw material is complete
Portion has reacted, and with saline solution and distillation water washing, ethyl acetate extraction, is dried with anhydrous magnesium sulfate, filters, be spin-dried for obtaining formula 3
Intermediate.Wherein, (2S, 4R) -4- fluoro proline tert-butyl ester or (2S, 4S) -4- fluoro proline tert-butyl ester and diluted acid chemical combination
The mol ratio of thing, condensing agent and DIPEA is 1:1:1.1:3.Organic solvent be preferably remove water after tetrahydrofuran, dichloromethane,
Methanol, acetonitrile, toluene, dimethyl sulfoxide (DMSO) or N,N-dimethylformamide；Most preferably N,N-dimethylformamide.More preferably
Scheme, the condensing agent include dicyclohexylcarbodiimide, 2- (7- aoxidizes BTA)-N, N, N', N'- tetramethylureas six
Fluorophosphoric acid ester, BTA-N, N, N', N'- tetramethylurea hexafluorophosphate or hexafluorophosphoric acid BTA -1- bases-epoxide
Tripyrrole alkyl phosphorus.
Preferable scheme, in step 2), the intermediate of formula 3 and alkaline matter, 6~12h is reacted at room temperature.More preferably side
Case, the intermediate of formula 3 is dissolved in organic solvent, adds alkaline matter, in room temperature reaction 9h, be quenched with saturated ammonium chloride, acetic acid
Ethyl ester is extracted, and merges organic phase, and anhydrous magnesium sulfate is dried, and is filtered, is spin-dried for, obtains the intermediate of formula 4.Preferable organic solvent is first
Alcohol, ethanol, isopropanol, the tert-butyl alcohol or tetrahydrofuran；Most preferably ethanol.More preferably scheme, the alkaline matter are methanol
Sodium, caustic alcohol, sodium isopropylate, sodium tert-butoxide, lithium ethoxide, potassium ethoxide or TBAH hydrate.
Preferable scheme, in step 3), the intermediate of formula 4 and trifluoroacetic acid, after reacting 10~20h at room temperature, separation is thick
Product, gained crude product and BOP, DIPEA and NaBH4, 0.5~3h is reacted at room temperature.More preferably scheme, the crude product
5~20min is stirred at room temperature with BOP, DIPEA, NaBH is added in batches under 0 DEG C of temperature below4, then react at room temperature
0.5~3h.Further preferred scheme, the intermediate of formula 4 are dissolved in organic solvent, and TFA is added at a temperature of 0 DEG C, room temperature reaction
16h, treat that raw material all consumes, be spin-dried for solvent and obtain crude product, crude product directly casts single step reaction without purifying, by crude product
It is dissolved in organic solvent, adds BOP, DIPEA, after 10min is stirred at room temperature, NaBH is added at a temperature of 0 DEG C4, it is anti-in room temperature
A hour is answered, is quenched with saturated ammonium chloride solution, ethyl acetate extraction, merges organic phase, is dried, taken out with anhydrous magnesium sulfate
Filter, is spin-dried for, obtains target product.The organic solvent is dichloromethane, tetrahydrofuran, methanol, ethanol or acetonitrile；Most preferably
Dichloromethane.
Present invention also offers a kind of fluoro (±)-Penibrugiueramine A application, and it should as antibacterials
With.
Preferable scheme, using fluoro (±)-Penibrugiueramine A as to staphylococcus aureus and large intestine bar
The inhibited Antibiotics usage of bacterium activity.
Compared with the prior art, the advantageous effects that technical scheme is brought：
1) fluoro (±)-Penibrugiueramine A of the invention are compared with Penibruguieramine A, 8
Hydroxyl is substituted by fluorine, and it has the bioactivity similar with Penibruguieramine A, Antibiotics usage can be used as to press down
System, such as has higher inhibitory action to staphylococcus aureus and E. coli Activity, but after fluorine substitutes, property of medicine hair
Substantial variations have been given birth to, better inhibition effect is respectively provided with to staphylococcus aureus and E. coli Activity, particularly (6S) -6- fluorine
P.A is better than to the inhibitory action of staphylococcus aureus activity for Penibruguieramine A, and (6R) -6- fluoro
Penibruguieramine A are better than P.A to the inhibitory action of E. coli Activity.
2) technical solution of the present invention is first with (2S, 4R/S) -4- fluoro proline tert-butyl ester and diluted acid compound for raw material,
Pass sequentially through condensation, intramolecular aldol reaction and hydrolysis and reduction reaction take off, obtain fluoro (±)-
Penibrugiueramine A, compared to existing synthesis Penibruguieramine A method, have step simple, react
Mild condition, the features such as side reaction is few, yield is high.
Brief description of the drawings
【Fig. 1】For the proton nmr spectra of compound 3；
【Fig. 2】For the carbon-13 nmr spectra of compound 3；
【Fig. 3】For the proton nmr spectra of compound 4；
【Fig. 4】For the carbon-13 nmr spectra of compound 4；
【Fig. 5】For the proton nmr spectra of compound 5；
【Fig. 6】For the carbon-13 nmr spectra of compound 5；
【Fig. 7】For the proton nmr spectra of compound 7；
【Fig. 8】For the carbon-13 nmr spectra of compound 7；
【Fig. 9】For the proton nmr spectra of compound 8；
【Figure 10】For the carbon-13 nmr spectra of compound 8；
【Figure 11】For the proton nmr spectra of compound 9；
【Figure 12】For the carbon-13 nmr spectra of compound 9.
Embodiment
The following example is intended to further illustrate present invention, rather than the protection model of limitation the claims in the present invention
Enclose.
Raw material (2S, the 4S) -4- fluoro proline tert-butyl ester of the present invention and (2S, 4R) -4- fluoro proline tert-butyl esters are
Obtained by the synthesis of setting out of (2S, 4R) -4- hydroxy-prolines.[reference：(1)M.S.Chorghade,D.K.Mohapatra,
G.Sahoo,M.K.Gurjar,M.V Mandlecha,N.Bhoite,S.Moghe and R.T.Raines,
J.Fluor.Chem.,2008,129,781–784；(2)H.Marusawa,H.Setoi,A.Sawada,A.Kuroda,
J.Seki, Y.Motoyama and H.Tanaka, Bioorg.Med.Chem., 2002,10,1399-1415.], it is prepared by raw material 2
With reference to [(1) J.H.Kim, S.Lee and S.Kim, Angew.Chemie-Int.Ed., 2015,54,10875-10878.].Will
(2S, 4R) -4- fluoro proline tert-butyl ester 2 reacts to obtain condensation product 3 with acid, then under ethanol as solvent with ethanol
The aldol that intramolecular occurs for sodium reacts to obtain cyclization product 4, is then passed through a step ester hydrolysis and reduction obtains final product 5.Instead
Answer formula as follows：
This method can efficiently obtain (6S) -6- fluoro Penibrugiueramine A.Simultaneously by (2S, 4R) -4- fluoro
Proline tert-butyl ester reacts with acid 2, and same step can obtain (6R) -6- fluoro Penibruguieramine A.Reaction equation
It is as follows：
Embodiment 1
Compound 2 (120mg, 0.60mmol) is dissolved in the DMF of 20ml dryings, addition HATU (250mg,
0.66mmol), compound 1 (113mg, 0.6mmol) is added after stirring 10min, 20min is reacted at room temperature, is added into system
DIPEA (0.28mL, 1.74mmol), continue to react 24h, treat that raw material total overall reaction is complete, with saline solution and distillation water washing, acetic acid
Ethyl ester extracts, and is dried with anhydrous magnesium sulfate, filters, is spin-dried for obtaining product 3 (101mg, 46%).m.p.:73-75℃；(c 0.19,CH3OH)；IR(cm-1):962,1014,1057,1153,1222,1632；1H NMR(400MHz,
(CD3)2SO):δ 5.45-5.24 (m, 5H), 4.47 (d, J=9.9Hz, 1H), 3.97-3.84 (m, 2H), 3.82-3.65 (m,
2H),3.62-3.48(m,1H),2.64-2.53(m,1H),2.53-2.50(m,4H),2.48-2.43(m,3H),2.39(dd,J
=9.3Hz, 5.2Hz, 1H), 2.23 (ddd, J=19.8Hz, 14.6Hz, 5.4Hz, 1H), 1.94-1.89 (m, 3H), 1.60-
1.59(m,5H),1.47-1.43(m,1H),1.42-1.41(m,7H),1.38-1.36(m,11H),1.30-1.20(m,5H),
1.21-1.14(m,3H),1.12-1.09(m,3H)；13C NMR(100MHz,(CD3)2SO):δ206.8,206.5,206.2,
170.9,170.7,170.6,169.9,169.8,169.6,169.6,131.6,131.5,131.5,125.0,124.9,
124.9,93.1 (d, J=174.7Hz), 91.8 (d, J=174.7Hz), 82.1,82.1,81.1,80.9,58.8,58.1,
58.0,54.1,53.9,51.3,51.2,38.1,36.2,35.9,32.3,32.1,28.9,28.8,28.7,28.0,27.9,
27.9,23.2,23.0,22.9,22.8,18.2,13.8,13.2,12.9,12.6；19F NMR(376MHz,(CD3)2SO):δ-
171.2(s,1F),-171.3(s,1F),-171.5(s,1F),-171.9(s,1F)；19F{1H}NMR(376MHz,(CD3)2SO):
δ-171.2；HRMS(ESI):m/z calcd for C20H32 [M+Na]+392.22063,found 392.22076.
Compound 3 (257mg, 0.69mmol) is dissolved in 3ml ethanol, adds caustic alcohol (234mg, 3.5mmol), room temperature
9h is reacted, is quenched with saturated ammonium chloride, ethyl acetate extraction, merges organic phase, anhydrous magnesium sulfate is dried, and is filtered, is spin-dried for, obtains
Product 4 (163mg, 65%).m.p.:142-143℃；(c 0.5,CH3OH)；IR(cm-1):668,759,843,
964,1016,1153,1284,1368,1430,1669,2361,2854,2931；1H NMR(400MHz,CD3OD):δ5.51-
5.48 (m, 1/2H, H6), 5.47-5.45 (m, 2H, H15, H16), 5.37-5.35 (m, 1/2H, H1), 3.68 (ddd, J=
34.7Hz, 13.6Hz, 4.4Hz, 1H, H5b), 3.33 (qd, J=3.4Hz, 2.2Hz, 1.6Hz, 1H, H5a), 3.31-3.24 (m,
1H), 2.91 (q, J=7.1Hz, 1H, H2), 2.62 (dd, J=18.3Hz, 14.4Hz, 1H, H7b), 2.46 (ddd, J=
42.5Hz, 14.4Hz, 4.1Hz, 1H, H7a), 2.06 (td, J=7.5Hz, 4.7Hz, 2H), 1.75-1.69 (m, 1H), 1.67-
1.65 (m, 3H, H17), 1.51 (s, 9H, H18), 1.38-1.36 (m, 2H), 1.34-1.31 (m, 2H), 1.03 (d, J=
7.3Hz,3H,H10)；13C NMR(100MHz,CD3OD):δ 176.6,170.8,130.9,124.5,95.6 (d, J=
174.7Hz), 82.5,81.3,79.8,49.6,48.5 (d, J=25.6Hz), 35.2 (d, J=20.8Hz), 32.3,30.1,
26.7,22.7,16.7,6.2；19F NMR(376MHz,CD3OD):δ-169.9(s,1F)；19F{1H}NMR(376MHz,
CD3OD):δ -169.9 (ddddd, J=52.8Hz, 42.3Hz, 34.7Hz, 27.6Hz, 18.3Hz)；HRMS(ESI):m/z
calcd for C20H32 [M+Na]+392.22063,found 392.22076.
Compound 4 (180mg, 0.49mmol) is dissolved in 5ml dichloromethane, TFA (1.6ml) is added at 0 DEG C, room temperature is anti-
Answer 16h, treat raw material all consume, be spin-dried for solvent obtain crude product directly throw in next step.Crude product is dissolved in 2.5ml tetrahydrochysene furan
In muttering, BOP (150mg, 0.35mmol) is added, DIPEA (30.0 μ L, 0.48mmol), after 10min is stirred at room temperature, is added at 0 DEG C
NaBH4(60.0mg, 1.60mmol), a hour is reacted at room temperature, is quenched with saturated ammonium chloride solution, ethyl acetate extraction, closed
And organic phase, dried with anhydrous magnesium sulfate, filter, be spin-dried for, obtain product 5 (93.0mg, 81%).m.p.:189-190℃；(c 0.5,CH3OH)；IR(cm-1):860,964,1049,1299,1635,2199,3422；1H NMR(400MHz,
CD3OD):δ 5.48-5.45 (m, 2H, H15, H16), 5.42-5.23 (m, 1H, H6), 3.94 (ddd, J=23.9Hz, 13.4Hz,
6.0Hz, 1H, H5a), 3.80 (d, J=12.2Hz, 1H), 3.68 (d, J=12.2Hz, 1H), 3.37-3.31 (m, 1H, H5b),
3.25 (ddd, J=24.4Hz, 12.1Hz, 2.3Hz, 1H, H7a), 3.11 (q, J=7.3Hz, 1H, H2), 2.75-2.62 (m,
2H, H7b), 2.06-2.01 (m, 1H), 1.85-1.80 (m, 1H), 1.78-1.76 (m, 1H), 1.71 (dt, J=8.1Hz,
3.4Hz, 1H), 1.66 (dq, J=2.5Hz, 1.2Hz, 3H), 1.63-1.56 (m, 1H), 1.42 (q, J=7.4Hz, 1H),
1.33-1.24 (m, 2H), 1.02 (d, J=7.3Hz, 3H, H10)；13C NMR(100MHz,CD3OD):δ178.2,131.0,
124.5,94.5 (d, J=177.6Hz), 81.1,76.2,63.6,49.4,48.6 (d, J=27.5Hz, 1C), 33.6 (d, J=
20.0Hz,1C),33.4,32.1,29.9,23.0,16.7,6.2；19FNMR(376MHz,CD3OD):δ-167.1(s,1F)；19F
{1H}NMR(376MHz,CD3OD):δ -167.1 (tt, J=31.6Hz, 24.6Hz)；HRMS(ESI):m/z calcd for
C16H27 [M+Na]+322.17876,found 322.17889.
Embodiment 2
Compound 2 (438mg, 2.2mmol) is dissolved in the DMF of 30ml dryings, adds HATU (912mg, 2.4mmol),
Stir 10min after add compound 6 (416mg, 2.2mmol), react at room temperature 20min, into system addition DIPEA (0.99mL,
6.6mmol), continue to react 24h, treat that raw material total overall reaction is complete, with saline solution and distillation water washing, ethyl acetate extraction, with nothing
Water magnesium sulfate is dried, and is filtered, is spin-dried for obtaining product 7 (270mg, 37%).(c 0.34,CHCl3)；IR(cm-1):
771,846,964,1081,1189,1209,1367,1457,1653,2340,2853,2923；1H NMR(400MHz,CD3OD):
δ5.45-5.41(m,4H),5.39-5.30(m,1H),4.46-4.39(m,1H),4.15-4.01(m,2H),3.93-3.88(m,
1H),3.86-3.82(m,1H),3.81-3.76(m,1H),2.70-2.60(m,2H),2.58-2.48(m,2H),2.24-2.16
(m,1H),2.14-2.05(m,1H),2.14-2.05(m,1H),2.04-1.94(m,3H),1.65-1.63(m,4H),1.61-
1.54 (m, 3H), 1.53-1.52 (m, 2H), 1.50-1.48 (m, 11H), 1.39-1.34 (m, 3H), 1.31 (d, J=6.9Hz,
3H), 1.28 (d, J=6.9Hz, 3H)；13C NMR(100MHz,CD3OD):δ206.5,205.9,170.8,170.7,170.7,
170.5,130.9,130.8,130.7,124.6,124.5,92.9,92.0 (d, J=177.9Hz), 81.7,81.6,58.6,
54.2,53.9,53.7,51.7,51.6,39.9,39.8,35.5,35.3,31.9,28.7,28.6,26.8,26.8,26.7,
22.7,22.6,16.9,11.7,11.4；19F NMR(376MHz,CD3OD):δ-179.1(s,1F),-179.3(s,1F),-
179.4(s,1F)；19F{1H}NMR(376MHz,CD3OD):δ-179.1；HRMS(ESI):m/z calcd for C20H32 [M+Na]+392.22071,found 392.22076.
Compound 8 (150mg, 88%) can be by compound 7 by operating to obtain with 3 to 4 identicals in case study on implementation 1.(c 0.3,CH3OH)；IR(cm-1):758,842,965,984,1078,1156,1255,1287,2855,2934,
3420；1H NMR(400MHz,CD3OD):δ5.50-5.44(m,2H,H15,H16),5.41-5.25(m,1H,H6),3.83(dd,
J=21.9Hz, 13.4Hz, 1H, H5b), 3.14 (dddd, J=28.4Hz, 13.5Hz, 4.9Hz, 1.5Hz, 1H, H5a), 2.90
(qd, J=7.3Hz, 1.3Hz, 1H, H2), 2.80-2.72 (m, 1H, H7a), 2.70-2.62 (m, 1H, H7b), 2.03 (td, J=
7.2Hz,4.1Hz,2H),1.76-1.69(m,1H),1.67-1.65(m,1H),1.51(s,9H,H18),1.40-1.38(m,
2H), 1.36-1.31 (m, 2H), 1.10 (d, J=7.3Hz, 3H, H10)；13C NMR(100MHz,CD3OD):δ176.4,
(171.0,130.9,124.5,93.9 d, J=182.5Hz), 82.9,81.0,79.7,48.8,35.4,34.7 (d, J=
23.4Hz),32.2,30.0,26.7,22.6,16.7,6.5；19F NMR(376MHz,CD3OD):δ-174.7(s,1F)；19F
{1H}NMR(376MHz,CD3OD):δ -174.7 (ddd, J=60.4Hz, 29.0Hz, 23.1Hz)；HRMS(ESI):m/z calcd
for C20H32 [M+Na]+392.22043,found 392.22076.
Compound 9 (43mg, 92%) can be by compound 7 by operating to obtain with 4 to 5 identicals in case study on implementation 1.
m.p.:162-163℃；(c 0.6,CH3OH)；IR(cm-1):559,601,651,724,837,893,966,997,
1055,1101,1136,1168,1250,2851,2985；1H NMR(400MHz,CD3OD):δ5.51-5.45(m,2H,H12,
), H13 5.45-5.44 (m, 1H, H1), 3.82 (ddd, J=23.7Hz, 13.2Hz, 1.5Hz, 1H, H2b), 3.71 (d, J=
11.5Hz, 1H, H7a), 3.48 (d, J=11.6Hz, 1H, 7b), 3.40 (ddd, J=13.4Hz, 5.0Hz, 1.5Hz, 1H,
H2a), 3.34-3.32 (m, 1H), 2.94 (q, J=7.24Hz, 1H, H4), 2.69-2.57 (m, 1H, H3b), 2.08-1.97 (m,
3H),1.71-1.68(m,1H),1.67-1.64(m,3H),1.63-1.59(m,1H),1.42-1.36(m,2H),1.34-1.19
(m, 2H), 1.08 (d, J=7.3Hz, 3H, H5)；13C NMR(100MHz,CD3OD):δ176.8,130.9,124.6,95.2(d,
), J=179.5Hz 80.3,76.9,64.6,49.1 (d, J=4.1Hz), 48.9,34.2 (d, J=23.0Hz), 33.4,32.0,
29.8,22.9,16.9,6.3；19F NMR(376MHz,CD3OD):δ-170.9(s,1F)；19F{1H}NMR(376MHz,
CD3OD):δ -170.9 (dtt, J=55.1Hz, 30.5Hz, 24.2Hz)；HRMS(ESI):m/z calcd for C16H27 [M+Na]+322.17889,found 322.17889.
Embodiment 3
(6S) -6- fluoro Penibrugiueramine A and (6R) -6- fluoro prepared by embodiment 1 and embodiment 2
Penibruguieramine A and Penibrugiueramine A have carried out antibacterial test together, mainly test golden yellow
Staphylococcus and Escherichia coli.
Golden yellow coccus, Escherichia coli bacteriostatic experiment method：
1. raw material
Escherichia coli, staphylococcus aureus, buy and bacterium is prepared as before China typical culture collection center, experiment hangs
Liquid, concentration are 1 × 108cfu/mL。
MH fluid nutrient mediums.
Streptomysin (tester) 0.25mg/ml.
Experimental drug (Liu Ting and upright sample), is 4mg/ml.
2. experimental method
In 96 hole elisa Plates, 1-8 holes add 50 μ l MH fluid nutrient mediums, and No. 1 hole is sample blank, in No. 2 holes
50 μ l experimental drugs or streptomysin are added, pipettes 50 μ l mixtures after well mixed from No. 2 holes again to No. 3 holes, so behaviour
Make to No. 8 holes, discard 50 μ l mixtures in No. 8 holes.Then 150 μ l MH fluid nutrient mediums are added in 1-8 holes, are mixed
50 μ l Escherichia coli or staphylococcus aureus suspension are added after uniformly.Finally there are 250 μ l solution in so each hole.Sample
Compare to replace bacteria suspension with 50 μ l sterilized waters, all samples do three it is parallel.
ELISA Plate determines its absorbance A at 410nm with ELIASA at once after adding sample0, then ELISA Plate is put
16h is cultivated at 37 DEG C, then takes out and determines its absorbance A at 410nm with ELIASAs。
Calculate the Δ A in each holes=As-A0, sample controls group is Δ Abs
Blank group is Δ A0, the control group of sample blank is Δ Ab0
According to various concentrations sample or the bacteriostasis rate of streptomysin, suppression curve is drawn, calculates the 503nhibiting concentration of sample
IC50Value.It is as shown in the table to obtain result：
It can be drawn from upper table, PA and two fluoro derivatives show preferable antibiotic property.But (6S) -6- fluorine
P.A is better than to the inhibitory action of staphylococcus aureus activity for Penibruguieramine A, and (6R) -6- fluoro
Penibruguieramine A are better than P.A to the inhibitory action of E. coli Activity.
Claims (10)
- A kind of 1. fluoro (±)-Penibrugiueramine A, it is characterised in that：With the structure of formula 1：Wherein, F substituents are R configurations or S configurations.
- A kind of 2. fluoro (±)-Penibrugiueramine A preparation method, it is characterised in that：Comprise the following steps：1) (2S, 4R) -4- fluoro proline tert-butyl ester or (2S, 4S) -4- fluoro proline tert-butyl ester enter with the diluted acid compound of formula 2 Row condensation reaction obtains the intermediate of formula 3；2) intermediate of formula 3 carries out intramolecular aldol reactions, obtains the intermediate of formula 4；3) intermediate of formula 4 is hydrolyzed and reduction reaction, obtains fluoro (±)-Penibrugiueramine A；Wherein, F substituents are R configurations or S configurations.
- 3. a kind of fluoro (±)-Penibrugiueramine A according to claim 1 preparation method, its feature exist In：In step 1), (2S, 4R) -4- fluoro proline tert-butyl ester or (2S, 4S) -4- fluoro proline tert-butyl ester and the acid of formula 2 Compound reacts 18~30h at room temperature under condensing agent effect.
- 4. a kind of fluoro (±)-Penibrugiueramine A according to claim 3 preparation method, its feature exist In：The condensing agent includes dicyclohexylcarbodiimide, 2- (7- aoxidizes BTA)-N, N, N', N'- tetramethylurea hexafluoros Phosphate, BTA-N, N, N', N'- tetramethylurea hexafluorophosphate or hexafluorophosphoric acid BTA -1- bases-epoxide three Pyrrolidinyl phosphorus.
- 5. a kind of fluoro (±)-Penibrugiueramine A according to claim 2 preparation method, its feature exist In：In step 2), the intermediate of formula 3 and alkaline matter, 6~12h is reacted at room temperature.
- 6. a kind of fluoro (±)-Penibrugiueramine A according to claim 5 preparation method, its feature exist In：The alkaline matter is sodium methoxide, caustic alcohol, sodium isopropylate, sodium tert-butoxide, lithium ethoxide, potassium ethoxide or tetrabutylammonium hydroxide Ammonium hydrate.
- 7. a kind of fluoro (±)-Penibrugiueramine A according to claim 2 preparation method, its feature exist In：In step 3), the intermediate of formula 4 and trifluoroacetic acid, at room temperature react 10~20h after, separate crude product, gained crude product with BOP, DIPEA and NaBH4, 0.5~3h is reacted at room temperature.
- 8. a kind of fluoro (±)-Penibrugiueramine A according to claim 7 preparation method, its feature exist In：5~20min is stirred at room temperature with BOP, DIPEA in the crude product, and NaBH is added in batches under 0 DEG C of temperature below4, React 0.5~3h at room temperature again.
- A kind of 9. application of fluoro (±)-Penibrugiueramine A described in claim 1 or 2, it is characterised in that：Make For Antibiotics usage.
- A kind of 10. fluoro (±)-Penibrugiueramine A according to claim 9 application, it is characterised in that： As to the inhibited Antibiotics usage of staphylococcus aureus and E. coli Activity.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH01211589A (en) * | 1988-02-19 | 1989-08-24 | Lederle Japan Ltd | (5s)-3-substituted thio-8-oxo-1-azabicyclo(3.3.0)octa-2-ene-2-carboxylic acid derivative |
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2017
- 2017-10-31 CN CN201711045180.5A patent/CN107629061B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH01211589A (en) * | 1988-02-19 | 1989-08-24 | Lederle Japan Ltd | (5s)-3-substituted thio-8-oxo-1-azabicyclo(3.3.0)octa-2-ene-2-carboxylic acid derivative |
Non-Patent Citations (2)
| Title |
|---|
| JAE HYUN KIM ET AL.: "Biomimetic Total Synthesis of (¢)-Penibruguieramine A Using Memory of Chirality and Dynamic Kinetic Resolution", 《ANGEWANDTE CHEMIE, INTERNATIONAL EDITION》 * |
| ZHEN-FANG ZHOU ET AL.: "Penibruguieramine A, a Novel Pyrrolizidine Alkaloid from the Endophytic Fungus Penicillium sp. GD6 Associated with Chinese Mangrove Bruguiera gymnorrhiza", 《ORGANIC LETTERS》 * |
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