CN109734660A - A kind of class peptides of serine and its preparation method and application replaced containing tert-butyl - Google Patents

A kind of class peptides of serine and its preparation method and application replaced containing tert-butyl Download PDF

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CN109734660A
CN109734660A CN201910049054.XA CN201910049054A CN109734660A CN 109734660 A CN109734660 A CN 109734660A CN 201910049054 A CN201910049054 A CN 201910049054A CN 109734660 A CN109734660 A CN 109734660A
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tert
butyl
serine
bromo
class peptides
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CN109734660B (en
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张�杰
潘晓艳
梁丽媛
卢闻
王嗣岑
贺浪冲
司茹
王瑾
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Xian Jiaotong University
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    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract

A kind of class peptides of serine and its preparation method and application replaced containing tert-butyl; utilize the reaction synthesising target compounds such as acylation, Suzuki coupling, condensation; and compound library is constructed, such compound is the Bcr-Abl small molecule tyrosine kinase inhibitors with new molecular architecture.The present invention uses the drug design strategies based on segment, using biphenyl pyridine as hinge area binding fragment, introducing the Serine that tert-butyl replaces is flexibility Linker, to construct the class peptides small molecule compound library with kinase inhibiting activity, and the tyrosine kinase inhibitor for being found to have Bcr-Abl kinase inhibiting activity is screened by the kinase activity of ADP-Glo.Kinases screening test shows that such compound all has certain inhibitory activity to Abl kinases, T315I mutation Abl kinases.

Description

A kind of class peptides of serine and preparation method thereof replaced containing tert-butyl And application
Technical field
The class peptides of serine and its preparation method and application that the present invention relates to a kind of to replace containing tert-butyl.
Background technique
Chronic myelocytic leukemia (CML) is a kind of malignant clone proliferative disease for betiding marrow hemopoietic stem cells, Proportion is up to 15%~20% in adult leukaemic, it is characterized in that CML patient's body can detect Ph chromosome. Ph chromosome is the breaking point aggregation cluster-Ai Erbei formed by No. 22 chromosomes and No. 9 chromosome reciprocal translocations of human normal Inferior (BCR-ABL) fusion, the Bcr-Abl that this fusion coding generates tyrosine kinase activity sustained activation merge egg It is white.Have listed currently on the market for Bcr-Abl be target small molecule tyrosine kinase inhibitors, but all exist drug resistance with And the problems such as other clinical adverses.Therewith, the novel Bcr-Abl tyrosine kinase inhibitor of research and development has become medicine One of the hot spot in field.
Summary of the invention
The purpose of the present invention is to provide a kind of class peptides of serine replaced containing tert-butyl and its preparations Methods and applications.
To achieve the above object, the present invention adopts the following technical scheme that:
A kind of class peptides of the serine replaced containing tert-butyl, the structural formula of such compound are as follows:
Wherein, R is-NH2、
A kind of preparation method of the class peptides of the serine replaced containing tert-butyl, comprising the following steps:
1) the acylated bromo- 2-aminopyridine of 5- of acylation reaction preparation occurs for the bromo- 2-aminopyridine of 5- and chloride compounds；
2)N2Under protection, 5- bromo-nicotinic acid, thionyl chloride and aminated compounds, which react, prepares the 5- bromo-nicotinic acid of ammonification；
3) under tetra-triphenylphosphine palladium catalysis, the 5- bromo-nicotinic acid and carboxyl benzene of the bromo- 2-aminopyridine of acylated 5- or ammonification Suzuki coupling reaction occurs for boric acid, obtains biphenol compound；
4) Fmoc-O- tert-butyl-Serine and the chloro- 3- 5-trifluoromethylaniline condensation of 4- generate (9H- fluorenes -9- base) methyl (S) -3- (tert-butoxy) -1- ((4- chloro- 3- (trifluoromethyl) phenyl) amino) -1- oxo propyl- 2- yl) carbamate；
5) (9H- fluorenes -9- base) methyl (S) -3- (tert-butoxy) -1- ((4- chloro- 3- (trifluoromethyl) phenyl) amino) -1- Oxo propyl- 2- yl) carbamate take off Fmoc protecting group generate (S) -2- amino -3- (tert-butoxy)-N- (chloro- 3- (three of 4- Methyl fluoride) phenyl) propionamide；
6) (S) -2- amino -3- (tert-butoxy)-N- (4- chloro- 3- (trifluoromethyl) phenyl) propionamide and biphenol compound Condensation generates the class peptides of the serine replaced containing tert-butyl.
A further improvement of the present invention lies in that the step 1) detailed process are as follows: the bromo- 2-aminopyridine of 5- is dissolved in nothing In water methylene chloride, triethylamine is added, under condition of ice bath, chloride compounds is added dropwise and removes ice bath after being added dropwise and rises to After reacting at room temperature 12h, is post-processed, obtain the bromo- 2-aminopyridine of acylated 5-.
A further improvement of the present invention lies in that the step 2) detailed process are as follows: in N2Under protection, thionyl chloride is dripped It is added in 5- bromo-nicotinic acid, after dripping, is heated to reflux 2-3h and is clarified to solution, decompression rotation removes thionyl chloride, obtains faint yellow The faint yellow solid is added in anhydrous methylene chloride by solid, and the two of aminated compounds is then added drop-wise under condition of ice bath In chloromethanes solution；After dripping, it is warmed to room temperature reaction 12h and is post-processed after reaction, obtain the bromo- cigarette of 5- of ammonification Acid.
A further improvement of the present invention lies in that the step 3) detailed process are as follows: by the acylated bromo- 2-aminopyridine of 5- It is added in reaction vessel with right/Carboxybenzeneboronic acid, or the bromo- niacin of the 5- of ammonification and right/Carboxybenzeneboronic acid is added to In reaction vessel, cesium carbonate and tetra-triphenylphosphine palladium are sequentially added；Then the mixed solution of acetonitrile and water, N are added2It protects Shield, is warming up to 90 DEG C of reaction 48h；After reaction, it is post-processed, obtains biphenol compound.
A further improvement of the present invention lies in that the detailed process of the step 4) are as follows: by the chloro- 3- 5-trifluoromethylaniline of 4-, HOBT, HATU are dissolved in anhydrous methylene chloride, and DIPEA is then added dropwise, and after being added dropwise, are added dropwise Fmoc-O- tert-butyl-L- The dichloromethane solution of propylhomoserin reacts at room temperature 5h, is post-processed, obtain (9H- fluorenes -9- base) methyl (S) -3- (tertiary fourth oxygen Base) -1- ((4- chloro- 3- (trifluoromethyl) phenyl) amino) -1- oxo propyl- 2- yl) carbamate.
A further improvement of the present invention lies in that the detailed process of the step 5) are as follows: at 0 DEG C, by (9H- fluorenes -9- base) first Base (S) -3- (tert-butoxy) -1- ((4- chloro- 3- (trifluoromethyl) phenyl) amino) -1- oxo propyl- 2- yl) carbamate is molten In anhydrous methylene chloride, the DMF solution of 20% piperidines of volumetric concentration is then added dropwise, after reacting 1h, is post-processed, is obtained (S) -2- amino -3- (tert-butoxy)-N- (4- chloro- 3- (trifluoromethyl) phenyl) propionamide.
A further improvement of the present invention lies in that the detailed process of the step 6) are as follows: biphenol compound, PyBOP to be dissolved in In anhydrous DMF, DIPEA solution is added dropwise, after reacting at room temperature 5min, (S) -2- amino -3- (tert-butoxy)-N- (the chloro- 3- of 4- is added (trifluoromethyl) phenyl) propionamide, 12h is reacted at room temperature, is post-processed, the class peptide of the serine replaced containing tert-butyl is obtained Class compound.
A kind of class peptides of the serine replaced containing tert-butyl, such compound is in preparation for inhibiting Abl Application in kinases, T315I mutation Abl kinase activity drug.
A kind of class peptides of the serine replaced containing tert-butyl, such peptides are preparing antineoplastic Application in object.
Compared with prior art, the invention has the benefit that the present invention utilizes acylated, Suzuki coupling, condensation etc. Synthesising target compound is reacted, and constructs compound library, such compound is that have small point of the Bcr-Abl of new molecular architecture Sub- tyrosine kinase inhibitor, and characterize by means such as MS, NMR the structure of target compound.The present invention, which uses, is based on piece The drug design strategies of section, using biphenyl pyridine as hinge area binding fragment, introducing the Serine that tert-butyl replaces is flexibility Linker to construct the class peptides small molecule compound library with kinase inhibiting activity, and is sieved by the kinase activity of ADP-Glo Choosing is found to have the tyrosine kinase inhibitor of Bcr-Abl kinase inhibiting activity.Kinases screening test shows such compound pair Abl kinases, T315I mutation Abl kinases all have certain inhibitory activity.Structure-activity analysis discovery: it introduces tert-butyl and replaces Serine derivative and the site ATP of Abl kinases spatial match it is good, binding mode and her horse is replaced referring to small molecule Buddhist nun is consistent, illustrates that the introducing for the Serine that tert-butyl replaces plays a significant role the inhibitory activity of compound.In pyridine ring The upper amide side chains that introduce can be used as the tyrosine kinase using Bcr-Abl as target to improve the affinity of small molecule and receptor The novel drug effect segment inhibited.
Detailed description of the invention
Fig. 1 is synthetic route chart of the invention.
Specific embodiment
The present invention is described in detail with reference to the accompanying drawing.
Referring to Fig. 1, a kind of structural formula of class peptides replacing serine containing tert-butyl of the invention are as follows:
Wherein, R is specific as follows, is shown in Table 1:
Group representated by 1 R of table
It is illustrated below by specific embodiment.
Referring to Fig. 1, the preparation method of the class peptides for the serine of above structure replaced containing tert-butyl, including Following steps:
1) with corresponding chloride compounds the acylated bromo- 2- amino of 5- of acylation reaction preparation occurs for the bromo- 2-aminopyridine of 5- Pyridine；
Step 1) the detailed process are as follows: the bromo- 2-aminopyridine of 5- is dissolved in anhydrous methylene chloride, three second are added Corresponding chloride compounds are slowly dropped in above-mentioned solution by amine under condition of ice bath, after being added dropwise, remove ice bath It is warmed to room temperature reaction 12h.After reaction, methylene chloride dilution, washing is added, saturated sodium bicarbonate water is washed, saturated sodium-chloride Washing, anhydrous sodium sulfate is dry, and vacuum distillation, pillar layer separation obtains white solid, the bromo- 2- amino of the 5- being as acylated Pyridine.
2)N2Under protection, 5- bromo-nicotinic acid reacts with thionyl chloride and corresponding aminated compounds and prepares the 5- of ammonification Bromo-nicotinic acid；
Step 2) the detailed process are as follows: in N2Under protection, thionyl chloride is added dropwise in 5- bromo-nicotinic acid, is dripped Afterwards, it is heated to reflux 2-3h to clarify to solution, decompression rotation removes thionyl chloride, obtains faint yellow solid, which is dissolved in The two of corresponding aminated compounds is slowly dropped under condition of ice bath into anhydrous methylene chloride, and by this reactive intermediate solution In chloromethanes solution；After dripping, it is warmed to room temperature reaction 12h and K is added into reaction system after reaction2CO3Solution, point Liquid takes methylene chloride phase, and water phase is extracted with dichloromethane, and merges organic phase, anhydrous Na2SO4It is dry；Column chromatography separating purification obtains White solid, as by the bromo- niacin of the 5- of ammonification.
3) under tetra-triphenylphosphine palladium catalysis, the 5- bromo-nicotinic acid and right/carboxylic of the bromo- 2-aminopyridine of acylated 5- or ammonification Suzuki coupling reaction occurs for base phenyl boric acid, obtains biphenol compound；
Step 3) the detailed process are as follows: be added to the acylated bromo- 2-aminopyridine of 5- and right/Carboxybenzeneboronic acid In reaction vessel, or the bromo- niacin of the 5- of ammonification and right/Carboxybenzeneboronic acid is added in reaction vessel, sequentially adds carbon Sour caesium and tetra-triphenylphosphine palladium；The mixed solution of acetonitrile/water, N are added into said mixture2Protection, oil bath are warming up to 90 DEG C React 48h；After reaction, reaction solution is down to room temperature, filtered.It is 4 that filtrate, which is adjusted to pH value with hydrochloric acid, and white solid is precipitated, It filters, filter cake is dried in vacuo to obtain product, as biphenol compound.
4) Fmoc-O- tert-butyl-Serine and the condensation of 3- trifluoromethyl -4- chloroaniline generate (9H- fluorenes -9- base) methyl (S) -3- (tert-butoxy) -1- ((4- chloro- 3- (trifluoromethyl) phenyl) amino) -1- oxo propyl- 2- yl) carbamate；
Step 4) the detailed process are as follows: the chloro- 3- 5-trifluoromethylaniline of 4-, HOBT, HATU are dissolved in anhydrous methylene chloride In, DIPEA is then added dropwise, after completion of dropwise addition, the solution that Fmoc-O- tert-butyl-Serine is dissolved in anhydrous methylene chloride is added dropwise. React at room temperature 6h；After reaction, water is added to terminate reaction；Methylene chloride extraction, merges organic phase, and saturation NaCl washing is anhydrous NaSO4Dry, pillar layer separation obtains (9H- fluorenes -9- base) methyl (S) -3- (tert-butoxy) -1- ((chloro- 3- (fluoroform of 4- Base) phenyl) amino) -1- oxo propyl- 2- yl) carbamate；
5) (9H- fluorenes -9- base) methyl (S) -3- (tert-butoxy) -1- ((4- chloro- 3- (trifluoromethyl) phenyl) amino) -1- Oxo propyl- 2- yl) carbamate take off Fmoc protecting group generate (S) -2- amino -3- (tert-butoxy)-N- (chloro- 3- (three of 4- Methyl fluoride) phenyl) propionamide；
The detailed process of the step 5) are as follows: at 0 DEG C, by (9H- fluorenes -9- base) methyl (S) -3- (tert-butoxy) -1- ((4- chloro- 3- (trifluoromethyl) phenyl) amino) -1- oxo propyl- 2- yl) carbamate is dissolved in anhydrous methylene chloride, then The DMF solution of 20% piperidines of volumetric concentration is added dropwise, after reacting 1h, is post-processed.Obtain (S) -2- amino -3- (tertiary fourth oxygen Base)-N- (4- chloro- 3- (trifluoromethyl) phenyl) propionamide.
6) (S) -2- amino -3- (tert-butoxy)-N- (4- chloro- 3- (trifluoromethyl) phenyl) propionamide and biphenol compound Condensation generates the class peptides of the serine replaced containing tert-butyl.
The detailed process of the step 6) are as follows: biphenol compound, PyBOP are dissolved in anhydrous DMF, DIPEA solution is added dropwise, After reacting at room temperature 5min, (S) -2- amino -3- (tert-butoxy)-N- (4- chloro- 3- (trifluoromethyl) phenyl) propionamide is added.Room Temperature reaction 12h, is post-processed, obtains the class peptides containing serine.
A kind of class peptides of the serine replaced containing tert-butyl prepared such as the above method, such compound exist For inhibiting Abl kinases, T315I to be mutated the application in Abl kinase activity.
Such compound has antineoplastic action, can apply in the preparation of antitumor drugs.
Embodiment 1
A kind of class peptides of the serine replaced containing tert-butyl, R areWhen, the preparation method is as follows:
1) synthesis of N- (5- bromopyridine -2- base) acetamide: the bromo- 2-aminopyridine of 5- (5.19g, 30mmol) is dissolved in In 100ml anhydrous methylene chloride, triethylamine 20ml is added.Under condition of ice bath, chloroacetic chloride (2.54ml) is slowly dropped to It states in solution, after dripping, removes ice bath, be warmed to room temperature reaction (i.e. reaction 12h) overnight.After reaction, dichloro is added Methane dilution, is washed (30ml × 3), is saturated NaHCO3Solution is washed (30ml × 3), and saturation NaCl washes (30ml), and organic phase is anhydrous Na2SO4It is dry.Pillar layer separation obtains white solid 5.65g, yield 88%.Mp 78-81℃；EI-MS(m/z):214[M]+。
2) synthesis of 4- (6- (acetylamino) pyridin-3-yl) benzoic acid: N- (5- bromopyridine -2- base) acetamide (4.30g, 20mmol), Carboxybenzeneboronic acid (3.66g, 22mmol) are added in 250ml pear shape bottle, sequentially add cesium carbonate (13.0g, 40mmol), tetra-triphenylphosphine palladium (1.2g, 1mmol).Acetonitrile/water (V:V=3:2) is added into said mixture 200ml。N2Under protection, oil bath is warming up to 90 DEG C of reaction 48h.After reaction, reaction solution is down to room temperature, filtered.Filtrate is used It is 4 that 6mol/L hydrochloric acid, which is adjusted to pH value, and white solid is precipitated, and is filtered, and filter cake is dried in vacuo to obtain product 3.89g, yield 76%.Mp 156-158℃；EI-MS(m/z):256[M]+。
3) by the chloro- 3- 5-trifluoromethylaniline of 4- (1.07g, 5.46mmol), HOBT (1.92g, 11.7mmol), HATU (4.45g, 11.7mmol) is dissolved in anhydrous methylene chloride, and DIPEA (3.02g, 23.4mmol) then is added dropwise, after completion of dropwise addition, The solution that Fmoc-O- tert-butyl-Serine (3.0g, 7.8mmol) is dissolved in anhydrous methylene chloride is added dropwise.React at room temperature 6h；Instead After answering, water is added to terminate reaction；Methylene chloride extracts (3 × 30ml), merges organic phase, and saturation NaCl (3 × 30ml) is washed, Anhydrous Na SO4Dry, pillar layer separation obtains (9H- fluorenes -9- base) methyl (S) -3- (tert-butoxy) -1- ((the chloro- 3- (three of 4- Methyl fluoride) phenyl) amino) -1- oxo propyl- 2- yl) carbamate；Faint yellow oily solid (5.4g).
4) at 0 DEG C, by (9H- fluorenes -9- base) methyl (S) -3- (tert-butoxy) -1- ((4- chloro- 3- (trifluoromethyl) phenyl) Amino) -1- oxo propyl- 2- yl) carbamate (5.4g, 9.6mmol) is dissolved in anhydrous methylene chloride, it is dense that volume is then added dropwise DMF (1ml) solution of 20% piperidines is spent, after reacting 1h, is post-processed.Obtain (S) -2- amino -3- (tert-butoxy)-N- (4- chloro- 3- (trifluoromethyl) phenyl) propionamide.Faint yellow oily solid (3.04g)；
5) biphenol compound (0.3g, 1.17mmol), PyBOP (0.51g, 0.98mmol) are dissolved in anhydrous DMF (10ml) In, DIPEA (0.5ml) solution is added dropwise, after reacting at room temperature 5min, (S) -2- amino -3- (tert-butoxy)-N- (the chloro- 3- of 4- is added (trifluoromethyl) phenyl) propionamide (0.33g, 0.98mmol).12h is reacted at room temperature, is post-processed, obtains taking containing tert-butyl The class peptides F4 0.22g of the serine in generation.White solid, yield 68%；EI-MS(m/z):575[M]+；577 [M]-.MP:102.08~104.7 DEG C；1H NMR(400MHz,DMSO)δ10.66(s,1H),10.65(s,1H),8.83(d,J =7.3Hz, 1H), 8.74 (s, 1H), 8.29-8.18 (m, 4H), 7.92 (t, J=12.9Hz, 4H), 7.69 (d, J=8.9Hz, 1H), 7.60 (t, J=7.7Hz, 1H), 4.73 (d, J=7.0Hz, 1H), 3.73 (dt, J=15.5,8.8Hz, 2H), 2.77 (t, J=40.7Hz, 1H), 2.13 (s, 3H), 1.14 (s, 9H)
Embodiment 2
A kind of class peptides of the serine replaced containing tert-butyl, when R isThe preparation method is as follows:
1) in N2Under protection, thionyl chloride (36ml, 494mmol) is added dropwise to 5- bromo-nicotinic acid (5.00g, 24.7mmol) In, after dripping, it is heated to reflux 2-3h and is clarified to solution, decompression rotation removes thionyl chloride, obtains faint yellow solid.The solid is dissolved in Cyclopropylamine is slowly dropped under condition of ice bath into 30ml anhydrous methylene chloride, and by this reactive intermediate solution In (3.77ml) methylene chloride (30ml) solution.After dripping, it is warmed to room temperature reaction overnight.After reaction, to reaction system Middle addition 2mol/L K2CO3Solution 20ml.Liquid separation takes methylene chloride phase, and water phase is extracted with dichloromethane (15ml × 3), is associated with Machine phase, anhydrous Na2SO4It is dry.Column chromatography separating purification.(petroleum ether: ethyl acetate=1:1), obtains white solid 5.27g, yield 89%.Mp 140-142℃；EI-MS(m/z):240[M]+。
Step 2)~step 5) is same as Example 1, obtains compound F10, white solid 0.3g, yield 65%.EI-MS (m/z):601[M]+；603[M]-.MP:90.1~91.3 DEG C；1H NMR(400MHz,DMSO)δ10.66(s,1H),9.11(t, J=7.0Hz, 1H), 8.99 (d, J=1.8Hz, 1H), 8.89 (d, J=7.5Hz, 1H), 8.79 (d, J=4.1Hz, 1H), 8.50 (t, J=1.9Hz, 1H), 8.31 (d, J=13.8Hz, 1H), 8.27 (t, J=7.1Hz, 1H), 8.00-7.95 (m, 3H), 7.71-7.65 (m, 2H), 4.74 (q, J=6.8Hz, 1H), 3.74 (dt, J=9.0,5.8Hz, 2H), 2.51 (dt, J=3.5, 1.7Hz,1H),1.14(s,9H),0.78–0.73(m,2H),0.66–0.58(m,2H).
F1, F2, F5, F6, F7, F8 are identical as the synthesis step of F4；
F1, faint yellow solid, yield 65%；EI-MS(m/z):617[M]+；616[M]-.MP:50.1~52.3 DEG C；1H NMR (400MHz, DMSO) δ 10.67 (d, J=10.1Hz, 1H), 10.02 (d, J=4.5Hz, 1H), 8.77-8.68 (m, 2H), 8.26 (d, J=2.4Hz, 1H), 8.19 (s, 2H), 8.04 (d, J=8.2Hz, 2H), 7.97-7.85 (m, 3H), 7.70 (t, J= 6.9Hz, 1H), 4.71 (q, J=6.4Hz, 1H), 3.78-3.66 (m, 2H), 1.28 (d, J=12.2Hz, 9H), 1.14 (s, 9H).
F2, faint yellow solid, yield 65%；EI-MS(m/z):617[M]+；616[M]-；1H NMR(400MHz,DMSO) δ 9.99 (s, 1H), 8.86-8.72 (m, 2H), 8.31-8.17 (m, 4H), 7.91 (ddd, J=13.3,12.7,10.9Hz, 4H), 7.74-7.57 (m, 2H), 4.68 (dq, J=13.6,6.5Hz, 1H), 3.82-3.63 (m, 3H), 1.24 (d, J=18.5Hz, 9H), 1.14 (d, J=4.0Hz, 9H)
F5, white solid, yield 56%；EI-MS(m/z):533[M]+；535[M]-.~86.7 DEG C MP:84.9.；1H NMR (400MHz, DMSO) δ 10.62 (s, 1H), 8.70-8.63 (m, 3H), 8.25 (d, J=2.4Hz, 1H), 7.97 (t, J= 6.7Hz, 2H), 7.91 (dd, J=8.8,2.4Hz, 1H), 7.77 (d, J=8.5Hz, 2H), 7.69 (d, J=8.8Hz, 1H), 6.93 (s, 2H), 4.69 (q, J=6.7Hz, 1H), 3.72 (ddd, J=24.1,9.2,6.8Hz, 2H), 2.56-2.47 (m, 2H), 1.13 (d, J=7.8Hz, 9H)
F6, white solid, yield 70%；EI-MS(m/z):611[M]+；613[M]-.MP:202.2~203.1 DEG C；1H NMR (400MHz, DMSO) δ 10.62 (d, J=24.5Hz, 1H), 8.81 (d, J=7.5Hz, 1H), 8.69 (s, 1H), 8.18 (ddd, J=16.6,13.5,5.2Hz, 3H), 7.96-7.81 (m, 3H), 7.74-7.53 (m, 2H), 7.10 (t, J=9.5Hz, 1H), 4.73 (q, J=6.9Hz, 1H), 3.79-3.66 (m, 2H), 3.01 (td, J=6.6,4.0Hz, 1H), 2.89 (s, 2H), 2.57–2.43(m,2H),1.77–1.67(m,1H),1.22–1.02(m,9H).
F7, white solid, yield 70%；EI-MS(m/z):611[M]+；613[M]-.MP:120.8~122.1 DEG C；1H NMR (400MHz, DMSO) δ 10.62 (s, 1H), 8.75-8.63 (m, 2H), 8.28-8.09 (m, 3H), 8.02 (dt, J=17.0, 7.7Hz, 3H), 7.83 (d, J=8.4Hz, 3H), 7.10 (d, J=8.6Hz, 1H), 4.79-4.60 (m, 1H), 3.84-3.62 (m, 2H), 2.70 (dd, J=9.7,9.3Hz, 3H), 1.17-1.09 (m, 9H)
F8, white solid；Yield 60%；EI-MS(m/z):575[M]+；577[M]-.MP:104.8~107.4 DEG C；1H NMR (400MHz, DMSO) δ 10.62 (s, 1H), 8.60 (d, J=7.4Hz, 1H), 8.36 (d, J=2.4Hz, 1H), 8.25 (d, J =2.5Hz, 1H), 7.99-7.93 (m, 3H), 7.84-7.78 (m, 1H), 7.69 (t, J=8.2Hz, 3H), 6.55 (d, J= 8.6Hz, 1H), 4.69 (q, J=6.8Hz, 1H), 3.72 (ddd, J=23.6,9.2,6.8Hz, 2H), 2.51 (dd, J=3.5, 1.7Hz 1H), 1.77-1.70 (m, 2H), 1.13 (d, J=8.7Hz, 9H)
The synthesis step of F3, F9, F11, F12, F13 and F10 are identical；
F3, white solid, yield 60%；EI-MS(m/z):601[M]+；603[M]-.MP:229.0~231.3 DEG C；1H NMR (400MHz, DMSO) δ 11.05 (s, 1H), 10.67 (s, 1H), 9.08 (s, 2H), 8.82 (d, J=7.5Hz, 1H), 8.32- 8.24 (m, 2H), 7.95 (ddd, J=18.3,9.6,7.2Hz, 3H), 7.71-7.60 (m, 2H), 4.74 (q, J=6.9Hz, 1H),3.79–3.50(m,3H),2.22–2.11(m,1H),1.14(s,9H),1.11(s,2H),0.86(s,2H).
F9, white solid, yield 65%；EI-MS(m/z):601[M]+；603[M]-.MP:91.8~93.4 DEG C；1H NMR (400MHz, DMSO) δ 10.63 (s, 1H), 9.09 (t, J=9.0Hz, 1H), 8.99 (d, J=2.0Hz, 1H), 8.79- 8.75 (m, 2H), 8.49 (t, J=2.1Hz, 1H), 8.26 (d, J=2.5Hz, 1H), 8.08 (d, J=8.5Hz, 2H), 7.94 (dd, J=9.8,4.6Hz, 2H), 7.70 (d, J=8.8Hz, 1H), 4.71 (q, J=6.8Hz, 1H), 3.79-3.66 (m, 2H), 2.74(s,2H),1.78–1.68(m,2H),1.15(s,9H),0.81–0.71(m,2H),0.68–0.58(m,2H).
F11, white solid, yield 65%；EI-MS(m/z):617[M]+；619[M]-.MP:52.3~53.9 DEG C；1H NMR (400MHz, DMSO) δ 10.64 (s, 1H), 9.05 (d, J=2.1Hz, 1H), 8.79 (dd, J=21.0,7.5Hz, 1H), 8.60 (t, J=4.2Hz, 1H), 8.26 (d, J=2.4Hz, 1H), 8.17 (dd, J=4.5,2.3Hz, 1H), 8.08 (s, 1H), 7.97-7.93 (m, 3H), 7.68 (d, J=8.8Hz, 1H), 4.72 (q, J=6.7Hz, 1H), 3.73 (dd, J=10.1, 4.4Hz, 2H), 3.49 (d, J=6.8Hz, 2H), 3.38 (s, 2H), 3.24 (d, J=6.8Hz, 2H), 1.19 (t, J=6.7Hz, 3H), 1.12 (d, J=14.6Hz, 9H), 1.08 (d, J=6.9Hz, 3H)
F12, white solid；Yield 65%；EI-MS(m/z):617[M]+；619[M]-.MP:85.1~87.4 DEG C；1H NMR (400MHz, DMSO) δ 10.66 (s, 1H), 9.07 (dd, J=4.9,2.2Hz, 1H), 8.90 (d, J=7.5Hz, 1H), 8.61 (d, J=1.9Hz, 1H), 8.30 (s, 1H), 8.26 (d, J=2.2Hz, 1H), 8.20 (dd, J=4.9,2.9Hz, 1H), 8.00 (d, J=7.8Hz, 1H), 7.96 (d, J=6.8Hz, 1H), 7.67 (d, J=6.9Hz, 1H), 7.65-7.60 (m, 1H), 4.79-4.73 (m, 1H), 3.73 (dd, J=14.1,5.3Hz, 2H), 3.49 (d, J=6.8Hz, 2H), 3.38 (s, 2H), 3.25 (s, 2H), 1.20 (d, J=6.7Hz, 3H), 1.14 (s, 9H), 1.09 (s, 3H)
F13, faint yellow solid, yield 60%；EI-MS(m/z):617[M]+；619[M]-.1H NMR(400MHz, DMSO) δ 10.66 (s, 1H), 9.07 (t, J=3.7Hz, 1H), 8.90 (d, J=7.6Hz, 1H), 8.59 (dd, J=11.2, 1.9Hz, 1H), 8.32-8.21 (m, 2H), 8.00-7.95 (m, 2H), 7.69 (d, J=8.8Hz, 2H), 7.61 (dd, J=4.5, 2.2Hz, 3H), 7.56 (dd, J=4.8,2.3Hz, 3H), 4.75 (q, J=6.9Hz, 1H), 3.79-3.68 (m, 2H), 3.54- 3.46(m,2H),3.25(s,1H),2.89(s,2H),2.74–2.68(m,2H),1.14(s,9H).
The derivative of the serine with anti-tumor activity replaced containing tert-butyl produced by the present invention is carried out below The screening of Bcr-Abl kinase inhibiting activity.
Measuring method is specific as follows:
Kinases ABL1, ABL (T315I) and substrate A bltide are purchased from Signal-Chem company, select Promega company ADP-GloTMKinase Assays detection kit detects the Inhibiting enzyme activity of target compound, and operating method is said according to kit Bright progress.
In Abl experiment, ATP (1mM) is used into buffer (2 ×) (Tris 80mM, MgCl2 20mM,BSA 0.2mg/ml, DTT 2mM) dilute 80 times of buffer (2 ×) solution for being configured to ATP (125 μM)；125 μM of ATP solution and Abltide is molten The mixed solution that liquid product 1:1 is hybridly prepared into ATP (62.5 μM)-Abltide (0.5 μ g/ μ l) is spare；ABL1 kinase solution is used buffer(1×)(Tris 40mM,MgCl210mM, BSA 0.1mg/ml, DTT 1mM) dilution 100 times be configured to ABL1 Buffer (1 ×) solution for standby of (1ng/ μ l).
The preparation steps of ATP-Abltide and ABL1 (T315I) in Abl (T315I) experiment are same as above, unlike ATP concentration is 12.5 μM, and the concentration of ABL1 (T315I) is 2ng/ μ l.
Target compound and positive control drug (Imatinib) are configured to 1.5 × 10 with buffer (1 ×) respectively-6mol/ The sample solution of L concentration gradient sequentially adds the mixed solution of 2 μ l ATP-Abltide, 1 μ l sample in hole every on 384 orifice plates Solution, 2 μ l enzyme solutions；Blank well adds the mixed solution of 3 μ l buffers and 2 μ l ATP-Abltide；Control wells add 2 μ lATP- The mixed solution of Abltide, 1 μ l buffer, 2 μ l enzyme solutions finish, are incubated for 60min at 30 DEG C；5 μ of ADP-Glo reagent is added L is incubated for 40min at 25 DEG C；Kinase detection reagent is added, then is incubated for 30min at 25 DEG C.Using The chemiluminescence module of PerkinElmer multi-function microplate reader measures the luminous value in every hole, calculates compound to the inhibiting rate of Abl
A kind of structural formula of the class peptides of serine replaced containing tert-butyl of the invention are as follows:
Kinase inhibiting activity such as 2 institute of table of the class peptides for the serine of structure above replaced containing tert-butyl Show
The class peptides for the serine that table 2 replaces containing tert-butyl are to Bcr-Abl/Bcr-AblT315IInhibiting rate (%)
As can be seen from Table 2, most compound has certain inhibitory activity to Bcr-Abl kinases, to Bcr- AblT315Kinases, majority of compounds have certain inhibitory activity, and inhibiting rate is part of in 40% to 100% range Compound (F1, F9) is to the inhibiting rate of T315I mutation Abl kinases 90% or more.It is active preferable.Activity Results show to replace The difference of base will have a direct impact on compound to the inhibitory activity of kinases.
Growth inhibitory activity of the class peptides to tumour cell of the serine replaced containing tert-butyl is measured below. The class peptides of the serine replaced containing tert-butyl are examined to make the growth inhibitory activity of tumour cell using mtt assay With.
The class peptides of the serine provided by the invention replaced containing tert-butyl have antineoplastic action.To swollen Oncocyte has external inhibition increment active effect, has the increasing for inhibiting tumour cell in human leukemia cell (K562 cell) It is worth active effect, can be used for the treatment to leukaemia.
Human leukemia cell's (K562 cell) of logarithmic growth phase, is diluted to 10 with RPMI1640 culture medium4A/ml number The cell solution of magnitude is inoculated in 96 well culture plates (2000-4000/hole) in parallel, and every hole inoculation volume is 180 μ l, and 37 DEG C, 5%CO212h is cultivated in incubator；
The 20 μ l of untested compound of various concentration is added in every hole, makes the final concentration of of compound in hole: 1.5 × 10-5mol/ L, each concentration set 3 multiple holes, and compound is not added in negative control refinement born of the same parents, if 6 multiple holes, nilotinib or Imatinib are sun Property control, continue cultivate 48h；
MTT (5mg/ml) 20 μ l is added in every hole, makes the final concentration 0.5mg/ml of MTT in hole, 37 DEG C of incubators are incubated for 4h, small The heart, which is inhaled, abandons supernatant, and every hole adds 150 μ l of DMSO, vibrates 15min, and enzyme-linked immunosorbent assay instrument measures the UV absorption at each hole 490nm It is worth (OD value), then calculates cell inhibitory rate, and calculate the IC for finding out compound using linear regression method according to inhibiting rate50Value；
The calculation formula of cell inhibitory rate are as follows:
Inhibiting rate %=(control wells mean OD value-medication group mean OD value)/control wells mean OD value × 100%；
Testing result is shown: compared with negative control group, the class peptides containing alanine are to above-mentioned tumour cell With different degrees of In-vitro Inhibitory Effect, as shown in table 3.
K562 cell-proliferation activity:
The class peptides for the serine that table 3 replaces containing tert-butyl are to K562 cell inhibitory rate (%)
From table 3 it can be seen that cell activity screening test shows that compound has certain cell proliferation to K562 cell Inhibitory activity inhibiting rate is between 10.49% to 70%, wherein most preferably F7, inhibiting rate reach the preferable compound activity of activity To 68%, activity is suitable with Imatinib.For the class peptides of the serine replaced containing tert-butyl, in pyrrole Different substituent groups is introduced in phenazine ring, there are biggish differences for the influence to bioactivity, and the position difference of substituent group is to life The active influence of object is also different.Compound F1, F4 and F9 are to Bcr-AblT315IThe inhibitory activity of kinases is preferable；F7 pairs of compound The inhibitory activity of K562 cell is preferable, is close with Imatinib, is worth the further further investigation of expansion.
The present invention is based on to early period Bcr-Abl tyrosine kinase inhibitor and Bcr-Abl albumen and ligand it is mutual The research such as function analysis, using biphenyl pyridine as hinge area binding fragment, introduces uncle L- using the drug design strategies based on segment The serine that butyl replaces is flexibility Linker, to construct the class peptides library with kinase inhibiting activity, and is passed through The kinase activity screening of ADP-Glo is found to have the tyrosine kinase inhibitor of Bcr-Abl kinase inhibiting activity.The compound energy It is enough in and prepares in antitumor (chronic myelocytic leukemia) drug, have and inhibit Bcr-Abl, Bcr-AblT315IKinase activity, And there is cell proliferation inhibitory activity to K562 cell.The ser structure that L- tert-butyl replaces is introduced, Bcr- can be extended The structure diversity of Abl kinase inhibitor, while activity test shows that the serine that tert-butyl replaces is living to the inhibition of compound Property plays a significant role, and can be improved the affinity between receptor and compound.It can be used as the inhibition of Bcr-Abl tyrosine kinase The drug effect segment of agent.

Claims (10)

1. a kind of class peptides of the serine replaced containing tert-butyl, which is characterized in that the structural formula of such compound It is as follows:
Wherein, R is-NH2、
2. a kind of preparation method of the class peptides of the serine replaced as described in claim 1 containing tert-butyl, It is characterized in that, comprising the following steps:
1) the acylated bromo- 2-aminopyridine of 5- of acylation reaction preparation occurs for the bromo- 2-aminopyridine of 5- and chloride compounds；
2)N2Under protection, 5- bromo-nicotinic acid, thionyl chloride and aminated compounds, which react, prepares the 5- bromo-nicotinic acid of ammonification；
3) under tetra-triphenylphosphine palladium catalysis, the 5- bromo-nicotinic acid and Carboxybenzeneboronic acid of the bromo- 2-aminopyridine of acylated 5- or ammonification Suzuki coupling reaction occurs, obtains biphenol compound；
4) Fmoc-O- tert-butyl-Serine and the chloro- 3- 5-trifluoromethylaniline condensation of 4- generate (9H- fluorenes -9- base) methyl (S) - 3- (tert-butoxy) -1- ((4- chloro- 3- (trifluoromethyl) phenyl) amino) -1- oxo propyl- 2- yl) carbamate；
5) (9H- fluorenes -9- base) methyl (S) -3- (tert-butoxy) -1- ((4- chloro- 3- (trifluoromethyl) phenyl) amino) -1- oxo Propyl- 2- yl) carbamate take off Fmoc protecting group generate (S) -2- amino -3- (tert-butoxy)-N- (chloro- 3- (fluoroform of 4- Base) phenyl) propionamide；
6) (S) -2- amino -3- (tert-butoxy)-N- (4- chloro- 3- (trifluoromethyl) phenyl) propionamide and biphenol compound are condensed Generate the class peptides of the serine replaced containing tert-butyl.
3. a kind of preparation method of the class peptides of the serine replaced as claimed in claim 2 containing tert-butyl, It is characterized in that, the step 1) detailed process are as follows: the bromo- 2-aminopyridine of 5- is dissolved in anhydrous methylene chloride, three second are added Amine, under condition of ice bath, be added dropwise chloride compounds, after being added dropwise, remove ice bath be warmed to room temperature reaction 12h after, after progress Processing, obtains the bromo- 2-aminopyridine of acylated 5-.
4. a kind of preparation method of the class peptides of the serine replaced as claimed in claim 2 containing tert-butyl, It is characterized in that, the step 2) detailed process are as follows: in N2Under protection, thionyl chloride is added dropwise in 5- bromo-nicotinic acid, is added dropwise After complete, it is heated to reflux 2-3h and is clarified to solution, decompression rotation removes thionyl chloride, obtains faint yellow solid, and the faint yellow solid is molten Enter into anhydrous methylene chloride, in the dichloromethane solution for being then added drop-wise to aminated compounds under condition of ice bath；After dripping, It is warmed to room temperature reaction 12h to be post-processed after reaction, obtains the bromo- niacin of 5- of ammonification.
5. a kind of preparation method of the class peptides of the serine replaced as claimed in claim 2 containing tert-butyl, It is characterized in that, the step 3) detailed process are as follows: the acylated bromo- 2-aminopyridine of 5- and right/Carboxybenzeneboronic acid are added It is added in reaction vessel, sequentially adds into reaction vessel, or by the bromo- niacin of the 5- of ammonification and right/Carboxybenzeneboronic acid Cesium carbonate and tetra-triphenylphosphine palladium；Then the mixed solution of acetonitrile and water, N are added2Protection, is warming up to 90 DEG C of reaction 48h；Instead It after answering, is post-processed, obtains biphenol compound.
6. a kind of preparation method of the class peptides of the serine replaced as claimed in claim 2 containing tert-butyl, It is characterized in that, the detailed process of the step 4) are as follows: the chloro- 3- 5-trifluoromethylaniline of 4-, HOBT, HATU are dissolved in anhydrous dichloromethane In alkane, DIPEA is then added dropwise, after being added dropwise, Fmoc-O- tert-butyl-Serine dichloromethane solution, room temperature is added dropwise 5h is reacted, is post-processed, obtains (9H- fluorenes -9- base) methyl (S) -3- (tert-butoxy) -1- ((the chloro- 3- of 4- (trifluoromethyl) Phenyl) amino) -1- oxo propyl- 2- yl) carbamate.
7. a kind of preparation method of the class peptides of the serine replaced as claimed in claim 2 containing tert-butyl, It is characterized in that, the detailed process of the step 5) are as follows: at 0 DEG C, by (9H- fluorenes -9- base) methyl (S) -3- (tert-butoxy) -1- ((4- chloro- 3- (trifluoromethyl) phenyl) amino) -1- oxo propyl- 2- yl) carbamate is dissolved in anhydrous methylene chloride, then The DMF solution of 20% piperidines of volumetric concentration is added dropwise, after reacting 1h, is post-processed, obtains (S) -2- amino -3- (tertiary fourth oxygen Base)-N- (4- chloro- 3- (trifluoromethyl) phenyl) propionamide.
8. a kind of preparation method of the class peptides of the serine replaced as claimed in claim 2 containing tert-butyl, It is characterized in that, the detailed process of the step 6) are as follows: biphenol compound, PyBOP are dissolved in anhydrous DMF, it is molten that DIPEA is added dropwise After reacting at room temperature 5min, (S) -2- amino -3- (tert-butoxy)-N- (4- chloro- 3- (trifluoromethyl) phenyl) propionyl is added in liquid Amine reacts at room temperature 12h, is post-processed, and obtains the class peptides of the serine replaced containing tert-butyl.
9. a kind of class peptides of the serine replaced containing tert-butyl as described in any one of claim 1-8, It is characterized in that, such compound is in preparation for inhibiting Abl kinases, T315I to be mutated the application in Abl kinase activity drug.
10. a kind of class peptides of the serine replaced containing tert-butyl as described in any one of claim 1-8, It is characterized in that, such peptides application in preparation of anti-tumor drugs.
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