CN104761572A - Flueggea suffruticosa-type alkaloid dimer-type compound or pharmaceutically acceptable salt thereof, preparation method and application thereof - Google Patents

Flueggea suffruticosa-type alkaloid dimer-type compound or pharmaceutically acceptable salt thereof, preparation method and application thereof Download PDF

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CN104761572A
CN104761572A CN201510106974.2A CN201510106974A CN104761572A CN 104761572 A CN104761572 A CN 104761572A CN 201510106974 A CN201510106974 A CN 201510106974A CN 104761572 A CN104761572 A CN 104761572A
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securinine
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CN104761572B (en
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叶文才
陈卫民
师蕾
王英
唐根云
刘鑫
董晓
黄小杰
张文
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Jinan University
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Abstract

The invention discloses a flueggea suffruticosa-type alkaloid dimer-type compound or a pharmaceutically acceptable salt thereof, a preparation method and an application thereof. The flueggea suffruticosa-type alkaloid dimer-type compound or the pharmaceutically acceptable salt thereof has a chemical structure formula represented as the formula (1), wherein X refers to a group represented as follows or a sulfur atom. In the group that the X refers to, the R is one from the following groups: CH3, C2H5, n-C3H7, n-C4H9, n-C5H11 or a hydrogen atom. The m is an integer selected from 0 to 9. The n is 0 or 1. The number 1, 2, 3, 4, 5, 6, 7 and 8 in the formula indicate the position of a chiral center, wherein the position is in an R configuration or an S configuration. The flueggea suffruticosa-type alkaloid dimer-type compound or the pharmaceutically acceptable salt thereof can be used for preparing a drug for treating dysplasia in nerve, nerve injury, neurodegenerative disease and learning and memory disorder.

Description

Suffrutescent Securinega Twig type alkaloid dimer compounds or its pharmacologically acceptable salt and method for making thereof and application
Technical field
The invention belongs to field of medicaments, be specifically related to a kind of Suffrutescent Securinega Twig type alkaloid dimer compounds or its pharmacologically acceptable salt and method for making thereof and application.
Background technology
Neuronic early development comprises a series of metamorphosis, as the growth of nervous process, extension, aixs cylinder and process (the Polleux and Snider such as the differentiation of dendron and the maturation of nerve synapse, Cold Spring Harb Perspect Biol, 2010,2:a001925; Lewis et al., J Cell Biol, 2013,202:837-48).The precision control of these growth courses determines neurone and is formed accurately and contact and form complicated neural network, regulates and controls the nervous activities such as our study, memory, emotion thus.In the disease of brain such as nerve degenerative diseases and nerve injury, the breakdown of nervous process, atrophy and neuronal death are the item keys (Medana and Esiri, Brain, 2003,126:515-30) of PD.Therefore, the important means that effectively can promote that the medicine of precursor cell Differentiating Into Neurons and neurite-outgrowth will be these diseases for the treatment of is found.The main method that the treatment of these diseases is generally taked comprise neuroprotective unit when damage or stress better survive, promote neuronic new life's differentiation and promote the regeneration of nervous process or regrow, extend; make neurone keep thus or again form normal contact, guaranteeing stability and the plasticity-of neural network.
In addition, in the diseases such as nerve degenerative diseases (as Alzheimer's disease) and Affective Disorder (as dysthymia disorders), usually there will be the exception that nerve synapse transmission and neural circuitry are constructed, cause cognitive function and dysmnesia thus.Therefore, exploitation promotes that medicine that is cognitive and memory is also the key of these diseases for the treatment of.Transitive dependency between neurone is in a special construction---the nerve synapse formed each other.Nerve synapse in human central nervous system is divided into excitatory synapse and inhibitory synapse, the running balance quantitatively of two kinds of nerve synapses is for the information processing of brain and the very important (McAllister of thinking activities, AnnuRev Neurosci, 2007,30:425-50).Wherein, the normal function of excitatory synapse is the basis determining learning and m emaory.Excitatory synapse has unique post-synaptic structures---dendritic spine (dendritic spines), namely sour jujube shape pimple (the Hering and Sheng on neurone dendron is positioned at, Nat Rev Neurosci, 2001,2 (12): 880-8).Increasing research in recent years shows, dendritic spine is the damaged site of learning and Memory obstacle and multiple sacred disease.Therefore, medicinal design is carried out for the form of dendritic spine, molecular composition and electro physiology character or intervention is one of important method of these diseases for the treatment of.
Summary of the invention
For solving the shortcoming and defect part of prior art, primary and foremost purpose of the present invention is to provide a kind of Suffrutescent Securinega Twig type alkaloid dimer compounds or its pharmacologically acceptable salt.
Another object of the present invention is to the preparation method that above-mentioned Suffrutescent Securinega Twig type alkaloid dimer compounds or its pharmacologically acceptable salt are provided.
Another object of the present invention is the application providing above-mentioned Suffrutescent Securinega Twig type alkaloid dimer compounds or its pharmacologically acceptable salt.
For achieving the above object, the present invention adopts following technical scheme:
A kind of Suffrutescent Securinega Twig type alkaloid dimer compounds or its pharmacologically acceptable salt, have such as formula the chemical structure shown in (1):
In formula (1): X is or one in S (sulphur atom), wherein r group be CH 3, C 2h 5, n-C 3h 7, n-C 4h 9, n-C 5h 11or one in H; M is one in 0,1,2,3,4,5,6,7,8 or 9; N is one in 0 or 1; Numeral 1,2,3,4,5,6,7 and 8 in formula indicates chiral centre position, and the configuration of this position is the one in R or S configuration.
Described Suffrutescent Securinega Twig type alkaloid dimer compounds or its pharmacologically acceptable salt, its form is optical siomerism mixture or optical purity monomer (left-handed or dextrorotatory form).
The first preparation method of above-mentioned Suffrutescent Securinega Twig type alkaloid dimer compounds or its pharmacologically acceptable salt, comprises the following steps: (1) is by left-handed Securinine ((-)-Securinine) and TMSA (Me 3siN 3) react, obtain compound S-SN-1 and R-SN-1; (2) compound S-SN-1 and R-SN-1 is reacted with hydrogen respectively, obtain compound S-SN-2 and R-SN-2 respectively; (3) compound S-SN-2 and R-SN-2 is reacted with the diacid chloride of different carbon chain lengths respectively, obtain Securinine dimer compounds SN0-L2, SN0-L3, SN0-L4, SN0-L5 and SN0-L6 respectively;
Wherein, left-handed Securinine structural formula is:
Compound S-SN-1 structural formula is:
Compound R-SN-1 structural formula is:
Compound S-SN-2 structural formula is:
Compound R-SN-2 structural formula is:
Compound S N0-L2 structural formula is:
Compound S N0-L3 structural formula is:
Compound S N0-L4 structural formula is:
Compound S N0-L5 structural formula is:
Compound S N0-L6 structural formula is:
The diacid chloride of described different carbon chain lengths is oxalyl chloride, malonyl chloride, succinic chloride, glutaryl chlorine and Adipoyl Chloride.
The first preparation method's concrete steps above-mentioned are: (1) is with methylene dichloride (CH 2cl 2) be solvent, be 1:(5-8 by mol ratio) left-handed Securinine (-)-Securinine and TMSA (Me 3siN 3) at the DBU (1 of acetic acid (AcOH) and catalytic amount, 8-diazabicyclo [5.4.0] 11 carbon-7-alkene) under catalysis, react 7-10 hour under normal temperature, the mol ratio of left-handed Securinine (-)-Securinine and acetic acid is 1:(5-8); After stopped reaction, ammonium chloride (NH 4cl) cancellation, washing, CH 2cl 2extraction, silicagel column separation and purification, obtains compound S-SN-1 and R-SN-1; (2) respectively the palladium-carbon catalyst (10%Pd/C) of compound S-SN-1 and R-SN-1 and catalytic amount is joined CH 2cl 2in solvent, vacuumize, fill hydrogen, repeatedly replace 3-4 time, stirring at normal temperature reaction is after 3-5 hour, and filter, filtrate decompression is spin-dried for; Silicagel column separation and purification, obtains compound S-SN-2 and R-SN-2 respectively; (3) compound S-SN-2 decompression be spin-dried for, vacuum oil pump drains solvent, makes alkali, anhydrous CH at anhydrous DIPEA (DIPEA) 2cl 2for under the condition of solvent ,-15 DEG C of low temperature respectively with the diacid chloride (oxalyl chloride, malonyl chloride, succinic chloride, glutaryl chlorine and Adipoyl Chloride) of different carbon chain lengths according to mol ratio 1:(0.5-0.6) react 4-6 hour after, NH 4cl cancellation, washes 2 times, CH successively respectively with saturated sodium bicarbonate and saturated aqueous common salt 2cl 2extraction, decompression is spin-dried for, silicagel column separation and purification, obtains Securinine dimer compounds SN0-L2, SN0-L3, SN0-L4, SN0-L5 and SN0-L6 respectively.
The second preparation method of above-mentioned Suffrutescent Securinega Twig type alkaloid dimer compounds or its pharmacologically acceptable salt, comprise the following steps: left-handed Securinine ((-)-Securinine) and methylamine, ethamine, Tri N-Propyl Amine, n-Butyl Amine 99 and n-amylamine react by (1) respectively, obtain compound S-SN-5, R-SN-5, S-SN-3, S-SN-4, S-SN-6 and S-SN-7 respectively; (2) by compound S-SN-5 and R-SN-5 mixing, then react with Adipoyl Chloride, being obtained the dimer compound of 3 diastereomers each other again by high performance liquid phase (HPLC) disposable separation, is SN3-L6, RS-SN3-L6 and RR-SN3-L6 respectively; (3) compound S-SN-5 is reacted with succinic chloride, glutaryl chlorine, pimeloyl chloride and suberoyl chlorine respectively, obtain dimer compound SN3-L4, SN3-L5, SN3-L7 and SN3-L8 respectively; (4) compound S-SN-3, S-SN-4, S-SN-6 and S-SN-7 are reacted with Adipoyl Chloride respectively, obtain dimer compound SN1-L6, SN2-L6, SN4-L6 and SN5-L6 respectively; (5) compound S-SN-5 and R-SN-5 is reacted with propionyl chloride respectively, obtain compound S-SN-8 and R-SN-8 respectively;
Wherein, left-handed Securinine structural formula is:
Compound S-SN-5 structural formula is:
Compound R-SN-5 structural formula is:
Compound S-SN-3 structural formula is:
Compound S-SN-4 structural formula is:
Compound S-SN-6 structural formula is:
Compound S-SN-7 structural formula is:
Compound S N3-L6 structural formula is:
Compound RS-SN3-L6 structural formula is: compound R R-SN3-L6 structural formula is: compound S N3-L4 structural formula is:
Compound S N3-L5 structural formula is: compound S N3-L7 structural formula is:
Compound S N3-L8 structural formula is:
Compound S N1-L6 structural formula is:
Compound S N2-L6 structural formula is:
Compound S N4-L6 structural formula is:
Compound S N5-L6 structural formula is:
Compound S-SN-8 structural formula is:
Compound R-SN-8 structural formula is:
Above-mentioned the second preparation method concrete steps are: (1) by left-handed Securinine (-)-Securinine respectively with methylamine, ethamine, Tri N-Propyl Amine, n-Butyl Amine 99 and n-amylamine according to mol ratio 1:(5-10) at potassiumphosphate (K 3pO 4) catalysis condition under react 12-18 hour, the mol ratio of left-handed Securinine (-)-Securinine and potassiumphosphate is 1.0:(0.05-0.1), NH 4cl cancellation, washing, CH 2cl 2extraction, silicagel column separation and purification, obtains compound S-SN-5, R-SN-5, S-SN-3, S-SN-4, S-SN-6 and S-SN-7 respectively; (2) by compound S-SN-5 and R-SN-5 mixing, then mixture is made alkali, anhydrous CH at anhydrous DIPEA (DIPEA) 2cl 2for under the condition of solvent ,-15 DEG C of low temperature with Adipoyl Chloride according to mol ratio 1.0:(0.5-0.6) carry out reaction 4-6 hour after, NH 4cl cancellation, washes 2 times, CH successively respectively with saturated sodium bicarbonate and saturated aqueous common salt 2cl 2extraction, decompression is spin-dried for, silicagel column separation and purification, then obtains the dimer compound of 3 diastereomers each other by high performance liquid phase (HPLC) disposable separation, is SN3-L6, RS-SN3-L6 and RR-SN3-L6 respectively; (3) compound S-SN-5 is made alkali, anhydrous CH at anhydrous DIPEA (DIPEA) 2cl 2under condition for solvent ,-15 DEG C of low temperature, respectively with succinic chloride, glutaryl chlorine, pimeloyl chloride and suberoyl chlorine according to mol ratio 1.0:(0.5-0.6) carry out reaction 4-6 hour after, NH 4cl cancellation, washes 2 times, CH successively respectively with saturated sodium bicarbonate and saturated aqueous common salt 2cl 2extraction, decompression is spin-dried for, silicagel column separation and purification, obtains dimer compound SN3-L4, SN3-L5, SN3-L7 and SN3-L8 respectively; (4) the same step of operational condition (3), by compound S-SN-3, S-SN-4, S-SN-6 and S-SN-7 respectively with Adipoyl Chloride according to mol ratio 1.0:(0.5-0.6) react, obtain dimer compound SN1-L6, SN2-L6, SN4-L6 and SN5-L6 respectively; (5) the same step of operational condition (3), by compound S-SN-5 and R-SN-5 respectively with propionyl chloride according to mol ratio 1.0:(1.5-1.8) react, obtain compound S-SN-8 and R-SN-8 respectively.
The third preparation method of above-mentioned Suffrutescent Securinega Twig type alkaloid dimer compounds or its pharmacologically acceptable salt, comprise the following steps: dextrorotation Securinine ((+)-Securinine) and Tri N-Propyl Amine react by (1), obtain compound (+)-S-SN-5 and (+)-R-SN-5; (2) compound (+)-R-SN-5 is reacted with Adipoyl Chloride, obtain compound (+)-SN3-L6;
Wherein, dextrorotation Securinine structural formula is:
Compound (+)-S-SN-5 structural formula is:;
Compound (+)-R-SN-5 structural formula is:
Compound (+)-SN3-L6 structural formula is:
The third preparation method's concrete steps above-mentioned are: dextrorotation Securinine ((+)-Securinine) is dissolved in CH by (1) 2cl 2in, add K 3pO 4, add Tri N-Propyl Amine subsequently, stirring at room temperature reaction 12-18 hour, dextrorotation Securinine ((+)-Securinine) and K 3pO 4mol ratio be 1.0:(0.05-0.1), the mol ratio of dextrorotation Securinine ((+)-Securinine) and Tri N-Propyl Amine is 1:(5-10), NH 4cl cancellation, washing, CH 2cl 2extraction, silicagel column separation and purification, obtains compound (+)-S-SN-5 and (+)-R-SN-5; (2) compound (+)-R-SN-5 decompression is spin-dried for, and vacuum oil pump drains solvent, then makes alkali, anhydrous CH in anhydrous DIPEA catalysis 2cl 2solvent be under the condition of solvent ,-15 DEG C of low temperature and Adipoyl Chloride according to mol ratio 1.0:(0.5-0.6) react 4-6 hour after, NH 4cl cancellation, washes 2 times, CH successively respectively with saturated sodium bicarbonate and saturated aqueous common salt 2cl 2extraction, decompression is spin-dried for, silicagel column separation and purification, obtains compound (+)-SN3-L6.
4th kind of preparation method of above-mentioned Suffrutescent Securinega Twig type alkaloid dimer compounds or its pharmacologically acceptable salt, comprise the following steps: by left-handed Securinine ((-)-Securinine) respectively with two different thiol reactants, obtain compound S S-L2, SS-L3, SS-L4, SS-L5, SS-L6, SS-L8 and SS-L9 respectively;
Wherein, left-handed Securinine structural formula is:
Compound S S-L2 structural formula is:
Compound S S-L3 structural formula is:
Compound S S-L4 structural formula is:
Compound S S-L5 structural formula is:
Compound S S-L6 structural formula is:
Compound S S-L8 structural formula is:
Compound S S-L9 structural formula is:
Described two different mercaptan be dithioglycol, dimercaptopropane, succinimide mercaptans, pentane disulfide thioalcohol, ethanthiol, pungent two mercaptan and the ninth of the ten Heavenly Stems two mercaptan.
Above-mentioned 4th kind of preparation method's concrete steps are: be 1.0:(0.2-0.5 by mol ratio) left-handed Securinine ((-)-Securinine) and K 3pO 4be dissolved in the CH that volume ratio is 4:1 2cl 2and CH 3in the mixed solvent of OH, stir, by different two mercaptan (dithioglycol, dimercaptopropane, succinimide mercaptans, pentane disulfide thioalcohol, ethanthiol, pungent two mercaptan and the ninth of the ten Heavenly Stems two mercaptan) be dissolved in the addition of C H respectively 3oH, and slowly add in reaction system, room temperature for overnight, left-handed Securinine ((-)-Securinine) is 1.0:(0.5-0.6 with the mol ratio of two mercaptan :); Reaction solvent is spin-dried for, washing, CH 2cl 2extraction, decompression is spin-dried for, silicagel column separation and purification, obtains compound S S-L2, SS-L3, SS-L4, SS-L5, SS-L6, SS-L8 and SS-L9 respectively.
Above-mentioned Suffrutescent Securinega Twig type alkaloid dimer compounds or the application of its pharmacologically acceptable salt in preparation promotes the medicine that Neural Differentiation (neuronaldifferentiation) and nervous process (neurite) grow, the described preferred SN1-L6 of Suffrutescent Securinega Twig type alkaloid dimer compounds, SN2-L6, SN3-L6, SN4-L6, SN5-L6, SN3-L4, SN3-L5, SN3-L7, RS-SN3-L6, RR-SN3-L6, (+)-SN3-L6 or their pharmacologically acceptable salt.
Above-mentioned Suffrutescent Securinega Twig type alkaloid dimer compounds or its pharmacologically acceptable salt promote the application in the medicine of CaMKII, Akt and ERK protein-active in preparation, described Suffrutescent Securinega Twig type alkaloid dimer compounds preferred SN3-L5, SN3-L6 or their pharmacologically acceptable salt.
Above-mentioned Suffrutescent Securinega Twig type alkaloid dimer compounds or its pharmacologically acceptable salt are preparing the application in the neurotoxicity medicine that antagonism amyloid beta causes, the described Suffrutescent Securinega Twig type alkaloid preferred SN3-L6 of dimer compounds or its pharmacologically acceptable salt.
Above-mentioned Suffrutescent Securinega Twig type alkaloid dimer compounds or its pharmacologically acceptable salt are preparing the application in the medicine promoting dendritic spine (dendritic spine) formation and function, the described Suffrutescent Securinega Twig type alkaloid preferred SN3-L6 of dimer compounds or its pharmacologically acceptable salt.
Above-mentioned Suffrutescent Securinega Twig type alkaloid dimer compounds or its pharmacologically acceptable salt promote the application in the medicine of protein synthesis (proteinsynthesis) in preparation, the described Suffrutescent Securinega Twig type alkaloid preferred SN3-L6 of dimer compounds or its pharmacologically acceptable salt.
Above-mentioned Suffrutescent Securinega Twig type alkaloid dimer compounds or its pharmacologically acceptable salt promote the application in learning and memory medicine in preparation, the described Suffrutescent Securinega Twig type alkaloid preferred SN3-L6 of dimer compounds or its pharmacologically acceptable salt.
Above-mentioned Suffrutescent Securinega Twig type alkaloid dimer compounds or its pharmacologically acceptable salt are treated by the application in nervous process or nerve synapse (synapse) heteroplasia or impaired caused cognitive disorder, nerve degenerative diseases, nerve injury or emotionally disturbed symptom in preparation.
The application in the pharmaceutical composition for the preparation for the treatment of neurodevelopment exception, nerve injury, nerve degenerative diseases and learning memory disorder of above-mentioned Suffrutescent Securinega Twig type alkaloid dimer compounds or its pharmacologically acceptable salt.
With Chinese medicine and natural drug for source, the research mode combined by Natural Medicine Chemistry, molecular biology and evaluating drug effect, is therefrom screened and finds lead compound, is the unique pattern carrying out innovation drug research.This patent with extract in euphorbia plant left-handed (or dextrorotation) Securinine is that precursor compound carries out modifying for chemical structure, obtains a series of novel Suffrutescent Securinega Twig type alkaloid dimer compounds and intermediate product thereof.By the evaluating drug effect of the inside and outside models such as the hippocampal neuron of neurocyte strain, original cuiture and experiment mice, find that multiple novel Suffrutescent Securinega Twig type alkaloid dimer compounds has and promote neurite-outgrowth, neuro-protective, nerve synapse to be formed and strengthen the effect of learning and memory function.
Novel Suffrutescent Securinega Twig type alkaloid dimer compounds provided by the invention or its pharmacologically acceptable salt can prepare treatment by the application in nervous process or nerve synapse (synapse) heteroplasia or impaired caused cognitive disorder, nerve degenerative diseases, nerve injury or emotionally disturbed symptom.This novel Suffrutescent Securinega Twig type alkaloid dimer compounds or its pharmacologically acceptable salt also can prepare the medicine of the neurotoxic substances amyloid beta in antagonism Alzheimer's disease.
In addition, novel Suffrutescent Securinega Twig type alkaloid dimer compounds provided by the invention or its pharmacologically acceptable salt can prepare the medicine promoting CaMKII, Akt and ERK protein-active, described Suffrutescent Securinega Twig type alkaloid dimer compounds preferred SN3-L5, SN3-L6 or their pharmacologically acceptable salt.
Novel Suffrutescent Securinega Twig type alkaloid dimer compounds provided by the invention also can prepare the medicine promoting protein synthesis (proteinsynthesis), the described Suffrutescent Securinega Twig type alkaloid preferred SN3-L6 of dimer compounds or its pharmacologically acceptable salt.
Pharmaceutically useful salt described above includes but not limited to: inorganic anion, such as chlorion, bromide anion, iodide ion, sulfate radical, inferior sulfate radical, nitrate radical, nitrite anions, phosphate radical and hydrogen phosphate etc.; Organic anion, such as acetate moiety, propionate, cinnamate, benzene first sulphur root, citrate, lactate and glucose acid group etc.
Suffrutescent Securinega Twig type alkaloid dimer compounds and derivative thereof can make multiple formulation, comprise solid dosage, semisolid dosage form, liquid dosage form and aerosol-type.Concrete formulation in this few class formulation comprises tablet, pill, dragee, granule, gelifying agent, paste, solution, suppository, injection, inhalation and sprays.These formulations can be used for local or Formulations for systemic administration can be used for quick-release or sustained-release administration again, the administering mode of this type of medicine has a variety of, except aforesaid way, also have orally administering, buccal administration, rectal administration, peritoneal administration, Intraperitoneal medication, epidermis administration, subcutaneous administration and intrarterial etc.
When Suffrutescent Securinega Twig type alkaloid dimer compounds and derivative drug administration by injection thereof, with water-soluble or fat-soluble solvent, this compounds can be mixed with solution, clouding agent and emulsion.Fat-soluble solvent specifically comprises vegetables oil and similar oils, synthetic fat acid glyceride, high-grade aliphatic ester and glycol ester.
When Suffrutescent Securinega Twig type alkaloid dimer compounds and derivative oral administration thereof, can adopt common technology that itself and pharmaceutically useful vehicle are made mixture.These compounds can be made the multiple formulation that can be accepted by patient by these vehicle, as tablet, pill, suspensoid, gelifying agent etc.The preparation of oral preparations has multiple method, and as first compound and solid excipient mixed, abundant grinding mixture, add suitable auxiliary material, processing treatment becomes particle.The auxiliary material that may be used for making oral dosage form comprises: carbohydrate is as lactose, sucrose, N.F,USP MANNITOL or sorbyl alcohol; Cellulose family is as W-Gum, wheat starch, yam starch, gelatin, western twelve month yam glue, methylcellulose gum, Walocel MT 20.000PV, cellulose sodium carboxymethyl, Povidone etc.
The Suffrutescent Securinega Twig type alkaloid dimer compounds that the present invention relates to and derivative thereof also can make sprays, and this kind of formulation is realized by a pressurizer and an atomizer or a powder inhaler.Propellant suitable in injector can be used as Refrigerant 12, fluoro trichloromethane, dichloro tetrafluoro ethane, carbonic acid gas and dme etc.The dosage of aerosol drug delivery can be regulated by the valve of injector.
Compared with prior art, the present invention has the following advantages and beneficial effect:
The invention provides a kind of compound of brand new, the synthetic route adopted applies green chemical reaction, more environmental protection, has more fuel economy.These compounds can be used for developing treatment and prevention due to nervous process or nerve synapse heteroplasia or the impaired new drug such as nerve degenerative diseases, nerve injury or emotionally disturbed caused.
Accompanying drawing explanation
Fig. 1 is the synthetic route of Suffrutescent Securinega Twig type dimer compounds.
Fig. 2 is that LDH detects the alkaloidal cytotoxicity of novel Suffrutescent Securinega Twig type.
Fig. 3 is the dose study that compound S N3-L6, RS-SN3-L6 and SN3-L7 urge neurocyte strain differentiation activity.
Fig. 4 is that compound S N3-L5 and SN3-L6 activates ERK, Akt equimolecular signaling pathway protein.
Fig. 5 is the Neural Differentiation effect that many signal paths participate in mediates chemical compound SN3-L6 induction.
Fig. 6 is that the neurone of compound S N3-L6 to the beta induced damage of A has provide protection.
Fig. 7 is the formation that compound S N3-L6 promotes hippocampal neuron dendritic spine.
Fig. 8 is the increase that compound S N3-L6 promotes PSD95 bunch of collection quantity.
Fig. 9 is the new life that compound S N3-L6 promotes protein.
Figure 10 is the new life of protein is that SN3-L6 promotes the committed step that dendritic spine increases.
Figure 11 is the escape latent period of compound S N3-L6 shortening mouse in water maze laboratory.
Embodiment
Below in conjunction with embodiment and accompanying drawing, the present invention is described in further detail, but embodiments of the present invention are not limited thereto.
Embodiment 1:(S) preparation of-azido-Securinine (S-SN-1) and diastereomer R-SN-1 thereof
Securinine ((-)-Securinine, 200mg, be roughly equal to 0.90mmol), acetum (0.32mL, 5.4mmol, d=1.05g/mL), CH is added in 50mL single port flask 2cl 2(methylene dichloride, 5mL), stirred at ambient temperature dissolves.TMSA (Me is added after 2 minutes 3siN 30.71mL, 5.40mmol, d=0.876g/mL) and DBU (0.07mL, 0.45mmol, d=1.04g/mL), stirred at ambient temperature reaction 7 ~ 10 hours, reaction solution is light red, stops and cancellation reaction, twice, CH is washed respectively successively with saturated sodium bicarbonate aqueous solution and saturated aqueous common salt 2cl 2extraction, merge organic phase, with anhydrous sodium sulfate drying 15 minutes, decompression was spin-dried for solvent, silica column purification (chloroform: acetone=80:1 wash-out), obtains weak yellow liquid compound S-SN-1 (67%) and solid chemical compound R-SN-1 (33%).
S-SN-1：IR:2937,2852,2094,1764,1648cm -1；ESI-MS:m/z 261.2[M+H] +；HRESIMS:m/z261.1347[M+H] +,calc for C 13H 16N 4O 2＝261.1346； 1H NMR(300MHz,CDCl 3)δ5.68(d,J＝2.4Hz,1H),3.36(m,1H),3.24～3.15(m,1H),3.12～2.97(m,3H),2.96～2.90(m,1H),2.80(dd,J＝7.4,2.5Hz,1H),2.80～2.73(m,1H),1.94～1.81(m,1H),1.67～1.51(m,1H),1.50～1.33(m,5H)。
R-SN-1：IR:2935,2855,2112,1758,1645cm -1；ESI-MS:m/z 261.0[M+H] +；HRESIMS:m/z261.1347[M+H] +,calc for C 13H 16N 4O 2＝261.1346； 1H NMR(300MHz,CDCl 3)δ5.69(d,J＝2.4Hz,1H),3.92～3.84(m,1H),3.35～3.31(m,1H),3.06～2.90(m,4H),2.81(d,J＝16.8Hz,1H),2.57(dd,J＝11.1,6.1Hz,1H),1.95(m,1H),1.84(d,J＝11.1Hz,1H),1.67～1.62(m,1H),1.54～1.33(m,4H)。
Embodiment 2:(S) preparation of-amino Securinine (S-SN-2) and diastereomer R-SN-2 thereof
Compound S-SN-1 (100mg is roughly equal to 0.37mmol) puts into 50mL single port bottle, adds 5mLCH 2cl 2stirring and dissolving, adds palladium carbon (10%Pd/C, 30mg), bottleneck connects T-valve, and sealing, vacuumizes, fill hydrogen, stir 3 ~ 5 hours under normal temperature, stopped reaction, diatomite filtration, filtrate was with anhydrous sodium sulfate drying 15 minutes, decompression is spin-dried for solvent, and silica column purification (chloroform: methyl alcohol=30:1 wash-out), obtains weak yellow liquid compound S-SN-2 (90%).
Can be used the same method by compound R-SN-1 and obtain compound R-SN-2.
S-SN-2：IR:3368,3292,2939,2856,1740cm -1；ESI-MS:m/z 235.3[M+H] +；HRESIMS:m/z235.1449[M+H] +,calc for C 13H 18N 2O 2＝235.1441； 1H NMR(300MHz,CDCl 3)δ5.46(d,J＝2.4Hz,1H),3.04～2.75(m,6H),2.59(dd,J＝10.8,6.5Hz,1H),2.20(ddd,J＝14.9,8.9,2.4Hz,1H),1.83～1.68(m,1H),1.57～1.44(m,3H),1.42～1.22(m,5H)。
R-SN-2：IR:3360,3298,2930,2855,1724cm -1；ESI-MS:m/z 235.3[M+H] +；HRESIMS:m/z235.1449[M+H] +,calc for C 13H 18N 2O 2＝235.1441； 1H NMR(300MHz,CDCl 3)δ5.61(d,J＝2.4Hz,1H),3.34(dd,J＝6.8,4.1Hz,1H),3.08(t,J＝5.0Hz,1H),2.98～2.82(m,4H),2.54～2.43(m,2H),1.83(dd,J＝15.7,8.9Hz,2H),1.58(d,J＝10.1Hz,3H),1.46～1.30(m,4H)。
Embodiment 3:(S, S) preparation of-oxalyl amido-bis--Securinine (SN0-L2) and similar dimer compound (SN0-L3, SN0-L4, SN0-L5 and SN0-L6) thereof
Joined in the twoport round-bottomed flask of 50mL by compound S-SN-2 (87.06mg is roughly equal to 0.35mmol), be spin-dried for solvent, then drain solvent (3 hours) with vacuum pump, add stirrer, anti-chewing-gum plug seals one of them bottleneck.Another bottleneck connects biexhaust pipe, adds dry CH with syringe needle 2cl 24mL, stirring and dissolving at-15 DEG C, is vacuumized by biexhaust pipe after dissolving, inflated with nitrogen, repeatedly replaces 4 times, adds anhydrous DIPEA (DIPEA, 0.10mL, 0.58mmol, d=0.74g/mL), stir 5 minutes.Get oxalyl chloride (0.02mL, 0.21mmol, d=1.5g/mL), be diluted in rapidly the CH of the drying of 1.0mL 2cl 2in, take out with glass needle tubing immediately, a small amount of repeatedly slowly joining in twoport reaction flask (adds) for about 60 minutes, after adding, continues stirring 30 minutes under-15 DEG C of conditions, under afterwards normal temperature condition being transferred in reaction, stirring reaction 4 ~ 6 hours, reaction solution is chocolate, stops and cancellation reaction, twice, CH is washed respectively successively with saturated sodium bicarbonate aqueous solution and saturated aqueous common salt 2cl 2extraction, merges organic phase, and with anhydrous sodium sulfate drying 15 minutes, decompression was spin-dried for solvent, and silica column purification (chloroform: methyl alcohol=60:1 wash-out), obtains weak yellow liquid compound S N0-L2 (89%).
Convert different diacid chlorides, use the same method and can obtain compound S N0-L3 respectively, SN0-L4, SN0-L5 and SN0-L6.
SN0-L2：IR:3327,2935,2852,1753,1671,1498cm -1；ESI-MS:m/z 523.5[M+H] +；HRESIMS:m/z 523.2553[M+H] +,calc for C 28H 34N 4O 6＝523.2551； 1H NMR(300MHz,DMSO-d6)δ8.85(d,J＝7.5Hz,2H),5.75(s,2H),4.08～3.94(m,2H),3.31～3.25(m,2H),3.11～2.97(m,2H),2.87(d,J＝12.6Hz,6H),2.75(d,J＝17.4Hz,2H),2.49～2.41(m,2H),1.77(d,J＝10.9Hz,4H),1.38(d,J＝10.6Hz,10H)。
SN0-L3：IR:3276,2936,2851,1754,1648,1541cm -1；ESI-MS:m/z 537.8[M+H] +；HRESIMS:m/z 537.2709[M+H] +,calc for C 29H 36N 4O 6＝537.2708； 1H NMR(300MHz,CDCl 3)δ7.68(dd,J＝14.0,4.9Hz,2H),5.65(d,J＝1.9Hz,2H),4.21(dd,J＝9.1,5.6Hz,2H),3.41(d,J＝3.0Hz,2H),3.15(s,2H),2.99(s,6H),2.71～2.61(m,2H),2.57(dd,J＝11.3,5.9Hz,2H),1.87(s,2H),1.67～1.56(m,4H),1.48～1.31(m,8H),1.22(d,J＝11.6Hz,2H)。
SN0-L4：IR:3289,2935,2852,1753,1671,1498cm -1；ESI-MS:m/z 551.8[M+H] +；HRESIMS:m/z 551.2862[M+H] +,calc for C 30H 38N 4O 6＝551.2864； 1H NMR(300MHz,CDCl 3)δ6.84(d,J＝6.9Hz,2H),5.66(d,J＝2.1Hz,2H),4.23(dd,J＝5.8,3.7Hz,2H),3.41(s,2H),3.22～3.07(m,2H),2.94(d,J＝30.3Hz,6H),2.69～2.44(m,8H),1.89(s,2H),1.68～1.57(m,4H),1.39(dd,J＝18.3,10.4Hz,8H)。
SN0-L5：IR:3308,2937,2851,1753,1644,1539cm -1；ESI-MS:m/z 565.9[M+H] +；HRESIMS:m/z 565.3023[M+H] +,calc for C 31H 40N 4O 6＝565.3021； 1H NMR(300MHz,CDCl 3)δ6.98(s,2H),5.54(s,2H),4.16(s,2H),3.34(s,2H),3.04(dd,J＝20.4,11.0Hz,2H),2.92(s,6H),2.52(dd,J＝32.4,10.5Hz,4H),2.17(s,4H),1.82(s,4H),1.61(d,J＝11.0Hz,2H),1.50～1.24(m,10H)。
SN0-L6：IR:3356,2938,2851,1753,1644,1543cm -1；ESI-MS:m/z 579.5[M+H] +；HRESIMS:m/z 579.3178[M+H] +,calc for C 32H 42N 4O 6＝579.3177； 1H NMR(300MHz,CDCl 3)δ6.76(d,J＝7.4Hz,2H),5.59(d,J＝1.8Hz,2H),4.22(dd,J＝11.4,7.4Hz,2H),3.44～3.33(m,2H),3.15～3.03(m,2H),2.93(dd,J＝15.3,4.2Hz,6H),2.65～2.55(m,2H),2.52～2.45(m,2H),2.24～2.15(m,4H),1.85(s,2H),1.69～1.52(m,8H),1.37(dd,J＝20.4,11.7Hz,8H)。
Embodiment 4:(S)-Tri N-Propyl Amine base Securinine (S-SN-5) and analogue R-SN-5, (+)-S-SN-5, S-SN-3, S-SN-4, S-SN-6 and S-SN-7 preparation
Get Securinine (300mg is roughly equal to 1.38mmol) to join in 50mL round-bottomed flask, add CH 2cl 2(4mL) stirring and dissolving, then add anhydrous K 3pO 4(30mg is roughly equal to 0.14mmol) and Tri N-Propyl Amine (0.68mL, 8.28mmol), react 13 hours, reaction solution is faint yellow, stops and cancellation reaction, washes twice, CH respectively successively with saturated sodium bicarbonate aqueous solution and saturated aqueous common salt 2cl 2extraction, merge organic phase, with anhydrous sodium sulfate drying 15 minutes, decompression was spin-dried for solvent, silica column purification (chloroform: methyl alcohol=90:1 wash-out), obtains weak yellow liquid compound S-SN-5 (65%) and R-SN-5 (25%).
S-SN-5：IR:2939,2860,1744,1628,1451cm -1；ESI-MS:m/z 277.5[M+H] +；HRESIMS:m/z277.1901[M+H] +,calc for C 16H 24N 2O 2＝277.1911； 1H NMR(300MHz,CDCl 3)δ5.57(d,J＝2.1Hz,1H),3.22～3.16(m,1H),3.01(dd,J＝6.3,4.2Hz,1H),2.92～2.75(m,3H),2.58～2.40(m,4H),1.89～1.79(m,2H),1.59～1.25(m,9H),0.85(t,J＝7.4Hz,3H)。
R-SN-5：IR:2934,2851,1744,1635,1442cm -1；ESI-MS:m/z 277.5[M+H] +；HRESIMS:m/z277.1905[M+H] +,calc for C 16H 24N 2O 2＝277.1911； 1H NMR(300MHz,CDCl 3)δ5.55(s,1H),3.34(d,J＝6.3Hz,1H),3.07～2.84(m,4H),2.72～2.47(m,4H),2.32～2.22(m,1H),1.84(s,1H),0.89(dd,J＝8.2,6.6Hz,3H)。
Under similarity condition, with dextrorotation Securinine displacement Securinine, obtain weak yellow liquid compound (+)-R-SN-5 (66%) and (+)-S-SN-5 (22%).
(+)-R-SN-5：IR:2937,2851,1744,1625,1456cm -1；ESI-MS:m/z 277.5[M+H] +；HRESIMS:m/z 277.1907[M+H] +,calc for C 16H 24N 2O 2＝277.1911； 1H NMR(300MHz,CDCl 3)δ5.63～5.54(m,1H),3.26～3.13(m,1H),3.02(dt,J＝12.4,6.3Hz,1H),2.95～2.75(m,4H),2.50(tdd,J＝18.2,13.9,7.9Hz,4H),1.92～1.79(m,2H),1.62～1.50(m,1H),1.52～1.23(m,7H),0.86(q,J＝7.0Hz,3H)。
(+)-S-SN-5：IR:2935,2860,1745,1663,1455cm -1；ESI-MS:m/z 277.5[M+H] +；HRESIMS:m/z 277.1912[M+H] +,calc for C 16H 24N 2O 2＝277.1911； 1H NMR(300MHz,CDCl 3)δ5.55(s,1H),3.34(d,J＝6.3Hz,1H),3.07～2.84(m,4H),2.72～2.47(m,4H),2.32～2.22(m,1H),1.84(s,1H),0.89(dd,J＝8.2,6.6Hz,3H)。
Same condition, by Securinine and different primary amine reactions, obtains compound S-SN-3, S-SN-4, S-SN-6 and S-SN-7.
S-SN-3：IR:2935,2851,1723,1643,1435cm -1；ESI-MS:m/z 249.3[M+H] +；HRESIMS:m/z249.1591[M+H] +,calc for C 14H 20N 2O 2＝249.1598； 1H-NMR(300MHz,CDCl 3)δ:5.60(d,J＝2.1Hz,1H),3.20～3.23(m,1H),2.88～2.94(m,4H),2.77～2.85(m,1H),2.57～2.62(m,1H),2.42～2.49(dd,J＝6.0,10.8Hz,1H),2.36(s,3H),1.82～1.87(m,2H),1.55～1.59(m,2H),1.31～1.43(m,4H)。
S-SN-4：IR:2935,2852,1743,1644,898cm -1；ESI-MS:m/z 263.3[M+H] +；HRESIMS:m/z263.1754[M+H] +,calc for C 15H 22N 2O 2＝263.1742； 1H-NMR(300MHz,CDCl 3)δ:5.59(d,J＝2.4Hz,1H),3.18～3.21(m,1H),3.02～3.06(m,1H),2.88～2.94(m,3H),2.79～2.86(m,1H),2.51～2.64(m,3H),2.46(dd,J＝6.0,12.0Hz,1H),1.87(d,1H,J＝10.1Hz),1.80～1.85(m,1H),1.55～1.61(m,1H),1.15～1.50(m,5H),1.05(t,J＝6.9Hz,3H)。
S-SN-6：IR:2937,2851,1744,1634,898cm -1；ESI-MS:m/z 291.2[M+H] +；HRESIMS:m/z291.2060[M+H] +,calc for C 17H 26N 2O 2＝291.2067； 1H NMR(300MHz,CDCl 3)δ5.51(s,1H),3.13(s,1H),2.94(dt,J＝9.9,5.1Hz,1H),2.87～2.69(m,4H),2.53～2.33(m,4H),1.84～1.71(m,2H),1.48(d,J＝11.9Hz,1H),1.44～1.11(m,9H),0.83～0.77(m,3H)。
S-SN-7：IR:2936,2855,1744,1635,898cm -1；ESI-MS:m/z 305.0[M+H] +；HRESIMS:m/z305.2225[M+H] +,calc for C 18H 28N 2O 2＝305.2224； 1H NMR(300MHz,CDCl 3)δ5.50(d,J＝2.2Hz,1H),3.16～3.08(m,1H),2.93(dt,J＝9.6,4.8Hz,1H),2.86～2.69(m,4H),2.52～2.33(m,4H),1.83～1.71(m,2H),1.49(dd,J＝10.2,6.7Hz,1H),1.42～1.21(m,7H),1.21～1.12(m,4H),0.78(t,J＝6.8Hz,3H)。
Embodiment 5:(S, S)-hexanedioyl Tri N-Propyl Amine base-bis--Securinines (SN3-L6) and similar dimer compound RS-SN3-L6, RR-SN3-L6, (+)-SN3-L6, SN1-L6, SN2-L6, SN4-L6 and SN5-L6 preparation
By compound S-SN-5 and R-SN-5 (400mg altogether, being roughly equal to 1.52mmol) 1:1 is mixed to join in the twoport round-bottomed flask of 50mL, is spin-dried for solvent, then drains solvent (3 hours) with vacuum pump, add stirrer, anti-chewing-gum plug seals one of them bottleneck.Another bottleneck connects biexhaust pipe, adds anhydrous CH with syringe needle 2cl 24mL, stirring and dissolving at-15 DEG C, is vacuumized by biexhaust pipe after dissolving, inflated with nitrogen, repeatedly replaces 4 times, adds anhydrous DIPEA (DIPEA, 0.5mL, 2.88mmol, d=0.74g/mL), stir 5 minutes.Get Adipoyl Chloride (0.13mL, 0.91mmol, d=1.25g/mL), be diluted in rapidly the anhydrous CH of 1.0mL 2cl 2in, take out with glass needle tubing immediately, repeatedly slowly join on a small quantity in twoport reaction flask and (within about 60 minutes, add), after adding, stirring is continued 30 minutes under-15 DEG C of conditions, under afterwards normal temperature condition being transferred in reaction, stirring reaction 4 ~ 6 hours, reaction solution look darker, in chocolate, stop and cancellation reaction, wash twice, CH respectively successively with saturated sodium bicarbonate aqueous solution and saturated aqueous common salt 2cl 2extraction, merge organic phase, with anhydrous sodium sulfate drying 15 minutes, decompression is spin-dried for solvent, silica column purification (chloroform: methyl alcohol=90:1 – 60:1 gradient elution), disposablely obtains three faint yellow solid compound S N3-L6, RS-SN3-L6 and RR-SN3-L6 (overall yield 91%).
SN3-L6：IR:2923,2851,1760,1637,1384cm -1；ESI-MS:m/z 663.7[M+H] +；HRESIMS:m/z663.4126[M+H] +,calc for C 38H 54N 4O 6＝663.4116； 1H NMR(300MHz,CDCl 3)δ5.60(s,2H),4.25(d,J＝6.3Hz,2H),3.42(s,2H),3.18～3.06(m,4H),2.87(d,J＝24.1Hz,10H),2.44(dd,J＝11.0,5.8Hz,2H),2.24(d,J＝3.7Hz,4H),1.80(s,2H),1.55(s,12H),1.34(d,J＝21.2Hz,8H),0.81(t,J＝7.3Hz,6H)。
RS-SN3-L6：IR:2938,2862,1759,1637,909cm -1；ESI-MS:m/z 663.6[M+H] +；HRESIMS:m/z 663.4166[M+H] +,calc for C 38H 54N 4O 6＝663.4116； 1H NMR(300MHz,CDCl 3)δ5.60(s,2H),4.49(t,J＝8.7Hz,1H),4.25(s,1H),3.55～3.40(m,2H),3.20～3.06(m,4H),3.00～2.82(m,8H),2.77(t,J＝7.3Hz,3H),2.62(dd,J＝10.9,6.6Hz,1H),2.45(dd,J＝10.9,5.8Hz,1H),2.33～2.21(m,4H),1.80(s,2H),1.46(ddd,J＝24.4,23.0,17.1Hz,19H),0.83(dd,J＝7.0,4.7Hz,6H)。
RR-SN3-L6：IR:2937,2862,1759,1636,909cm -1；ESI-MS:m/z 663.6[M+H] +；HRESIMS:m/z 663.4150[M+H] +,calc for C 38H 54N 4O 6＝663.4116； 1H NMR(300MHz,CDCl 3)δ5.65(s,2H),4.54(t,J＝8.7Hz,2H),3.60～3.48(m,2H),3.27(dd,J＝11.1,5.0Hz,2H),3.16(d,J＝6.4Hz,2H),3.03(dd,J＝10.8,4.1Hz,2H),2.98～2.76(m,10H),2.67(dd,J＝10.8,6.6Hz,2H),2.40～2.27(m,4H),1.85(s,2H),1.60～1.31(m,20H),0.89(d,J＝7.4Hz,6H)。
Under similarity condition, raw material S-SN-5 and R-SN-5 is replaced as (+)-R-SN-5, then obtains dimer compound (+)-SN3-L6.
(+)-SN3-L6：IR:2924,2851,1761,1637,1384cm -1；ESI-MS:m/z 663.7[M+H] +；HRESIMS:m/z 663.4094[M+H] +,calc for C 38H 54N 4O 6＝663.4116； 1H NMR(300MHz,CDCl 3)δ5.66(s,2H),4.31(s,2H),3.48(s,2H),3.15(d,J＝10.6Hz,4H),3.02～2.83(m,10H),2.54～2.46(m,2H),2.30(s,4H),1.87(s,2H),1.62(s,12H),1.36(s,8H),0.88(t,J＝7.2Hz,6H)。
Under similarity condition, raw material S-SN-5 and R-SN-5 is replaced as S-SN-3, S-SN-4, S-SN-6 and S-SN-7, then obtains dimer compound SN1-L6, SN2-L6, SN4-L6 and SN5-L6.
SN1-L6：IR:2925,2851,1757,1637,1384cm -1；ESI-MS:m/z 607.5[M+H] +；HRESIMS:m/z607.3468[M+H] +,calc for C 34H 46N 4O 6＝607.3490； 1H-NMR(300MHz,CDCl 3)δ:5.07(s,2H),4,56～4.60(m,2H),3.44～3.47(m,2H),3.12～3.21(m,2H),2.92～3.05(m,4H),2.88(s,6H),2.72～2.78(d,J＝17.4Hz,4H),2.53～2.58(m,2H),2.31(s,4H),1.24～1.87(m,18H)。
SN2-L6：IR:2924,2852,1761,1637,1371cm -1；ESI-MS:m/z 635.6[M+H] +；HRESIMS:m/z635.3784[M+H] +,calc for C 36H 50N 4O 6＝635.3803； 1H-NMR(300MHz,CDCl 3)δ:5.65(s,2H),4.29～4.31(m.2H),3.44(m,2H),3.27～3.34(m,2H),3.02～3.18(m,4H),2.95～3.00(m,2H),2.80～2.92(m,6H),2.45～2.51(m,2H),2.20～2.39(m,4H),1.84(m,2H),1.55～1.62(m,4H),1.06～1.25(m,18H)。
SN4-L6：IR:2927,2851,1743,1637,1381cm -1；ESI-MS:m/z 691.3[M+H] +；HRESIMS:m/z691.4421[M+H] +,calc for C 40H 58N 4O 6＝691.4429； 1H NMR(300MHz,CDCl 3)δ：5.66(s,2H),4.32(s,2H),3.48(s,2H),3.18(d,J＝10.4Hz,6H),3.02～2.85(m,10H),2.51(dd,J＝10.3,5.8Hz,2H),2.30(s,4H),1.87(s,2H),1.63(s,12H),1.37～1.27(m,10H),0.94(t,J＝7.3Hz,6H)。
SN5-L6：IR:2926,2850,1761,1643,1384cm -1；ESI-MS:m/z 719.3[M+H] +；HRESIMS:m/z719.4761[M+H] +,calc for C 42H 62N 4O 6＝719.4742； 1H NMR(300MHz,CDCl 3)δ：5.66(s,2H),4.43～4.17(m,2H),3.48(s,2H),3.17(d,J＝10.1Hz,4H),2.90(dd,J＝31.1,17.5Hz,10H),2.51(dd,J＝10.5,5.8Hz,2H),2.44～2.11(m,6H),1.87(s,2H),1.62(s,10H),1.39～1.21(m,16H),0.91(t,J＝7.1Hz,6H)。
Embodiment 6:(S, S) preparation of-succinyl Tri N-Propyl Amine base-bis--Securinines (SN3-L4) and similar dimer compound SN3-L5, SN3-L7 and SN3-L8
By compound S-SN-5 (130mg, be roughly equal to 0.49mmol) join in the twoport round-bottomed flask of 50mL, be spin-dried for solvent, solvent (3 hours) is drained again with vacuum pump, add stirrer, anti-chewing-gum plug seals one of them bottleneck, and another bottleneck connects biexhaust pipe, adds anhydrous CH with syringe needle 2cl 24mL, stirring and dissolving at-15 DEG C, is vacuumized by biexhaust pipe after dissolving, inflated with nitrogen, repeatedly replaces 4 times, adds anhydrous DIPEA (DIPEA, 0.13mL, 0.74mmol, d=0.74g/mL), stir 5 minutes.Get succinic chloride (0.03mL, 0.25mmol, d=1.4g/mL), be diluted in rapidly the anhydrous CH of 1.0mL 2cl 2in, take out with glass needle tubing immediately, repeatedly slowly join on a small quantity in twoport reaction flask and (within about 60 minutes, add), after adding, stirring is continued 30 minutes under-15 DEG C of conditions, under afterwards normal temperature condition being transferred in reaction, stirring reaction 4 ~ 6 hours, reaction solution look darker, in chocolate, stop and cancellation reaction, wash twice, CH respectively successively with saturated sodium bicarbonate aqueous solution and saturated aqueous common salt 2cl 2extraction, merges organic phase, and with anhydrous sodium sulfate drying 15 minutes, decompression was spin-dried for solvent, and silica column purification (chloroform: methyl alcohol=60:1 wash-out), obtains faint yellow solid compound S N3-L4 (90%).
SN3-L4：IR:2924,2850,1761,1644,1384cm -1；ESI-MS:m/z 635.2[M+H] +；HRESIMS:m/z635.3850[M+H] +,calc for C 36H 50N 4O 6＝635.3803； 1H-NMR(300MHz,CDCl 3)δ:5.63(s,2H),4.27～4.29(m,2H),3.22～3.40(m,4H),3.06～3.14(m,2H),2.79～2.99(m,9H),2.55～2.63(m,5H),2.43～2.48(m,2H),1.74～1.84(m,4H),1.50～1.61(m,4H),1.22～1.40(m,10H),0.87(t,J＝7.2Hz,6H)。
Under similarity condition, raw material succinic chloride is replaced as glutaryl chlorine, pimeloyl chloride, suberoyl chlorine, then obtains dimer compound SN3-L5, SN3-L7 and SN3-L8 respectively.
SN3-L5：IR:2926,2851,1752,1633,1384cm -1；ESI-MS:m/z 649.3[M+H] +；HRESIMS:m/z649.3956[M+H] +,calc for C 37H 52N 4O 6＝649.3959； 1H NMR(300MHz,CDCl 3)δ5.65(s,2H),4.25(d,J＝24.8Hz,2H),3.46(s,2H),3.17(d,J＝10.7Hz,4H),2.92(d,J＝30.2Hz,10H),2.53～2.46(m,2H),2.36(d,J＝7.3Hz,4H),1.89(d,J＝9.2Hz,4H),1.62(d,J＝19.5Hz,6H),1.30(d,J＝35.4Hz,10H),0.88(t,J＝7.1Hz,6H)。
SN3-L7：IR:2924,2846,1772,1655,909cm -1；ESI-MS:m/z 677.4[M+H] +；HRESIMS:m/z677.4310[M+H] +,calc for C 39H 56N 4O 6＝677.4272； 1H NMR(300MHz,CDCl 3)δ5.67(s,2H),4.28(d,J＝37.1Hz,2H),3.50(s,2H),3.16(d,J＝9.6Hz,4H),2.91(dd,J＝31.9,15.5Hz,10H),2.55～2.48(m,2H),2.27(t,J＝6.9Hz,4H),1.88(s,2H),1.63(d,J＝6.4Hz,12H),1.35(d,J＝6.9Hz,10H),0.89(t,J＝7.1Hz,6H)。
SN3-L8：IR:2925,2846,1771,1655,909cm -1；ESI-MS:m/z 691.8[M+H] +；HRESIMS:m/z691.4459[M+H] +,calc for C 40H 58N 4O 6＝691.4429； 1H NMR(300MHz,CDCl 3)δ5.57(s,2H),4.21(d,J＝5.6Hz,2H),3.38(s,2H),3.07(dt,J＝15.1,9.2Hz,4H),2.90～2.76(m,10H),2.40(dd,J＝10.8,5.7Hz,2H),2.21～2.10(m,4H),1.76(s,2H),1.51(d,J＝10.7Hz,12H),1.23(s,12H),0.79(t,J＝7.2Hz,6H)。
Embodiment 7:(S) preparation of-propionyl chloride Tri N-Propyl Amine base Securinine S-SN-8 and diastereomer R-SN-8 thereof
Joined in the twoport round-bottomed flask of 50mL by compound S-SN-5 (125mg is roughly equal to 0.47mmol), be spin-dried for solvent, then drain solvent (3 hours) with vacuum pump, add stirrer, anti-chewing-gum plug seals one of them bottleneck.Another bottleneck connects biexhaust pipe, adds anhydrous CH with syringe needle 2cl 24mL, stirring and dissolving at-15 DEG C, is vacuumized by biexhaust pipe after dissolving, inflated with nitrogen, repeatedly replaces 4 times, adds anhydrous DIPEA (DIPEA, 0.2mL, 1.19mmol, d=0.74g/mL), stir 5 minutes.Get positive propionyl chloride (0.06mL, 0.71mmol, d=1.06g/mL), be diluted in rapidly the anhydrous CH of 1.0mL 2cl 2in, take out with glass needle tubing immediately, a small amount of repeatedly slowly joining in twoport reaction flask (adds) for about 60 minutes, after adding, stirring is continued 30 minutes under-15 DEG C of conditions, under afterwards normal temperature condition being transferred in reaction, stirring reaction 4 ~ 6 hours, reaction solution look darker, in chocolate, stop and cancellation reaction, twice is washed respectively successively with saturated sodium bicarbonate aqueous solution and saturated aqueous common salt, CH2Cl2 extracts, merge organic phase, with anhydrous sodium sulfate drying 15 minutes, decompression is spin-dried for solvent, silica column purification (chloroform: methyl alcohol=60:1 wash-out), obtain weak yellow liquid compound S-SN-8 (91%).
S-SN-8：IR:2927,2862,1760,1635,909cm -1；ESI-MS:m/z 333.4[M+H] +；HRESIMS:m/z333.2198[M+H] +,calc for C 19H 28N 2O 3＝333.2172； 1H NMR(300MHz,CDCl 3)δ5.60(s,1H),4.24(s,1H),3.43(s,1H),3.10(dd,J＝16.4,7.1Hz,2H),2.84(dd,J＝20.9,14.0Hz,4H),2.48～2.39(m,1H),2.23(ddd,J＝9.3,6.8,3.0Hz,3H),1.78(s,1H),1.60(d,J＝11.1Hz,1H),1.51(d,J＝11.7Hz,2H),1.41～1.25(m,5H),1.08～1.01(m,5H),0.81(t,J＝6.3Hz,3H)。
Under similarity condition, raw material S-SN-5 is replaced as R-SN-5, obtains weak yellow liquid compound R-SN-8 (92%).
R-SN-8：IR:2941,2875,1765,1639,905cm -1；ESI-MS:m/z 333.6[M+H] +；HRESIMS:m/z333.2198[M+H] +,calc for C 19H 28N 2O 3＝333.2172； 1H NMR(300MHz,CDCl 3)δ5.67(s,1H),4.54～4.40(m,1H),3.52(dd,J＝18.6,7.9Hz,1H),3.36～3.20(m,2H),3.11(dd,J＝11.2,4.1Hz,1H),2.89(ddd,J＝21.2,13.8,8.0Hz,4H),2.70(dd,J＝11.1,6.5Hz,1H),1.86(s,1H),1.60(dd,J＝6.5,4.2Hz,2H),1.46(d,J＝12.5Hz,3H),1.39～1.32(m,2H),1.13(dd,J＝7.4,1.8Hz,6H),0.90(t,J＝7.3Hz,3H)。
Embodiment 8:(S, S)-1,9-the ninth of the ten Heavenly Stems dimercapto-bis--Securinines (SS-L9) preparation
Securinine (120mg is roughly equal to 0.55mmol) and anhydrous phosphoric acid potassium (35mg is roughly equal to 0.17mmol) are added round vase flask, adds 4mL CH 2cl 2with 1mL CH 3oH is stirred to dissolve, and after stirring 5 ~ 10min, 1,9-mercaptan in the ninth of the ten Heavenly Stems two (0.12mL is roughly equal to 0.33mmol, d=0.95g/mL) is dissolved in 1mL methyl alcohol and slowly adds system, room temperature for overnight; Stopped reaction being spin-dried for by system solvent afterwards, toward wherein adding CH 2cl 26 ~ 8mL, then uses saturated NaHCO successively 3solution and saturated nacl aqueous solution wash, and organic layer adds anhydrous Na 2sO 4drying, then in concetrated under reduced pressure, enriched material is with chloroform: methyl alcohol=30:1 is that silicagel column crossed by elutriant, obtains white foam solid SS-L9 (62.5mg, 36.3%).
SS-L9：IR:2926,2841,1745,1639,898cm -1；ESI-MS:m/z 627.4[M+H] +；HRESIMS:m/z627.3287[M+H] +,calc for C 35H 50N 2O 4S 2＝627.3285； 1H NMR(300MHz,CDCl 3)δ5.82(s,2H,H-12,12’),3.87～3.71(m,4H),3.70～3.55(m,2H),3.17～3.01(m,4H),2.76～2.55(m,6H),2.46～2.36(m,2H),2.04～1.82(m,8H),1.72～1.56(m,12H),1.41～1.23(m,10H)。
Under similarity condition, by raw material 1,9-mercaptan in the ninth of the ten Heavenly Stems two is replaced as two mercaptan (dithioglycol, dimercaptopropane, succinimide mercaptans, pentane disulfide thioalcohol, ethanthiol, pungent two mercaptan) of different carbon chain lengths, obtains solid chemical compound SS-L2, SS-L3, SS-L4, SS-L5, SS-L6 and SS-L8.
SS-L2：IR:2927,2854,1765,1619,899cm -1；ESI-MS:m/z 529.6[M+H] +；HRESIMS:m/z529.2174[M+H] +,calc for C 28H 36N 2O 4S 2＝529.2189； 1H NMR(300MHz,CDCl 3)δ:5.66(d,J＝1.8Hz,2H),3.31～3.34(m,2H),3.10～3.20(m,4H),2.90～2.97(m,6H),2.77～2.81(d,J＝14.7Hz,2H),2.52～2.65(m,6H),1.92(d,J＝10.8Hz,2H),1.82～1.88(m,2H),1.59～1.60(m,2H),1.33～1.48(m,8H)。
SS-L3：IR:2923,2844,1755,1637,898cm -1；ESI-MS:m/z 543.6[M+H] +；HRESIMS:m/z543.2336[M+H] +,calc for C 29H 38N 2O 4S 2＝543.2346； 1H NMR(300MHz,CDCl 3)δ:5.63(s,2H),3.29～3.31(m,2H),3.10～3.17(m,4H),2.91～2.92(m,6H),2.76(d,J＝14.7Hz,2H),2.56～2.62(m,4H),2.48～2.54(dd,J＝6.0,10.8Hz,2H),1.88(d,J＝10.8Hz,2H),1.77～1.86(m,4H),1.52～1.56(m,2H),1.92～1.45(m,8H)。
SS-L4：IR:2924,2844,1771,1639,899cm -1；ESI-MS:m/z 557.4[M+H] +；HRESIMS:m/z557.2505[M+H] +,calc for C 30H 40N 2O 4S 2＝557.2502； 1H NMR(300MHz,CDCl 3)δ5.64(d,2H,J＝1.8Hz),3.35～3.26(m,2H),3.20～3.07(m,4H),2.99～2.87(m,6H),2.82～2.72(m,2H),2.56～2.47(m,6H),1.93～1.79(m,4H),1.68～1.61(m,4H),1.60～1.27(m,10H)。
SS-L5：IR:2926,2841,1765,1619,898cm -1；ESI-MS:m/z 571.6[M+H] +；HRESIMS:m/z571.2656[M+H] +,calc for C 31H 42N 2O 4S 2＝571.2659； 1H NMR(300MHz,CDCl 3)δ5.61(s,2H),3.34～3.21(m,2H),3.17～3.04(m,4H),2.96～2.83(m,6H),2.80～2.68(m,2H),2.54～2.42(m,6H),1.91～1.75(m,4H),1.60～1.47(m,6H),1.47～1.26(m,10H)。
SS-L6：IR:2927,2845,1765,1645,898cm -1；ESI-MS:m/z 585.2[M+H] +；HRESIMS:m/z585.2805[M+H] +,calc for C 32H 44N 2O 4S 2＝585.2815； 1H NMR(300MHz,CDCl 3)δ:5.65(s,2H),3.31～3.33(m,2H),3.09～3.16(m,4H),2.92～2.95(m,6H),2.79(d,J＝15.0Hz,2H),2.49～2.56(m,6H),1.92(d,J＝11.1Hz),1.88～1.91(m,2H),1.31～1.58(m,18H)。
SS-L8：IR:2925,2844,1761,1639,899cm -1；ESI-MS:m/z 613.6[M+H] +；HRESIMS:m/z613.3138[M+H] +,calc for C 34H 48N 2O 4S 2＝613.3128； 1H NMR(300MHz,CDCl 3)δ:5.62(s,2H),3.29～3.31(m,2H),3.07～3.13(m,4H),2.89～2.92(m,6H),2.74～2.84(m,2H),2.46～2.53(m,6H),1.90(d,J＝10.8Hz,2H),1.84～1.86(m,2H’),1.21～1.57(m,24H)。
Embodiment 9: novel Suffrutescent Securinega Twig type alkaloid dimer compounds urgees screening and the analysis of Neural Differentiation activity
After Neuro-2a cell (being purchased from American type culture collection cell bank) recovery, cultivate with growth medium (penicillin of MEM+10%FBS+100U/mL and the Streptomycin sulphate of 100 μ g/mL), be planted in the culture dish of 100mm, put into 37 DEG C, cultivate containing the constant incubator of 5%CO2.Cell grows to 60 ~ 70% and goes down to posterity, and sucks the nutrient solution in culture dish, add appropriate PBS clean after with 0.25% tryptic digestion 45 seconds, be add growth medium after spherical shape to stop digesting until attached cell, mix and go down to posterity by 1:10, three days one biographies.Inducing nerve cell strain differentiation phase, cell seeding density is 2 × 10 4individual/35mm culture dish or 1 × 10 4individual/hole (12 orifice plate), be changed to division culture medium (penicillin of MEM+0.5%FBS+100U/mL and the Streptomycin sulphate of 100 μ g/mL) after cultivating 24 hours with growth medium, and add Suffrutescent Securinega Twig type alkaloid compound process 48 hours.The differentiation form of neurocyte strain and nervous process are observed by the method for immunofluorescence dyeing, and concrete steps are as follows:
1) use PBS (containing Ca 2+/ Mg 2+) wash cell 1 time after, add 800 μ L 4% paraformaldehyde/4% sucrose, room temperature fixes 20 ~ 30 minutes;
2) wash 3 times with PBS, add confining liquid (PBS of the bovine serum albumin containing 1%, the sheep blood serum albumin of 4% and the Triton X-100 of 0.4%) and close 20 minutes;
3) confining liquid is discarded, add the primary antibodie diluent (PBS of the bovine serum albumin containing 1%, the sheep blood serum albumin of 1% and the Triton X-100 of 0.4%) containing β-tubulin III antibody (1:2000), incubated at room 1 hour or 4 DEG C of overnight incubation;
4) 3 times are washed with PBS, add the diluent PBS of Triton X-100 of 0.4% (bovine serum albumin containing 1% and) containing fluorescence two anti-Alexa Fluor-546goat anti-mouse IgG antibody (1:4000), incubated at room 1 hour;
5) last, then after washing 3 times with PBS, can take pictures.
Adopt high intension instrument to carry out autoscan to take pictures, and utilize Cellomics view software to carry out statistical study.The cell that definition nervous process length is greater than twice cell space is neurocyte, and carries out statistical study.The parameter of main Measurement and analysis has three: 1) cytodifferentiation rate; 2) mean length of total nervous process of each noble cells; 3) mean length of the longest nervous process of each noble cells.The results are shown in Table 1.
Table 1 has the representation compound result of Neural Differentiation activity
The data of experimental result represent with mean ± S.E.M (standard error of the mean), and the method utilizing ANOVA to check carries out statistical procedures, * P<0.05, * * P<0.01, * * * P<0.001.
Embodiment 10:LDH measures the cytotoxicity of novel Suffrutescent Securinega Twig type alkaloid dimer compounds
The cultural method of Neuro-2a cell is see embodiment 9.To take the logarithm phase grown cell, by 5 × 10 3the density in individual/hole is inoculated in 96 orifice plates, every hole 100 μ L cell suspension.If blank group, the sample sets of control group and different concns, add different concns medicine after plate overnight, often group establishes 4 parallel multiple holes.Cultivate after 24 hours, every hole is got 50 μ L cell culture mediums and is transferred to 96 new orifice plates, adds 50 μ L LDH reaction substrates, and after mixing, lucifuge reacts 20 minutes, adds terminator and makes reaction terminating (Roche LDH detection kit).Use U.S. uncle to rise the multi-functional microplate reader of SynergyHT and detect light absorption value at 490nm wavelength place, result as shown in Figure 2.
As can be seen from Figure 2, the present invention's novel Suffrutescent Securinega Twig type alkaloid dimer class representative compound (10 ~ 60 μMs) does not have significantly increasing action the release of LDH, and these compounds no cytotoxicity when 60 μMs or following concentration is described.
Embodiment 11: compound S N3-L6, RS-SN3-L6 and SN3-L7 urge the dose study of neurocyte strain differentiation activity
Take the concentration of 5 μMs, 15 μMs and 25 μMs to carry out short Neural Differentiation determination of activity respectively for compound S N3-L6, RS-SN3-L6 and SN3-L7, experimental technique is identical with described in embodiment 9, and result as shown in Figure 3.As can be seen from Figure 3, SN3-L6, RS-SN3-L6 and SN3-L73 compound all reaches best promotion Neural Differentiation and the activity of neurite-outgrowth 15 μMs time.Though can not promote more multicellular differentiated when 5 μMs, can promote that nervous process length increases.
Embodiment 12: compound S N3-L6 can activate CaMKII, ERK and Akt path
The cultural method of Neuro-2a cell is see embodiment 9.Cell is after SN3-L5 (5 μMs or 30 μMs) or SN3-L6 (15 μMs) processes 5 ~ 120 minutes, wash once with the DPBS of precooling on ice, add RIPA lysate (containing proteinase inhibitor), with cell spatula collecting cell and cracking; Collect supernatant cell pyrolysis liquid with 12000rpm after centrifugal 10 minutes at 4 DEG C, measure protein concentration with Bio-Rad protein assay reagents.Albumen loading 20 μ g/ hole, carries out SDS-PAGE electrophoretic separation, after by protein delivery to pvdf membrane.Close with 5% skim-milk, primary antibodie overnight incubation, then with the anti-incubated at room of horseradish peroxidase-labeled two 1 hour of against murine or anti-rabbit, finally use ECL detection system test strip, signal is exposed to X-mating plate, scans with scanner, result as shown in Figure 4.
The Western blot result of Fig. 4 shows, SN3-L5 have activated the phosphorylation of Akt and ERK albumen in 5 minutes, and its phosphorylation level is increased, and can sustained activation at least 2 hours.SN3-L6 have activated CaMKII respectively 15 minutes time, Akt and ERK albumen, its respective phosphorylation level is raised, and this kind of activation at least can continue 2 hours.
Embodiment 13: many signal paths participate in the short Neural Differentiation effect of mediates chemical compound SN3-L6 induction
First by the inhibitor pre-treatment 1 hour of various signal protein, then add SN3-L6 (25 μMs) co-processing 48 hours, the experimental technique detecting neurocyte strain differentiation is identical with described in embodiment 9.The concentration of inhibitor is respectively: LY294002,10 μMs; SB202190,10 μMs; SP600125,5 μMs; U0126,10 μMs; NSC23766,10 μMs; H89,0.5 μM; Chelerythrine chloride 0.5 μM; KN92,1 μM; KN93,1 μM.
Result as shown in Figure 5, as can be seen from FIG., the inhibitor NSC23766 of inhibitor SP600125 and Rac1 of inhibitor KN93, JNK of inhibitor U0126, CaMKII of inhibitor LY290042, MEK of PI3K significantly suppress short Neural Differentiation and the neurite outgrowth of SN3-L6 induction, points out these signal transduction pathways to have vital role in SN3-L6 activity.
Embodiment 14: the compound S N3-L6 damage beta induced to A has provide protection
Amyloid beta (β-Amyloid 1-42 is called for short A β 1-42), is the polypeptide of the aminoacid sequence design and synthesis according to the toxicant amyloid beta in alzheimer's disease people brain, is purchased from rPeptide biotech company.With the ammonia solvent of 500 μ l 1%, ultrasonic 1 minute, then the mother liquor adding that PBS is made into 100 μMs, divide after mixing and put-80 DEG C of preservations.Before use, get as required appropriate volume put 37 DEG C aging 20 hours.Si Pula-the Dao getting 18 days embryonic stages carrys out the hippocampal tissue of (Sprague Dawley) rat fetus, with obtaining single separation neurone after trysinization, plant and wrap on the 18mm slide of quilt in poly-lysine (Poly-D-Lysine), density is 2 × 10 5/ slide, is placed in the Neurobasal substratum that with the addition of 2%B27 and cultivates.Within every three days, change a not good liquor (adding the Neurobasal substratum of 2%B27), partly change at every turn.Add A β 1-42 (1 μM) process 48 hours at the 7th day, add DMSO or SN3-L6 (25 μMs) simultaneously.Neurone is fixed with 4% paraformaldehyde, and with original position ruddiness cell apoptosis detection kit (In Situ Cell Death Detection kit, TMR Red, Roche company) neurone of apoptosis is dyeed, use DAPI (1:4000) transfect cell core simultaneously.With the shooting of Zeiss Imager A2 fluorescent microscope after mounting, calculate the percentage (namely ruddiness cell accounts for the per-cent of DAPI number) of apoptotic cell.
Statistics as shown in Figure 6; Fig. 6 shows; the normal neurons of only ~ 9.9% is in apoptotic state; after A β process apoptosis rate rise to ~ 18.1%; and the apoptosis rate of SN3-L6 and A β 1-42 co-processing obviously reduces (~ 3.4%), the SN3-L6 hippocampal neurons injury beta induced to A is pointed out to have provide protection.
Embodiment 15: compound S N3-L6 can promote that dendritic spine quantity increases
The preparation method of the hippocampal neuron of isolated culture is identical with described in embodiment 14, and density is 1 × 10 5/ slide, changes a not good liquor (adding the Neurobasal substratum of 2%B27) for every three days, partly changes at every turn.Within 10th day, adopt calcium phosphate procedure transfection green fluorescent protein (GFP) in vitro culture, when the 14th day, add DMSO or SN3-L6 (25 μMs).Process after 48 hours, fix with 4% paraformaldehyde, with Zeiss Imager A2 fluorescent microscope shooting GFP neurone (3 independent experiments after mounting, each 15 neurones), with Image-Pro Plus software, statistical study is carried out to dendritic spine, obtain the dendritic spine quantity in unit dendron length.As shown in Figure 7, Fig. 7 shows result, and SN3-L6 can promote that dendritic spine quantity increases.
Embodiment 16: compound S N3-L6 can promote the PSD-95 bunch of increase collecting quantity
The preparation method of the hippocampal neuron of isolated culture is identical with described in embodiment 14, and density is 0.2 × 10 5/ slide, changes a not good liquor (adding the Neurobasal substratum of 2%B27) for every three days, partly changes at every turn.DMSO or SN3-L6 (25 μMs) is added when cultivation the 14th day.Process after 48 hours, first fix 5 minutes with 4% paraformaldehyde, then fix 15 minutes with the methyl alcohol of precooling on ice.Carry out fluorescence immunization coloration afterwards, primary antibodie PSD95 (1:300) 4 DEG C spends the night, and then hatches two anti-Mouse 488 (1:300) 2 hours.Take pictures with Zeiss Imager A2 fluorescent microscope.As shown in Figure 8, Fig. 8 shows result, and SN3-L6 promotes the increase of PSD-95 bunch of collection quantity.
Embodiment 17: compound S N3-L6 controllable albumen synthesizes
Albumen synthesis number puromycin (tetracycline) marking method can be used to measure.Puromycin has the structure similar with tRNA molecular end, can combine with amino acid, replaces the tRNA of aminoacylation to combine with ribosomal A site, and is incorporated in the peptide chain of growth.Although puromycin can combine with A site, any reaction subsequently can not be participated in, thus cause the termination of protein synthesis and discharge the jejune polypeptide that C-end contains Puromycin.OPP (O-propargyl-puromycin) is the oxo propargyl modifier of puromycin, the same with puromycin, also can mix in newborn peptide chain, the albumen of the new synthesis of mark.
The present embodiment respectively in the hippocampal neuron of Neuro-2a cell and isolated culture (cultural method is see embodiment 9 and embodiment 14) measure compound S N3-L6 whether modulin synthesis by the method that puromycin marks.Cell is through DMSO, SN3-L6 (25 μMs), protein synthesis inhibitor cycloheximide (CHX; 50 μMs) or anisomycin (AS; 2 μMs) process 2 hours after, use The plus OPP Alexa 488Protein Synthesis Assay test kit (Life Technologies) is by the OPP with green fluorescence on the protein labeling that newly synthesizes, with Zeiss Imager A2 fluorescent microscope shooting cell (3 independent experiments, each bat 15) after mounting.With ImageJ software, statistical study is carried out to the fluorescence intensity often opening photo, often organized the average optical of cell OPP.Result shows, and SN3-L6 promotes that nascent protein is expressed and increases (optical density(OD) of OPP increases), and protein synthesis inhibitor CHX and AS suppresses nascent protein to be expressed, and (optical density(OD) of OPP reduces; Fig. 9 A – D).
In another approach, Neuro-2a cell after 1 ~ 24 hour, adds puromycin (1 μM) process 30 minutes mark nascent protein through SN3-L6 (25 μMs) or CHX (25 μMs) process.Then, with RIPA lysate (containing proteinase inhibitor) collecting cell crack protein, Western blot experiment is carried out subsequently, the protein content marked with the antibody test puromycin of puromycin.Result shows, and SN3-L6 all increased puromycin mark nascent protein at 1,2,4 and 24 hour is expressed, and this effect significantly can be suppressed by protein synthesis inhibitor CHX (Fig. 9 E, F).
Embodiment 18: compound S N3-L6 is by promoting that albumen synthesis promotes that dendritic spine increases
The preparation method of the hippocampal neuron of isolated culture is identical with described in embodiment 14, and density is 1 × 10 5/ slide, changes a not good liquor (adding the Neurobasal substratum of 2%B27) for every three days, partly changes at every turn.Within 10th day, adopt calcium phosphate procedure transfection green fluorescent protein (GFP) in vitro culture, when the 14th day, add DMSO, SN3-L6 (25 μMs), CHX (12.5 μMs)+SN3-L6 (25 μMs), AS (0.5 μM)+SN3-L6 (25 μMs) respectively.Process after 48 hours, fix with 4% paraformaldehyde, with Zeiss Imager A2 fluorescent microscope shooting GFP neurone (3 independent experiments after mounting, each 15 neurones), with Image-Pro Plus software, statistical study is carried out to dendritic spine, obtain the dendritic spine quantity in unit dendron length.As shown in Figure 10, Figure 10 shows result, and SN3-L6 promotes that this effect that dendritic spine quantity increases can be suppressed by protein synthesis inhibitor CHX and AS, illustrates that SN3-L6 synthesizes to regulate and control dendritic spine by stimulatory protein(SP) and formed.
Embodiment 19: compound S N3-L6 shorten mouse Morris water maze test in escape latent period
The main body of Morris water maze is a diameter 1.2 meters of ponds, and one of them region, pond is placed with a hiding platform under water, and the surrounding in pond arranges the mark can located for mouse.Mouse, through the training of continuous several days, finds reflect the ability of learning and memory of mouse for space the time needed for platform (namely escaping latent period).The escape of normal mouse greatly can be shortened latent period from the 3rd day, and represent the enhancing of learning and memory, result as shown in figure 11.From Figure 11, we find, continuous three weeks abdominal injection SN3-L6 (50mg/kg) mouse find platform quickly, illustrates that SN3-L6 has the activity of promotion Spatial memory ability.
The data of the experimental result in above-described embodiment 10 – 19 represent with mean ± S.E.M, and carry out statistical procedures by the method that ANOVA inspection and Student ' s-t are checked, statistical significance is had as P<0.05, * P<0.05, * P<0.01, * * * P<0.001.
Above-described embodiment is the present invention's preferably embodiment; but embodiments of the present invention are not restricted to the described embodiments; change, the modification done under other any does not deviate from spirit of the present invention and principle, substitute, combine, simplify; all should be the substitute mode of equivalence, be included within protection scope of the present invention.

Claims (13)

1. Suffrutescent Securinega Twig type alkaloid dimer compounds or its pharmacologically acceptable salt, is characterized in that, has such as formula the chemical structure shown in (1):
In formula: X is or one in S, wherein r group be CH 3, C 2h 5, n-C 3h 7, n-C 4h 9, n-C 5h 11or one in H; M is one in 0,1,2,3,4,5,6,7,8 or 9; N is one in 0 or 1; Numeral 1,2,3,4,5,6,7 and 8 in formula indicates chiral centre position, and the configuration of this position is the one in R or S configuration.
2. Suffrutescent Securinega Twig type alkaloid dimer compounds according to claim 1 or its pharmacologically acceptable salt, is characterized in that, its form is optical siomerism mixture or optical purity monomer.
3. the preparation method of Suffrutescent Securinega Twig type alkaloid dimer compounds according to claim 1 or its pharmacologically acceptable salt, it is characterized in that, comprise the following steps: left-handed Securinine and TMSA react by (1), obtain compound S-SN-1 and R-SN-1; (2) compound S-SN-1 and R-SN-1 is reacted with hydrogen respectively, obtain compound S-SN-2 and R-SN-2 respectively; (3) compound S-SN-2 and R-SN-2 is reacted with the diacid chloride of different carbon chain lengths respectively, obtain Securinine dimer compounds SN0-L2, SN0-L3, SN0-L4, SN0-L5 and SN0-L6 respectively;
Wherein, left-handed Securinine structural formula is:
Compound S-SN-1 structural formula is:
Compound R-SN-1 structural formula is:
Compound S-SN-2 structural formula is:
Compound R-SN-2 structural formula is:
Compound S N0-L2 structural formula is:
Compound S N0-L3 structural formula is:
Compound S N0-L4 structural formula is:
Compound S N0-L5 structural formula is:
Compound S N0-L6 structural formula is:
4. the preparation method of Suffrutescent Securinega Twig type alkaloid dimer compounds according to claim 3 or its pharmacologically acceptable salt, is characterized in that, the diacid chloride of described different carbon chain lengths is oxalyl chloride, malonyl chloride, succinic chloride, glutaryl chlorine and Adipoyl Chloride.
5. the preparation method of Suffrutescent Securinega Twig type alkaloid dimer compounds according to claim 3 or its pharmacologically acceptable salt, it is characterized in that, described preparation method's concrete steps are: (1) take methylene dichloride as solvent, be 1:(5-8 by mol ratio) left-handed Securinine and TMSA under the DBU catalysis of acetic acid and catalytic amount, react 7-10 hour under normal temperature, the mol ratio of left-handed Securinine and acetic acid is 1:(5-8); After stopped reaction, ammonium chloride cancellation, washing, CH 2cl 2extraction, silicagel column separation and purification, obtains compound S-SN-1 and R-SN-1; (2) respectively 10% palladium-carbon catalyst of compound S-SN-1 and R-SN-1 and catalytic amount is joined CH 2cl 2in solvent, vacuumize, fill hydrogen, repeatedly replace 3-4 time, stirring at normal temperature reaction is after 3-5 hour, and filter, filtrate decompression is spin-dried for; Silicagel column separation and purification, obtains compound S-SN-2 and R-SN-2 respectively; (3) compound S-SN-2 decompression be spin-dried for, vacuum oil pump drains solvent, makes alkali, anhydrous CH at anhydrous DIPEA 2cl 2for under the condition of solvent ,-15 DEG C of low temperature respectively with the diacid chloride of different carbon chain lengths according to mol ratio 1.0:(0.5-0.6) react 4-6 hour after, NH 4cl cancellation, washes 2 times, CH successively respectively with saturated sodium bicarbonate and saturated aqueous common salt 2cl 2extraction, decompression is spin-dried for, silicagel column separation and purification, obtains Securinine dimer compounds SN0-L2, SN0-L3, SN0-L4, SN0-L5 and SN0-L6 respectively.
6. the preparation method of Suffrutescent Securinega Twig type alkaloid dimer compounds according to claim 1 or its pharmacologically acceptable salt, it is characterized in that, comprise the following steps: left-handed Securinine reacts with methylamine, ethamine, Tri N-Propyl Amine, n-Butyl Amine 99 and n-amylamine by (1) respectively, obtains compound S-SN-5, R-SN-5, S-SN-3, S-SN-4, S-SN-6 and S-SN-7 respectively; (2) by compound S-SN-5 and R-SN-5 mixing, then reacting with Adipoyl Chloride, then obtain the dimer compound of 3 diastereomers each other by the disposable separation of high performance liquid phase, is SN3-L6, RS-SN3-L6 and RR-SN3-L6 respectively; (3) compound S-SN-5 is reacted with succinic chloride, glutaryl chlorine, pimeloyl chloride and suberoyl chlorine respectively, obtain dimer compound SN3-L4, SN3-L5, SN3-L7 and SN3-L8 respectively; (4) compound S-SN-3, S-SN-4, S-SN-6 and S-SN-7 are reacted with Adipoyl Chloride respectively, obtain dimer compound SN1-L6, SN2-L6, SN4-L6 and SN5-L6 respectively; (5) compound S-SN-5 and R-SN-5 is reacted with propionyl chloride respectively, obtain compound S-SN-8 and R-SN-8 respectively;
Wherein, left-handed Securinine structural formula is:
Compound S-SN-5 structural formula is:
Compound R-SN-5 structural formula is:
Compound S-SN-3 structural formula is:
Compound S-SN-4 structural formula is:
Compound S-SN-6 structural formula is:
Compound S-SN-7 structural formula is:
Compound S N3-L6 structural formula is:
Compound RS-SN3-L6 structural formula is:
Compound R R-SN3-L6 structural formula is:
Compound S N3-L4 structural formula is:
Compound S N3-L5 structural formula is:
Compound S N3-L7 structural formula is:
Compound S N3-L8 structural formula is:
Compound S N1-L6 structural formula is:
Compound S N2-L6 structural formula is:
Compound S N4-L6 structural formula is:
Compound S N5-L6 structural formula is:
Compound S-SN-8 structural formula is:
Compound R-SN-8 structural formula is:
7. the preparation method of Suffrutescent Securinega Twig type alkaloid dimer compounds according to claim 6 or its pharmacologically acceptable salt, it is characterized in that, described preparation method's concrete steps are: (1) by left-handed Securinine respectively with methylamine, ethamine, Tri N-Propyl Amine, n-Butyl Amine 99 and n-amylamine according to mol ratio 1:(5-10) under the condition of potassiumphosphate catalysis, react 12-18 hour, the mol ratio of left-handed Securinine and potassiumphosphate is 1.0:(0.05-0.1), NH 4cl cancellation, washing, CH 2cl 2extraction, silicagel column separation and purification, obtains compound S-SN-5, R-SN-5, S-SN-3, S-SN-4, S-SN-6 and S-SN-7 respectively; (2) by compound S-SN-5 and R-SN-5 mixing, then mixture is made alkali, anhydrous CH at anhydrous DIPEA 2cl 2for under the condition of solvent ,-15 DEG C of low temperature with Adipoyl Chloride according to mol ratio 1.0:(0.5-0.6) carry out reaction 4-6 hour after, NH 4cl cancellation, washes 2 times, CH successively respectively with saturated sodium bicarbonate and saturated aqueous common salt 2cl 2extraction, decompression is spin-dried for, silicagel column separation and purification, then obtains the dimer compound of 3 diastereomers each other by the disposable separation of high performance liquid phase, is SN3-L6, RS-SN3-L6 and RR-SN3-L6 respectively; (3) compound S-SN-5 is made alkali, anhydrous CH at anhydrous DIPEA 2cl 2under condition for solvent ,-15 DEG C of low temperature, respectively with succinic chloride, glutaryl chlorine, pimeloyl chloride and suberoyl chlorine according to mol ratio 1.0:(0.5-0.6) carry out reaction 4-6 hour after, NH 4cl cancellation, washes 2 times, CH successively respectively with saturated sodium bicarbonate and saturated aqueous common salt 2cl 2extraction, decompression is spin-dried for, silicagel column separation and purification, obtains dimer compound SN3-L4, SN3-L5, SN3-L7 and SN3-L8 respectively; (4) the same step of operational condition (3), by compound S-SN-3, S-SN-4, S-SN-6 and S-SN-7 respectively with Adipoyl Chloride according to mol ratio 1.0:(0.5-0.6) react, obtain dimer compound SN1-L6, SN2-L6, SN4-L6 and SN5-L6 respectively; (5) the same step of operational condition (3), by compound S-SN-5 and R-SN-5 respectively with propionyl chloride according to mol ratio 1.0:(1.5-1.8) react, obtain compound S-SN-8 and R-SN-8 respectively.
8. the preparation method of Suffrutescent Securinega Twig type alkaloid dimer compounds according to claim 1 or its pharmacologically acceptable salt, it is characterized in that, comprise the following steps: dextrorotation Securinine and Tri N-Propyl Amine react by (1), obtain compound (+)-S-SN-5 and (+)-R-SN-5; (2) compound (+)-R-SN-5 is reacted with Adipoyl Chloride, obtain compound (+)-SN3-L6;
Wherein, dextrorotation Securinine structural formula is:
Compound (+)-S-SN-5 structural formula is:;
Compound (+)-R-SN-5 structural formula is:
Compound (+)-SN3-L6 structural formula is:
9. the preparation method of Suffrutescent Securinega Twig type alkaloid dimer compounds according to claim 8 or its pharmacologically acceptable salt, is characterized in that, described preparation method's concrete steps are: dextrorotation Securinine is dissolved in CH by (1) 2cl 2in, add K 3pO 4, add Tri N-Propyl Amine subsequently, stirring at room temperature reaction 12-18 hour, dextrorotation Securinine and K 3pO 4mol ratio be 1.0:(0.05-0.1), the mol ratio of dextrorotation Securinine and Tri N-Propyl Amine is 1.0:(5-10), NH 4cl cancellation, washing, CH 2cl 2extraction, silicagel column separation and purification, obtains compound (+)-S-SN-5 and (+)-R-SN-5; (2) compound (+)-R-SN-5 decompression is spin-dried for, and vacuum oil pump drains solvent, then makes alkali, anhydrous CH in anhydrous DIPEA catalysis 2cl 2solvent be under the condition of solvent ,-15 DEG C of low temperature and Adipoyl Chloride according to mol ratio 1.0:(0.5-0.6) react 4-6 hour after, NH 4cl cancellation, washes 2 times, CH successively respectively with saturated sodium bicarbonate and saturated aqueous common salt 2cl 2extraction, decompression is spin-dried for, silicagel column separation and purification, obtains compound (+)-SN3-L6.
10. the preparation method of Suffrutescent Securinega Twig type alkaloid dimer compounds according to claim 1 or its pharmacologically acceptable salt, it is characterized in that, comprise the following steps: by left-handed Securinine respectively with two different thiol reactants, obtain compound S S-L2, SS-L3, SS-L4, SS-L5, SS-L6, SS-L8 and SS-L9 respectively;
Wherein, left-handed Securinine structural formula is:
Compound S S-L2 structural formula is:
Compound S S-L3 structural formula is:
Compound S S-L4 structural formula is:
Compound S S-L5 structural formula is:
Compound S S-L6 structural formula is:
Compound S S-L8 structural formula is:
Compound S S-L9 structural formula is:
The preparation method of 11. Suffrutescent Securinega Twig type alkaloid dimer compounds according to claim 10 or its pharmacologically acceptable salt, it is characterized in that, described two different mercaptan be dithioglycol, dimercaptopropane, succinimide mercaptans, pentane disulfide thioalcohol, ethanthiol, pungent two mercaptan and the ninth of the ten Heavenly Stems two mercaptan.
The preparation method of 12. Suffrutescent Securinega Twig type alkaloid dimer compounds according to claim 10 or its pharmacologically acceptable salt, is characterized in that, described preparation method's concrete steps are: be 1.0:(0.2-0.5 by mol ratio) left-handed Securinine and K 3pO 4be dissolved in the CH that volume ratio is 4:1 2cl 2and CH 3in the mixed solvent of OH, stir, two different mercaptan are dissolved in the addition of C H respectively 3oH, and slowly add in reaction system, room temperature for overnight, the mol ratio of left-handed Securinine and two mercaptan is 1.0:(0.5-0.6 :); Reaction solvent is spin-dried for, washing, CH 2cl 2extraction, decompression is spin-dried for, silicagel column separation and purification, obtains compound S S-L2, SS-L3, SS-L4, SS-L5, SS-L6, SS-L8 and SS-L9 respectively.
13. Suffrutescent Securinega Twig type alkaloid dimer compounds according to claim 1 or its pharmacologically acceptable salt promote the medicine of Neural Differentiation and neurite-outgrowth in preparation, preparation promotes CaMKII, the medicine of Akt and ERK protein-active, prepare the neurovirulent medicine that antagonism amyloid beta causes, preparation promotes the medicine of dendritic spine formation and function, preparation promotes the medicine of protein synthesis, preparation treatment is by nervous process or nerve synapse heteroplasia or impaired caused cognitive disorder, nerve degenerative diseases, nerve injury or emotionally disturbed symptom, and abnormal for the preparation for the treatment of neurodevelopment, nerve injury, application in the pharmaceutical composition of nerve degenerative diseases and learning memory disorder.
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