CN103965177B - A kind of anti-tumor activity natural product Herba Peperomiae pellucidae element E semisynthesis - Google Patents
A kind of anti-tumor activity natural product Herba Peperomiae pellucidae element E semisynthesis Download PDFInfo
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Abstract
A kind of anti-tumor activity natural product Herba Peperomiae pellucidae element E semisynthesis, relates to the semisynthesis of a kind of natural product Herba Peperomiae pellucidae element E (peperomin E) with anti-tumor activity first.Extract in Chinese medicine Herba Peperomiae Dindygulensis herb and obtain Herba Peperomiae pellucidae element A (peperomin A) for raw material, obtain Herba Peperomiae pellucidae element E through de-phenylseleno two step of phenylseleno nucleophilic displacement of fluorine and oxidation, obtain the purity Herba Peperomiae pellucidae element E fine work more than 99.0% then through silica gel column chromatography refinement.
Description
Technical field
The invention belongs to pharmaceutical synthesis field, relate to a kind of anti-tumor activity natural product Herba Peperomiae pellucidae element E semisynthesis.
Background technology
Herba Peperomiae pellucidae element E be from anti-tumor Chinese medicine Herba Peperomiae Dindygulensis (PeperomiadindygulensisWhat find in Miq.) containsα-methylene-γ-butyrolactone ring split Lignanoids compounds (JLWu, NLi, THasegawa,etal.BioactivesecolignansfromPeperomiadindygulensis.JournalofNaturalProducts, 2006,69:790-794), structural formula is as follows:
Research finds, splits Lignanoids compounds and is respectively provided with the effect suppressing tumor cell proliferation in various degree, wherein with Herba Peperomiae pellucidae element E containing for representativeα-methylene-γThe compound activity of-butyrolactone cyclic group is the strongest.External activity research shows, Herba Peperomiae pellucidae element E is to human lung cancer cell line WI-38, VA-13 and A549, human breast carcinoma cell lines MCF-7, Human cervical cancer cell lines HeLa, human acute myeloid leukaemia system HL-60 and human hepatoma cell line HepG2 have stronger cell inhibitory effect effect, IC50Value scope (JLWu, NLi, THasegawa, etal.Bioactivesecolignansfrom between 1.2-12.1 μMPeperomiadindygulensis.JournalofNaturalProducts,2006,69:790-794;SXu,NLi,MMNing,etal.BioactivecompoundsfromPepermiapellucida.JournalofNaturalProducts,2006,69,247-250；Xu Su. Herba Peperomiae pellucidae and hair watermelon begonia chemical composition and pharmacology activity research .2006, the outstanding master's thesis in Shanghai institute of materia medica of the Chinese Academy of Sciences: 49).With the exception of this, applicant place laboratory finds that SGC-7901 SGC-7901, human esophageal carcinoma cell line Eca-109, Bel7402 SMMC-7721 are also had stronger cell inhibitory effect activity, IC by Herba Peperomiae pellucidae element E50Value is between 1.5-9.2 μM；And to people stomach normal mucosa cell GES-1 and people normal cell lines of human liver L-02 without obvious cytotoxicity, point out it to there is selectivity between tumor cell and normal cell.By further research, we find that Herba Peperomiae pellucidae element E antineoplastic mechanism is relevant with its inducing apoptosis of tumour cell effect first, find that tumor cell mitochondrial membrane potential is gradually reduced along with the rising of its drug level, it was shown that Herba Peperomiae pellucidae element E inducing apoptosis of tumour cell is likely to relevant to mitochondria pathway simultaneously.In sum, Herba Peperomiae pellucidae element E activity is high, anticancer spectrum wide, without obvious in vitro toxicity, is expected to become the lead compound of a new generation's antitumor drug.
At present, Herba Peperomiae pellucidae element E obtains from Herba Peperomiae Dindygulensis medical material only by traditional separation means of purification, owing to this compound content in medical material is very low, the medical material in some place of production even can't detect, and isolation and purification method is complicated, relatively costly, product purity is poor, and this becomes the key factor restricting its further investigation, constrains the further medicinal study of this antitumor lead compound simultaneously.Therefore, want Herba Peperomiae pellucidae element E is further furtherd investigate, it is necessary to first expand the source of Herba Peperomiae pellucidae element E.Carrying out source problem in order to what solve Herba Peperomiae pellucidae element E, we attempt, with Herba Peperomiae pellucidae element A for raw material, to prepare Herba Peperomiae pellucidae element E by semi-synthesis method first.
Summary of the invention
Solve the technical problem that:For solving prior art problem, the invention provides a kind of anti-tumor activity natural product Herba Peperomiae pellucidae element E semisynthesis.
Technical scheme:A kind of anti-tumor activity natural product Herba Peperomiae pellucidae element E semisynthesis, comprises the following steps:
(1) with Herba Peperomiae pellucidae element A(I) for raw material; it is initially charged the triethylamine stirring of its 10-20 times of mole; add the trimethylsilyl triflate stirring of 10-20 times of mole; the chloroformic solution being eventually adding the phenylseleno chlorine containing 2-8 times of mole stirs; omnidistance temperature control is 0 DEG C, and reacts under nitrogen protection；Adding saturated ammonium chloride solution in above-mentioned reactant liquor, then be extracted with ethyl acetate, combining extraction liquid also reclaims ethyl acetate, extractum purification by silica gel column chromatography, and petroleum ether-ethyl acetate is eluent, obtains (3R, 4R)-2-phenylseleno Herba Peperomiae pellucidae element A(II) sterling；
(2) it is at 0 DEG C in temperature, dissolves (3 with oxolaneR, 4R)-2-phenylseleno Herba Peperomiae pellucidae element A(II) adding glacial acetic acid stirring afterwards, described glacial acetic acid is (3R, 4R)-2-phenylseleno Herba Peperomiae pellucidae element A(II) and 1.5-6 times of mole, add mass fraction be 30% hydrogenperoxide steam generator continue stirring, described 30% hydrogenperoxide steam generator is (3R, 4R)-2-phenylseleno Herba Peperomiae pellucidae element A(II) and 1.5-6 times of mole；Above-mentioned reactant liquor is moved to room temperature, add saturated nacl aqueous solution, it is extracted with ethyl acetate, combining extraction liquid, ethyl acetate is reclaimed with saturated sodium bicarbonate solution after washing again, extractum purification by silica gel column chromatography, petroleum ether-ethyl acetate is eluent, obtains high-purity product Herba Peperomiae pellucidae element E(III).
As preferably, triethylamine described in step (1), trimethylsilyl triflate, phenylseleno chlorine and raw material Herba Peperomiae pellucidae element A(I) mol ratio is (13-15): (11-12): (4-5): 1.
As preferably, the volume ratio of step (1) described eluent petroleum ether and ethyl acetate is 4:1.
As preferably, the glacial acetic acid described in step (2), 30% hydrogenperoxide steam generator and (3R, 4R)-2-phenylseleno Herba Peperomiae pellucidae element A(II) mol ratio is 3:(3-4): 1.
As preferably, the volume ratio of step (2) described eluent petroleum ether and ethyl acetate is 2:1.
Beneficial effect
The method of the semi-synthetic Herba Peperomiae pellucidae element E of the present invention is the Herba Peperomiae pellucidae element A(I of rich content in Herba Peperomiae Dindygulensis) for raw material, method is simple, mild condition, productivity is good, end-product purity reaches 99.0%, greatly expand the source of Herba Peperomiae pellucidae element E, provide solid foundation for the further antineoplastic agent exploitation of this compound.
Accompanying drawing explanation
Fig. 1 is the first step flow chart of a kind of anti-tumor activity natural product Herba Peperomiae pellucidae element E semisynthesis；
Fig. 2 is the second step flow chart of a kind of anti-tumor activity natural product Herba Peperomiae pellucidae element E semisynthesis.
Detailed description of the invention
The following examples can make those skilled in the art more fully understand the present invention, but does not limit the present invention in any way.
Embodiment 1
(3R, 4R) preparation of-2-phenylseleno Herba Peperomiae pellucidae element A (II)
By Herba Peperomiae pellucidae element A(I) (5g, 12mmol) it is dissolved in triethylamine (22.5mL, 162mmol), trifluoromethyl sulfonic acid trimethylsilyl ester (25mL, 138mmol) is added, after continuing 0 DEG C of stirring 40min after 0 DEG C of stirring 10min, add containing phenylseleno chlorine (9.5g, 50.0mmol) chloroformic solution (50mL), 0 DEG C of stirring reaction 30min, reaction is omnidistance at N2Carry out under gas shielded.After adding 500mL saturated ammonium chloride solution in reactant liquor, extracting 3 times by ethyl acetate (800mL), combining extraction liquid, reclaim ethyl acetate, silica gel column chromatography [200-300 order silica gel, petroleum ether-ethyl acetate (volume ratio 4:1)] is refined, and obtains (3R, 4R)-2-phenylseleno Herba Peperomiae pellucidae element A (II) (5.95g, productivity 87%): m.p.77-79oC；[α]20 D+ 50.1(c0.40, CHCl3);ESI-MSm/z593.0676[M+Na]+,1H-NMRδ H7.60(2H,m,m-PhSe),7.39(1H,m,p-PhSe),7.29(2H,m,o-PhSe),6.45(1H,brs,H-6’),6.53(1H,brs,H-2’),6.62(1H,brs,H-2”),6.68(1H,brs,H-6”),5.93-5.95(4H,m,-OCH2O-),4.13(1H,d,J=11.7Hz,H-5),4.02(1H,dd,J=9.6,7.5Hz),3.95(3H,s,-OCH3),3.92(3H,s,-OCH3),3.71(1H,dd,J=9.6,11.3Hz),3.06(1H,m,H-3),1.15(3H,s,H-6)；13C-NMRδ C176.4(C-1),149.5,149.2(C-3’,3”),143.7,143.4(C-5’,5”),135.9,135.8(C-4’,4”),108.9,107.8(C-6’,6”),102.0,101.2(C-2’,2”),101.5(-OCH2O-),124.6(PhSe),138.3(m-PhSe),129.9(p-PhSe),129.1(o-PhSe),68.7(C-4),57.0(-OCH3),52.3(C-5),52.1(C-3),50.9(C-2),23.6(C-6)。
Herba Peperomiae pellucidae element E(III) preparation
By (3R, 4R)-2-phenylseleno Herba Peperomiae pellucidae element A (II) (4g, 7.2mmol) it is dissolved in oxolane (72mL), adds glacial acetic acid (1.2mL, 21.2mmol), the hydrogenperoxide steam generator (3mL, 23.2mmol) adding 30% after 0 DEG C of stirring 10min continues 0 DEG C of stirring reaction 40min.After reactant liquor adds saturated nacl aqueous solution (400mL), ethyl acetate (640mL) extracts 3 times, combining extraction liquid, ethyl acetate is reclaimed with appropriate saturated sodium bicarbonate solution (1000mL) after washing twice, silica gel column chromatography [200-300 order silica gel, petroleum ether-ethyl acetate (volume ratio 2:1)] is refined, and obtains Herba Peperomiae pellucidae element E(2.76g, productivity 93%), product purity is 99%:ESI-MSm/z435.1041[M+Na]+;1H-NMRδ H6.456,6.442(s, H-6 ', 6 ", 2H), 6.38,6.37 (s, H-2 ', 2 ", 2H), 6.15 (d, H-6a, J=1.8Hz, 1H), 5.93 (s, 4H ,-OCH2O-),4.94(d,H-6b,J=1.5Hz,1H),4.32(dd,H-4a,J=7.5,9.3Hz,1H),3.94(dd,H-4b,J=4.2,9.3Hz,1H),3.89(3H,s,-OCH3),3.90(3H,s,-OCH3),3.74(m,H-3,1H).13C-NMRδ C170.4(C-1),135.9(C-2),124.7(C-6),134.4,134.3(C-1,1”),149.4,149.6(C-3’,3”),143.7,143.5(C-5’,5”),136.1,136.2(C-4’,4”),108.2,108.4(C-6’,6”),101.7,101.2(C-2’,2”),101.5(-OCH2O-),42.5(C-3),55.3(C-5),56.9,57.0(-OCH3),69.7(C-4)。
Embodiment 2
(3R, 4R) preparation of-2-phenylseleno Herba Peperomiae pellucidae element A (II)
By Herba Peperomiae pellucidae element A(I) (15g, 36mmol) it is dissolved in triethylamine (70mL, 0.50mol), trifluoromethyl sulfonic acid trimethylsilyl ester (80mL, 0.44mol) is added, after continuing 0 DEG C of stirring 40min after 0 DEG C of stirring 10min, add containing phenylseleno chlorine (30g, chloroformic solution (150mL) 0.16mol), 0 DEG C of stirring reaction 30min, reaction is omnidistance at N2Carry out under gas shielded.After adding 1000mL saturated ammonium chloride solution in reactant liquor, extracting 3 times by ethyl acetate (1.5L), combining extraction liquid, reclaim ethyl acetate, silica gel column chromatography [200-300 order silica gel, petroleum ether-ethyl acetate (volume ratio 4:1)] is refined, and obtains (3R, 4R)-2-phenylseleno Herba Peperomiae pellucidae element A (II) (16.9g, productivity 82.4%).
Herba Peperomiae pellucidae element E(III) preparation
By (3R, 4R)-2-phenylseleno Herba Peperomiae pellucidae element A (II) (10g, 18mmol) it is dissolved in oxolane (180mL), adds glacial acetic acid (3mL, 53mmol), the hydrogenperoxide steam generator (7.5mL, 58mmol) adding 30% after 0 DEG C of stirring 10min continues 0 DEG C of stirring reaction 40min.After reactant liquor adds saturated nacl aqueous solution (800mL), ethyl acetate (1.5L) extracts 3 times, combining extraction liquid, ethyl acetate is reclaimed with appropriate saturated sodium bicarbonate solution (2L) after washing twice, silica gel column chromatography [200-300 order silica gel, petroleum ether-ethyl acetate (volume ratio 2:1)] is refined, and obtains Herba Peperomiae pellucidae element E(6.8g, productivity 91.7%), product purity is 99%.
Embodiment 3
(3R, 4R) preparation of-2-phenylseleno Herba Peperomiae pellucidae element A (II)
By Herba Peperomiae pellucidae element A(I) (200g, 0.48mol) it is dissolved in triethylamine (1000mL, 7.2mol), trifluoromethyl sulfonic acid trimethylsilyl ester (1000mL, 5.5mol) is added, after continuing 0 DEG C of stirring 40min after 0 DEG C of stirring 20min, add containing phenylseleno chlorine (400g, chloroformic solution (1000mL) 2.08mol), 0 DEG C of stirring reaction 40min, reaction is omnidistance at N2Carry out under gas shielded.After adding 8L saturated ammonium chloride solution in reactant liquor, extracting 3 times by ethyl acetate (10L), combining extraction liquid, reclaim ethyl acetate, silica gel column chromatography [200-300 order silica gel, petroleum ether-ethyl acetate (volume ratio 4:1)] is refined, and obtains (3R, 4R)-2-phenylseleno Herba Peperomiae pellucidae element A (II) (219.2g, productivity 80.1%).
Herba Peperomiae pellucidae element E(III) preparation
By (3R, 4R)-2-phenylseleno Herba Peperomiae pellucidae element A (II) (100g, 0.18mol) it is dissolved in oxolane (1000mL), adds glacial acetic acid (30mL, 0.53mol), the hydrogenperoxide steam generator (80mL, 0.62mol) adding 30% after 0 DEG C of stirring 30min continues 0 DEG C of stirring reaction 60min.After reactant liquor adds saturated nacl aqueous solution (5L), ethyl acetate (8L) extracts 3 times, combining extraction liquid, ethyl acetate is reclaimed with appropriate saturated sodium bicarbonate solution (10L) after washing twice, silica gel column chromatography [200-300 order silica gel, petroleum ether-ethyl acetate (volume ratio 2:1)] is refined, and obtains Herba Peperomiae pellucidae element E(66.5g, productivity 89.7%), product purity 99%.
Claims (5)
1. an anti-tumor activity natural product Herba Peperomiae pellucidae element E semisynthesis, it is characterised in that comprise the following steps:
(1) with Herba Peperomiae pellucidae element A(I) for raw material; it is initially charged the triethylamine stirring of its 10-20 times of mole; add the trimethylsilyl triflate stirring of 10-20 times of mole; the chloroformic solution being eventually adding the phenylseleno chlorine containing 2-8 times of mole stirs; omnidistance temperature control is 0 DEG C, and reacts under nitrogen protection；Adding saturated ammonium chloride solution in above-mentioned reactant liquor, then be extracted with ethyl acetate, combining extraction liquid also reclaims ethyl acetate, extractum purification by silica gel column chromatography, and petroleum ether-ethyl acetate is eluent, obtains (3R, 4R)-2-phenylseleno Herba Peperomiae pellucidae element A(II) sterling；
(2) it is at 0 DEG C in temperature, dissolves (3 with oxolaneR, 4R)-2-phenylseleno Herba Peperomiae pellucidae element A(II) adding glacial acetic acid stirring afterwards, described glacial acetic acid is (3R, 4R)-2-phenylseleno Herba Peperomiae pellucidae element A(II) and 1.5-6 times of mole, add mass fraction be 30% hydrogenperoxide steam generator continue stirring, described 30% hydrogenperoxide steam generator is (3R, 4R)-2-phenylseleno Herba Peperomiae pellucidae element A(II) and 1.5-6 times of mole；Above-mentioned reactant liquor is moved to room temperature, add saturated nacl aqueous solution, it is extracted with ethyl acetate, combining extraction liquid, ethyl acetate is reclaimed with saturated sodium bicarbonate solution after washing again, extractum purification by silica gel column chromatography, petroleum ether-ethyl acetate is eluent, obtains high-purity product Herba Peperomiae pellucidae element E(III).
2. a kind of anti-tumor activity natural product Herba Peperomiae pellucidae element E semisynthesis according to claim 1, it is characterised in that: triethylamine described in step (1), trimethylsilyl triflate, phenylseleno chlorine and raw material Herba Peperomiae pellucidae element A(I) preferred molar ratio is (13-15): (11-12): (4-5): 1.
3. a kind of anti-tumor activity natural product Herba Peperomiae pellucidae element E semisynthesis according to claim 1, it is characterised in that: the volume ratio of step (1) described eluent petroleum ether and ethyl acetate is 4:1.
4. a kind of anti-tumor activity natural product Herba Peperomiae pellucidae element E semisynthesis according to claim 1, it is characterised in that: the glacial acetic acid described in step (2), 30% hydrogenperoxide steam generator and (3R, 4R)-2-phenylseleno Herba Peperomiae pellucidae element A(II) preferred molar ratio is 3:(3-4): 1.
5. a kind of anti-tumor activity natural product Herba Peperomiae pellucidae element E semisynthesis according to claim 1, it is characterised in that: the volume ratio of step (2) described eluent petroleum ether and ethyl acetate is 2:1.
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| CN107595773A (en) * | 2017-10-09 | 2018-01-19 | 南京图艾生物医药科技有限公司 | Herba Peperomiae pellucidae element E sub-micellar emulsions used for intravenous injection and its application |
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| CN107266431A (en) * | 2017-07-13 | 2017-10-20 | 南京中医药大学 | Herba Peperomiae pellucidae element E or derivatives thereof and application thereof |
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| US5981577A (en) * | 1998-06-18 | 1999-11-09 | Development Center For Biotechnology | α-methylene peperomins and halogenated derivatives thereof |
| CN102204903A (en) * | 2011-04-18 | 2011-10-05 | 上海交通大学医学院 | Application of peperomin E and peperomin B compounds to medicament for suppressing angiogenesis |
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Patent Citations (2)
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| US5981577A (en) * | 1998-06-18 | 1999-11-09 | Development Center For Biotechnology | α-methylene peperomins and halogenated derivatives thereof |
| CN102204903A (en) * | 2011-04-18 | 2011-10-05 | 上海交通大学医学院 | Application of peperomin E and peperomin B compounds to medicament for suppressing angiogenesis |
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| CN107595773A (en) * | 2017-10-09 | 2018-01-19 | 南京图艾生物医药科技有限公司 | Herba Peperomiae pellucidae element E sub-micellar emulsions used for intravenous injection and its application |
| CN107595773B (en) * | 2017-10-09 | 2021-01-05 | 南京图艾生物医药科技有限公司 | Peperomin E submicron emulsion for intravenous injection and application thereof |
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