类黄酮AChE抑制剂的设计、合成和构效关系研究
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摘要
阿尔茨海默氏病(Alzheimer's disease,AD)又称早老性痴呆,是一种以进行性记忆和认知功能缺损为特征的神经退行性疾病,典型症状与脑内胆碱能功能缺陷有关,是造成老年人痴呆最常见的原因。临床治疗AD最为有效的药物是乙酰胆碱酯酶抑制剂(Acetylcholinesterase Inhibitor,AChEI)。但是,已上市药物仍存在许多不足,因此研制新型AChE抑制剂仍然是目前AD新药研发的热点。
在前期工作中,本课题组从AChE具有中心和外周两个活性结合位点的结构特性出发,分别保留多奈哌齐中的二甲氧基茚酮(与外周位点结合)和利伐司替明中的苄基叔胺(与中心位点结合)药效团,通过氧原子或碳原子进行连接,设计并合成了新型的茚酮类AChE抑制剂,绝大多数化合物都具有较强的AChE抑制活性。
基于前期工作基础,本文对茚酮部分进行了结构改造,以考察该部分结构对活性的影响。用苯并呋喃酮、苯并吡喃酮、苯并二氢吡喃酮以及开环的苯乙酮结构替代茚酮类衍生物中的茚酮结构部分,同时保留叔胺结构,设计合成了拥有类似结构的一系列新的类黄酮衍生物,分别为噢弄、二氢噢弄、查耳酮、黄酮、异黄酮和黄烷酮。这些化合物保留了能与AChE结合的4个主要的官能团,分别为苯环、酮羰基、苄基以及叔胺,而且分子的长度与茚酮类衍生物相近,预计它们能同时与AChE的中心和外周两个活性位点发生结合,不但能够显著抑制脑内乙酰胆碱的水解,提高ACh浓度,而且还能抑制由AChE引起的Aβ聚集,起到保护神经细胞的作用,达到更好治疗AD的效果。
经过文献调研,设计了原料易得、操作简便、收率较高的类黄酮衍生物的合成路线。共制备了目标化合物36个,其中噢弄、二氢噢弄、查耳酮、黄酮、黄烷酮和异黄酮衍生物各6个,均为新化合物。所有目标物的结构经~1HNMR、IR测试确证。
对合成的36个类黄酮目标物进行了体外乙酰胆碱酯酶(AChE)抑制活性测试,结果表明:绝大多数化合物都显示较强的AChE抑制活性,IC_(50)≤10~(-6)mol/L,其中3个化合物的IC_(50)达到4～5nmol/L,相对于多奈哌齐抑酶活性有所提高。它们是一类非常有前景的治疗AD的先导化合物。
根据目标物AChE抑制活性测定结果,对该类化合物进行了初步构效关系讨论,
Alzheimer's disease (AD), which is also called early aged dementia, is a neurodegenerative disorder characterized by a progressive impairment of cognitive function. AD is also one of the most common causes of mental deterioration in elderly people. Acetylcholinesterase (AChE) inhibitors are the first and the most developed group of drugs approved for AD symptomatic treatment. Unfortunately, all the drugs used in clinic showed insufficiency. So we are interested in searching for new AChE inhibitors,The crystallographic structure of AChE exhibits that it contains central site and peripheral site. In our prophase work, 5,6-dimethoxy-indan-l-one from donepezil (interacting with the peripheral site), dialkylbenzylamine from rivastigmine (interacting with the central site) were chosen as the two pharmacophoric moieties and linked with O, CH_2 and CH, thus, three series of indanone derivatives were synthesized and most of these derivatives exhibited high AChE inhibitory activity in vitro.On the basis of our prophase work, modification of the indan-1-one part of the indanone derivatives v/ere taken to investigate the contribution to the AChE inhibitory activity of this part. Benzofuran-3-one、 benzopyran-4-one、 benzodihydropyran-4-one and 2-hydroxyacetophenone were chosen to replace the indan-1-one of the indanone derivatives, thus, a series of new flavonoid derivatives were synthesized, containing aurones、 dihydroaurones、 chalcones、 flavones、 flavanones and isoflavones. All these derivatives maintain the four functional groups interacting with AChE, which are phenyl、 carbonyl、 benzyl and alkylamine. Therefore, they should be able to interact with both central and peripheral binding sites of AChE, through which they could prevent not only the hydrolysis of ACh, but also β-amyloid peptide deposition caused by AChE.Totally, thirty-six target compounds were prepared, containing aurone、 dihydroaurone、chalcone、flavone、flavanone and isoflavone derivatives each six, which are all new compounds. All the structures were confirmed by ~1HNMR and IR.Thirty-six flavonoid derivatives were tested for their AChE inhibitory activity in vitro. Most of these derivatives exhibited high AChE inhibitory activity, and the IC50 values of
three compounds were lower than that of Donepezil. Therefore, these compounds are very promising lead compounds for the treatment of AD.On the basis of AChE inhibitory activity of the target compounds, structure-activity relationships discussion was taken, which will give us some useful information in the design of new drugs.
在前期工作中,本课题组从AChE具有中心和外周两个活性结合位点的结构特性出发,分别保留多奈哌齐中的二甲氧基茚酮(与外周位点结合)和利伐司替明中的苄基叔胺(与中心位点结合)药效团,通过氧原子或碳原子进行连接,设计并合成了新型的茚酮类AChE抑制剂,绝大多数化合物都具有较强的AChE抑制活性。
基于前期工作基础,本文对茚酮部分进行了结构改造,以考察该部分结构对活性的影响。用苯并呋喃酮、苯并吡喃酮、苯并二氢吡喃酮以及开环的苯乙酮结构替代茚酮类衍生物中的茚酮结构部分,同时保留叔胺结构,设计合成了拥有类似结构的一系列新的类黄酮衍生物,分别为噢弄、二氢噢弄、查耳酮、黄酮、异黄酮和黄烷酮。这些化合物保留了能与AChE结合的4个主要的官能团,分别为苯环、酮羰基、苄基以及叔胺,而且分子的长度与茚酮类衍生物相近,预计它们能同时与AChE的中心和外周两个活性位点发生结合,不但能够显著抑制脑内乙酰胆碱的水解,提高ACh浓度,而且还能抑制由AChE引起的Aβ聚集,起到保护神经细胞的作用,达到更好治疗AD的效果。
经过文献调研,设计了原料易得、操作简便、收率较高的类黄酮衍生物的合成路线。共制备了目标化合物36个,其中噢弄、二氢噢弄、查耳酮、黄酮、黄烷酮和异黄酮衍生物各6个,均为新化合物。所有目标物的结构经~1HNMR、IR测试确证。
对合成的36个类黄酮目标物进行了体外乙酰胆碱酯酶(AChE)抑制活性测试,结果表明:绝大多数化合物都显示较强的AChE抑制活性,IC_(50)≤10~(-6)mol/L,其中3个化合物的IC_(50)达到4～5nmol/L,相对于多奈哌齐抑酶活性有所提高。它们是一类非常有前景的治疗AD的先导化合物。
根据目标物AChE抑制活性测定结果,对该类化合物进行了初步构效关系讨论,
Alzheimer's disease (AD), which is also called early aged dementia, is a neurodegenerative disorder characterized by a progressive impairment of cognitive function. AD is also one of the most common causes of mental deterioration in elderly people. Acetylcholinesterase (AChE) inhibitors are the first and the most developed group of drugs approved for AD symptomatic treatment. Unfortunately, all the drugs used in clinic showed insufficiency. So we are interested in searching for new AChE inhibitors,The crystallographic structure of AChE exhibits that it contains central site and peripheral site. In our prophase work, 5,6-dimethoxy-indan-l-one from donepezil (interacting with the peripheral site), dialkylbenzylamine from rivastigmine (interacting with the central site) were chosen as the two pharmacophoric moieties and linked with O, CH_2 and CH, thus, three series of indanone derivatives were synthesized and most of these derivatives exhibited high AChE inhibitory activity in vitro.On the basis of our prophase work, modification of the indan-1-one part of the indanone derivatives v/ere taken to investigate the contribution to the AChE inhibitory activity of this part. Benzofuran-3-one、 benzopyran-4-one、 benzodihydropyran-4-one and 2-hydroxyacetophenone were chosen to replace the indan-1-one of the indanone derivatives, thus, a series of new flavonoid derivatives were synthesized, containing aurones、 dihydroaurones、 chalcones、 flavones、 flavanones and isoflavones. All these derivatives maintain the four functional groups interacting with AChE, which are phenyl、 carbonyl、 benzyl and alkylamine. Therefore, they should be able to interact with both central and peripheral binding sites of AChE, through which they could prevent not only the hydrolysis of ACh, but also β-amyloid peptide deposition caused by AChE.Totally, thirty-six target compounds were prepared, containing aurone、 dihydroaurone、chalcone、flavone、flavanone and isoflavone derivatives each six, which are all new compounds. All the structures were confirmed by ~1HNMR and IR.Thirty-six flavonoid derivatives were tested for their AChE inhibitory activity in vitro. Most of these derivatives exhibited high AChE inhibitory activity, and the IC50 values of
three compounds were lower than that of Donepezil. Therefore, these compounds are very promising lead compounds for the treatment of AD.On the basis of AChE inhibitory activity of the target compounds, structure-activity relationships discussion was taken, which will give us some useful information in the design of new drugs.
引文
1. McGeer PL, McGeer EG. Alzheimer's disease: arthritis of the brain. Drugs News Prospect, 1995, 8(2): 80-83.
2. Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science, 2002, 297: 353-356.
3. Sussman JL, Harel M, Frolow F, et al. Atomic structure of acetylcholinesterase from torpedo California:a prototypic acetylcholine-binding protein. Science, 1991, 253: 872-879.
4. Inestrosa NC, Alvarez A, Perez CA, et al. Acetylcholinesterase accelerates assembly of amyloid-beta-peptides into Alzheimer's fibrils: possible role of the peripheral site of the enzyme. Neuron. 1996, 16: 881-891.
5. Harborne JB, Williams CA. Advances in flavonoid research since 1992. Phytochemistry, 2000, 55: 481-504.
6. Guzrnan JA, Mendoza V, Garcia E, et al. Baeyer-Villiger Oxidation of β-aryl substituted unsaturated carbonyl compounds with hydrogen peroxide and catalytic selenium dioxide. Synthetic Communications, 1995, 25(14): 2121-2133.
7. Jones GH, Mackenzie JBD, Robertson A, et al. Chemistry of fungi. Ⅱ. Derivatives of 3,4-dimethoxyphenol. Journal of the Chemical Society, 1949, 562-569.
8. Beney C, Mariotte AM, Boumendjel A. An Efficient Synthesis of 4,6-Dimethoxy aurones. Heterocycles, 2001, 55(5): 967-972.
9. Joseph S, Heinz F, Bhabatosh C, et al. Structure-Based Design and Synthesis of 2-Benzylidene-benzofuran-3-ones as Flavopiridol Mimics. Journal of Medicinal Chemistry, 2002, 45: 1741-1747.
10. Varma RS, Varma M. Alumina-mediated condensation. A simple synthesis of aurones. Tetrahedron Letters, 1992, 33(40): 5937-5940.
11. Knowles MB, Kingsport T, Rochester NY. Process for production of 2,4,5-trihydroxyacetophenone. US: 2763691.
12. Xi F, Hang XT, Lu YH. A new synthetic method for some 2-hydroxy-4,5-dialkoxyacetophenones. Huaxue Shift, 1990, 12(5): 299-312.
13. Shubhasish M, Vijayendra K, Ashok KP, et al. Synthetic and Biological Activity Evaluation Studies on Novel 1,3-Diarylpropenones. Bioorganic and Medicinal Chemistry, 2001,9:337-345.
14. Zhang QZ, Nigel PB. The synthesis of [2,3,4-13C3]glycitein. Tetrahedron, 2004, 60:12211-12216.
15. Shaw J, Lee AR, Huang WH. Methods of synthesizing flavonoids and chalcones. US: 2004242907.
16. Kumazawa T, Minatogawa T, Matsuba S, et al. An effective synthesis of isoorientin:the regioselective synthesis of a 6-C-glucosylflavone. Carbohydrate Research, 2000, 329(3): 507-513.
17. Xiao L, Tan WF, Li YL. First total synthesis of (±)-kenusanone B. Synthetic Communications, 1998, 28(15): 2861-2869.
18. Masao T, Hironari W, Yasuhiko K. et al. Regioselective Synthesis of 6-Alkyl- and 6-Prenylpolyhydroxyisoflavones and 6-Alkylcoumaronochromone Derivatives. Chem. Pharm. Bull. 2004, 52(11): 1285-1289.
19. Farkas L, Gottsegen A, Nogradi M, et al. Direct conversion of 2'-hydroxychalcones into isoflavones using thallium(Ⅲ) nitrate. Synthesis of (±)-sophorol and (±)-mucronulatol. Journal of the Chemical Society, Chemical Communications, 1972,14: 825-826.
20. Yasuhiko K, Masashi M, Takanori T, et al. Synthesis of Isoflavones from 2'-Hydroxy-chalcones Using Poly[4-(diacetoxy)iodo]styrene or Related Hypervalent Iodine Reagent. Synthesis, 2002,17: 2490-2496.
21. Mulzer J, Angermann A, Schubert B, et al. A General and Practical Synthesis of (R)-Phthalimido Aldehydes and D-α-Amino Acids from D-Mannitol. Journal of Organic Chemistry, 1986, 51: 5294-5299.
22. Ellman GL, Courtney KD, Andres VJ, et al. A new rapid colorimetric determination of acetylcholinesterase activity. Biochem. Pharm. 1961,7: 88-95.
23. Aizpurua JM, Lecea B, Palomo C. Reagents and synthetic methods. 57. Reduction of carbonyl compounds promoted by silicon hydrides under the influence of trimethylsilyl-based reagents. Canadian Journal of Chemistry, 1986, 64(12): 2342-2347.
24. Turner FA, Gearien JE. Synthesis of reserpine analogs. Journal of Organic Chemistry, 1959, 24: 1952-1955.
25. Tibor M, Xavier L, Heinz H, et al. Structural variations of 1-[4-(phenoxymethyl)benzyl] piperidines as nonimidazole histamine H3 receptor antagonists. Bioorganic and Medicinal Chemistry, 2004, 12: 2727-2736.
26. Schmiz C, Eiden F. Pyrans. 84. Hexahydrobenzotripyrans. Liebigs Annalen der Chemie, 1980,12: 2021-2030.
2. Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science, 2002, 297: 353-356.
3. Sussman JL, Harel M, Frolow F, et al. Atomic structure of acetylcholinesterase from torpedo California:a prototypic acetylcholine-binding protein. Science, 1991, 253: 872-879.
4. Inestrosa NC, Alvarez A, Perez CA, et al. Acetylcholinesterase accelerates assembly of amyloid-beta-peptides into Alzheimer's fibrils: possible role of the peripheral site of the enzyme. Neuron. 1996, 16: 881-891.
5. Harborne JB, Williams CA. Advances in flavonoid research since 1992. Phytochemistry, 2000, 55: 481-504.
6. Guzrnan JA, Mendoza V, Garcia E, et al. Baeyer-Villiger Oxidation of β-aryl substituted unsaturated carbonyl compounds with hydrogen peroxide and catalytic selenium dioxide. Synthetic Communications, 1995, 25(14): 2121-2133.
7. Jones GH, Mackenzie JBD, Robertson A, et al. Chemistry of fungi. Ⅱ. Derivatives of 3,4-dimethoxyphenol. Journal of the Chemical Society, 1949, 562-569.
8. Beney C, Mariotte AM, Boumendjel A. An Efficient Synthesis of 4,6-Dimethoxy aurones. Heterocycles, 2001, 55(5): 967-972.
9. Joseph S, Heinz F, Bhabatosh C, et al. Structure-Based Design and Synthesis of 2-Benzylidene-benzofuran-3-ones as Flavopiridol Mimics. Journal of Medicinal Chemistry, 2002, 45: 1741-1747.
10. Varma RS, Varma M. Alumina-mediated condensation. A simple synthesis of aurones. Tetrahedron Letters, 1992, 33(40): 5937-5940.
11. Knowles MB, Kingsport T, Rochester NY. Process for production of 2,4,5-trihydroxyacetophenone. US: 2763691.
12. Xi F, Hang XT, Lu YH. A new synthetic method for some 2-hydroxy-4,5-dialkoxyacetophenones. Huaxue Shift, 1990, 12(5): 299-312.
13. Shubhasish M, Vijayendra K, Ashok KP, et al. Synthetic and Biological Activity Evaluation Studies on Novel 1,3-Diarylpropenones. Bioorganic and Medicinal Chemistry, 2001,9:337-345.
14. Zhang QZ, Nigel PB. The synthesis of [2,3,4-13C3]glycitein. Tetrahedron, 2004, 60:12211-12216.
15. Shaw J, Lee AR, Huang WH. Methods of synthesizing flavonoids and chalcones. US: 2004242907.
16. Kumazawa T, Minatogawa T, Matsuba S, et al. An effective synthesis of isoorientin:the regioselective synthesis of a 6-C-glucosylflavone. Carbohydrate Research, 2000, 329(3): 507-513.
17. Xiao L, Tan WF, Li YL. First total synthesis of (±)-kenusanone B. Synthetic Communications, 1998, 28(15): 2861-2869.
18. Masao T, Hironari W, Yasuhiko K. et al. Regioselective Synthesis of 6-Alkyl- and 6-Prenylpolyhydroxyisoflavones and 6-Alkylcoumaronochromone Derivatives. Chem. Pharm. Bull. 2004, 52(11): 1285-1289.
19. Farkas L, Gottsegen A, Nogradi M, et al. Direct conversion of 2'-hydroxychalcones into isoflavones using thallium(Ⅲ) nitrate. Synthesis of (±)-sophorol and (±)-mucronulatol. Journal of the Chemical Society, Chemical Communications, 1972,14: 825-826.
20. Yasuhiko K, Masashi M, Takanori T, et al. Synthesis of Isoflavones from 2'-Hydroxy-chalcones Using Poly[4-(diacetoxy)iodo]styrene or Related Hypervalent Iodine Reagent. Synthesis, 2002,17: 2490-2496.
21. Mulzer J, Angermann A, Schubert B, et al. A General and Practical Synthesis of (R)-Phthalimido Aldehydes and D-α-Amino Acids from D-Mannitol. Journal of Organic Chemistry, 1986, 51: 5294-5299.
22. Ellman GL, Courtney KD, Andres VJ, et al. A new rapid colorimetric determination of acetylcholinesterase activity. Biochem. Pharm. 1961,7: 88-95.
23. Aizpurua JM, Lecea B, Palomo C. Reagents and synthetic methods. 57. Reduction of carbonyl compounds promoted by silicon hydrides under the influence of trimethylsilyl-based reagents. Canadian Journal of Chemistry, 1986, 64(12): 2342-2347.
24. Turner FA, Gearien JE. Synthesis of reserpine analogs. Journal of Organic Chemistry, 1959, 24: 1952-1955.
25. Tibor M, Xavier L, Heinz H, et al. Structural variations of 1-[4-(phenoxymethyl)benzyl] piperidines as nonimidazole histamine H3 receptor antagonists. Bioorganic and Medicinal Chemistry, 2004, 12: 2727-2736.
26. Schmiz C, Eiden F. Pyrans. 84. Hexahydrobenzotripyrans. Liebigs Annalen der Chemie, 1980,12: 2021-2030.