小檗碱衍生物的合成与药理活性研究
|
摘要
近年来，随着癌症放疗、化疗、器官移植、艾滋病患者的增加，广谱抗生素与免疫抑制剂的广泛应用，免疫功能低下的患者不断增多，深部真菌感染的发生率急剧升高，真菌感染已成为上述患者的主要死亡原因之一。另一方面，随着抗真菌药物的长期大量应用，真菌的耐药问题也越来越严重，而且真菌在人体内或惰性材料表面如各种导管等可形成菌丝或生物被膜，使之对药物的敏感性下降几十倍甚至几百倍，成为临床抗真菌治疗失败的主要原因。
小檗碱(berberine)又名黄连素为一种天然的异喹啉生物碱，是一种季胺离子型异喹啉生物碱，其自然资源丰富，主要存在于毛茛科植物黄连、芸香科植物黄檗、小檗科植物小檗根茎中，同时黄连科、罂粟科、防己科、鼠李科等植物中也有发现。随着近年来得研究，人们发现小檗碱有着广泛的生物学活性如抗菌、抗病毒、抗肿瘤、抗心律失常、抗疟、降血糖、降血脂、镇痛等活性，成为近年来的研究热点。在前期的研究中，我们发现小檗碱有作为协同唑类抗真菌药物抗耐药真菌的新用途。
作为异喹啉生物碱的小檗碱，与其他生物碱一样存在较强的生物毒性，如在临床上大量使用小檗碱时出现不可预见性的猝死现象。同时由于小檗碱的化学结构呈现出高度的平面特性，使其在水或有机溶剂中的溶解性均比较差，从而影响临床使用时的生物利用度。尽管人们以对小檗碱进行了多年的研究，但依然未能解决上述问题，因此本研究试图从化学结构改造方面来解决小檗碱作为抗真菌药物增效剂在临床使用时出现毒性、溶解度差、生物利用度差、生物活性有限等方面的缺陷。
一、小檗碱的结构改造与构效关系研究
我们开展了小檗碱的结构改造和结构修饰两方面研究工作，结果成功发现了13位取代小檗碱衍生物、四氢小檗碱衍生物、二氢异喹啉衍生物、四氢异喹啉衍生物、苯乙胺衍生物等五类具有协同氟康唑抗临床分离耐药白色念珠球菌的新型化合物，并对其协同氟康唑抗耐药白色念珠球菌作用的构效关系进行了初步研究，清楚阐明了其构效关系。另一方面，通过对小檗碱的结构进行改造，突破了小檗碱因其结构的高度平面性而导致溶解性差的缺陷，找到了既能保持或提高其生物活性同时又能提高其溶解性的新型化合物（如3、4、5类化合物），为寻找抗真菌药物增效剂提供了新方向。
二、小檗碱及其类似物的生物活性研究
在对以上五类小檗碱及其类似物的生物活性测试时，我们采用耐药性白念珠菌模型进行抗真菌增效活性筛选。从生物活性测试结果可以看出：第5类化合物的生物活性与溶解性均比小檗碱好；同时1、2、3、4、5与6类化合物间的生物活性指标（MIC80与FICI值）呈现规律性变化，为小檗碱作为氟康唑抗耐药白色念珠球菌的增效剂的构效关系研究提供了依据。
In recent years, with the increase of cancer radiotherapy, chemotherapy, organtransplants, AIDS patients, and wide use of broad-spectrum antibiotics andimmunosuppressive agents, immunocompromised patients keep to increase, and thusresult in sharp rise in the incidence of deep fungal infections, fungal infections havebeen one of the leading cause of death for these patients. On the other hand, with thelong-term large-scale application of the antifungal agents, fungal resistance problemsbecome increasingly serious, and fungi can form various catheters mycelium orbiofilm in the human body or the surface of inert materials, to make it rightdrugsensitivity decreased by tens or even hundreds of times, that’s the main reason forclinical antifungal treatment failure.
Berberine, as a natural isoquinoline alkaloid, mainly comes from plant Coptis asa quaternary ammonium ion of isoquinoline alkaloids, its rich in natural resources,mainly present in the Ranunculaceae Coptisthe Rutaceae Huang Bo, Berberidaceaeplant Berberis roots, while it was found in plants of Coptis, Papaveraceae,Menispermaceae, and Rhamnaceae. From the study results in recent years, it wasfound that berberine has a wide range of biological activity such as antibacterial,antiviral, anti-tumor, anti-arrhythmic, antimalarial, lowering blood sugar, loweringblood pressure, analgesic activity, becoming a research hotspot in recent years. In ourprevious study, we found that berberine can be used for collaborative azole antifungalagents against drug-resistant fungi.
Like other isoquinoline alkaloids, there is a strong biological toxicity inberberine. Such as a large number of clinical appliaction of berberine, it will result inthe unpredictability of the sudden death phenomenon. Due to the chemical structure ofberberine showing a high degree of planar features, so that it is nither dissolved inwater nor in organic solvents, thus affecting the clinical appliaction of bioavailability.Although people have investigated berberine for mang years, but the above problemshaven’t been solved still. This study tried to solve the toxicity, poor solubility, poorbioavailability, and limited biological activity of berberine in clinical use as asynergist of antifungal agents in terms of reconstructure chemical structure.
1. The reconstructure of berberine and structure-activity relationship research
The reconstructure of berberine start from basis chemical structure of berberine,on one hand some chemical groups were added to berberine, on the other hand we removed some structure from the berberine. As a result, we have got five kinds ofnovel compounds (13-replaced Berberine derivatives, tetrahydroberberine derivatives,dihydroisoquinoline derivatives, tetrahydroisoquinoline derivatives, andphenylethylamine derivatives) which could be used to as a synergist of fluconazoleagainst clinical isolated resistant Candida albicans, and the structure-activityrelationship of berberine as a synergist of fluconazole against clinical isolatedresistant Candid albicans was summarized reasonably. On the other hand, by thetransformation of the structure of berberine, it’s planal charater of structure have beenbroken which caused the poor solubility. So we have found not only to maintain orenhance its biological activity, but also to improve its solubility compounds (such as3,4,5-compounds), provide a new direction to find antifungal synergist.
2. Biological activity of berberine and its analogues
Biological activity of all kinds of berberine analogues were screened bysynergistic activity of fluconazolel e in resistant Candida albicans model, while goodin vitro biological activity of compounds were used to test in vivo activity by mousedeep fungal infection action model too. It can be seen from the biological tests: Thebioactivity and solubility of category5is better than berberine; Biological activityindex (MIC80value and FICI value) of compound category1,2,3,4,5and6showregular changes, and provide a basis for structure-activity relationship studies ofberberine as fluconazole anti-drug-resistant Candida albicans synergist.
小檗碱(berberine)又名黄连素为一种天然的异喹啉生物碱，是一种季胺离子型异喹啉生物碱，其自然资源丰富，主要存在于毛茛科植物黄连、芸香科植物黄檗、小檗科植物小檗根茎中，同时黄连科、罂粟科、防己科、鼠李科等植物中也有发现。随着近年来得研究，人们发现小檗碱有着广泛的生物学活性如抗菌、抗病毒、抗肿瘤、抗心律失常、抗疟、降血糖、降血脂、镇痛等活性，成为近年来的研究热点。在前期的研究中，我们发现小檗碱有作为协同唑类抗真菌药物抗耐药真菌的新用途。
作为异喹啉生物碱的小檗碱，与其他生物碱一样存在较强的生物毒性，如在临床上大量使用小檗碱时出现不可预见性的猝死现象。同时由于小檗碱的化学结构呈现出高度的平面特性，使其在水或有机溶剂中的溶解性均比较差，从而影响临床使用时的生物利用度。尽管人们以对小檗碱进行了多年的研究，但依然未能解决上述问题，因此本研究试图从化学结构改造方面来解决小檗碱作为抗真菌药物增效剂在临床使用时出现毒性、溶解度差、生物利用度差、生物活性有限等方面的缺陷。
一、小檗碱的结构改造与构效关系研究
我们开展了小檗碱的结构改造和结构修饰两方面研究工作，结果成功发现了13位取代小檗碱衍生物、四氢小檗碱衍生物、二氢异喹啉衍生物、四氢异喹啉衍生物、苯乙胺衍生物等五类具有协同氟康唑抗临床分离耐药白色念珠球菌的新型化合物，并对其协同氟康唑抗耐药白色念珠球菌作用的构效关系进行了初步研究，清楚阐明了其构效关系。另一方面，通过对小檗碱的结构进行改造，突破了小檗碱因其结构的高度平面性而导致溶解性差的缺陷，找到了既能保持或提高其生物活性同时又能提高其溶解性的新型化合物（如3、4、5类化合物），为寻找抗真菌药物增效剂提供了新方向。
二、小檗碱及其类似物的生物活性研究
在对以上五类小檗碱及其类似物的生物活性测试时，我们采用耐药性白念珠菌模型进行抗真菌增效活性筛选。从生物活性测试结果可以看出：第5类化合物的生物活性与溶解性均比小檗碱好；同时1、2、3、4、5与6类化合物间的生物活性指标（MIC80与FICI值）呈现规律性变化，为小檗碱作为氟康唑抗耐药白色念珠球菌的增效剂的构效关系研究提供了依据。
In recent years, with the increase of cancer radiotherapy, chemotherapy, organtransplants, AIDS patients, and wide use of broad-spectrum antibiotics andimmunosuppressive agents, immunocompromised patients keep to increase, and thusresult in sharp rise in the incidence of deep fungal infections, fungal infections havebeen one of the leading cause of death for these patients. On the other hand, with thelong-term large-scale application of the antifungal agents, fungal resistance problemsbecome increasingly serious, and fungi can form various catheters mycelium orbiofilm in the human body or the surface of inert materials, to make it rightdrugsensitivity decreased by tens or even hundreds of times, that’s the main reason forclinical antifungal treatment failure.
Berberine, as a natural isoquinoline alkaloid, mainly comes from plant Coptis asa quaternary ammonium ion of isoquinoline alkaloids, its rich in natural resources,mainly present in the Ranunculaceae Coptisthe Rutaceae Huang Bo, Berberidaceaeplant Berberis roots, while it was found in plants of Coptis, Papaveraceae,Menispermaceae, and Rhamnaceae. From the study results in recent years, it wasfound that berberine has a wide range of biological activity such as antibacterial,antiviral, anti-tumor, anti-arrhythmic, antimalarial, lowering blood sugar, loweringblood pressure, analgesic activity, becoming a research hotspot in recent years. In ourprevious study, we found that berberine can be used for collaborative azole antifungalagents against drug-resistant fungi.
Like other isoquinoline alkaloids, there is a strong biological toxicity inberberine. Such as a large number of clinical appliaction of berberine, it will result inthe unpredictability of the sudden death phenomenon. Due to the chemical structure ofberberine showing a high degree of planar features, so that it is nither dissolved inwater nor in organic solvents, thus affecting the clinical appliaction of bioavailability.Although people have investigated berberine for mang years, but the above problemshaven’t been solved still. This study tried to solve the toxicity, poor solubility, poorbioavailability, and limited biological activity of berberine in clinical use as asynergist of antifungal agents in terms of reconstructure chemical structure.
1. The reconstructure of berberine and structure-activity relationship research
The reconstructure of berberine start from basis chemical structure of berberine,on one hand some chemical groups were added to berberine, on the other hand we removed some structure from the berberine. As a result, we have got five kinds ofnovel compounds (13-replaced Berberine derivatives, tetrahydroberberine derivatives,dihydroisoquinoline derivatives, tetrahydroisoquinoline derivatives, andphenylethylamine derivatives) which could be used to as a synergist of fluconazoleagainst clinical isolated resistant Candida albicans, and the structure-activityrelationship of berberine as a synergist of fluconazole against clinical isolatedresistant Candid albicans was summarized reasonably. On the other hand, by thetransformation of the structure of berberine, it’s planal charater of structure have beenbroken which caused the poor solubility. So we have found not only to maintain orenhance its biological activity, but also to improve its solubility compounds (such as3,4,5-compounds), provide a new direction to find antifungal synergist.
2. Biological activity of berberine and its analogues
Biological activity of all kinds of berberine analogues were screened bysynergistic activity of fluconazolel e in resistant Candida albicans model, while goodin vitro biological activity of compounds were used to test in vivo activity by mousedeep fungal infection action model too. It can be seen from the biological tests: Thebioactivity and solubility of category5is better than berberine; Biological activityindex (MIC80value and FICI value) of compound category1,2,3,4,5and6showregular changes, and provide a basis for structure-activity relationship studies ofberberine as fluconazole anti-drug-resistant Candida albicans synergist.
引文
[1] Goffeau, A. The fight against fungi [J]. Nature,2008,425,541.
[2] Goffeau, A. Outwitting multidrug resistance to antifungals [J]. Science,2008,321,367.
[3] Snydman D R. Shifting patterns in the epidemiology of nosocomial candida infections[J]. Chest,2003,123,500.
[4] Chiou C C. et al. New drugs and novel targets for treatment of invasive fungalinfections in patients with cancer [J]. Oncologist,2000,5,120.
[5] White T C，Hoimman S, Dy F, et al. Resistance mechanisms in clinical isolates ofCandida albicans [J]. Antimicrob. Agents. Chemother.,2002,46,1704-1713.
[6] Georgiev V S. Membrane transporters and antifungal drug resistance [J]. Curr. Drug.Target.,2000,1,261-284.
[7] Wirsching S, Michel S, Kohler G, et al. Activate of the multipale drug resistance geneMDR1in fluconazole-resistant clinical Candida albicans strains is caused bymutations in a trans-regulatoy factor [J]. Bacteriol,2000,182,400-404.
[8] Coste A T, Karababa M, Ischer F, et al. TAC1, transcriptional activator of CDR genes,is a new transcription factor involved in the regulation of Candida albicans ABCtransporters CDR1and CDR2[J]. Eukaryotic Cell,2004,3,1639-1652.
[9] Jha S, Dabas N, Karnani N, et al. ABC multidrug transporter Cdr1p of Candidaalbicans has divergent nucleotide-binding domains which display functionalasymmetry [J]. FEMS Yeast Res.,2004,5,63-72.
[10]Prasad R，Wergifosse P，Goffeau A, et al. Molecular cloning and characterization of anovel gene of Candid albicans, CDR1conferring multiple resistance to drugs andantifungals [J]．Curr. Genet.,1995,27,320-329.
[11]Sanglard D, Ischer F, Monod M, et al. Cloning of Candida albicans genes conferringresistance to zaole antifungal agents: characterization of CDR2, a new multidrug ABCtransporter gene [J]. Microbiol.,1997,143,405.
[12]Albertson G D, Niimi M, Cannon R D, et al. Multiple efflux mechanism are involvedin Candida albicans fluconazole resistance [J]. Antimicrob. Agents. Chemother.,1996,40,2835-2841.
[13]张佩英等.生物有机化学[M].北京医科大学中国协和医科大学联合出版社.1992，337.
[14]Clark F S, Paskinson T, Hitchcock C A, et al. Correntlation between fhodamine123accumulation and azol sensitivity in candida species: possible role for drug efflux indrug resistance [J]. Antimicrob. Agents. Chemother.,1996,40,419.
[15]Kelly S L, Lamb D C, Kelly D E, et al. Resistance to fluconazole and cross-resistanceto amphotericin B in Candida albicans from AIDS patients caused by defective steroldelta5,6-desaturation [J]. FEBS Lett.，1997,400,80-82.
[16]Maebashi K, Kudoh M, Nishiyama Y, et al. A novel mechanism of fluconazoleresistance associated with fluconzaole sequestration in Candida albicans isolates froma myelofibrosis patient [J]．Microbiol. Immunol.,2002,46,317-326.
[17]Chandrs J, Kuhn D M, Mukherjee P K, et al. Biofilm formation by the fungalpathogen Candida albican: Development, architecture, and drug resisitance [J], J.Bacteriol.,2001,183,5385-5394.
[18]Kumamoto C A. Candida biofilms [J]. Opin Microbiol.,2002,5,608-611.
[19]Douglas L J. Candida biofilms and there role in infection [J]. Curr. Trends. Microbiol.,2003,11,30-36.
[20]Richard D C, Erwin L, Ann R H, et al. Candida albicans drug resistance-another wayto cope with stress [J]. Microbiology,2007,153,3211-3217.
[21]Bader T, Schroppel K, Bentink K, et al. Role of calcineurin in stress resistance,morphogenesis, and virulence of a Candida albicans wild-type strain [J]. Infection andImmunity,2006,74,4366-4369.
[22]Sanglard D, Ischer F, Marchetti O, et al. Calcineurin A of Candida albicans:Involvement in antifungal tolerance, cell morphogenesis and virulence [J]. Mol.Microbiol.,2003,48,959-976.
[23]Jia X M, Wang Y, Jiang Y Y, et al. RTA2is involved in calcineurin-mediated azoleresistance and sphingoid long-chain base release in Candida albicans [J]. Cell. Mol.Life-Sci.,2009,66,122-134.
[24]Jia X M, Ma Z P, Jiang Y Y, et al. RTA2, a novel gene involved in azole resistance inCandida albicans [J]. Biochem. Biophys. Res. Commun.,2008,373,631-636.
[25] Awe W, Wichmann H, Buerhop R. Hydrierungen von C=C-doppelbindungen inberberin-und anderen isochinolin-basen mit natriumboranat und lithiumboranat [J].Chemische Berichte,1957,90,1997-2003.
[26]Li Y H, Yang P, Kong W J, et al. Berberine analogues as a novel class of thelow-density-lipoprotein receptor up-regulators: synthesis, structure-activityrelationships, and cholesterol-lowering efficacy [J]. J. Med. Chem.,2009,52,492–501.
[27]Lee G E, Lee H S, Lee S D, et al. Synthesis and structure–activity relationships ofnovel, substituted5,6-dihydrodibenzo[a,g]quinolizinium P2X7antagonists [J]. Bio.Med. Chem. Lett.,2009,19,954-958.
[28]Takemoto T, Kondo Y. Reactions of protoberberine-type alkaloids. I. Reaction ofdihydroberberine with alkylhalide [J].Yakugaku Zasshih,1962,82,1408.
[29]Ishii H, Taked S, Ogata K, et al. Re-examination of the synthesis of7,8-dimethoxy-2-methyl-3-(4′,5′-methylenedioxy-2′-vinylphenyl)-isocarbonstyril [J].Chem. Pharm. Bull.,1991,39,2712-2714.
[30]Tani Y, Ishibashi K. Deriveratives of berberine and allied alkaloids. Ⅱ. Synthesis ofN-methylderiveratives of d-and l-canadine [J]. Yakugaku Zasshih,1954,74,315.
[31]Suau R, Nájera F, Rico R. The Polonovski–Potier reaction of berbine N-oxides.Synthesis of8-hydroxymethyl and8-methylberbines [J]. Tetrahedron,2000,56,9713-9723.
[32]Srivastava P C, Tedjamuliat M L, Knapp J F. Potential cerebral perfusion agents.Synthesis and evaluation of berberine analogues [J]. J. Heterocyclic Chem.,1986,23,1167.
[33]Ma Y, Ou T M, Hou J Q, et al.9-N-Substituted berberine derivatives: Stabilization ofG-quadruplex DNA and down-regulation of oncogene c-myc [J]. Bio. Med. Chem.,2008,16,7582-7591.
[34]Frerichs G, Stoepel P. Beitr ge zur kenntnis des berberins. Ueber berberrubin [J]. Arch.Pharm.,1913,251,321.
[35]Park K D, Lee J H, Kim S H, et al. Synthesis of13-(substituted benzyl) berberine andberberrubine derivatives as antifungal agents [J]. Bioorg. Med. Chem. Lett.,2006,16,3913-3916.
[36]Hanaoka M, Yoshida S, Mukai C. A novel and efficient synthesis of13-methylprotoberberine alkaloids [J]. J. Chem. Soc. Chem. Commun.,1985,745,1257.
[37]Samosom S, Tanwirat B, Muhamad N, et al. Antibacterial activity of berberine-Nor Apump inhibitor hybrids with a methylene ether linking group [J]. Bio. Med. Chem.,2009,17,3866-3872.
[38]Iwasa K, Nanba H, Lee D U, et al. Structure-activity relationships of protoberberineshaving antimicrobial activity [J]. Planta. Med.,1998,64,748.
[39]Yasuda S, Hirasawa T, Hanaoka M. A new and convenient synthesis of protobeiberinealkaloids:(t)-Tetrahydropalmatine,(±)-sinactine,(±)-canadine, and (±)-stylopine [J].Tetrahedron Lett.,1987,28,2399-2402.
[40]Yang P, Song D Q, Li Y H, et al. Synthesis and structure–activity relationships ofberberine analogues as a novel class of low-density-lipoprotein receptor up-regulators[J]. Bio. Med. Chem. Lett.,2008,18,4675-4677.
[41]Hanaoka M, Kabayashi N, Mukai C. A new total synthesis of oxyterihanine [J].Hetrocycles,1987,26,1499-1501.
[42]Paul S, Cutter R, Miller B, et al. Synthesis of protoberberines useing a silyl-directedPictet-Spengler cyclization [J]. Terahedron,2002,58,1471-1478.
[43]Valpuesta M, Ariza M, Diaz A, et al. Total synthesis of new8-(arylmethyl) berberines[J]. Eur. J. Org. Chem.,2010,638-645.
[44]Fukutake M, Yokota S, Kawamura H, et al. Inhibitory effect of coptidis rhizoma andscutellariae radix on azoxymethane-induced aberrant cryptfociformation in rat colon[J]. Biol. Pharm. Bull.,1998,21,814-817.
[45]Lizuka N, Miyamoto K, Okita K, et al. Inhibitory effect of coptidis rhizoma andberberine on the proliferation of human esophageal cancer cell lines [J]. Cancer Lett.,2000,148,19-51.
[46]Akio H, Tetsuro I, Yoshiaki I, et al., Antitumor activity of berberrubine derivatives [J],Gann,1976,67,321-325.
[47]Creasey W A. Biochemical effects of berberine [J]. Biochem. Pharm.,1979,28,1081-1084.
[48]Manohar L S. Enzyme inhibitionV: Inhibition reverse transcriptase activity byprotoberberin alkaloids and structure-activity relationships [J]. Pharm. Sci.,1983,72,538-541.
[49]Kobayashi Y, Yamashita Y, Fujii N, et al. Inhibitor of DNA topoisomerase I and IIisolated from thcoptis rhizomcs [J]. Planta. Med.,1995,61,414-418.
[50]谢义明.小梁碱的药理研究及临床应用[J].中国医院药学杂志,1991,11,538.
[51]Yin J, Hu R M, Tang J F, et al. Glucose-lowering effect of berberine in vitro [J]. Acta.Univ. Med. Second Shang hai,2001,21,425-427.
[52]黄伟民,等.黄连素抗心律失常机制-电压钳制术观察延迟激活钾离子流的变化[J].中华心血管病杂志,1992,20,310.
[53]王玉,等.小檗碱对心脏传导性能的影响[J].中国药理学报,1991,12,40.
[54]杨顺裕,等.黄连素的正性肌力作用及其研究[J].中国中西医结合杂志,1994,14,570.
[55]黄才国,等.小檗碱对兔血小板TXA4和血浆中PGI2生成的影响[J].中国药理学报,1991,12,526.
[56]Hui k k, et al. Interaction of berberine with human platelet2adrenoceptors [J].Life-Sci.,1991,49,315.
[57]Hattori T, et al. Studies on the anti-nephritic effect of plant compounds: Reduction ofprotein excretion by berberine and coptisine in rats with original-type anti-GBMnephritis [J]. Jpn. J. Pharm.,1992,59,159.
[58]郑红艳.原小檗碱类生物碱作用差异的机制研究[C].天津.天津医科大学.2004.
[59]Orskov C, Hartmann B, Poulsen S S, et al. GLP-2Stimulate colonic growth via KGFreleased by subeptithelial myofibroblasts with GLP-2receptors [J]. Regul. Pept.,2005,124,105-112.
[60]Parka K S, Kanga K C, Kima J H, et al. Differential inhibitory effects ofprotoberberines on sterol and chitin biosyntheses in Candida albicans [J]. J.Antimicrob. Chemother.,1999,43,667-674.
[61]Qin Y, Pang J Y, Chen W H, et al. Synthesis, DNA-binding affinities, and bindingmode of berberine dimers [J]. Bioorg. Med. Chem.,2006,14,25-32.
[62]Quan H, Cao Y Y, Xu Z, et al. Potent in vitro synergism of fluconazole and berberinechloride against clinical isolates of Candida albicans resistant to fluconazole [J].Antimicrob. Agents. Chemother.,2006,50,1096.
[63]Li Y H, Yang P, Kong W J, et al. Berberine analogues as a novel class of thelow-density-lipoprotein receptor up-regulators: synthesis, structure-activityrelationships, and cholesterol-lowering efficacy [J]. J. Med. Chem.2009,52,492.
[64]Lee G E, Lee H S, Lee S D, et al. Synthesis and structure-activity relationships ofnovel, substituted5,6-dihydrodibenzo[a,g]quinolizinium P2X7antagonists [J]. Bioorg.Med. Chem. Lett.2009,19,954.
[65]Li Y H, Yang P, Kong W J, et al. Berberine analogues as a novel class of thelow-density-lipoprotein receptor up-regulators: synthesis, structure-activityrelationships, and cholesterol-lowering efficacy [J]. J. Med. Chem.,2009,52,492.
[66]Zhao X, Jia M X, Jiang X K, et al. Zipper-featured delta-peptide foldamers driven bydonor--acceptor interaction. Design, synthesis, and characterization [J]. J. Org. Chem.2004,69,270-279.
[67]Zubkov F I, Ershova J D, Orlova A A, et al. A new approach to construction ofisoindolo[1,2-a]isoquinoline alkaloids Nuevamine, Jamtine, and Hirsutine via IMDAFreaction [J]. Tetrahedron,2009,65,3789-3803.
[68]Tóth J, DancsóA, BlaskóG, et al.1,7-Electrocyclization reactions of stabilized,β:γ,-unsaturated azomethine ylides [J]. Tetrahedron,2006,62,5725-5735.
[69] Yokoyama A, Ohwada T, Shudo K. Prototype Pictet-Spengler reactions catalyzed bysuperacids involvement of dicationic superelectrophiles [J]. J. Org. Chem.,1999,64,611-617.
[70]Xu R, Lever J R, Lever S Z. Synthesis and in vitro evaluation oftetrahydroisoquinolinyl benzamides as ligands for sigma receptors [J]. Bioorg. Med.Chem. Lett.,2007,17,2594-2597.
[71]Imura Y, Shimojuh N, Kawano Y, et al. Novel preparation of ion-supportedtriphenylphosphines and their synthetic utility [J]. Tetrahedron,2010,66,3421-3426.
[72]Zhao X, Jia M X, Jiang X K, et al. Zipper-featured delta-peptide foldamers driven bydonor--acceptor interaction. Design, synthesis, and characterization [J]. J. Org. Chem.2004,69,270-279.
[73]Parikh V, Welch W M, Schmidt A W. Discovery of a Series of (4,5-Dihydroimidazol-2-yl)-biphenylamine5-HT7Agonists [J]. Bioorg. Med. Chem. Lett.,2003,13,269-271.
[74]Li Z B, Qian X H, Song G H, et al. Synthesis and biological activitys offluroine-containing N,N'-diphenylcarbamimidothioates [J]. Jorunal of FluorineChemistry,2001,108,143-146.
[75] Zhang L, Sathunuru S, Luong T L, et al. New imidazolidinedione derivatives asantimalarial agents [J]. Bioorg. Med. Chem.,2011,19,1541-1549.
[2] Goffeau, A. Outwitting multidrug resistance to antifungals [J]. Science,2008,321,367.
[3] Snydman D R. Shifting patterns in the epidemiology of nosocomial candida infections[J]. Chest,2003,123,500.
[4] Chiou C C. et al. New drugs and novel targets for treatment of invasive fungalinfections in patients with cancer [J]. Oncologist,2000,5,120.
[5] White T C，Hoimman S, Dy F, et al. Resistance mechanisms in clinical isolates ofCandida albicans [J]. Antimicrob. Agents. Chemother.,2002,46,1704-1713.
[6] Georgiev V S. Membrane transporters and antifungal drug resistance [J]. Curr. Drug.Target.,2000,1,261-284.
[7] Wirsching S, Michel S, Kohler G, et al. Activate of the multipale drug resistance geneMDR1in fluconazole-resistant clinical Candida albicans strains is caused bymutations in a trans-regulatoy factor [J]. Bacteriol,2000,182,400-404.
[8] Coste A T, Karababa M, Ischer F, et al. TAC1, transcriptional activator of CDR genes,is a new transcription factor involved in the regulation of Candida albicans ABCtransporters CDR1and CDR2[J]. Eukaryotic Cell,2004,3,1639-1652.
[9] Jha S, Dabas N, Karnani N, et al. ABC multidrug transporter Cdr1p of Candidaalbicans has divergent nucleotide-binding domains which display functionalasymmetry [J]. FEMS Yeast Res.,2004,5,63-72.
[10]Prasad R，Wergifosse P，Goffeau A, et al. Molecular cloning and characterization of anovel gene of Candid albicans, CDR1conferring multiple resistance to drugs andantifungals [J]．Curr. Genet.,1995,27,320-329.
[11]Sanglard D, Ischer F, Monod M, et al. Cloning of Candida albicans genes conferringresistance to zaole antifungal agents: characterization of CDR2, a new multidrug ABCtransporter gene [J]. Microbiol.,1997,143,405.
[12]Albertson G D, Niimi M, Cannon R D, et al. Multiple efflux mechanism are involvedin Candida albicans fluconazole resistance [J]. Antimicrob. Agents. Chemother.,1996,40,2835-2841.
[13]张佩英等.生物有机化学[M].北京医科大学中国协和医科大学联合出版社.1992，337.
[14]Clark F S, Paskinson T, Hitchcock C A, et al. Correntlation between fhodamine123accumulation and azol sensitivity in candida species: possible role for drug efflux indrug resistance [J]. Antimicrob. Agents. Chemother.,1996,40,419.
[15]Kelly S L, Lamb D C, Kelly D E, et al. Resistance to fluconazole and cross-resistanceto amphotericin B in Candida albicans from AIDS patients caused by defective steroldelta5,6-desaturation [J]. FEBS Lett.，1997,400,80-82.
[16]Maebashi K, Kudoh M, Nishiyama Y, et al. A novel mechanism of fluconazoleresistance associated with fluconzaole sequestration in Candida albicans isolates froma myelofibrosis patient [J]．Microbiol. Immunol.,2002,46,317-326.
[17]Chandrs J, Kuhn D M, Mukherjee P K, et al. Biofilm formation by the fungalpathogen Candida albican: Development, architecture, and drug resisitance [J], J.Bacteriol.,2001,183,5385-5394.
[18]Kumamoto C A. Candida biofilms [J]. Opin Microbiol.,2002,5,608-611.
[19]Douglas L J. Candida biofilms and there role in infection [J]. Curr. Trends. Microbiol.,2003,11,30-36.
[20]Richard D C, Erwin L, Ann R H, et al. Candida albicans drug resistance-another wayto cope with stress [J]. Microbiology,2007,153,3211-3217.
[21]Bader T, Schroppel K, Bentink K, et al. Role of calcineurin in stress resistance,morphogenesis, and virulence of a Candida albicans wild-type strain [J]. Infection andImmunity,2006,74,4366-4369.
[22]Sanglard D, Ischer F, Marchetti O, et al. Calcineurin A of Candida albicans:Involvement in antifungal tolerance, cell morphogenesis and virulence [J]. Mol.Microbiol.,2003,48,959-976.
[23]Jia X M, Wang Y, Jiang Y Y, et al. RTA2is involved in calcineurin-mediated azoleresistance and sphingoid long-chain base release in Candida albicans [J]. Cell. Mol.Life-Sci.,2009,66,122-134.
[24]Jia X M, Ma Z P, Jiang Y Y, et al. RTA2, a novel gene involved in azole resistance inCandida albicans [J]. Biochem. Biophys. Res. Commun.,2008,373,631-636.
[25] Awe W, Wichmann H, Buerhop R. Hydrierungen von C=C-doppelbindungen inberberin-und anderen isochinolin-basen mit natriumboranat und lithiumboranat [J].Chemische Berichte,1957,90,1997-2003.
[26]Li Y H, Yang P, Kong W J, et al. Berberine analogues as a novel class of thelow-density-lipoprotein receptor up-regulators: synthesis, structure-activityrelationships, and cholesterol-lowering efficacy [J]. J. Med. Chem.,2009,52,492–501.
[27]Lee G E, Lee H S, Lee S D, et al. Synthesis and structure–activity relationships ofnovel, substituted5,6-dihydrodibenzo[a,g]quinolizinium P2X7antagonists [J]. Bio.Med. Chem. Lett.,2009,19,954-958.
[28]Takemoto T, Kondo Y. Reactions of protoberberine-type alkaloids. I. Reaction ofdihydroberberine with alkylhalide [J].Yakugaku Zasshih,1962,82,1408.
[29]Ishii H, Taked S, Ogata K, et al. Re-examination of the synthesis of7,8-dimethoxy-2-methyl-3-(4′,5′-methylenedioxy-2′-vinylphenyl)-isocarbonstyril [J].Chem. Pharm. Bull.,1991,39,2712-2714.
[30]Tani Y, Ishibashi K. Deriveratives of berberine and allied alkaloids. Ⅱ. Synthesis ofN-methylderiveratives of d-and l-canadine [J]. Yakugaku Zasshih,1954,74,315.
[31]Suau R, Nájera F, Rico R. The Polonovski–Potier reaction of berbine N-oxides.Synthesis of8-hydroxymethyl and8-methylberbines [J]. Tetrahedron,2000,56,9713-9723.
[32]Srivastava P C, Tedjamuliat M L, Knapp J F. Potential cerebral perfusion agents.Synthesis and evaluation of berberine analogues [J]. J. Heterocyclic Chem.,1986,23,1167.
[33]Ma Y, Ou T M, Hou J Q, et al.9-N-Substituted berberine derivatives: Stabilization ofG-quadruplex DNA and down-regulation of oncogene c-myc [J]. Bio. Med. Chem.,2008,16,7582-7591.
[34]Frerichs G, Stoepel P. Beitr ge zur kenntnis des berberins. Ueber berberrubin [J]. Arch.Pharm.,1913,251,321.
[35]Park K D, Lee J H, Kim S H, et al. Synthesis of13-(substituted benzyl) berberine andberberrubine derivatives as antifungal agents [J]. Bioorg. Med. Chem. Lett.,2006,16,3913-3916.
[36]Hanaoka M, Yoshida S, Mukai C. A novel and efficient synthesis of13-methylprotoberberine alkaloids [J]. J. Chem. Soc. Chem. Commun.,1985,745,1257.
[37]Samosom S, Tanwirat B, Muhamad N, et al. Antibacterial activity of berberine-Nor Apump inhibitor hybrids with a methylene ether linking group [J]. Bio. Med. Chem.,2009,17,3866-3872.
[38]Iwasa K, Nanba H, Lee D U, et al. Structure-activity relationships of protoberberineshaving antimicrobial activity [J]. Planta. Med.,1998,64,748.
[39]Yasuda S, Hirasawa T, Hanaoka M. A new and convenient synthesis of protobeiberinealkaloids:(t)-Tetrahydropalmatine,(±)-sinactine,(±)-canadine, and (±)-stylopine [J].Tetrahedron Lett.,1987,28,2399-2402.
[40]Yang P, Song D Q, Li Y H, et al. Synthesis and structure–activity relationships ofberberine analogues as a novel class of low-density-lipoprotein receptor up-regulators[J]. Bio. Med. Chem. Lett.,2008,18,4675-4677.
[41]Hanaoka M, Kabayashi N, Mukai C. A new total synthesis of oxyterihanine [J].Hetrocycles,1987,26,1499-1501.
[42]Paul S, Cutter R, Miller B, et al. Synthesis of protoberberines useing a silyl-directedPictet-Spengler cyclization [J]. Terahedron,2002,58,1471-1478.
[43]Valpuesta M, Ariza M, Diaz A, et al. Total synthesis of new8-(arylmethyl) berberines[J]. Eur. J. Org. Chem.,2010,638-645.
[44]Fukutake M, Yokota S, Kawamura H, et al. Inhibitory effect of coptidis rhizoma andscutellariae radix on azoxymethane-induced aberrant cryptfociformation in rat colon[J]. Biol. Pharm. Bull.,1998,21,814-817.
[45]Lizuka N, Miyamoto K, Okita K, et al. Inhibitory effect of coptidis rhizoma andberberine on the proliferation of human esophageal cancer cell lines [J]. Cancer Lett.,2000,148,19-51.
[46]Akio H, Tetsuro I, Yoshiaki I, et al., Antitumor activity of berberrubine derivatives [J],Gann,1976,67,321-325.
[47]Creasey W A. Biochemical effects of berberine [J]. Biochem. Pharm.,1979,28,1081-1084.
[48]Manohar L S. Enzyme inhibitionV: Inhibition reverse transcriptase activity byprotoberberin alkaloids and structure-activity relationships [J]. Pharm. Sci.,1983,72,538-541.
[49]Kobayashi Y, Yamashita Y, Fujii N, et al. Inhibitor of DNA topoisomerase I and IIisolated from thcoptis rhizomcs [J]. Planta. Med.,1995,61,414-418.
[50]谢义明.小梁碱的药理研究及临床应用[J].中国医院药学杂志,1991,11,538.
[51]Yin J, Hu R M, Tang J F, et al. Glucose-lowering effect of berberine in vitro [J]. Acta.Univ. Med. Second Shang hai,2001,21,425-427.
[52]黄伟民,等.黄连素抗心律失常机制-电压钳制术观察延迟激活钾离子流的变化[J].中华心血管病杂志,1992,20,310.
[53]王玉,等.小檗碱对心脏传导性能的影响[J].中国药理学报,1991,12,40.
[54]杨顺裕,等.黄连素的正性肌力作用及其研究[J].中国中西医结合杂志,1994,14,570.
[55]黄才国,等.小檗碱对兔血小板TXA4和血浆中PGI2生成的影响[J].中国药理学报,1991,12,526.
[56]Hui k k, et al. Interaction of berberine with human platelet2adrenoceptors [J].Life-Sci.,1991,49,315.
[57]Hattori T, et al. Studies on the anti-nephritic effect of plant compounds: Reduction ofprotein excretion by berberine and coptisine in rats with original-type anti-GBMnephritis [J]. Jpn. J. Pharm.,1992,59,159.
[58]郑红艳.原小檗碱类生物碱作用差异的机制研究[C].天津.天津医科大学.2004.
[59]Orskov C, Hartmann B, Poulsen S S, et al. GLP-2Stimulate colonic growth via KGFreleased by subeptithelial myofibroblasts with GLP-2receptors [J]. Regul. Pept.,2005,124,105-112.
[60]Parka K S, Kanga K C, Kima J H, et al. Differential inhibitory effects ofprotoberberines on sterol and chitin biosyntheses in Candida albicans [J]. J.Antimicrob. Chemother.,1999,43,667-674.
[61]Qin Y, Pang J Y, Chen W H, et al. Synthesis, DNA-binding affinities, and bindingmode of berberine dimers [J]. Bioorg. Med. Chem.,2006,14,25-32.
[62]Quan H, Cao Y Y, Xu Z, et al. Potent in vitro synergism of fluconazole and berberinechloride against clinical isolates of Candida albicans resistant to fluconazole [J].Antimicrob. Agents. Chemother.,2006,50,1096.
[63]Li Y H, Yang P, Kong W J, et al. Berberine analogues as a novel class of thelow-density-lipoprotein receptor up-regulators: synthesis, structure-activityrelationships, and cholesterol-lowering efficacy [J]. J. Med. Chem.2009,52,492.
[64]Lee G E, Lee H S, Lee S D, et al. Synthesis and structure-activity relationships ofnovel, substituted5,6-dihydrodibenzo[a,g]quinolizinium P2X7antagonists [J]. Bioorg.Med. Chem. Lett.2009,19,954.
[65]Li Y H, Yang P, Kong W J, et al. Berberine analogues as a novel class of thelow-density-lipoprotein receptor up-regulators: synthesis, structure-activityrelationships, and cholesterol-lowering efficacy [J]. J. Med. Chem.,2009,52,492.
[66]Zhao X, Jia M X, Jiang X K, et al. Zipper-featured delta-peptide foldamers driven bydonor--acceptor interaction. Design, synthesis, and characterization [J]. J. Org. Chem.2004,69,270-279.
[67]Zubkov F I, Ershova J D, Orlova A A, et al. A new approach to construction ofisoindolo[1,2-a]isoquinoline alkaloids Nuevamine, Jamtine, and Hirsutine via IMDAFreaction [J]. Tetrahedron,2009,65,3789-3803.
[68]Tóth J, DancsóA, BlaskóG, et al.1,7-Electrocyclization reactions of stabilized,β:γ,-unsaturated azomethine ylides [J]. Tetrahedron,2006,62,5725-5735.
[69] Yokoyama A, Ohwada T, Shudo K. Prototype Pictet-Spengler reactions catalyzed bysuperacids involvement of dicationic superelectrophiles [J]. J. Org. Chem.,1999,64,611-617.
[70]Xu R, Lever J R, Lever S Z. Synthesis and in vitro evaluation oftetrahydroisoquinolinyl benzamides as ligands for sigma receptors [J]. Bioorg. Med.Chem. Lett.,2007,17,2594-2597.
[71]Imura Y, Shimojuh N, Kawano Y, et al. Novel preparation of ion-supportedtriphenylphosphines and their synthetic utility [J]. Tetrahedron,2010,66,3421-3426.
[72]Zhao X, Jia M X, Jiang X K, et al. Zipper-featured delta-peptide foldamers driven bydonor--acceptor interaction. Design, synthesis, and characterization [J]. J. Org. Chem.2004,69,270-279.
[73]Parikh V, Welch W M, Schmidt A W. Discovery of a Series of (4,5-Dihydroimidazol-2-yl)-biphenylamine5-HT7Agonists [J]. Bioorg. Med. Chem. Lett.,2003,13,269-271.
[74]Li Z B, Qian X H, Song G H, et al. Synthesis and biological activitys offluroine-containing N,N'-diphenylcarbamimidothioates [J]. Jorunal of FluorineChemistry,2001,108,143-146.
[75] Zhang L, Sathunuru S, Luong T L, et al. New imidazolidinedione derivatives asantimalarial agents [J]. Bioorg. Med. Chem.,2011,19,1541-1549.
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |