抗HIV香豆素的結(jié)構(gòu)修飾與合成

1、抗抗HIVHIV香豆素的結(jié)構(gòu)修飾與合成香豆素的結(jié)構(gòu)修飾與合成Content 1. Introduction 2. Anti-HIV therapeutic agent 3. Anti-HIV agent from Natural products 4. Khellactone Coumarin Analogs as Anti- HIV Agents 5. Synthesis of Calophyllum coumarins 全球感染者全球感染者4000萬萬 20余年已奪去余年已奪去2500萬人生命萬人生命 每天全球有約每天全球有約16000人新感染人新感染 中國已有中國已有85萬人感染，處于高

2、速增長期，每年萬人感染，處于高速增長期，每年以以30%的驚人速度增長。的驚人速度增長。 中國每年經(jīng)濟損失達人民幣中國每年經(jīng)濟損失達人民幣4600-7700億億1. Introduction 由人由人 免免 疫疫 病毒病毒(HIV)(HIV)感染引起的獲得性免疫缺陷綜合感染引起的獲得性免疫缺陷綜合癥癥(AIDS)(AIDS)俗稱愛滋病，自美國報道首例愛滋病病例以來，愛俗稱愛滋病，自美國報道首例愛滋病病例以來，愛滋病迅速在全球傳播，已成為嚴重威脅人類生命的重要疾病滋病迅速在全球傳播，已成為嚴重威脅人類生命的重要疾病之一之一. .1-5051-100101-500501-10001001-50005

3、000Cumulative China HIV infectious (From 1985 to 2001,9)HIV-1 casesBeijingShan Xi provinceXinjiangYunnanSichuanGuangxiGuangdongHebeiHenanAnhuiHubei抗HIV藥物作用靶點目標目標病毒受體和進入途徑病毒受體和進入途徑逆轉(zhuǎn)錄病毒逆轉(zhuǎn)錄病毒RNA酶酶整合整合病毒基因表達病毒基因表達病毒蛋白合成病毒蛋白合成病毒出芽病毒出芽治療治療Fusion 抑制劑抑制劑化學因子受體阻斷劑化學因子受體阻斷劑抑制劑抑制劑DNA 鏈終止因子鏈終止因子抑制劑抑制劑病毒整合酶抑制劑病

4、毒整合酶抑制劑Tat, Rev, Nef Tat, Rev, Nef 抑制劑抑制劑蛋白酶抑制劑蛋白酶抑制劑 (PIs)(PIs)干擾素干擾素抗體抗體配體配體2. Anti-HIV therapeutic agentNucleoside Analogs,核苷類逆轉(zhuǎn)錄酶抑制劑核苷類逆轉(zhuǎn)錄酶抑制劑Non-Nucleoside非核苷類逆轉(zhuǎn)錄酶抑制劑（非核苷類逆轉(zhuǎn)錄酶抑制劑（3種）種）Protease Inhibitors蛋白酶抑制劑（蛋白酶抑制劑（6種）種）NucleosideNucleoside Analogs, Analogs,核苷類逆轉(zhuǎn)錄酶抑制劑核苷類逆轉(zhuǎn)錄酶抑制劑 Zidovudine; AZ

5、T; Azidothymidine; Retrovir Didanosine; Dideoxyinosine; ddI; Videx Zalcitabine; Dideoxycytidine; ddC; Hivid Lamivudine; 3TC; Epivir Stavudine; 2,3-Didehydro-3-deoxythymidine; D4T; Zerit Abacavir Succinate; 1592U89 Succinate; Ziagen Tenofovir; VireadTM2. Anti-HIV therapeutic agentNon-NucleosideNon-Nu

6、cleoside非核苷類逆轉(zhuǎn)錄酶抑制劑（非核苷類逆轉(zhuǎn)錄酶抑制劑（3 3種）種）Nevirapine; BI-RG-587; Viramune Delavirdine; BHAP; U-90152; Rescriptor Efavirenz; DMP-266; Sustiva NHSCH3OONHONHNNHCH3H3C.CH3SO2.O HDelavirdineNNNNH3COHNevirapineNOFFFCLHOEfavirenzNH2Tenofovir disoproxil(CH3)22(CH3)CHCHOOOOCCOCH2OCH2OOOPONNCH3NNNNRTI的臨床應(yīng)用Protea

7、seProtease Inhibitors Inhibitors蛋白酶抑制劑（蛋白酶抑制劑（6 6種）種）Saquinavir; Ro 31-8959; Fortovase; Invirase Indinavir; MK639; L-735,524; Crixivan Ritonavir; ABT-538; Norvir Nelfinavir; Viracept; AG-1343 Amprenavir; Agenerase; VX-478; 141W94 Lopinavir/RitonavirNNNNOHHONC H3HOH3CC H3IndinavirNHOC H3OHSOHNONHH3CC

8、 H3C H3.C H3SO2.OHNelfinavirSNNNNNOH3CC H3OC H3H3CC H3OHOHNSORitonavirPINNNOHHN H2OOHNONHH3CC H3C H3SaquinavirOONNSOHOHH3CC H3N H2OOAmprenavirLopinavirH3CC H3OHONOHOHNH3C C H3HONNProductionFormulationADMETLeadDiscoveryLeadOptimization Natural Products Bioactivity-Directed Fractionation & Isolati

9、on (BDFI)Clinical Trial StageDrug Discovery StageDrug DevelopmentStageTarget IdentificationCombinatorialLibrariesHigh-ThroughputScreening (HTS)Structure-based:De novo DesignVirtual ScreeningDesignSynthesisScreeningAnalysisRational Drug Design-Based Analog Synthesis3. Anti-HIV agent from Natural prod

10、ucts 從具從具 有有 清清 熱解毒，扶正祛邪或免疫調(diào)節(jié)作用的中草藥中熱解毒，扶正祛邪或免疫調(diào)節(jié)作用的中草藥中尋找抗尋找抗HIV活性物質(zhì)受到研究人員的極大關(guān)注?；钚晕镔|(zhì)受到研究人員的極大關(guān)注。1. Bioactivity-directed fractionation and isolation (BDFI) is a major approach for new lead generation. 2. Rational drug design, synthesis, bio-evaluation, and structure-activity relationship (SAR) and q

11、uantitive-SAR (QSAR) studies form a design circle, which optimizes the lead until it reaches preclinical trial. 3. Currently, driven by exciting technologic advances, enhanced efficiency in gathering absorption, distribution, metabolism, excretion and toxicity (ADMET) data has been realized, permitt

12、ing ADMET scientists to contribute more effectively to the drug discovery process as well. 1) Kadsura interior A. C. Smith (Schizandraceae) (“JiXue Teng”),(EC50 ) 0.006 g/mL; (TI ) 600) 0.5, 110(EC50 ) 0.8 g/mL; (TI ) 56) 1.2, 33.32) Tripterygium wilfordii Hook.(Celastraceae) (“Lai Gong Teng”)EC50 o

13、f 25 nM anda TI of 125EC50 and TI values of 5 M (1 g/mL) and 5, 1000.Tripterygium wilfordii Hook.(Celastraceae) (“Lai Gong Teng”)3)4) EC50 1.4g, TIs 9.3 6.5, 13.85EC50 20 000;EC50 1.7 g/mL, TI ) 12.8; 101: EC50 ) 0.0039 g/mL, TI )3,750.8(EC50 186).5) 香豆素類化合物香豆素類化合物 香豆素類化合物由于分子量小、合成相對簡單、生香豆素類化合物由于分子量

14、小、合成相對簡單、生物利用度高等優(yōu)點物利用度高等優(yōu)點.引起了藥物學家們的高度重視。以這引起了藥物學家們的高度重視。以這些天然香豆索類化合物為先導(dǎo)物，篩選出許多顯著抑制些天然香豆索類化合物為先導(dǎo)物，篩選出許多顯著抑制HIV的衍生物的衍生物簡單香豆素類簡單香豆素類 報道了wafarin對HIV-1的復(fù)制、擴散抑制能力。再經(jīng)大規(guī)模篩選，發(fā)現(xiàn)化合物phenprocouman (2)有明顯抑制HIV-1的活性(Ki=1 mol/L )。在HIV-1感染的PBMC中，也表現(xiàn)出一定的抗病毒活性ED=100-300mol/L 以以phenprocouman( 2)為先導(dǎo)物，通過分析它與為先導(dǎo)物，通過分析它與H

15、IV蛋蛋白酶形成結(jié)晶復(fù)合物的結(jié)構(gòu)設(shè)計并合成了新型抗白酶形成結(jié)晶復(fù)合物的結(jié)構(gòu)設(shè)計并合成了新型抗HIV環(huán)辛環(huán)辛烷并吡喃酮類烷并吡喃酮類(cyclooctylpyrelnne)化合物化合物, 這類化合物對這類化合物對HIV PR的親和力大大強于的親和力大大強于4-羥基吡喃酮類，其中化合物羥基吡喃酮類，其中化合物4活性最強，現(xiàn)已進人一期臨床試驗。活性最強，現(xiàn)已進人一期臨床試驗。OOOOOOOSuksdorfin (1)34(+)-calanolideA 吡喃香豆素類吡喃香豆素類EC50 1.3 M, TI 140EC50 0.0004 M, TI 136 7194. Khellactone Couma

16、rin Analogs as Anti-HIV AgentsOOOOOOOSuksdorfin (1)344.1 Suksdorfin as a new anti-HIV agentIn 1994, the anti-HIV activity of suksdorfin (1), a dihydroseselin type angular pyranocoumarin, which was isolated from the methanolic extract of Lomatium suksdorfii through BDFI. It suppressed viral replicati

17、on in eleven separate acute HIV-1 (IIIB isolate) infections of H9 lymphocyte cells with an average EC50 value of 2.6 2.1 M. It also suppressed acute HIV-1 infections in fresh peripheral blood mononuclear cells, monocyte / macrophages, and U937 cells, a promonocytic cell line. 化合物化合物suksdorfin 是從中草藥狹

18、縫芹是從中草藥狹縫芹(Lomatium suksdorfii)及福參及福參(Angelica mornii)中分離到的一類中分離到的一類7, 8-吡喃香豆素吡喃香豆素類化合物類化合物, 它能明顯抑制它能明顯抑制HIV在在H9淋巴細胞中的復(fù)制淋巴細胞中的復(fù)制(EC50為為1.3mol /L，治療指數(shù)，治療指數(shù)(TI,TC 50/IC50)大于大于40OOOOOOO1.1.酰基的改變?；母淖?.3,4,5,62.3,4,5,6位的取代位的取代3.3.骨架的變化骨架的變化Syntheses of cis-Khellactone DerivativesSyntheses of trans-Khell

19、actone DerivativesOOOOR1OR219. (+)-cis R1=H, R2= 20. (+)-cis R1=Ac, R2=21. (+)-cis R2=H, R1=22. (+)-trans R1=H, R2=23. (+)-trans R1=Ac, R2=OOOOOOOOROClO28. (+)-trans R=Ac29. (+)-trans R=Me30. (+)-trans R=CH2PhO24. (+)-trans R1=CH2Ph, R2=Ac25. (+)-trans R1=Me, R2=Ac26. (+)-trans R1= R2=27. (+)-trans

20、R1= R2=AcOOOOR1R233. cis/trans R1=H, R2=N334. cis/trans R1=Ac, R2=N335. cis R1=H, R2=NHAc36. trans R1=H, R2=NH237. trans R1=H, R2=38. trans R1=Ac, R2=31. (+)-trans R=32. (+)-trans R=NHOOOOOROR 6. (+)-cis R=Ac 7. (+)-trans R=Ac 8. (+)-cis R= 9. (+)-trans R=10. (+)-cis R=11. (+)-cis R=12. (+)-cis R=OO

21、OOO13. (+)-cis R=14. (+)-cis R=15. (-)-cis R=OCO-CHMe216. (+)-trans R=Me17. (+)-trans R= COOPh18. (+)-trans R=O4.2 Pyrano-3,4 Stereoselectivity and ModificationA. 3,4 StereoselectivityEC50 2.610-4 MTI: 137,000, OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO2 (cis-3R, 4R)3 (cis-3S, 4S)4 (trans-3R,4S)5

22、(trans-3S, 4R) EC50 51 M TI: 33 EC50 6.4 M TI : 1 EC50 32 M TI: 1Table 9-1 Anti-HIV activities of khellactone derivatives No.IC50 ( M) bEC50 ( M) cTI dSuksdorfin (1)522.6 2.130.6 22.42352.56 10-41.37 105317005133.346.4 but 6.4 but 323218147210101714.41116.54.73.5133.12.2AZT18750.04541,667a Inhibitor

23、y of HIV-1 IIIB in H9 lymphocytes; b Concentration that inhibits uninfected H9 cell growth by 50%; c Concentration that inhibits viral replication by 50%; d Therapeutic Index, TI= IC50 An X-ray crystallographic analysis confirms that the isovaleryl group in 1 is more conformationally flexible and it

24、s terminal carbon atoms are disordered over two orientations, while in DCK (2), the 4-camphanoyl group neighbors another bulky camphanoyl substituent making the isovaleryl moiety more rigid. The study data showed that a rigid stereochemistry of 3 and 4-configured khellactone derivatives is crucial f

25、or anti-HIV activity.B. 3R, 4R modification. OOOOR1OR239. R1=R2=Ac40. R1=R2=41. R1=R2=42. R1=R2=43. R1=R2=44. R1=H, R2=45. R1=Ac, R2=OBrNHOOOO46. R1=H, R2=47. R1=Ac, R2=48. R1= R2=H49. R1= R2=H50. R1= R2=OOOOOOSO2-SO2-OOOOHOClK2CO3,KI, DMF/N2OOON,N-diethylanilinerefluxK2OsO2(OH)4, K3Fe(CN)6(DHQ)2-PH

26、AL, K2CO3OOOOOOOHOH Camphanoyl chloride DMAP/CH2Cl2OOOORORSyntheses of Khellactone Skeleton4.3 Coumarin Skeleton ModificationA. Substituents on coumarin skeletonOOOOOOOSuksdorfin (1)34a. Mono-substituted analogs b. Di-substituted analogsa. Mono-substituted analogs No. OO-campO-campOO3456 IC50 (M) EC

27、50 (M) TI DCK(2) 35.0 2.5610-4 1.37105 51 3-substitution CH3 113 5.2510-5 2.15106 52 OCH3 153 2.3810-3 6.43104 53 4-substitution CH3 126 1.8310-6 6.89107 54 OCH3 153 2.9910-3 5.12104 55 CH2CH2CH3 151 1.7510-2 8.63103 56 CH(CH3)2 151 3.1510-2 4.79103 57 C6H5 143 0.12 1.19103 58 CF3 145 1.81 80.1 595-

28、substitutionCH3952.3910-73.9710860OCH31531.9210-47.97105616-substitutionCH3330.15121862OCH315315.89.68AZT18750.04541,667 No. OO-campO-campOO3456 IC50 (M) EC50 (M) TI DCK(2) 35.0 2.5610-4 1.37105 b. Di-substituted analogsStructures and anti-HIV activities of di-substituted DCK analogs (63 72)OOOOOOOO

29、OOOR2R1R3R434567823412No.StructureIC50 (M) EC50 (M) TI 63R1 = R2 = CH3, R3 = R4 = H1.9210-38.0210464R1 = Cl, R2 = CH3, R3 = R4 = H2.0110-35.1710465R1 = Ph, R2 = CH3, R3 = R4 = H43.73.2066R1 = R2 = (CH2)4, R3 = R4 = H2.1210-36.9810467R1 = R3 = CH3, R2 = R4 = H9.1010-31.6910468R2 = R3 = CH3, R1 = R4 =

30、 H4.1910-33.6810469R2 = CH3, R3 = OCH3, R1 = R4 = H7.2110-62.0810770R2 = CH(CH3)2, R3 = CH3, R1= R4 = HNo suppression71R2 = CH3, R3 = OCH2C6H5, R1 = R4 = H1.5487.772R2 = R4 = CH3, R1 = R3 = H4.6910-31.25103AZT18750.04541,667B. Bioisosteric replacement Bioisosteres are defined as groups or molecules

31、that have chemical and physical properties producing broadly similar biological properties. Bioisosteres likely affect the same receptor site or pharmacological mechanism. This analog design principle was applied to our DCK modification, and thio-DCK and DCK lactam derivatives were developed.a. Thio

32、-DCK analogsOOSOOOOOOOOR1R2R3R4 The thio bioisosteres of DCK contain S rather than O in the 2-ketone moiety and retain anti-HIV activity in comparison to the substituted DCKs. . Among the khelthiolactone analogs shown in Table 9-4, thioDCK (73), 4-methyl-thio (75), 3-methyl-thio (74), and 5-methyl-t

33、hio (76) analogs showed the highest potency in the H9-lymphocyte cell line, but were less active than correspondent DCK (2), 4-methyl (53), 3-methyl (51), and 5-methyl (59) DCK analogs. However, in the CEM-SS cell line, 75 showed promising potency with EC50 = 0.0635 M and TI 3,149, and was more pote

34、nt than 2 and equipotent to 53. Structures and anti-HIV activities of khelthiolactone analogs (73 84)OOSOOOOOOOOR1R2R3R4CompdStructureH9 Lymphocytes aCEM-SS Cell Line bEC50 (M) TIEC50 (M)TI73R1 = R2 = R3 = R4 = H0.0295,3900.30713.7Mono-substitution74R1 = CH3, R2 = R3 = R4 = H0.011912,900*75R2 = CH3,

35、 R1 = R3 = R4 = H0.0071821,3000.06353,15076R2 = C3H7, R1 = R3 = R4 = H 0.1281,1530.1281,15377R2 = phenyl, R1 = R3 = R4 = H 2.4856.62.4856.678R3 = CH3, R1 = R2 = R4 = H0.01997,690*79R3 = OCH3, R1 = R2 = R4 = H1.28117*80R4 = OCH3, R1 = R2 = R3 = HN/S*H9 Lymphocytes a CEM-SS Cell Line b Compd Structure

36、 EC50 (M) TI EC50 (M) TI 73 R1 = R2 = R3 = R4 = H 0.029 5,390 0.307 13.7 Di-substitution81R2 = R3 = CH3, R1 = R4 = H0.262571*82R2 = CH3, R3 = OCH3, R1 = R4 = H1.461000*83R1 = R2 = CH3, R3 = R4 = H0.03344490*84R1 = C6H5, R2 = CH3, R3 = R4 = H4.956.24*AZT0.04541,6670.0038263DCK (2)2.5610-41.371050.14-

37、0.26100531.5710-71090.06353,150a Screened in H9 lymphocytes by Panacos Inc. b Screened in CEM-SS cells by NIHH3COPSSSPSOCH3Lawesson reagent (LR)H3COPSSH3COPSS22Lawessons reagent (LR) 37 was used to convert the khellactones to the corresponding khellactone thiones (khelthiolactones) in 50% to 85% yie

38、ldsb. DCK-lactam analogsNR2OOOOOOOOOOR185, R1 = H, R2=BOC, no supression86, R1 = CH3, R2=BOC, no supression87, R1 =R2 = H, IC50=28 M, EC50 = 0.00024 M, TI = 119,33388, R1 = CH3, R2 = H, IC50=42 M, EC50 = 0.0046 M, TI = 9,100The DCK lactam analogs (85 88) were also synthesized asymmetrically and eval

39、uated for antiviral activity against HIV-1 replication in H9 lymphocyte cells. the interchange of O and its bioisostere NH retains the anti-HIV activity in DCK series derivatives since 87 and 88 had comparable activity with corresponding DCKs (53 and 63). Thus, with the similar steric size of O and

40、NH and their ability to act as hydrogen bond acceptors, the hydrogen bond acceptor ability of NH or O at position-1 is likely involved in receptor binding. With the nitrogen protected by t-butoxycarbonyl (BOC) and unable to act as a hydrogen bond acceptor, the synthetic intermediates (85 and 86) did

41、 not inhibit HIV-1 replication. C. Approach to improve water solubilityFurther in vivo pharmacokinetics study showed that the poor water-solubility of 53 is a major obstacle to its further development as a drug candidate. Introducing polar functional groups into the DCK structure could improve water

42、 solubility and simultaneously provide the possibility of prodrugs. Scheme 9-2 shows our first approach: the parallel synthesis of 3R, 4R-di-O-cis-acyl-3-carboxyl khellactones (89 94) using Wang resin. However, none of the compounds, even the camphanoyl substituted 89, showed promising activity, ind

43、icating that a carboxylic acid is not favorable in this position.OOOOOOOHHOOOOOOROROHOOOOOOOOOORORpyridinepiperidine50% TFACH2Cl2OOOOOOOOO89. R=90. R=91. R=94. R=93. R=92. R=HOH2COCH2PWang ResinOROROOOOROROOOBrOROROOONH2OROROOONEt2519997969895OROROOOOAcOROROOOOHi. NBS / benzene, reflux; ii. Ac2O, Na

44、OAc, reflux;iii. 2N HCl / EtOH, reflux; iv. Hexamethylenetetramine/CHCl3; v. 2N HCl / EtOH;iv. Diethylamine / toluene, refluxiiiiiiiv, vviStructures and anti-HIV activities of DCK analogs 95 106 aOROROOOR3OROROOOR3OROROOOR6R = Camphanoyl95 - 99100 - 102103 - 106CompoundIC50 (M) bEC50 (M) cTherapeuti

45、c index d95R3 = Br11.10.05918696R3 = OAc11.60.01767697R3 = OH23.00.02980698R3 = NH215.40.6772399R3 = NEt214.13.674100R3 = Br20.90.00011189,600101R3 = OAc14.80.026567102R3 = OH24.90.00426000103R6 = Br13.70.15688104R6 = OAc14.10.54426105R6 = OH15.00.111135106R6 = NH215.00.148102DCK (2) e16.10.04932853

46、 f39.00.00596600OOOOOOOOOOOR3R2107. R2=R3=R6=H, DCP108 R2=R6=H, R3=CH3109. R2=R6=H, R3=C6H5110. R2=CH3, R3=R6=H111. R2=CH2CH3, R3=R6=H112. R2= CH2CH2CH3, R3=R6=H113. R2= CH(CH3)2, R3=R6=H114. R2= CH2OCH2CH3, R3=R6=H115. R2=C6H5, R3=R6=H116. R2=R3=CH3, R6=H117. R2=CH2CH3, R3=H, R6=C(CH3)3OOOROOOOOR21

47、18. R2=CH3, R=119. R2=CH3, R=120. R2=CH3, R=121. R2=CH2CH3, R=122. R2=CH2OCH2CH3, R=123. R2=ph, R=124. R2=ph, R=OOOOO2334OOR656D. Position isomersNon-drug resistant strain aMultiple RT inhibitor resistant strain bCompdIC50 (M)EC50 (M)TI IC50 (M)EC50 (M)TI107c14.200.001311,100NS10814.700.0009914,8003

48、.141.282.510935.821.5423.3NS11027.300.00318,60011.80.1962.511137.160.00032116,20043.080.0671811237.650.0201,86037.65040.0748315.040.14111.111415.10.115112.50.373411535.820.12927712.20.177111611.30.0071,5004.720.311511735.41.622214.157.361.911850.152.2921.940.162.218.211940.680.884617.10

49、.3056.312032.150.00575,60013.00.592212146.30.2518218.50.2866.712243.90.627017.521.0916.112344.602.24206.254.461.412442.471.6825.3NSDCK (2)d16.10.04932816.112.061.353 e39.30.00596,66015.79.431.7AZT18720.04442,70037.50.1375Non-drug resistant strain aMultiple RT inhibitor resistant strain bCompdIC50 (M

50、)EC50 (M) TI IC50 (M)EC50 (M) TIE. Other modifications126125R1R2OOOOOOOOOOOOOOOOOOOIC50= 41MEC50= 1.25MTI = 33OOOOOOOOOIC50 MEC50= 0.76MTI 218127 R1 = CH3, R2 = COCH3, NS128 R1 = OCH2C6H5, R2 = H, NS129 R1 = OCH2COC6H5, R2=H, NSThe naphthalene compound 125 and indanone analog 126 showed only slight

51、activity against a non-drug resistant HIV strain in H9 lymphocytes with EC50 values of 0.76 and 1.25 M, respectively, while compound 127 129 were inactive (Figure 9-7). These results suggested that a bi-ring system is a requirement for anti-HIV activity. 46 2.4 Structure-Activity Relationship Conclu

52、sions(1) A bi-ring system is a requirement and a planar system is probably an essential feature for potent anti-HIV activity. Steric compression between DCK C-4 and C-5 substituents or phenyl substituents on the skeleton can reduce the overall planarity and, thus, resonance of system, resulting in d

53、ecreased or completely lost activity. OOOOOOOOOOOR2R1R3R434567823412(2) The stereochemistry at the 3 and 4 positions should be R-configured, and an isovaleryl structural feature is essential on these positions. Camphanoyl moieties are the most potent substituents. OOOOOOOOOOOR2R1R3R434567823412(3) M

54、ethyl or other aliphatic substitutions on the DCK C-3, C-4, and C-5 are favorable for anti-HIV activity against the non-drug resistant strain, whereas aromatic substituents and 6-substitution are not. The DCK C-3 can tolerate polar but not charged or electron withdrawing substituents. OOOOOOOOOOOR2R

55、1R3R434567823412(4) The bioisosteric isomers, thio-DCK and DCK lactam retain activity. OOOOOOOOOOOR2R1R3R434567823412(5) The positional isomer, DCP, is even more promising since most DCP analogs are active against a multiple RT inhibitor resistant strain, while most DCK derivatives are ineffective a

56、gainst this drug-resistant HIV-1 strain. OOOOOOOOOOOR2R1R3R434567823412(6) An appropriate alkyl substituent at position 2 is critical for the anti-HIV activity of DCP analogs against both non-drug resistant and multi-RT resistant viral strains. In addition, most 2-substituted DCP analogs are less to

57、xic to the cells compared with DCP. Low water solubility, less potency against drug resistant HIV strains, and fast metabolism are three main obstacles that limit the development of DCK analogs. Further analog design is likely to use DCP as a new lead to increase the potency against drug resistant v

58、iral strains and improve water solubility, and pharmacological properties. In 1992, workers at the National Cancer Institute (NCI),a branch of the US National Institutes for Health, reportedthe isolation of coumarins, which they named calanolides,with potent activity against HIV-1 from the tree, Cal

59、ophyllumlanigerum, collected in Sarawak, Malaysia.5. Synthesis of Calophyllum coumarins5.1 Introduction 胡桐胡桐 屬屬 ( Calophyllum) ( Calophyllum) 植物富含甾體、三萜、香豆素植物富含甾體、三萜、香豆素和苯并吡喃等次級代謝物。和苯并吡喃等次級代謝物。19921992年年BoydBoyd等首次報道由生長于馬等首次報道由生長于馬來西亞熱帶雨林的同屬植物來西亞熱帶雨林的同屬植物C. LanigeruC. Lanigeru，中分出的香豆素化，中分出的香豆素化合物具有抗合

60、物具有抗HIVHIV活性。此后，采用生物活性導(dǎo)向分離，相繼從活性。此后，采用生物活性導(dǎo)向分離，相繼從該屬植物中篩選到一系列抗該屬植物中篩選到一系列抗HIVHIV活性的新型雙吡喃香豆素類化活性的新型雙吡喃香豆素類化合物，主要有合物，主要有calanolidecalanolide和和inophylluminophyllum兩種結(jié)構(gòu)類型，其兩種結(jié)構(gòu)類型，其C-4C-4位分別由正丙基或苯基取代。這是一類化學結(jié)構(gòu)新穎且具有高位分別由正丙基或苯基取代。這是一類化學結(jié)構(gòu)新穎且具有高度特異性的度特異性的HIV-1 RTHIV-1 RT抑制劑，它們對抗愛滋病藥物抑制劑，它們對抗愛滋病藥物AZTAZT耐藥的耐藥的病毒細胞