CN106806361B - 二芳基庚烷类化合物的用途 - Google Patents
二芳基庚烷类化合物的用途 Download PDFInfo
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- CN106806361B CN106806361B CN201611230519.4A CN201611230519A CN106806361B CN 106806361 B CN106806361 B CN 106806361B CN 201611230519 A CN201611230519 A CN 201611230519A CN 106806361 B CN106806361 B CN 106806361B
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Abstract
Description
技术领域
本发明涉及二芳基庚烷类化合物的新用途,具体涉及它们在制备一氧化氮生成抑制剂、治疗炎症、治疗败血症和/或治疗阿尔茨海默病的药物中的用途。
背景技术
二芳基庚烷类化合物是一类具有1、7-二取代芳基并以庚烷骨架为母体结构的化合物的统称。根据其成环与否以及两个苯环连接方式的不同,分为3种类型,即直线型、大环联苯型和环二苯醚型。该类化合物主要存在于植物的根、茎、皮、花以及果皮等部位。由于其独特的化学结构和广泛的药理活性尤其是抗癌活性,近年受到国内外植物化学和药学研究者的普遍关注。已有研究报道,姜属植物中的线性二芳基庚烷类化合物姜黄素,具有较强的抗癌活性以及癌化学预防作用。
体内的NO由一氧化氮合酶(Nitric oxide synthases,NOS)催化L-精氨酸(L-Arg)产生。已知的NOS有不同基因编码的3种同工酶,即神经型(nNOS)、内皮型(eNOS) 和诱导型(iNOS)。诱导型NO合酶iNOS可被一些外来刺激激活,如内毒素(LPS)、干扰素类、细菌、病毒及促炎症因子(TNF-α、IL-1、IL-6)等。NO在体内发挥双重作用,是免疫系统发挥作用不可缺少的调节因子。然而,NO的过度产生则会导致组织损伤,例如导致肝损伤或者炎症等等。
炎症(inflammation)是一种常见的疾病,可以由细菌、病毒感染,组织器官病理变化,免疫系统的异常或者有害物质刺激及物理损伤时引起。
败血症(septicemia)是指致病细菌侵入血液循环中生长繁殖引起的急性全身性感染,临床症状为寒战、高热、皮疹、关节痛及肝脾肿大,部分患者还可出现烦躁、四肢厥冷及紫绀、脉细速、呼吸加快、血压下降等。病死率可达30~50%,尤其是老人、儿童、有慢性病或免疫功能低下者、治疗不及时及有并发症者,预后更为恶劣。
阿兹海默病(Alzheimer's disease,AD)是发生在老年期及老年前期的一种原发性退行性脑病,指的是一种持续性高级神经功能活动障碍,即在没有意识障碍的状态下,记忆、思维、分析判断、视空间辨认、情绪等方面的障碍。其特征性病理变化为大脑皮层萎缩,并伴有β-淀粉样蛋白沉积,神经原纤维缠结,大量记忆性神经元数目减少,以及老年斑的形成。阿兹海默病病因复杂,其发生为多种因素相互作用的结果。目前尚无特效治疗或逆转疾病进展的治疗药物。
发明内容
为解决上述问题,本发明提供了式(Ⅰ)和/或式(Ⅱ)所示二芳基庚烷类化合物在制备一氧化氮生成抑制剂、治疗炎症、治疗败血症和/或治疗阿尔茨海默病的药物中的用途,
其中,R1~R4分别独立地表示无或者苯环上的1~5个取代基,所述取代基分别独立地选自羟基或C1~C4的烷氧基。
进一步地,R3、R4表示苯环上的1个取代基。
进一步地,所述C1~C4的烷氧基为甲氧基。
进一步地,所述式(Ⅰ)、式(Ⅱ)或式(Ⅲ)化合物为如下化合物之一:
进一步地,所述一氧化氮生成抑制剂是抑制巨噬细胞生成一氧化氮和/或抑制巨噬细胞增殖的药物。
进一步地,所述治疗炎症的药物是抑制巨噬细胞生成一氧化氮和/或抑制巨噬细胞增殖的药物。
进一步地,所述治疗败血症的药物是治疗由脂多糖引起的败血症的药物。
进一步地,它是以前述的化合物、或它们的组合、或其药学上可接受的盐、或其溶剂合物为活性成分,加上药学上可接受的辅料制备而成的制剂。
本发明还提供了一种治疗败血症的药物组合物,它是以前述的化合物、或它们的组合、或其药学上可接受的盐、或其溶剂合物为活性成分,加上药学上可接受的辅料制备而成的制剂。
本发明还提供了一种治疗阿尔茨海默病的药物组合物,它是以前述的化合物、或它们的组合、或其药学上可接受的盐、或其溶剂合物为活性成分,加上药学上可接受的辅料制备而成的制剂。
本发明中,所述一氧化氮生成抑制剂指的是对生物体中一氧化氮生成具有抑制作用的药物。
本发明中,C1~C4的烷氧基是指C1、C2、C3、C4的烷氧基,即具有1~4个碳原子的直链或支链的烷氧基。
在本发明的含义之内,“治疗”也包括复发性(relapse)预防或阶段性(phase)预防,以及急性或慢性体征、症状和/或功能失常的治疗。治疗可以是对症治疗,例如抑制症状。它可以在短期内实现,在中期内调整,或者可以说是长期治疗,例如在维持疗法里面。所述预防包括延迟和/或阻止病症、疾病或病况和/或其伴发症状的发作;防止对象染上病症、疾病或病况;或降低对象染上病症、疾病或病况的风险的方法。
试验证明,本发明的化合物可以有效抑制一氧化氮生成、治疗炎症、治疗败血症和治疗阿尔茨海默病,大幅扩展了二芳基庚烷类化合物应用范围,极具临床应用前景。
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式,对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
附图说明
图1为化合物1-37,39-49对LPS诱导RAW264.7巨噬细胞生成NO的影响。C(Curcumin)和D(Dexamethasone)为阳性药物。LPS,0.5μg/mL;Curcumin,5μM;Dexamethasone,10μM。
图2为化合物21、25、34-36抑制LPS诱导RAW264.7巨噬细胞生成NO的IC50值。
图3为化合物对巨噬细胞增殖的抑制作用。
具体实施方式
本发明化合物可以从生物资源获得或者通过有机合成获得。
实施例1二芳基庚烷类化合物的提取、分离和鉴定
1.1仪器设备及材料
Perkin-Elmer FT-IR红外分光光度计,KBr压片;核磁共振实验采用BrukerAVANCE 400核磁共振仪;使用ES-TOFMS和ES-MS质谱分别使用Bruker microTOF and aFinnigan LC-Q II mass spectrometer;旋光测定采用JASCO-1020polarimeter;高效液相色谱:Agilent 1260HPLC,制备柱使用Kromasil 100-10-C18;Merck硅胶60(细于0.063 毫米)和Pharmacia公司交联葡聚糖LH-20。
Curcuma comosa根茎在泰国的Nakhon Pathom Sakon Nakhon和Prachin Buri,凭证标本(Apichart Suksamrarn,052号和074)存放在Faculty of Science,RamkhamhaengUniversity。
1.2化合物分离提取
C.comosa的根茎被切片,风干,研磨并用正己烷和EtOH依次浸渍,然后分别进行减压蒸馏,得到正己烷和EtOH提取物。正己烷和EtOH萃取物通过柱层析(Merck硅胶 60PF254)分级分离,使用正己烷,正己烷-EtOAc,乙酸乙酯,乙酸乙酯-甲醇和甲醇的梯度洗脱。最终,5个新的二苯庚烷类化合物1-5和16个已知的二苯庚烷类化合物 6-21[1,2]。
1.3部分化合物波谱数据
1-(4-Hydroxy-3-methoxyphenyl)-7-phenyl-(6E)-6-hepten-3-one(化合物1)
无色油状物;IR:νmax:3426,2923,2845,1711,1597,1514,1453,1373,1267,1233,1208,1026,967, 811,748,699;1H NMR(400MHz,CDCl3):δ2.82(dd,7.32,7.36,H1),2.70(dd,7.36,7.03,H2),2.55 (dd,8.15,7.72,H4),2.45(dd,7.72,7.26,H5),6.14(dt,7.26,15.8,H6),6.55(d,15.8,H7),6.65(s,H2′), 6.79(d,8.0,H5′),6.64(d,8.0,H6′),7.18-7.28(m,H2″),7.18-7.28(m,H3″),7.17(m,H4″),7.18-7.28 (m,H5″),7.18-7.28(m,H6″),3.82(s,OMe3″);13C NMR(100MHz,CDCl3):δ29.4(C1),44.7(C2), 209.2(C3),37.0(C4),29.2(C5),128.7(C6),130.7(C7),132.9(C1′),111.1(C2′),146.3(C3′),143.7 (C4′),114.2(C5′),120.9(C6′),137.3(C1″),125.9(C2″),128.4(C3″),127.0(C4″),128.4(C5″),125.9 (C6″),55.8(OMe3′).
(3S)-and(3R)-1-(4-Hydroxy-3-methoxyphenyl)-7-phenyl-(6E)-6-hepten-3-ol(化合物2)
无色油状物;[α]D27.1=-1.59[EtOH,C=0.65w/v];IR:νmax:3359,3193,2923,2852,1659,1630,1515, 1466,1426,1373,1272,1233,1152,1035,965,816,794,735,693;1H NMR(400MHz,CDCl3):δ2.54, 2.66(m,H1),1.70(m,H2),3.63(m,H3),1.59(m,H4),2.26(m,H5),6.15(dt,6.8,15.8,H6),6.33 (d,15.8,H7),6.63(s,H2′),6.75(d,6.4,H5′),6.62(d,6.4,H6′),7.18-7.28(m,H2″),7.18-7.28(m,H3″), 7.12(t,7.0,H4″),7.18-7.28(m,H5″),7.18-7.28(m,H6″),3.78(s,OMe3);13C NMR(100MHz, CDCl3):δ31.7(C1),39.4(C2),70.9(C3),37.0(C4),29.2(C5),130.2(C6),130.3(C7),133.9(C1′), 120.8(C2′),146.4(C3′),143.7(C4′),114.2(C5′),110.9(C6′),137.5(C1″),125.9(C2″),128.4(C3″),126.9(C4″),128.4(C5″),125.9(C6″),55.8(OMe3′).
2:1Mixture of(3S)-and(3R)-1-(4-Hydroxy-3-methoxyphenyl)-7-phenyl-(4E,6E)-4,6- heptadien-3-ol(化合物3)
淡黄色油状物;IR:νmax:3398,3025,2933,2858,1613,1600,1515,1463, 1451,1369,1270,1234,1153,1123,1033,991,749,693;1H NMR(400MHz,CDCl3):δ2.65(m,H1), 1.88(m,H2),4.21(m,H3),5.83(dd,6.8,15.1,H4),6.38(dd,10.7,15.1,H5),6.76(dd,10.7,15.6,H6), 6.54(d,15.6,H7),6.70(brs,H2′),6.82(brd,7.4,H5′),6.69(brd,7.4,H6′),7.38(brd,7.2,H2″),7.30 (brt,7.6,H3″),7.24(m,H4″),7.30(brt,7.6,H5″),7.38(brd,7.2,H6″),3.86(brs,OMe3);13C NMR (100MHz,CDCl3):δ31.3(C1),39.0(C2),72.0(C3),136.2(C4),130.9(C5),128.1(C6),132.8(C7), 133.7(C1′),111.0(C2′),146.4(C3′),143.7(C4′),114.2(C5′),120.9(C6′),137.1(C1″),126.3(C2″),128.6(C3″),127.5(C4″),128.5(C5″),126.3(C6″),55.8(OMe3).
(3S)-1-Phenyl-7-(4-hydroxyphenyl)heptan-3-ol(化合物4)
无色油状物;[α]D 28=+1.63[EtOH,C=0.58w/v];IR:νmax:3297,3025,2930,2856,1598,1513,1495, 1453,1366,1228,1170,1028,824,745,697;1H NMR(400MHz,CDCl3):δ2.56,2.70(m,H1),1.67 (m,H2),3.52(H3),1.41(m,H4),1.29,1.41(m,H5),1.50(m,H6),2.44(t,7.56,H7),7.08-7.15(m, H2′),7.18-7.24(m,H3′),7.08-7.15(m,H4′),7.18-7.24(m,H5′),7.08-7.15(m,H6′),6.92(d,8.30,H2″), 6.66(d,8.30,H3″),6.66(d,8.30,H5″),6.92(d,8.30,H6″);13C NMR(100MHz,CDCl3):δ31.9(C1), 38.8(C2),71.1(C3),37.2(C4),25.0(C5),31.6(C6),34.8(C7),142.2(C1′),128.3(C2′),125.6(C3′), 128.3(C4′),125.6(C5′),128.3(C6′),133.8(C1″),129.2(C2″),115.0(C3″),154.2(C4″),115.0(C5″),129.2(C6″).
(3S)-1-(3,4-Dihydroxyphenyl)-7-phenyl-(4E,6E)-4,6-heptadien-3-ol(化合物5)
白色固体;m.p.105-106℃;IR:νmax:3396,3233,3022,2949,2924, 2849,1612,1596,1515,1447,1254,1228,1175,1096,1044,990,825,748,692,513;1H NMR(400 MHz,CDCl3):δ2.57(m,H1),1.77(m,H2),4.16(H3),5.19(dd,6.1,15.2,H4),6.41(dd,10.3,15.2, H5),6.89(dd,10.3,15.6,H6),6.56(d,15.6,H7),6.53(brs,H2′),6.70(brd,7.9,H5′),6.72(brd,7.9, H6′),7.44(brd,7.5,H2″),7.30(brd,7.5,H3″),7.20(brt,7.5,H4″),7.30(brd,7.5,H5″),7.44(brd,7.5, H6″),3.85(D,4.3,OH3),7.59(brs,OH3′4′);13C NMR(100MHz,CDCl3):δ30.85(C1),39.59(C2), 70.65(C3),138.36(C4),129.40(C5),128.90(C6),131.42(C7),134.01(C1′),119.50(C2′),142.89 (C3′),144.81(C4′),115.03(C5′),115.39(C6′),115.39(C1″),137.53(C2″),126.13(C3″),128.49 (C4″),127.19(C5″),128.49(C6″).
1,7-Diphenylhepta-l,3,5-trien(化合物21)
白色固体;mp 76.0-76.5℃;IR(KBr):3009.5-3101.9,2831.9-2925.9,1595.3,1490.6,1452.0,1427.3, 1073.0,1027.7,992.9,742.6,697.3cm-1;1H NMR(300MHz,CDCl3):δ3.45(d,2H,J=7.1Hz),5.89 (dt,1H,J=14.8,7.0Hz),6.14-6.34(m,3H),6.51(d,1H,J=15.6Hz),6.79(m,1H),7.17-7.39(m, 10H,ArH);MS m/e(intensity):246(65.0,M+),155(100.0),142(30.5),129(18.2),I15(20.7),103 (3.5),91(31.9).
2.1本发明涉及的二芳基庚烷类化合物可以根据以下路线制备
路线1:
备注:a)HCl.NH2OH,DMF,Pyridine
b)H2,Pd-C,EtOH
c)Ac2O,Pyridine
d)PhCH2Br,DMF,K2CO3 e)PCC,CH2Cl2
路线2:
备注:(i)excess acetaldehyde,20%aq NaOH,EtOH,0–10℃;
(ii)MeI,K2CO3,acetone,rt.;(iii)20%aq NaOH,EtOH,0℃–rt;(iv)H2(balloon)/10%Pd-C,EtOH.
如路线1所示,对化合物6,12和20进行结构修饰,可以获得化合物22-25,26-29,30-33。如路线2所示,不饱和trienone类似物34-37分别根据文献[3]中的条件,碱催化条件下醛醇缩合,在20%的NaOH的存在下,使用乙醇作为溶剂,用cinnamaldehydes 2a 和2b取代cinnamones 1a-d。三个新的二芳基庚烷类似物(39和40-41)和前面的合成方法类似。
2.2部分化合物波谱数据
3-Hydroxyoxime-1,7-diphenyl-(6E)-6-heptene(化合物22)
白色固体;m.p.55-56℃;IR:νmax:3240,3026,2924,1711,1656,1599,1495,1447,1333, 966,941,737,691;1H NMR(400MHz,CDCl3):δ2.93(dd,J=8.3,7.6Hz,2H,H-1),2.63(dd,J=8.3,7.6Hz,2H,H-2),2.49(m,2H,H-4),2.42,2.75(m,2H,H-5),6.24(m,1H, H-6),6.46(dd,J=15.3,10.3Hz,1H,H-7),7.23-7.38(m,9H,overlapping signal of H2′,3′,5′, 6′and H2″-6″);13C NMR(100MHz,CDCl3):δ29.55(C1),33.90(C2),161.6(C3),31.34(C4),27.95(C5),130.8(C6),131.0(C7),114.8(C1′),128.3(C2′,6′),126.2(C3′,5′),126.8 (C4′),140.7(C1″),128.3(C2″,4″,6″),126(C3″,5″);ESMS:m/z 280.9[M+H]+(100), [2M+Na]+HR-TOFMS(ES+):280.1703[M+H]+calcd for C19H21NO+H,280.1696.
1-(4-Benzyloxy-7-phenyl-(6E)-6-hepten-3-ol(化合物23)
白色固体;m.p.70-71℃;IR:νmax:3305,3028,2939,2868,1607,1583,1509,1453,1380, 1296,1237,1221,1175,1084,1007,963,896,819,737,691;1H NMR(400MHz,CDCl3):δ2.69,2.77(m,2H,H-1),1.81(m,2H,H-2),3.74(m,1H,H-3),1.69(m,2H,H-4),2.37(m, 2H,H-5),6.24(dt,J=15.8,6.8Hz,1H,H-6),6.45(d,J=15.8Hz,1H,H-7),7.16(d,J=8.3 Hz,2H,H-2′,6′),6.94(d,J=8.3Hz,2H,H-3′,5′),7.24-7.48(m,10H,H-2″-5″and H-2″′-5″′)5.07(s,2H,-CH 2-C6H5);13C NMR(100MHz,CDCl3):δ31.1(C1),39.2(C2),70.3(C3), 37.0(C4),29.2(C5),130.2(C6,C7),137.2(C1′),129.2(C2′,6′),114.8(C3′,5′),157.0(C4′),134.3(C1″),125.9(C2″,6″),126.9(C4″),127.4(C3″,5″),137.6(C1″′),127.4(C2″′,6″′),127.8 (C4″′),128.5(C3″′,5″′),70.0(-CH2-C6H5);ESMS:m/z 378.3[M+H]+;HR-TOFMS(ES+):m/z 395.1983[M+Na]+calcd for C26H28O2+Na,m/z 395.1982
1-(4-Acethoxy)-7-phenylheptan-3-one(化合物24)
无色油状物;IR:νmax:3027,2931,2862,1760,1710,1507,1453,1368,1191,1165,1017,910, 747,699;1H NMR(400MHz,CDCl3):δ2.94(t,J=7.50Hz,2H,H-1),2.77(t,J=7.50HZ, 2H,H-2),2.47(br t,J=7.56Hz,2H,H-4),1.67(br s,4H,H-5,6),2.67(br t,J=6.38Hz,2H, H-7),7.35(d,J=8.0Hz,2H,H-2′,6′),7.05(d,J=8.0Hz,2H,H-3′,5′),7.22-7.33(m,5H, H-2″-6″,2.36(s,3H,-CH 3-C=O);13C NMR(100MHz,CDCl3):δ29.0(C1),44.1(C2), 209.7(C3),42.8(C4),23.3(C5),30.9(C6),35.6(C7),142.1(C1′),129.2(C2′,6′),121.4 (C3′,5′),148.9(C4′),138.6(C1″),128.2(C2″,6″),125.7(4″),128.3 (C3″,5″)21.0,169.5(-CH3-C=O);ESMS:m/z 347.9[M+Na]+;HR-TOFMS(ES+):m/z 347.1637[M+Na]+calcd for C21H24O3+Na,347.1618.
1-(3,4-Diacetoxyphenyl)-7-phenyl-(6E)-6-hepten-3-ol(化合物25)
无色油状物;IR:νmax:3417,3027,2933,2862,1765,1597,1504,1425,1369,1257,1205, 1179,1109,1011,964,898,831,743,693;1H NMR(400MHz,CDCl3):δ2.65,2.77(m,2H,H-1),1.76(m,2H,H-2),3.67(m,2H,H-3),1.63(m,2H,H-4),2.30(m,2H,H-5),6.20(dt,J=15.8,8.6Hz,1H,H-6),6.39(d,J=15.8Hz,1H,H-7),7.00(s,2H,H-2′),7.05(s,2H,H-5′,6′), 7.17-7.29(m,5H,H-2″-6″),2.25(s,3H,-CH 3-C=O);13C NMR(100MHz,CDCl3):δ31.3(C1),38.7(C2),70.7(C3),37.0(C4),29.2(C5),130.1(C6,7),130.3(C1′),123.1(C2′),140.9 (C3′),137.5(C4′),123.2(C5′),126.5(C6′),130.3(C1″),125.9(C2″,6″),126.9(4″),128.4 (C3″,5″),20.6,168.4(-CH3-C=O);ESMS:m/z 405.8[M+Na]+,HR-TOFMS(ES+):m/z 405.1689[M+Na]+calcd for C23H26O5+Na,405.1672.
1-(3,4-Dihydroxyphenyl)-7-phenylheptan-3-ol(化合物26)
无色油状物;IR:νmax:3319,2931,2856,1603,1518,1495,1451,1361,1279,1191,1111, 1058,954,866,811,786,743,697,631;1H NMR(400MHz,CDCl3):δ2.58(m,2H,H-1),1.69(m,2H,H-2),3.60(m,1H,H-3),1.61(m,2H,H-4),1.31,1.47(m,2H,H-5),1.47(m,2H,H-6),2.58(t,J=7.65Hz,2H,H-7),6.66(s,2H,H-2′,6′),6.74(d,J=8.0Hz,1H,H-5′),6.59 (d,J=8.0Hz,1H,H-6′),7.13-7.17,7.20-7.27(m,5H,H-2″-6″);13C NMR(100MHz,CDCl3): δ31.4(C1),38.9(C2),71.5(C3),31.3(C4),25.2(C5),37.3(C6),35.8(C7),141.6(C1′), 115.3(C2′,6′),143.5(C3′),142.4(C4′),115.4(C5′),120.6(6′),134.9(C1″),128.2(C2″,6″), 125.6(C4″),128.3(C3″,5″);ESMS:m/z 599.8[2M-H]-HR-TOFMS(ES+):m/z323.1632[M+Na]+calcd for C19H24O3+Na,323.1618.
1-(3,4-Diacetoxyphenyl)-7-phenylheptan-3-ol(化合物27)
无色油状物;IR:νmax:3423,3026,2932,2857,1766,1603,1504,1425,1369,1257,1206, 1180,1109,1011,899,830,746,699;1H NMR(400MHz,CDCl3):δ2.64,2.76(m,2H,H-1), 1.77(m,2H,H-2),3.59(m,1H,H-3),1.62(m,2H,H-4),1.36,1.47(m,2H,H-5),1.47(m,2H, H-6),2.59(t,J=7.5Hz,2H,H-7),6.99(s,1H,H-2′),7.05(dd,J=8.2,8.2),2H,H-5′,6′), 7.14-7.16,7.24-7.27(m,5H,H-2″-6″),2.26(s,6H,-CH 3-C=O);13C NMR(100MHz,CDCl3):δ31.4(C1),38.9(C2),71.0(C3),31.3(C4),25.2(C5),37.4(C6),35.8(C7),141.0(C1′),123.1(C2′),142.5(C3′),141.8(C4′),123.2(C5′),125.6(6′),140.0(C1″),128.2(C2″,6″),128.2(C4″),128.3(C3″,5″),20.6(-CH3-),168.4(C=O);ESMS:m/z 791.0 [2M+Na]+HR-TOFMS(ES+):m/z 407.1847[M+Na]+calcd for C23H28O5+Na,407.1829.
3-Acetoxy-1-(3,4-diacetoxyphenyl)-7-phenylheptane(化合物28)
无色油状物;IR:νmax:2935,2868,1769,1730,1601,1505,1426,1369,1241,1204,1178, 1110,1011,896,831,747,699;1H NMR(400MHz,CDCl3):δ2.65(m,2H,H-1),1.91(m,2H,H-2),4.98(m,1H,H-3),1.66(m,4H,H-4,5),1.40(br s,2H,H-6),2.65(m,2H,H-7),6.99(s,1H,H-2′),7.13(d,J=8.3Hz,1H,H-5′),7.08(d,J=8.3Hz,1H,H-6′),7.20-7.25,7.30-7.34(m,5H,H-2″-6″),2.06,2.32(s,9H,-CH 3-C=O);13C NMR(100MHz,CDCl3):δ 35.3(C1),35.6(C2),73.5(C3),31.1(C4),24.7(C5),33.8(C6),31.1(C7),140.4(C1′),123.0(C2′),142.3(C3′),141.8(C4′),123.0(C5′),125.6(6′),140.0(C1″),128.1(C2″,6″),126.3 (C4″),128.3(C3″,5″),20.5,21.0,(-CH3),168.2,168.3,170.8(C=O);ESMS:m/z449.80 [M+Na]+HR-TOFMS(ES+):m/z 449.1936[M+Na]+calcd for C25H30O6+Na,449.1935
1-(3,4-Diacetoxyphenyl)-7-phenylheptan-3-one(化合物29)
无色油状物;IR:νmax:2934,2868,1767,1710,1602,1505,1425,1369,1257,1204,1178, 1109,1010,899,831,747,699;1H NMR(400MHz,CDCl3):δ2.84(t,J=7.5Hz,2H,H-1),2.68(t,J=7.5Hz,2H,H-2),2.36(t,J=6.0Hz,2H,H-4),1.58(m,2H,H-5),1.55(m,2H, H-6),2.58(t,J=6.5Hz,1H,H-7),6.97(s,1H,H-2′),7.04(dd,J=12.0Hz,8.2Hz,2H, H-5′,6′),7.13-7.16,7.24-7.26(m,5H,H-2″-6″),2.25(s,-CH 3-C=O);13C NMR(100MHz,CDCl3):δ28.9(C1),43.8(C2),209.4(C3),42.8(C4),23.3(C5),30.9(C6),35.6(C7),140.0(C1′),123.2(C2′,5′),142.1(C3′),141.8(C4′),123.2(C5′),125.7(C6′),140.2(C1″),128.2 (C2″,6″),126.5(4″),128.3(C3″,5″),20.6,168.3(-CH3-C=O);ESMS:m/z 405.8[M+Na]+; HR-TOFMS(ES+):m/z 405.1691[M+Na]+calcd for C23H226O5+Na,405.1672
Cinnamaldehyde(or(E)-3-(2,4-Dimethoxyphenyl)acrylaldehyde)).(化合物3c)
淡黄色固体;IR:νmax 2840,2767,1660,1606,1570,1502,1425,1324,1296,1275,1202, 1166,1023,969,921,835,783cm-1;1H NMR(400MHz,CDCl3):δ9.60(d,J=7.9Hz,1H),7.71(d,J=15.9Hz,1H),7.46(d,J=8.6Hz,1H),6.68(dd,J=15.9,7.9Hz,1H),6.51(dd,J= 8.6,2.3Hz,1H),6.44(d,J=2.3Hz,1H),3.86(s,3H),3.83(s,1H).;13C NMR(100MHz,CDCl3):δ194.6,163.7,159.9,148.4,130.5,126.8,116.2,105.6,98.3,55.53,55.51;ESMS(+ve):m/z 407[2M+Na]+.
Cinnamaldehyde 2d((E)-3-(2,5-Dimethoxyphenyl)acrylaldehyde).(化合物3d)
淡黄色固体;IR:νmax 2921,2839,2810,2738,2712,1668,1610,1493,1424,1224,1134, 1040,1022,973,846,804,711cm-1;1H NMR(400MHz,CDCl3):δ9.67(d,J=7.8Hz,1H),7.81(d,J=16.1Hz,1H),7.05(d,J=3.0Hz,1H),6.96(dd,J=9.0,3.0Hz,1H),6.87(d,J=9.0Hz,1H),6.73(dd,J=16.1,7.8Hz,1H),3.85(s,3H),3.78(s,3H).;13C NMR(100MHz,CDCl3):δ194.3,153.6,152.8,147.7,129.2,123.5,118.5,113.0,112.6,56.1,55.8;ESMS(+ve):m/z 193[M+H]+.
1,7-Bis(3-hydroxyphenyl)-1,4,6-heptatrien-3-one(化合物34).
橙黄色固体;m.p.191-194℃;ESMS(+ve):m/z 607[2M+Na]+;HR-TOFMS(ES–):m/z291.1019[M–H]–(Calcd.for C19H16O3–H,291.1021).
1-(3-Hydroxyphenyl)-7-(3-methoxyphenyl)-1,4,6-heptatrien-3-one(化合物35).
亮黄非晶固体;m.p.120-122℃;ESMS(+ve):m/z 307[M+H]+;HR-TOFMS(ES+):m/z329.1161[M+Na]+(Calcd.for C20H18O3+Na,329.1154).
1-(3-Methoxyphenyl)-7-(3-hydroxyphenyl)-1,4,6-heptatrien-3-one(化合物36).
亮黄非晶固体;m.p.120-121℃;ESMS(+ve):m/z 307[M+H]+;HR-TOFMS(ES+):m/z329.1157[M+Na]+(Calcd.for C20H18O3+Na,329.1154).
(1-(3-Hydroxyphenyl)-7-(2,4-dimethoxyphenyl)-1,4,6-heptatrien-3-one(化合物39).
橙色固体;IR:νmax 3281,2940,2837,1659,1594,1559,1446,1267,1206,1088,1024,996, 976,860,828,779,672cm-1;1H NMR(400MHz,acetone-d6):δ8.61(s,1H),7.53-7.65(m, 3H),7.16-7.34(m,5H),7.06(dd,J=15.6,11.2Hz,1H),6.90(m,1H),6.54-6.64(m,3H),3.91 (s,3H),3.84(s,3H);13C NMR(100MHz,acetone-d6):δ188.8,163.1,160.0,158.7,145.4, 142.5,137.6,137.3,130.8,129.5,128.8,126.2,126.1,120.7,118.9,118.2,115.5,106.8,99.1, 56.0,55.8.;ESMS(+ve):m/z 359[M+Na]+;HR-TOFMS(ES+):m/z359.1250[M+Na]+ (Calcd.for C21H20O4+Na,359.1254).
1-(3-Hydroxy-4-methoxyphenyl)-7-(2,4-dimethoxyphenyl)-1,4,6-heptatrien-3-one(化合物 40).
橙色固体;IR:νmax 3298,3005,2938,2838,1639,1571,1505,1438,1261,1199,1022,984, 836cm-1;1H NMR(400MHz,CDCl3):δ7.57(d,J=15.8Hz,1H),7.51(dd,J=15.2,11.2 Hz,1H),7.44(d,J=8.6Hz,1H),7.25(d,J=15.6Hz,1H),7.20(d,J=1.5Hz,1H),7.08(dd, J=8.3,1.5Hz,1H),6.91(dd,J=15.6,11.2Hz,1H),6.89(d,J=15.8Hz,1H),6.84(d,J=8.3 Hz,1H),6.50(d,J=15.2Hz,1H),6.49(dd,J=8.6,2.0Hz,1H),6.43(d,J=2.0Hz,1H),5.68 (s,1H),3.91(s,3H),3.85(s,3H),3.81(s,3H);13C NMR(100MHz,CDCl3):δ189.0,161.9, 158.9,148.6,145.9,144.8,142.3,136.8,128.7(2C),127.7,125.4,123.8,122.3,118.4,113.0, 110.6,105.3,98.5,56.0,55.5,55.4;ESMS(-ve):m/z 356[M-H]-;HR-TOFMS(ES+):m/z 389.1367[M+Na]+(Calcd.for C22H22O5+Na,389.1365)
(1-(3-Hydroxy-4-methoxyphenyl)-7-(2,5-dimethoxyphenyl)-1,4,6-heptatrien-3-one(化合物41).
黄色固体;IR:νmax 3228,3001,2945,2839,1635,1630,1557,1505,1233,1133,1016,874, 803cm-1;1H NMR(400MHz,CDCl3):δ7.58(d,J=15.8Hz,1H),7.51(dd,J=15.2,11.1Hz, 1H),7.30(d,J=15.6Hz,1H),7.20(d,J=1.8Hz,1H),7.08(dd,J=8.2,1.8Hz,1H),7.05(d, J=2.2Hz,1H),6.96(dd,J=15.6,11.1Hz,1H),6.88(d,J=15.8Hz,1H),6.84(d,J=8.2Hz, 1H),6.82(overlapped,1H),6.81(overlapped,1H),6.56(d,J=15.2Hz,1H),5.73(br s,1H), 3.91(s,3H),3.82(s,3H),3.79(s,3H);13C NMR(100MHz,CDCl3):δ189.0,153.6,152.1, 148.7,145.9,143.9,142.7,136.3,128.9,128.5,127.7,125.8,123.6,122.4,115.7,113.1,112.4, 112.1,110.6,56.2,56.0,55.8;ESMS(+ve):m/z 367[M+H]+;HR-TOFMS(ES+):m/z 389.1365[M+Na]+(Calcd.for C22H22O5+Na,389.1365)
1-(4-Methoxyphenyl)-7-(3-hydroxyphenyl)-heptan-3-one(化合物42).
无色油状物;IR:νmax 3384,2931,2859,1698,1511,1454,1242,1177,1154,1033,825,781, 695cm-1;1H NMR(400MHz,CDCl3):δ7.10(distorted t,J=8.5Hz,1H),7.07(d,J=8.5Hz, 2H),6.80(d,J=8.5Hz,2H),6.69(distorted d,J=7.5Hz,1H),6.63(distortedd,J=8.1Hz, 1H),6.56(br s,1H),3.77(s,3H),2.81(distorted t,J=7.4Hz,2H),2.66(distorted t,J=7.4 Hz,2H),2.50(distorted t,J=7.1Hz,2H),2.36(distorted t,J=6.8Hz,2H),1.44-1.69(m,4H);13C NMR(100MHz,CDCl3):δ211.0,158.0,155.8,144.0,133.1,129.4,129.3(2C),120.6, 115.3,113.9(2C),112.7,55.3,44.5,42.9,35.5,30.6,28.9,23.3;ESMS(-ve):m/z 311[M-H]-.
1-(3-Hydroxy-4-methoxyphenyl)-7-(3-hydroxyphenyl)-heptan-3-one(化合物43).
无色油状物;IR:νmax 3465,3326,2917,2853,1693,1594,1514,1446,1377,1275,1237, 1198,1131,1025,999,924,780,691cm-1;1H NMR(400MHz,CDCl3):δ7.10(t,J=7.7Hz, 1H),6.57-6.77(m,6H),3.83(s,3H),2.77(distorted t,J=7.1Hz,2H),2.65(distorted t,J=7.0 Hz,2H),2.50(distorted t,J=6.7Hz,2H),2.36(distorted t,J=6.5Hz,2H),1.44-1.63(m,4H);13C NMR(100MHz,CDCl3):δ211.0,155.8,145.4,144.9,144.0,134.3,129.4,120.7,119.8, 115.3,114.5,112.8,110.8,56.0,44.2,42.8,35.4,30.5,29.2,23.3;ESMS(-ve):m/z 327 [M-H]-.
1-(3-Hydroxyphenyl)-7-(2,4-dimethoxyphenyl)-heptan-3-one(化合物44).
无色油状物;IR:νmax 3436,2934,2836,1702,1610,1585,1502,1459,1209,1156,1124,1030, 844,778,687cm-1;1H NMR(400MHz,CDCl3):δ7.11(t,J=7.8Hz,1H),6.97(d,J=8.1Hz, 1H),6.71(d,J=7.6Hz,1H),6.59-6.67(m,2H),6.36-6.44(m,2H),5.13(br s,1H),3.77(s, 3H),3.75(s,3H),2.80(distorted t,J=7.5Hz,2H),2.66(distorted t,J=7.5Hz,2H),2.50 (distorted t,J=7.3Hz,2H),2.38(distorted t,J=7.2Hz,2H),1.43-1.65(m,4H);13C NMR (100MHz,CDCl3):δ211.1,159.0,158.2,155.9,142.9,129.9,129.6,123.0,120.4,115.2, 113.1,103.9,98.5,55.3,55.2,43.9,43.0,29.6,29.5,29.1,23.6.;ESMS(-ve):m/z 683[2M-H]-.
1-(3-Hydroxyphenyl)-7-(2,4-dimethoxyphenyl)-heptan-3-ol(化合物45).
无色油状物;IR:νmax 3317,2933,2857,1705,1611,1587,1505,1455,1285,1258,1206, 1153,1035,934,832,783,696cm-1;1H NMR(400MHz,CDCl3):δ7.12(t,J=8.2Hz,1H),6.98(d,J=8.1Hz,1H),6.74(d,J=7.5Hz,1H),6.64(m,2H),6.37-6.44(m,2H),3.77(s,3H),3.76(s,3H),3.60(m,1H),2.70(m,1H),2.60(m,1H),2.52(t,J=7.5Hz,2H),1.70(m,2H),1.27-1.60(m,6H);13C NMR(100MHz,CDCl3):δ158.9,158.3,155.9,144.0,129.9,129.6,123.4,120.6,115.4,112.8,103.9,98.6,71.5,55.4,55.3,38.6,37.3,31.9,30.0,29.4, 25.3;ESMS(-ve):m/z 687[2M-H]-.
1-(3-Hydroxy-4-methoxyphenyl)-7-(2,4-dimethoxyphenyl)-heptan-3-one(化合物46).
无色油状物;IR:νmax 3429,2935,2841,1707,1612,1587,1505,1270,1206,1153,1125, 1030,832,801,760cm-1;1H NMR(400MHz,CDCl3):δ6.97(d,J=8.0Hz,1H),6.73(m,2H),6.62(d,J=8.1Hz,1H),6.39(m,2H),5.56(br s,1H),3.83(s,3H),3.76(s,3H),3.75(s, 3H),2.77(distorted t,J=7.4Hz,2H),2.65(distorted t,J=7.5Hz,2H),2.50(distorted t,J= 7.3Hz,2H),2.37(distorted t,J=7.1Hz,2H),1.47-1.60(m,4H);13CNMR(100MHz, CDCl3):δ210.4,159.0,158.2,145.5,144.9,134.4,129.9,123.0,119.6,114.4,110.7,103.8, 98.5,56.0,55.3,55.2,44.3,42.9,29.6,29.2(2C),23.6;ESMS(+ve):m/z 767.9[2M+Na]+.
1-(3-Hydroxy-4-methoxyphenyl)-7-(2,4-dimethoxyphenyl)-heptan-3-ol(化合物47).
无色油状物;IR:νmax 3428,2932,2856,2835,1611,1587,1505,1454,1438,1271,1205, 1153,1128,957,920.832,802,760,631cm-1;1H NMR(400MHz,CDCl3):δ6.98(d,J=8.1 Hz,1H),6.76(br s,1H),6.74(distorted d,J=8.4Hz,1H),6.65(d,J=8.0Hz,1H),6.41(br s, 1H),6.39(distorted d,J=8.3Hz,1H),5.55(br s,1H),3.84(s,3H),3.77(s,6H),3.59(m,1H), 2.67(m,1H),2.57(m,1H),2.51(t,J=7.5Hz,2H),1.69(m,2H),1.26-1.60(m,6H);13C NMR (100MHz,CDCl3):δ159.0,158.3,145.5,144.7,135.6,129.9,123.4,119.7,114.6,110.7, 103.8,98.5,71.3,56.0,55.3,55.2,39.1,37.4,31.4,30.1,29.4,25.4.;ESMS(+ve):m/z 771.8 [2M+Na]+.
1-(3-Hydroxy-4-methoxyphenyl)-7-(2,5-dimethoxyphenyl)-heptan-3-one(化合物48).
无色油状物;IR:νmax 3406,2932,2835,1589,1497,1440,1272,1218,1128,1044,1025,957, 867,800,760cm-1;1H NMR(400MHz,CDCl3):δ6.60-6.76(m,6H),5.54(br s,1H),3.83(s, 3H),3.74(s,6H),2.77(distorted t,J=7.5Hz,2H),2.65(distorted t,J=7.4Hz,2H),2.54 (distorted t,J=7.3Hz,2H),2.38(distorted t,J=7.1Hz,2H),1.55(m,4H);13C NMR(100 MHz,CDCl3):δ210.3,153.4,151.7,145.5,144.9,134.4,131.9,119.6,116.2,114.4,111.2, 110.8,110.7,56.0,55.9,55.6,44.3,42.9,29.9,29.4,29.2,23.6;ESMS(+ve):m/z 767 [2M+Na]+.
1-(3-Hydroxy-4-methoxyphenyl)-7-(2,5-dimethoxyphenyl)-heptan-3-ol(化合物49).
无色油状物;IR:νmax 3406,2932,2857,2835,1589,1497,1440,1272,1218,1128,1044,1025, 957,867,800,760,710cm-1;1H NMR(400MHz,CDCl3):δ6.60-6.79(m,6H),5.56(br s,1H), 3.84(s,3H),3.75(s,3H),3.74(s,3H),3.59(m,1H),2.67(m,1H),2.56(m,3H),1.27-1.80(m, 8H);13C NMR(100MHz,CDCl3):δ153.4,151.7,145.4,144.7,135.5,132.3,119.6,116.2, 114.6,111.2,110.6(2C),71.2,55.9(2C),55.3,39.0,37.3,31.3,30.1,29.4,25.4;ESMS(+ve): m/z 771[2M+Na]+.
2.3参考文献:
1.Suksamrarn,A.,Ponglikitmongkol,M.,Wongkrajang,K.,Chindaduang,A.,Kittidanairak,S.,Jankam,A.,Yingyongnarongkul,B.,Kittipanumat,N.,Chokchaisiri,R., Khetkam,P.,Piyachaturawat,P.Diarylheptanoids,new phytoestrogens from therhizomes of Curcuma comosa:Isolation,chemical modification and estrogenicactivity evaluation.Bioorg. Med.Chem.2008,16,6891-6902.
2.Sornkaew,N.,Lin,Y.,Wang,F.,Zhang,G.,Chokchaisiri,R.,Zhang,A.,Wongkrajang, K.,Suebsakwong,P.,Piyachaturawat,P.and Suksamrarn,A.Diarylheptanoids of Curcuma comosa with Inhibitory Effects on Nitric OxideProduction in Macrophage RAW 264.7Cells. Natural Product Communications.2015,10(1),89-93.
3.Chuprajob,T.;Changtam,C.;Chokchaisiri,R.;Chunglok,W.;Sornkaew N.;Suksamrarn,A.Synthesis,cytotoxicity against human oral cancer KB cells andstructure-activity relationship studies of trinone analogues ofcurcuminoids.Bioorg.Med.Chem. lett.2014,16,2839-2844.
4.Sodsai,A.;Piyachaturawat,P.;Sophasan,S.;Suksamrarn,A.;Vongsakul,M.Suppression by Curcuma comosa Roxb.of pro-inflammatory cytokine secretion inphorbol-12-myristate-13-acetate stimulated human mononuclearcells.Int.Immunopharmacol. 2007,7,524-531.
实施例2二芳基庚烷类化合物抑制NO产生的活性作用。
1材料
化合物(1-37,39-49);小鼠RAW264.7巨噬细胞;内毒素(LPS,0.5μg/mL);BAY (10μM,阳性对照)NO检测试剂盒(Beyotime,Haimen,China)。
2主要仪器
荧光酶标仪(Thermo Scienti fic,Waltham,MA,USA)
3方法
3.1 LPS刺激RAW264.7巨噬细胞生成NO的测定
RAW264.7巨噬细胞接种于96-孔板,每孔接种量为1×104细胞,待接种细胞贴壁以后,加入待测化合物(1-37,39-49)孵育2h,然后加入LPS(终浓度为0.5μg/mL),继续培养24h。最后取96孔板培养基,用NO试剂盒进行检测,NO的含量通过测定其OD550来表示。每次实验取3个复孔,重复3次实验。
3.2 NO抑制率的计算
NO的抑制率(%),根据以下公式进行计算:
抑制率(%)=(A-B)/(A-C)×100,
A:LPS(+),化合物(-);B:LPS(+),化合物(+),C:LPS(-),化合物(-)。
3.3统计方法
所有的统计方法均使用GraphPad Prism 5.01软件进行处理。数据以平均数±标准误差表示,数据使用单因素方差分析(ANOVA)。p<0.05
4结果
结果如图1所示,结果表明化合物21,25,34-36在初筛浓度为5μM条件下,可明显抑制LPS诱导的NO生成,其抑制率在80%以上。
进一步测定活性较好的化合物21,25,34-36的IC50值,结果如图2所示,它们的IC50值在0.32-1.61μM。
实施例3二芳基庚烷类化合物对巨噬细胞增殖的抑制作用
1材料
化合物(1-37,39-49);小鼠RAW264.7巨噬细胞;Alamar-Blue试剂。
2主要仪器
荧光酶标仪(Thermo Scienti fic,Waltham,MA,USA)
3方法
3.1化合物(1-37,39-49)对RAW264.7巨噬细胞增殖的影响
接种RAW264.7巨噬细胞于96-孔板,每孔接种1×104细胞,待接种细胞贴壁以后,加入待测化合物(1-37,39-49)孵育24h。然后每个每孔加入Am-Blue细胞增殖与活性检测试剂(SunBioTM)10μL并于培养箱中孵育2~6小时。当培养基的颜色由靛青蓝变成粉红色后用荧光酶标仪测定各孔相对荧光单位(RFU值),激发光波长560nm,发射光波长590nm。每次实验取3个复孔,重复3次实验。
3.2统计方法
所有的统计方法均使用GraphPad Prism 5.01软件进行处理。数据以平均数±标准误差表示,数据使用单因素方差分析(ANOVA),当p<0.05时有统计学意义。
4结果
测定抑制NO生成活性较好的化合物21,25,27-29,34-37,39,41,40的IC50值,结果如图 3所示,化合物34-36在20μM的浓度下对细胞增殖有明显的抑制作用,IC50值19.26-21.12 μM。
实施例4化合物21、化合物34、化合物36抑制LPS诱导的大鼠败血症
1材料
化合物21、化合物34、化合物36;健康SD雄性大鼠,体重260~310g;LPS。
2方法
(1)SD雄性大鼠分成8组(control、LPS、化合物21、化合物34、化合物36),体重260~310g,每组10只。
(2)用化合物(化合物21、化合物34、化合物36,浓度均为25mg/kg)预处理组于尾静脉予,然后立即腹腔注射LPS(10mg/kg);LPS模型组尾静脉予以生理盐水后,立即腹腔注射LPS(10mg/kg);Control组仅尾静脉予以生理盐水。
(3)各组均于4h后予3%戊巴比妥钠(10ml/100g)麻醉,将充满肝素生理盐水的动脉插管插入右颈总动脉描记血压10min,10min后于左颈总动脉取血。
3结果
结果如表1。腹腔大剂量注射LPS后,LPS模型组血小板1min聚集度(PAG1)、5min 聚集度(PAG5)、最大聚集度(MA)、最大聚集时间(TMA)与Control组对比均显著下降;在化合物21、化合物34、化合物36预处理组血小板聚集性各项指标较LPS模型组明显升高。表明化合物21、化合物34、化合物36显著抑制LPS诱导的大鼠败血症。
表1化合物对败血症大鼠血小板聚集性的影响
备注:5min聚集度(PAG1)、5min聚集度(PAG5)、最大聚集度(MA)、最大聚集时间(TMA);**P<0.01各个化合物组vs LPS组。
实施例5化合物36抑制小鼠老年痴呆(AD)模型
1材料
化合物36健康昆明种小鼠雌雄各半,体重25~30g,随机分为6组,即正常对照组、模型组、化合物36实验组,每组10只。
2方法
2.1动物实验
(1)昆明种小鼠雌雄各半,体重25~30g,随机分为6组,正常对照组、模型组化合物36实验组,每组10只。
(2)模型组及各试验药物组小鼠每天颈背部皮下给予1%D-半乳糖(150mg/kg)注射,共6周,在2周对化合物36实验组进行灌胃给药实验(25mg/kg),模型组生理盐水处理,共4周。
2.2 Morris水迷宫系列试验
隐蔽平台试验水迷宫为直径100cm,高50cm的圆形水池,水池内壁被漆为黑色,池内水深25cm,水温保持在25度,房间内光照恒定,无光线直射在水池内。池壁上以4 个等距离点将水池分为4个象限,任选其中1个象限,正中放置1个圆形黑色安全平台,直径为12cm,高24cm,位于水面下1cm。迷宫上方安置连接显示系统的摄像机,同步记录大鼠运动轨迹。实验历时5d,每天上下午各1次,入池位置为平台所邻2个象限的池壁中点。将小鼠面向池壁分别从入水点放入水中,记录其在100s内寻找到平台的时间(逃避潜伏期)。如果小鼠在100s未找到平台,则由实验者用手牵引其至平台上,停留10s,逃避潜伏期记成100s。每天以两次潜伏期算术均值作为这一天的成绩进行统计分析。
探索试验撤除平台,任选1个入水点将小鼠放入水中,使小鼠在无平台情况下寻找记忆中平台,记录其100s内的游泳轨迹,计算其在原平台象限游泳时间和穿越原平台次数。
3结果
表2的结果表明,隐蔽平台试验从第1天起,模型组小鼠的逃避潜伏期明显长于正常组;化合物36实验组显著增加痴呆小鼠逃避潜伏期。因此表明在用化合物36后能改善痴呆小鼠的学习记忆能力。
表2各实验组隐蔽平台试验逃避潜伏期比较
备注:**P<0.01各个化合物组VS AD模型组;*P<0.05各个化合物组vs AD模型组。
表3结果表明,观察小鼠的空间探索能力,发现模型组小鼠基本围绕池壁游泳,其运动轨迹呈随机分布于各象限之中;化合物36实验组停留原平台象限时间和穿越原平台次数均明显多于模型组,再次表明化合物36可以提高痴呆小鼠的记忆能力。
表3各实验组小鼠探索试验比较
备注:**P<0.01化合物组VS AD模型组;*P<0.05化合物组vs AD模型组。
综上所述,本发明的化合物可以有效抑制一氧化氮生成、治疗炎症、治疗败血症和治疗阿尔茨海默病,大幅扩展了二芳基庚烷类化合物应用范围,极具临床应用前景。
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