CN112972441B - 单羰基姜黄素类化合物在制备预防和治疗牙周炎药物中的应用 - Google Patents

单羰基姜黄素类化合物在制备预防和治疗牙周炎药物中的应用 Download PDF

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CN112972441B
CN112972441B CN202110181046.8A CN202110181046A CN112972441B CN 112972441 B CN112972441 B CN 112972441B CN 202110181046 A CN202110181046 A CN 202110181046A CN 112972441 B CN112972441 B CN 112972441B
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邓辉
吴建章
王奕
赵雅
郑智伟
张梦涵
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Abstract

本发明属于医药技术领域，具体涉及特定的单羰基姜黄素类似物在制备预防和治疗牙周炎药物中的应用。经实验测得这些单羰基姜黄素类似物既能通过激活Nrf2/HO‑1信号通路发挥较好的抗氧化保护作用，也能通过抑制炎症因子TNFα和IL1‑β的释放起到抗炎作用，从而对大鼠牙周炎表现出显著的防治效果，对于牙周炎的预防和治疗具有良好的潜在价值和意义，有较好的研发前景。

Description

单羰基姜黄素类化合物在制备预防和治疗牙周炎药物中的 应用
技术领域：
本发明属药物化学领域，具体而言，本发明涉及特定的单羰基姜黄素类化合物在制备预防和治疗牙周炎药物中的应用。
背景技术：
局部过多的活性氧(reactive oxygen species，ROS)所导致的氧化应激(oxidative stress， OS)与炎症刺激下的牙周组织破坏密切相关。研究证实，牙周炎患者机体抗氧化能力下降，其唾液、龈沟液内的ROS水平上升且与牙周炎严重程度呈正相关。干预型研究也证实，抗氧化剂的使用可以有效延缓慢性牙周炎的进展速度。相比于单纯的牙周基础治疗，牙周基础治疗联合局部应用抗氧化剂对牙周炎的治疗效果更优。因此，进一步开发新型高效的抗氧化剂对于牙周炎的防治具有重要临床价值和意义。
姜黄素是从姜科植物，如姜黄等提取的一种药食同源的天然抗氧化剂，在牙周炎的抗氧化治疗中被证实具有临床应用价值和意义。然而，由于姜黄素分子结构中的β-二酮结构不稳定及较差的体内生物利用度，极大地限制了其成药性。
将姜黄素的β-二酮结构改构为单酮，其结构稳定性及抗氧化保护作用能得到一定的提高。但不同的中间桥接单酮具有不同的细胞毒性。本发明人首先设计和合成了一系列不同桥接酮的单羰基姜黄素骨架类似物，系统筛选出两个毒性较低的骨架。在此基础上进一步合成了两个系列单羰基姜黄素类似物，并筛选出抗氧化活性最优的化合物进行体外活性及初步机制的研究，得到了具有活性强和毒性低的的特定单羰基姜黄素类似物的抗氧化剂。
发明内容：
本发明目的在于提供2个单羰基姜黄素类化合物在制备预防和治疗牙周炎药物中的应用。
本发明的另一目的是提供一种用于预防和治疗牙周炎的药物组合物或者牙周基础治疗联合局部药物组合，其含有治疗有效量的作为活性成分的权利要求1所述的查尔酮类化合物中的任何一种或多种或其可药用盐及其药用辅料。
具体而然，本发明所述2个有效单羰基姜黄素类化合物(1A,1H)，18个对比化合物(2A-10A，2B-10B)及阳性对照姜黄素的的结构为如下所示：
Figure BDA0002941473980000011
Figure BDA0002941473980000021
姜黄素
1A的分子式为C19H16O5，化学名称为： 2,5-bis((E)-3,4-dihydroxybenzylidene)cyclopentan-1-one。1H的分子式为C19H16O6，化学名称为：3,5-bis((E)-3,4-dihydroxybenzylidene)tetrahydro-4H-pyran-4-one。
本发明的有益效果为：以上2个化合物对H2O2诱导的MC3T3-E1细胞氧化损伤模型中的细胞具有很好地抗氧化保护作用且明显优于阳性对照物姜黄素和抗氧化药物TBHQ。(详见实施例2)；其中化合物1A，在不同的细胞氧化损伤时间点均能够以剂量依赖的方式增加H2O2损伤后MC3T3-E1和人牙周膜细胞(hPDLCs)细胞的存活率(图4B，4C)；其形态学结果也表明化合物1A可缓解MC3T3-E1细胞氧化损伤后的形态变化；细胞内ROS水平的上调可导致包括蛋白质损伤、DNA损伤和脂质过氧化在内的牙周组织损伤，而MDA通常也被称为脂质过氧化损伤的标志物。研究发现化合物1A可显著降低MC3T3-E1细胞中的ROS生成以及MDA水平；本发明进行进一步机制研究发现，1A能够促进Nrf2向核中转移蓄积，同时也以剂量依赖的方式上调HO-1的表达。且在相同浓度下，1A较阳性对照药物槲皮素具有更强的促进作用；用siRNA沉默MC3T3-E1细胞中Nrf2基因的表达结果显示，在Nrf2基因沉默的细胞中，1A不仅促HO-1蛋白表达的能力显著下降，而且对H2O2诱导细胞氧化损伤的保护作用也明显减弱。这表明化合物1A的可通过中和ROS的直接机制以及激活 Nrf2/HO-1抗氧化通路的间接机制发挥双重保护作用；随后，我们对活性化合物1A的体内抗氧化、抗炎作用及初步机制进行了相关研究。HE染色结果显示，P组大鼠牙周组织的炎性细胞浸润明显。而1A干预后其炎性细胞浸润数量明显减少，并保留了较完整的牙龈和牙槽骨形态，表明1A对于牙周炎症组织具有一定的治疗潜力。TNF-α和IL-1β是激活破骨细胞的主要促炎细胞因子，可抑制成骨细胞的分化，并通过上调核因子κB受体活化因子配体(receptor activator of nuclear factorkappa B ligands，RANKL)受体的表达以及降低骨钙素生成的方式来抑制新骨的形成。结果显示，与P组相比，1A干预后组织病损区HO-1、Nrf2特异性染色增加，TNF-α、IL-1β特异性染色减少，表明活性化合物1A可促进组织中抗氧化相关蛋白的表达，并抑制牙周炎造成的炎性因子增多。本发明表明单羰基姜黄素类似物1A具有成为预防和治疗牙周炎药物的前景。
一种用于预防和治疗牙周炎的药物组合物，其含有治疗有效量的作为活性成分的以上所述2个查尔酮类化合物中的任何一种或多种或其可药用盐及其药用辅料。“药物组合物”指本发明所述2个单羰基姜黄素类化合物中的任何一种或多种或其可药用盐与现已上市的治疗牙周炎药物联合使用，制备得到的防治炎症疾病类药物的组合物，。
本文中所用“药用辅料”指药学领域常规的药物载体，例如：稀释剂、赋形剂如水等，填充剂如淀粉、蔗糖等；粘合剂如纤维素衍生物、藻酸盐、明胶和聚乙烯吡咯烷酮；湿润剂如甘油；崩解剂如琼脂、碳酸钙和碳酸氢钠；吸收促进剂如季铵化合物；表面活性剂如十六烷醇；吸附载体如高岭土和皂粘土；润滑剂如滑石粉、硬脂酸钙/镁、聚乙二醇等。另外还可以在组合物中加入其它辅剂如香味剂、甜味剂等。
本发明药物组合物的各种剂型可以按照药学领域的常规生产方法制备。例如使活性成分与一种或多种载体混合，然后将其制成所需的剂型。所述药物的制剂形式包括注射剂、片剂、胶囊剂、气雾剂、栓剂、膜剂、滴丸剂、软膏剂、控释或缓释剂或纳米制剂。本发明可以组合物的形式通过口服，鼻吸入、直肠或者肠胃外给药的方式施用于需要这种治疗的患者。用于口服时，可将其制成常规的固体制剂如片剂、粉剂、粒剂、胶囊等，制成液体制剂如水或油悬浮剂或其它液体制剂如糖浆、酏剂等；用于肠胃外给药时，可将其制成注射用的溶液、水或油性悬浮剂等。
下面将结合实施例及说明书附图详细说明本发明。
附图说明：
图1 MCACs骨架的设计和细胞毒性筛选。(A)MCAC的设计。(B)合成MCACs的具体结构。(C&D)细胞毒性筛选的方法：5，000个MC3T3-E1细胞用α-MEM培养液培养于 37℃，24小时后更新培养液并分别加入20μM和60μM受测化合物处理72小时，用MTT法在酶标仪上测OD(490nm)值，用DMSO处理的细胞的活力定义为100％，姜黄素为阳性对照，重复三次实验，每次三个复孔。
图2 A和H衍生物的合成，结构以及保护作用的筛选。(A)A和H衍生物的合成条件。(B)保护作用的筛选：5，000个MC3T3-E1细胞用α-MEM培养液培养于37℃，24小时后更新培养液并分别加入10μM A和H衍生物(1A-10A，1H-10H)预处理18小时，再用300μM 的H2O2处理24h。用MTT法在酶标仪上测OD(490nm)值，用DMSO处理的细胞的活力定义为100％，姜黄素为阳性对照，重复三次实验，每次三个复孔。
图3化合物1A对H2O2诱导的MC3T3-E1细胞和hPDLC细胞损伤的保护作用。(A&B) 将MC3T3-E1细胞用1A预处理18小时或1小时，然后用300μM的H2O2处理24小时，再用MTT法检测。(C&D)用1A预处理18h或1h可减轻hPDLC中H2O2诱导的细胞损伤。 (E&F)1A预处理降低了暴露于H2O2的MC3T3-E1细胞的MDA水平。(G)1A预处理减少了H2O2处理的MC3T3-E1细胞中的ROS生成。
图4 1A激活Nrf2/HO-1信号通路。(A)1A诱导Nrf2的核易位。用7.5μM 1A和10μMtBHQ (Nrf2激活剂)处理6小时，Nrf2(红色)在MC3T3-E1细胞中转移到核(蓝色)中，(B)Western Blot分析显示，1A处理18h，HO-1的蛋白表达增加。(C)Western Blot分析显示靶向Nrf2的siRNA显着减弱了1A诱导的HO-1蛋白表达。(D)靶向Nrf2的siRNA显着减弱了H2O2处理的MC3T3-E1中1A的保护作用.
图5 1A对实验性牙周炎大鼠发挥抗炎活性，并缓解其牙槽骨的丢失。(A)各组大鼠在上颌第二磨牙区的组织学变化(苏木精和伊红染色)。(B)体式显微镜下各组牙槽骨吸收情况。蓝色虚线表示牙槽嵴(AC)；红色虚线表示釉牙骨质界(ACJ)；白线表示AC-ACJ的距离，总共进行了6次测量。(C)各组大鼠上颌牙槽骨的Mirco-CT纵向截面图。白色圆圈为在上颌第一和第二磨牙周围区域骨丢失的典型图像。(D)定量分析测得各组ACJ-AC距离。(E)各组大鼠上颌第二磨牙周围牙槽骨BV/TV值比较(每组n＝10)。
图6 1A上调大鼠实验性牙周炎的HO-1和Nrf2水平，并降低TNF-α和IL-1β水平。通过 IHC染色分别测定上颌第二磨牙牙龈的HO-1(A)，Nrf2(B)，TNF-α(C)和IL-1β(D) 的水平。通过每个部分的六个随机选择区域中的平均光密度(MOD；MOD＝积分光密度/面积) 来测量染色强度。(E)HO-1，Nrf2，TNF-α和IL-1β表达水平的半定量分析。
具体实施方式：
本发明在以下的实施例中进一步说明。这些实施例只是为了说明的目的，而不是用来限制本发明的范围。
实施例1化合物的合成
将1mmol苯甲醛和不同的中间桥接酮溶于10-20mL无水乙醇中，加入40％NaOH溶液5-10滴，室温反应5-24h后，合成13个骨架化合物。将1mmol相应的不同取代基苯甲醛和环戊酮或者吡喃酮溶于10-20mL无水乙醇中，加入40％NaOH溶液5-10滴，室温反应5-24h 或者加入浓硫酸3-5滴，78℃油浴加热后，合成两个系列单羰基姜黄素对比化合物和有效化合物。用TLC检测反应的进行。反应完后，萃取，硅胶拌样经硅胶柱色谱纯化后得到目标化合物，其理化性质如下所述：
骨架化合物：2,5-di((E)-benzylidene)cyclopentan-1-one(A).Light yellowpowder,87.3％yield, m.p.189.2-190.3℃.1H NMR(600MHz,CDCl3),δ:7.62–7.60(m,6H,Ar-H2,Ar-H2’,Ar-H6,Ar-H6’,α-H×2), 7.45(t,J＝7.5Hz,4H,Ar-H3,Ar-H3’,Ar-H5,Ar-H5’),7.41–7.37(m,2H,Ar-H4,Ar-H4’),3.13(s,4H,CH2×2). LC-MS m/z:261.2(M+H)+,calcd forC19H16O:260.12.
骨架化合物：2,6-di((E)-benzylidene)cyclohexan-1-one(B).Light yellowpowder,85.0％yield, m.p.113.8-115.2℃.1H NMR(600MHz,CDCl3),δ:7.81(s,2H,α-H×2),7.47(d,J＝7.4Hz,4H,Ar-H2,Ar-H2’, Ar-H6,Ar-H6’),7.41(t,J＝7.6Hz,4H,Ar-H3,Ar-H3’,Ar-H5,Ar-H5’),7.34(t,J＝7.3Hz,2H,Ar-H4,Ar-H4’), 2.96–2.92(m,4H,CH2×2),1.82–1.78(m,2H,CH2).LC-MS m/z:275.1(M+H)+,calcd for C20H18O:274.14.
骨架化合物：(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one(C).Light yellowpowder,91.6％yield, m.p.107.5-109.3℃.1H NMR(600MHz,CDCl3),δ:7.75(d,J＝15.9Hz,2H,β-H×2),7.63(dd,J＝6.4,2.6Hz,4H, Ar-H2,Ar-H2’,Ar-H6,Ar-H6’),7.45–7.39(m,6H,Ar-H3,Ar-H3’,Ar-H4,Ar-H4’,Ar-H5,Ar-H5’),7.10(d,J＝15.9Hz, 2H,α-H×2).LC-MS m/z:235.1(M+H)+,calcd for C17H14O:234.10.
骨架化合物：3,5-di((E)-benzylidene)-1-propylpiperidin-4-one(D).Lightyellow powder,89.1％ yield,m.p.110.9-112.5℃.1H NMR(600MHz,CDCl3),δ:7.84(s,2H,α-H×2),7.43(dd,J＝9.7,4.9Hz,4H, Ar-H2,Ar-H2’,Ar-H6,Ar-H6’),7.41(d,J＝6.9Hz,4H,Ar-H3,Ar-H3’,Ar-H5,Ar-H5’),7.35–7.39(m,2H,Ar-H4, Ar-H4’),3.87(s,4H,CH2×2),2.54–2.50(m,2H,CH2),1.50–1.43(m,2H,CH2),0.85(t,J＝7.4Hz,3H,CH3). LC-MS m/z:318.2(M+H)+,calcd for C22H23NO:317.18.
骨架化合物：3,5-di((E)-benzylidene)-1-ethylpiperidin-4-one(E).Lightyellow powder,83.3％ yield,m.p.113.5-114.9℃.1H NMR(600MHz,CDCl3),δ:7.85(s,2H,α-H×2),7.43(dd,J＝9.6,4.9Hz,4H, Ar-H2,Ar-H2’,Ar-H6,Ar-H6’),7.41(d,J＝6.7Hz,4H,Ar-H3,Ar-H3’,Ar-H5,Ar-H5’),7.39–7.35(m,2H,Ar-H4, Ar-H4’),3.86(s,4H,CH2×2),2.67–2.59(m,2H,CH2),1.06(t,J＝7.2Hz,3H,CH3).LC-MS m/z:304.2(M+H)+, calcd forC21H21NO:303.16.
骨架化合物：3,5-di((E)-benzylidene)-1-methylpiperidin-4-one(F).Lightyellow powder,86.2％ yield,m.p.104.6-106.7℃.1H NMR(600MHz,CDCl3),δ:7.84(s,2H,α-H×2),7.45–7.42(m,4H,Ar-H2,Ar-H2’, Ar-H6,Ar-H6’),7.40(d,J＝6.9Hz,4H,Ar-H3,Ar-H3’,Ar-H5,Ar-H5’),7.36–7.39(m,2H,Ar-H4,Ar-H4’),3.80(s, 4H,CH2×2),2.47(s,3H,CH3).LC-MS m/z:290.2(M+H)+,calcd for C20H19NO:289.15.
骨架化合物：3,5-di((E)-benzylidene)piperidin-4-one(G).Light yellowpowder,90.3％yield,m.p. 175.5-178.6℃.1H NMR(600MHz,CDCl3),δ:7.81(s,2H,α-H×2),7.44–7.40(m,4H,Ar-H2,Ar-H2’,Ar-H6, Ar-H6’),7.39(d,J＝7.5Hz,4H,Ar-H3,Ar-H3’,Ar-H5,Ar-H5’),7.37–7.35(m,2H,Ar-H4,Ar-H4’),4.16(d,J＝1.7Hz, 4H,CH2×2),1.72(s,1H,NH).LC-MS m/z:276.2(M+H)+,calcd for C19H17NO:275.13.
骨架化合物：3,5-di((E)-benzylidene)tetrahydro-4H-pyran-4-one(H).Lightyellow powder, 92.5％yield,m.p.179.5-181.6℃.1H NMR(600MHz,CDCl3),δ:7.85(s,2H,α-H×2),7.45–7.42(m,4H,Ar-H2, Ar-H2’,Ar-H6,Ar-H6’),7.41–7.37(m,2H,Ar-H4,Ar-H4’),7.34–7.32(m,4H,Ar-H3,Ar-H3’,Ar-H5,Ar-H5’),4.94 (d,J＝1.9Hz,4H,CH2×2).LC-MS m/z:277.1(M+H)+,calcd for C19H16O2:276.12.
骨架化合物：3,5-di((Z)-benzylidene)tetrahydro-4H-thiopyran-4-one(I).Light yellow powder, 89.7％yield,m.p.146.1-148.3℃.1H NMR(600MHz,CDCl3),δ:7.79(s,2H,α-H×2),7.44–7.41(m,4H,Ar-H2, Ar-H2’,Ar-H6,Ar-H6’),7.40(d,J＝6.7Hz,4H,Ar-H3,Ar-H3’,Ar-H5,Ar-H5’),7.36–7.38(m,2H,Ar-H4,Ar-H4’), 3.92(s,4H,CH2×2).LC-MS m/z:293.1(M+H)+,calcd for C19H16OS:292.09.
骨架化合物：3,5-di((E)-benzylidene)-1-phenethylpiperidin-4-one(J).Light yellow powder, 82.5％yield,m.p.87.8-90.1℃.1H NMR(600MHz,CDCl3),δ:7.85(s,2H,α-H×2),7.45–7.41(m,4H,Ar-H2, Ar-H2’,Ar-H6,Ar-H6’),7.39(d,J＝7.0Hz,4H,Ar-H3,Ar-H3’,Ar-H5,Ar-H5’),7.38–7.34(m,2H,Ar-H4,Ar-H4’), 7.23(t,J＝7.4Hz,2H,Ar-H2”,Ar-H6”),7.16(t,J＝7.4Hz,1H,Ar-H4”),7.12(d,J＝7.1Hz,2H,Ar-H3”,Ar-H5”), 3.92(s,4H,CH2×2),2.85–2.80(m,2H,CH2),2.73–2.76(m,2H,CH2).LC-MS m/z:380.3(M+H)+,calcdfor C27H25NO:379.19.
骨架化合物：ethyl 3,5-di((E)-benzylidene)-4-oxopiperidine-1-carboxylate(K).Light yellow powder,86.6％yield,m.p.158.5-159.8℃.1H NMR(600MHz,CDCl3),δ:7.82(s,2H,α-H×2),7.45(s,4H, Ar-H2,Ar-H2’,Ar-H6,Ar-H6’),7.44(s,4H,Ar-H3,Ar-H3’,Ar-H5,Ar-H5’),7.39–7.41(m,2H,Ar-H4,Ar-H4’),4.79 (s,4H,CH2×2),4.07(q,J＝7.1Hz,2H,CH2),1.12(t,J＝7.1Hz,3H,CH3).LC-MS m/z:348.2(M+H)+,calcdfor C22H21NO3:347.15.
骨架化合物：1-benzyl-3,5-di((E)-benzylidene)piperidin-4-one(L).Lightyellow powder,84.8％ yield,m.p.154.2-156.1℃.1H NMR(600MHz,CDCl3),δ:7.83(s,2H,α-H×2),7.39–7.36(m,4H,Ar-H2,Ar-H2’, Ar-H6,Ar-H6’),7.35(s,4H,Ar-H3,Ar-H3’,Ar-H5,Ar-H5’),7.33(s,2H,Ar-H4,Ar-H4’),7.25(s,1H,Ar-H4”),7.24 (s,2H,Ar-H3”,Ar-H5”),7.19–7.22(m,2H,Ar-H2”,Ar-H6”),3.88(s,4H,CH2×2),3.71(s,2H,CH2).LC-MS m/z: 366.3(M+H)+,calcd for C26H23NO:365.18.
具体实施方式：3,5-di((E)-benzylidene)-1-cyclopropylpiperidin-4-one(M).Light yellow powder,88.1％yield,m.p.144.8-147.6℃.1H NMR(600MHz,CDCl3),δ:7.81(s,2H,α-H×2),7.45(d,J＝2.2Hz, 4H,Ar-H2,Ar-H2’,Ar-H6,Ar-H6’),7.44(s,4H,Ar-H3,Ar-H3’,Ar-H5,Ar-H5’),7.40–7.37(m,2H,Ar-H4,Ar-H4’), 4.01(s,4H,CH2×2),0.56–0.38(m,5H,CH2×2,CH).LC-MS m/z:316.2(M+H)+,calcd for C22H21NO:315.16.
骨架化合物：2,4-di((E)-benzylidene)-8-methyl-8-azabicyclo[3.2.1]octan-3-one(N).Light yellow powder,84.2％yield,m.p.144.6-146.0℃.1H NMR(600MHz,CDCl3),δ:7.85(s,2H,α-H×2),7.45–7.42 (m,4H,Ar-H2,Ar-H2’,Ar-H6,Ar-H6’),7.40(d,J＝7.3Hz,4H,Ar-H3,Ar-H3’,Ar-H5,Ar-H5’),7.38–7.32(m,2H, Ar-H4,Ar-H4’),4.42(s,2H,CH×2),2.67–2.58(m,2H,CH×2),2.32(s,3H,CH3),2.04(d,J＝7.3Hz,2H,CH×2). LC-MS m/z:316.2(M+H)+,calcd for C22H21NO:315.16.
对比化合物：2,5-bis((E)-3,4-dimethoxybenzylidene)cyclopentan-1-one(2A).Light yellow powder,90.4％yield,m.p.160.9-163.3℃.1H-NMR(600MHz,CDCl3),δ:7.54(s,2H,α-H×2), 7.23(d,J＝8.2Hz,2H,Ar-H6,Ar-H6’),7.13(s,2H,Ar-H2,Ar-H2’),6.94(d,J＝8.3Hz,2H,Ar-H5, Ar-H5’),3.93(s,12H,3-OCH3,3’-OCH3,4-OCH3,4’-OCH3),3.11(s,4H,CH2×2).LC-MS m/z: 381.25(M+H)+,calcd for C23H24O5:380.16.
对比化合物：2,5-bis((E)-4-hydroxy-3-methoxybenzylidene)cyclopentan-1-one(4A).Light yellow powder,81.9％yield,m.p.220.6-221.3℃.1H NMR(600MHz,DMSO),δ:9.27(s,2H,4-OH, 4’-OH),7.27(s,2H,α-H×2),7.18–7.07(m,4H,Ar-H6,Ar-H6’,Ar-H2,Ar-H2’),7.01(d,J＝7.8Hz,2H, Ar-H5,Ar-H5’),3.81(s,6H,4-OCH3,4’-OCH3),3.01(s,4H,CH2×2).LC-MS m/z:353.11(M+H)+,calcd for C21H20O5:352.13.
对比化合物： ((1E,1'E)-(2-oxocyclopentane-1,3-diylidene)bis(methanylylidene))bis(2-methoxy-4,1-phenylene) diacetate(5A).Light yellowpowder,79.8％yield,m.p.203.5-204.9℃.1H NMR(600MHz, CDCl3),δ:7.56(s,2H,α-H×2),7.22(d,J＝8.2Hz,2H,Ar-H6,Ar-H6’),7.17(s,2H,Ar-H2,Ar-H2’), 7.11(d,J＝8.2Hz,2H,Ar-H5,Ar-H5’),3.89(s,6H,3-OCH3,3’-OCH3),3.12(s,4H,CH2×2),2.34(s, 6H,4-OCOCH3,4’-OCOCH3).LC-MS m/z:437.2(M+H)+,calcd for C25H24O7:436.15.
对比化合物： ((1E,1'E)-(2-oxocyclopentane-1,3-diylidene)bis(methanylylidene))bis(6-methoxy-3,1-phenylene) diacetate(6A).Light yellowpowder,78.3％yield,m.p.223.5-225.4℃.1H-NMR(600MHz,CDCl3),δ:7.51(s, 2H,α-H×2),7.46(d,J＝8.5Hz,2H,Ar-H6,Ar-H6’),7.31(d,J＝1.5Hz,2H,Ar-H2,Ar-H2’),7.03(d,J＝8.6Hz,2H, Ar-H5,Ar-H5’),3.89(s,6H,4-OCH3,4’-OCH3),3.06(s,4H,CH2×2),2.35(s,6H,3-OCOCH3,3’-OCOCH3). LC-MS m/z:437.2(M+H)+,calcd for C25H24O7:436.15.
对比化合物：2,5-bis((E)-4-ethoxy-3-methoxybenzylidene)cyclopentan-1-one(7A).Light yellow powder,80.2％yield,m.p.164.8-165.9℃.1H NMR(600MHz,CDCl3),δ:7.54(s,2H, α-H×2),7.21(d,J＝8.3Hz,2H,Ar-H6,Ar-H6’),7.14(s,2H,Ar-H2,Ar-H2’),6.93(d,J＝8.4Hz,2H, Ar-H5,Ar-H5’),4.16(q,J＝7.0Hz,4H,4-OCH2-,4’-OCH2-),3.93(s,6H,3-OCH3,3’-OCH3),3.11 (s,4H,CH2×2),1.50(t,J＝7.0Hz,6H,CH3×2).LC-MSm/z:409.3(M+H)+,calcd for C25H28O5: 408.19.
对比化合物：2,5-bis((E)-3-ethoxy-4-methoxybenzylidene)cyclopentan-1-one(8A).Light yellow powder,86.5％yield,m.p.147.7-151.3℃.1H NMR(600MHz,CDCl3),δ:7.53(s,2H, α-H×2),7.22(d,J＝8.4Hz,2H,Ar-H6,Ar-H6’),7.14(s,2H,Ar-H2,Ar-H2’),6.94(d,J＝8.4Hz,2H, Ar-H5,Ar-H5’),4.15(q,J＝7.0Hz,4H,3-OCH2-,3’-OCH2-),3.93(s,6H,4-OCH3,4’-OCH3),3.10(s, 4H,CH2×2),1.50(t,J＝7.0Hz,6H,CH3×2).LC-MSm/z:409.2(M+H)+,calcd for C25H28O5: 408.19.
对比化合物：2,5-bis((E)-3-methoxybenzylidene)cyclopentan-1-one(9A).Light yellow powder,88.7％yield,m.p.137.9-138.6℃.1H-NMR(600MHz,CDCl3),δ:7.56(s,2H,α-H×2), 7.36(t,J＝7.9Hz,2H,Ar-H5,Ar-H5’),7.20(d,J＝7.6Hz,2H,Ar-H6,Ar-H6’),7.12(s,2H,Ar-H2, Ar-H2’),6.94(dd,J＝8.2,1.9Hz,2H,Ar-H4,Ar-H4’),3.85(s,6H,3-OCH3,3’-OCH3),3.12(s,4H, CH2×2).LC-MS m/z:321.2(M+H)+,calcd for C21H20O3:320.14.
对比化合物：3,5-bis((E)-3,4-dimethoxybenzylidene)tetrahydro-4H-pyran-4-one(2H). Light yellow powder,92.3％yield,m.p.163.6-164.1℃.1H-NMR(600MHz,CDCl3),δ:7.78(s, 2H,α-H×2),6.91(s,4H,Ar-H2,Ar-H2’,Ar-H6,Ar-H6’),6.87(s,2H,Ar-H5,Ar-H5’),4.95(s,4H, CH2×2),3.92(d,J＝9.0Hz,12H,3-OCH3,3’-OCH3,4-OCH3,4’-OCH3).LC-MS m/z:397.15 (M+H)+,calcd for C23H24O6:396.16.
对比化合物： 3,5-bis((E)-3-hydroxy-4-methoxybenzylidene)tetrahydro-4H-pyran-4-one(3H).Light yellow powder,84.5％yield,m.p.196.5-197.3℃.1H-NMR(600MHz,DMSO),δ:9.67(s,2H,3-OH, 3’-OH),7.58(s,2H,α-H×2),7.00(s,2H,Ar-H2,Ar-H2’),6.85(d,J＝8.1Hz,4H,Ar-H5,Ar-H5’, Ar-H6,Ar-H6’),4.89(s,4H,CH2×2),3.81(s,6H,4-OCH3,4’-OCH3).LC-MS m/z:369.07(M+H)+, calcd for C21H20O6:368.13.
对比化合物： 3,5-bis((E)-4-hydroxy-3-methoxybenzylidene)tetrahydro-4H-pyran-4-one(4H).Light yellow powder,85.9％yield,m.p.258.3-259.7℃.1H-NMR(600MHz,CDCl3),δ:9.27(s,2H,4-OH,4’-OH),7.50(s, 2H,α-H×2),7.00(d,J＝8.4Hz,2H,Ar-H6,Ar-H6’),6.88(d,J＝8.4Hz,2H,Ar-H2,Ar-H2’),6.84(d,J＝1.5Hz,2H, Ar-H5,Ar-H5’),4.86(s,4H,CH2×2),3.81(s,6H,3-OCH3,3’-OCH3).LC-MS m/z:369.2(M+H)+,calcdfor C21H20O6:368.13.
对比化合物： ((1E,1'E)-(4-oxo-2H-pyran-3,5(4H,6H)-diylidene)bis(methanylylidene))bis(6-methoxy-3,1-phe nylene)diacetate(6H).Light yellowpowder,73.3％yield,m.p.224.1-226.5℃.1H NMR(600 MHz,CDCl3),δ:7.73(s,2H,α-H×2),7.21(d,J＝7.8Hz,2H,Ar-H6,Ar-H6’),7.02(dd,J＝7.4,5.1 Hz,4H,Ar-H2,Ar-H2’,Ar-H5,Ar-H5’),4.91(s,4H,CH2×2),3.88(s,6H,4-OCH3,4’-OCH3),2.34 (s,6H,3-OCOCH3,3’-OCOCH3).LC-MS m/z:453.2(M+H)+,calcd for C25H24O8:452.15.
对比化合物：3,5-bis((E)-4-ethoxy-3-methoxybenzylidene)tetrahydro-4H-pyran-4-one(7H). Light yellow powder,76.8％yield,m.p.192.6-193.7℃.1H-NMR(600MHz,CDCl3),δ:7.78(s,2H,α-H×2), 6.91(d,J＝8.3Hz,2H,Ar-H6,Ar-H6’),6.90(s,2H,Ar-H2,Ar-H2’),6.88(s,2H,Ar-H5,Ar-H5’),4.96(s,4H, 3-OCH2-,3’-OCH2-),4.16–4.14(m,4H,CH2×2),3.91(s,6H,4-OCH3,4’-OCH3),1.49(dd,J＝4.4,2.5Hz,6H, Ar-CH3,Ar’-CH3).LC-MS m/z:425.2(M+H)+,calcd for C25H28O6:424.19.
对比化合物：3,5-bis((E)-3-ethoxy-4-methoxybenzylidene)tetrahydro-4H-pyran-4-one(8H). Light yellow powder,80.1％yield,m.p.167.9-169.7℃.1H NMR(600MHz,CDCl3),δ:7.77(s, 2H,α-H×2),6.92(s,4H,Ar-H6,Ar-H6’,Ar-H2,Ar-H2’),6.88(s,2H,Ar-H5,Ar-H5’),4.95(s,4H, 3-OCH2-,3’-OCH2-),4.13(q,J＝7.0Hz,4H,CH2×2),3.92(s,6H,4-OCH3,4’-OCH3),1.49(t,J＝7.0 Hz,6H,Ar-CH3,Ar’-CH3).LC-MS m/z:425.2(M+H)+,calcd for C25H28O6:424.19.
对比化合物：3,5-bis((E)-3-methoxybenzylidene)tetrahydro-4H-pyran-4-one(9H).Light yellow powder,89.0％yield,m.p.229.8-230.1℃.1H-NMR(600MHz,CDCl3),δ:7.81(s,2H,α-H×2),7.35(t, J＝8.0Hz,2H,Ar-H5,Ar-H5’),6.94(dd,J＝8.1,2.0Hz,2H,Ar-H6,Ar-H6’),6.91(d,J＝7.6Hz,2H,Ar-H2,Ar-H2’), 6.85(s,2H,Ar-H4,Ar-H4’),4.93(d,J＝1.3Hz,4H,CH2×2),3.84(s,6H,3-OCH3,3’-OCH3).LC-MS m/z:337.1 (M+H)+,calcd forC21H20O4:336.14.
实施例2不同单羰基姜黄素骨架结构的细胞毒性筛选，及两个系列单羰基姜黄素的抗氧化活性筛选
为了开发有效且毒性较小的MACA骨架，本研究系统地合成了13种具有不同中间桥酮的MCAC骨架(化合物A-N)。合成步骤见实施例1，结构及筛选结果见(图1A和B)。结果表明，在浓度为20和60μM的化合物A(含环戊酮)和H(含吡喃酮)处理72小时后， MC3T3-E1保留了其活力(图1C和D)，显示出明显的生物安全性比天然姜黄素。
根据以上结果，分别合成了一系列化合物A(1A至10A)和H(1H至10H)(图2A)。，将MC3T3-E1与化合物(10μM)预先孵育后，将其随后暴露于300μM H2O2中24h(P<0.05，与用DMSO预孵育的细胞进行比较)。结果如图2B所示，化合物1A和1H比对照组天然姜黄素具有更好的抗氧化应激的细胞保护作用(图2B)。其中，化合物1A的抗氧化活性最优。
实施例3 1A保护细胞免受H2O2诱导的细胞损伤和氧化应激
为了评估1A对MC3T3-E1和hPDLC的保护作用，以不同浓度(1.25、2.5、5、7.5μM) 的1A对细胞进行预处理，然后用H2O2(300μM)孵育24小时。结果显示，化合物预处理 18h可提高暴露于H2O2的MC3T3-E1的细胞活力(图3A)。此外，当浓度为7.5μM时，1A 能够增加MC3T3-E1在1小时内的存活率(图3B)。hPDLC在局部免疫反应中起关键作用，并在牙周疾病中启动骨重塑。同样，将1A预处理1h和18h均可显着提高暴露于H2O2的 hPDLC的细胞活力(图3C)，并且呈现剂量依赖性(图3D)。这些结果共同表1A抑制了 H2O2诱导的细胞损伤。
进一步测定化合物对MDA水平的影响。如图3E和F所示，1A预处理H2O2诱导的的MC3T3-E1细胞在18h和1h的MDA水平显著降低；其ROS水平也显著降低(图3G)。以上结果表明L42H23显着降低了H2O2诱导的氧化应激。
实施例4 1A激活了Nrf2/HO-1信号通路
Nrf2是抗氧化防御系统的重要转录因子，其转移到细胞核后，可激活下游保护性基因的表达。因此，本研究使用免疫荧光染色法观察Nrf2的转位情况。如图4A所示，在DMSO组细胞中，Nrf2主要在胞浆中表达。与DMSO组及阳性对照组相比，1A组在细胞核中显示出更强的Nrf2荧光信号，表明化合物1A促进Nrf2核转移。
HO-1是Nrf2通路的下游靶基因，具有清除ROS的功能，在抵御氧化应激诱导的损伤中发挥重要作用。Western blotting结果显示，1A以剂量依赖性的方式上调HO-1的表达，且在 5μmol/L的相同浓度下，1A较阳性药物具有更强的促进HO-1表达的作用(图4B)。
为了证明1A是否通过Nrf2/HO-1信号通路促进HO-1的表达，本研究利用siRNA沉默MC3T3-E1细胞的Nrf2基因后进行相关检测。如图4C所示，沉默了细胞Nrf2基因的表达后，1A促进HO-1蛋白表达的能力明显减弱。
为了进一步证明Nrf2在1A抗氧化作用中的重要性，本研究沉默MC3T3-E1细胞中Nrf2 基因的表达后，采用MTT法检测1A对H2O2诱导细胞损伤时细胞存活率的影响。如图4D所示，在未沉默Nrf2的细胞中，1A组的细胞存活率较单纯H2O2组显著上升(P<0.01)。在沉默Nrf2的细胞中，1A组的细胞存活率较单纯H2O2组略上升，但差异无统计学意义(P>0.05)。以上结果提示1A的抗氧化保护作用因Nrf2沉默而受损，表明1A通过Nrf2的激活发挥抗氧化保护作用。
实施例5 1A抑制牙周炎大鼠结扎诱导的牙槽骨丢失
在实验期间，三组之间在食物消耗和体重方面没有发现显着差异。我们首先研究了上颌第二磨牙周围区域1A的抗炎潜力。组织病理学分析显示，P组牙周组织中炎性细胞的浸润明显增强。相反，经1A处理的大鼠的组织显示炎性浸润物的数量明显减少，并保留了牙龈和牙槽骨的形态(图5A)。
结扎大鼠的ACJ-AC距离显着高于C组，表明结扎可引起牙槽骨丢失。施用1A(20mg/kg/d)可以显着减轻牙周破坏，如减少的ACJ-AC距离所示(图5B和D)。Micro-CT扫描进一步证实了1A对实验性牙周炎牙槽骨丢失的保护作用(图5C)。P组的BV/TV(％) 值显着低于C组(53.9％)，而降低的值通过1A处理恢复了高达72.3％(P<0.05)，表明摄入1A可能会抑制结扎诱导的牙周组织破坏。
实施例6 1A诱导的牙周炎大鼠抗氧化剂和炎症反应减少
免疫组化结果显示，各组大鼠的牙周组织中均可检测到被染为棕黄色的HO-1、Nrf2、 TNF-α及IL-1β特异性免疫标记。其中，1A组HO-1和Nrf2的特异性染色较C组与P组明显增加(P<0.01)。TNF-α及IL-1β的免疫组化结果则呈相反的趋势。C组两个炎性因子的表达呈弱阳性，P组较C组则明显增多(P<0.01)。而与P组相比，1A组的两个炎性因子表达则明显减少(P<0.05)。各组具体免疫组化染色的显微照片如图6，定量分析的结果见图6E。

Claims (1)

1.如下所示的化合物在制备预防和/或治疗牙周炎药物中的应用：
Figure DEST_PATH_IMAGE002
。
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