CN118161510A - 醉茄素a类化合物的应用 - Google Patents
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- CN118161510A CN118161510A CN202410426167.8A CN202410426167A CN118161510A CN 118161510 A CN118161510 A CN 118161510A CN 202410426167 A CN202410426167 A CN 202410426167A CN 118161510 A CN118161510 A CN 118161510A
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Abstract
本发明公开了一种醉茄素A类化合物WACl的新的药物应用。该化合物能够有效干扰骨肉瘤细胞的有丝分裂，导致G2/M期的周期阻滞，从而抑制细胞增殖；还能促进骨肉瘤细胞内活性氧的累积，并诱导细胞凋亡，进一步抑制肿瘤的生长，可作为抗骨肉瘤药物的新的候选药物。
Description
技术领域
本发明涉及一种醉茄素A类化合物的应用，尤其涉及一种醉茄素A类化合物在制备治疗骨肉瘤的药物中的应用。
背景技术
骨肉瘤(Osteosaroma，OS)是一种以间充质细胞或成骨前体细胞产生类骨质和未成熟骨为特征的恶性骨肿瘤，常见于四肢长骨干骺端，如股骨和胫骨的两端。骨肉瘤是儿童和青少年最常见的恶性骨肿瘤，也是12至18岁年龄段第三常见的癌症类型。骨肉瘤的死亡率较高，患者预后通常不佳，且常伴有由肿瘤生长破坏骨质引起的剧烈疼痛。
骨肉瘤既往的标准治疗方法以手术治疗为主。手术治疗包括保肢术和根治性截肢术，骨肉瘤患者的5年生存率从60％到70％不等。近年来主要治疗手段包括基于厄洛替尼、顺铂和大剂量甲氨蝶呤的新辅助化疗，随后手术及辅助化疗，虽提高了存活率和肢体保存率，但长期化疗对心脏、肝脏和肾脏等正常组织有损害，且可能导致不孕。化疗外的治疗手段未见明显突破。
南非醉茄(Withania somnifera)，属茄科植物，其有效成分醉茄内酯具有出色的抗炎、抗菌和免疫调节效果，展现出显著的开发潜力和应用前景。醉茄素A(WithaferinA)一种从醉茄提取的内酯化合物，不仅具有抗炎、抗菌的效果，在多种癌症如乳腺癌、胰腺癌、结肠癌、黑色素瘤、骨肉瘤中也展示抗肿瘤潜力。此外，WithaferinA在癌症治疗中的一个潜在优势是其多靶点作用，与单靶点药物易引发的逃逸机制、耐药性和复发相比，它能通过多通路抑制改善患者预后，预防或克服耐药问题。
尽管醉茄素A在抗菌、抗炎、抗癌方面已有突出作用。然而，由于醉茄素A脂溶性差、稳定性不足，以及口服生物利用度低等问题，其临床应用受限。
发明内容
发明目的：本发明旨在提供一种醉茄素A类化合物的新的药物应用。
技术方案：本发明所述的具有如下结构的醉茄素A类化合物(WACl)应用在制备治疗骨肉瘤的药物中，
本发明所述的醉茄素A类化合物WACl的分子式为C28H37ClO5，在对抗肺癌和乳腺癌方面展现出潜力，但其对骨肉瘤的影响尚未见报道。
其中，醉茄素A类化合物WACl的纯度优选为90％以上，更优选为95％以上，进一步优选为98％以上，更进一步优选为99％以上。
优选，所述药物为抑制骨肉瘤生长的药物。
优选，所述药物为促进骨肉瘤细胞死亡的药物。
优选，所述药物能够干扰骨肉瘤细胞的有丝分裂、阻滞G2/M期的周期、抑制骨肉瘤细胞的增殖。
优选，所述药物能够促进骨肉瘤细胞内活性氧的累积、诱导骨肉瘤细胞的凋亡。
优选，所述药物的给药剂量为1.0～4.0μM，更优选为1.0、2.0、4.0μM，进一步优选为2.0、4.0μM，最优选为4.0μM。
本发明所述的醉茄素A类化合物WACl的药学上可接受的盐应用在制备治疗骨肉瘤的药物中。
优选，所述药学上可接受的盐为所述化合物与碱金属阳离子或碱土金属阳离子的无机碱形成的盐。
“药学上可接受的盐”是指化合物的盐，由具有特定取代基的化合物与相对无毒的酸或碱制备。当化合物中含有相对酸性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的游离体形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机氨或镁盐或类似的盐。当化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的游离体形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸(形成碳酸盐或碳酸氢盐)、磷酸(形成磷酸盐、磷酸一氢盐、磷酸二氢盐、硫酸(形成硫酸盐或硫酸氢盐)、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；有机酸盐还包括氨基酸(如精氨酸等)、葡糖醛酸等有机酸的盐。当某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。优选地，以常规方式使盐与碱或酸接触，再分离母体化合物，由此再生化合物的游离体形式。化合物的游离体形式与其各种盐的形式的不同之处在于某些物理性质，例如在极性溶剂中的溶解度不同。
“药学上可接受的盐”可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。一般地，优选醚、乙酸乙酯、乙醇、异丙醇或乙腈等非水介质。
本发明所述的以醉茄素A类化合物WACl或其药学上可接受的盐作为活性成分的药物组合物应用在制备治疗骨肉瘤的药物中。
优选，醉茄素A类化合物WACl或其药学上可接受的盐作为所述药物的唯一活性成分。
优选，醉茄素A类化合物WACl或其药学上可接受的盐以及其他治疗骨肉瘤的活性分子共同作为所述药物的活性成分。
优选，醉茄素A类化合物WACl或其药学上可接受的盐作为活性成分的药物与以其他治疗骨肉瘤的活性分子作为活性成分的药物联合应用。
其中，其他治疗骨肉瘤的活性分子的纯度优选为90％以上，更优选为95％以上，进一步优选为98％以上，更进一步优选为99％以上。
优选，所述药物的制剂形式为胶囊剂、散剂、片剂、颗粒剂、丸剂、注射剂、糖浆剂、口服液、吸入剂、软膏剂、栓剂、贴剂。
优选，所述药物组合物还添加了药学上可接受的载体。
所述“药学上可接受的载体”可为药物生产领域中广泛采用的辅料。辅料主要用于提供一个安全、稳定和功能性的药物组合物，还可以提供方法，使受试者接受给药后活性成分以所期望的速率溶出，或促进受试者接受组合物给药后活性成分得到有效吸收。所述的药用辅料可以是惰性填充剂，或者提供某种功能，例如稳定该组合物的整体pH值或防止组合物活性成分的降解。所述的药用辅料可以包括下列辅料中的一种或多种：粘合剂、助悬剂、乳化剂、稀释剂、填充剂、成粒剂、胶粘剂、崩解剂、润滑剂、抗粘着剂、助流剂、润湿剂、胶凝剂、吸收延迟剂、溶解抑制剂、增强剂、吸附剂、缓冲剂、螯合剂、防腐剂、着色剂、矫味剂和甜味剂。
所述药物可根据公开的内容使用本领域技术人员已知的任何方法来制备。例如，常规混合、溶解、造粒、乳化、磨细、包封、包埋或冻干工艺。
所述药物可以以任何形式给药，包括注射(静脉内)、粘膜、口服(固体和液体制剂)、吸入、眼部、直肠、局部或胃肠外(输注、注射、植入、皮下、静脉内、动脉内、肌内)给药。所述的药物还可以是控释或缓释剂型(例如脂质体或微球)。固体口服制剂的实例包括但不限于粉末、胶囊、囊片、软胶囊剂和片剂。口服或粘膜给药的液体制剂实例包括但不限于悬浮液、乳液、酏剂和溶液。局部用制剂的实例包括但不限于乳剂、凝胶剂、软膏剂、乳膏剂、贴剂、糊剂、泡沫剂、洗剂、滴剂或血清制剂。胃肠外给药的制剂实例包括但不限于注射用溶液、可以溶解或悬浮在药学上可接受载体中的干粉制剂、注射用悬浮液和注射用乳剂。所述的药物组合物的其它合适制剂的实例包括但不限于滴眼液和其他眼科制剂；气雾剂，如鼻腔喷雾剂或吸入剂；适于胃肠外给药的液体剂型；栓剂以及锭剂。
有益效果：与现有技术相比，本发明具有如下显著优点：
发现了醉茄素A类化合物WACl的新的药物应用，其对骨肉瘤细胞展现出显著的抑制能力，能够有效干扰骨肉瘤细胞的有丝分裂，导致G2/M期的周期阻滞，从而抑制细胞增殖；还能促进骨肉瘤细胞内活性氧的累积，并诱导细胞凋亡，进一步抑制肿瘤的生长。其作为抗骨肉瘤药物的新的候选药物具有广阔的应用前景。
附图说明
图1为化合物WACl的结构确证图谱，A：WACl的氢谱，B：WACl的碳谱；
图2为化合物WACl对骨肉瘤细胞的增殖抑制结果，A：CCK-8实验结果，B：克隆形成实验结果；
图3为化合物WACl对骨肉瘤细胞周期的影响结构；
图4为化合物WACl对骨肉瘤细胞内活性氧水平的影响结果；
图5为化合物WACl对骨肉瘤细胞凋亡的影响结果。
具体实施方式
下面结合实施例对本发明的技术方案作进一步说明。
HOS细胞系由中国科学院干细胞库(中国上海)友情提供，化合物醉茄素A衍生物WACl由申请人实验室合成获得并经结构确认。
实施例1：化合物WACl的制备
将醉茄素A(20mg，0.04mmol)的无水CH2Cl2(3mL)溶液在0℃、氩气气氛下与亚硫酰氯(6μL，0.06mmol)反应。将反应混合物在室温下搅拌2小时，随后加入冰水(10mL)淬灭反应，接着以CHCl3(3×10mL)萃取。然后将合并的有机层以稀HCl水溶液和盐水洗涤，并以无水MgSO4干燥。过滤，浓缩滤液至油状物，以CH2Cl2/丙酮(9/1)的制备型TLC进一步纯化，得到WACl(3mg，15％)。
WACl的结构确证数据如下：
[α]25 D＝+73.0(c 1.02,CHCl3)；
IRγmax(film)3443,2924,2853,1708,1455,1395,1267,1191,1034,965,754cm-1；
UV(EtOH)λmax(logε)217(4.0)nm；
1H NMR(400MHz,CDCl3)δ0.71(3H,s,Me18),0.94(1H,m,H14),1.01(3H,d,J＝6.7Hz,Me21),1,02(1H,m,H9),1.08(1H,m,H17),1.12(1H,m,H12),1.16(1H,m,H15),1.26(1H,m,H7α),1.38(1H,m,H16),1.42(3H,s,Me19),1.47(1H,m,H11),1.52(1H,m,H8),1.65(1H,m,H15),1.68(1H,m,H16),1.85(1H,m,H11),1.96(1H,m,H12),2.01(1H,m,H20),2.04(1H,m,H23α),2.11(3H,s,Me28),2.15(1H,m,H7β),2.54(1H,m,H23β),3.24(1H,br s,H6),3.77(1H,dd,J＝2.2,5.9Hz,H4),4.34,4.44(2H,dAM,J＝11.3Hz,H27),4.41(1H,dt,J＝3.5,13.2Hz,H22),6.21(1H,d,J＝10.0Hz,H2),6.94(1H,dd,J＝5.9,10.0Hz,H3)；
13C NMR(100MHz,CDCl3)δ11.6(q,C18),13.3(q,C21),17.5(q,C19),20.5(q,C28),22.2(t,C11),24.3(t,C15),27.3(t,C16),29.8(d,C8),30.1(t,C23),31.2(t,C7),37.1(t,C27),38.8(d,C20),39.3(t,C12),42.6(s,C13),44.1(d,C9),47.7(s,C10),52.0(d,C17),56.1(d,C14),62.6(d,C6),63.8(s,C5),69.9(d,C4),78.3(d,C22),124.0(s,C25),132.3(d,C2),141.9(d,C3),156.2(s,C24),164.7(s,C26),202.3(s,C1)；ESIMS(positive)m/z(％)511[M+Na]+(100)；HRESIMS m/z511.2224[M+Na]+(calcd.for C28H37O5ClNa,511.2227).
WACl的氢、碳谱图如图1所示。
实施例2：WACl在CCK-8和克隆形成实验中抑制了骨肉瘤细胞的增殖
对于CCK-8实验，在96孔中接种HOS细胞(每孔2×103个细胞)。经不同浓度的WACl处理后，在指定时间点加入10μL CCK-8。37℃孵育2小时后，使用Molecular DevicesSpectraMaxPlus 384微孔板阅读器测量450nm处的吸光度。对于克隆形成实验，以每孔2×103个细胞的密度将HOS细胞接种到6孔板中。WACl处理24小时后，将培养基换成新鲜培养基，再培养7天。最后，用结晶紫对细胞菌落进行染色，并使用ImageJ软件进行计数。
结果如图2所示，WACl对骨肉瘤细胞的半抑制浓度为2.13±0.32μM，并且显著减少了HOS细胞的集落形成数量。表明该药物能显著抑制骨肉瘤增殖。
实施例3：WACl在流式细胞术测定细胞周期实验中显著诱导HOS细胞发生G2/M期周期阻滞
取对数生长期的人骨肉瘤HOS细胞，经过铺板、不同浓度的WACl给药处理后，收集细胞。PBS溶液清洗细胞沉淀后，加入1mL预冷的70％乙醇溶液混悬细胞，密封好后置于4℃冰箱固定12～24小时。室温条件下使用离心机3000rpm转速离心5min，小心吸除上清后，用预冷PBS溶液重悬细胞，并转移至1.5mL离心管中，3000rpm离心5min，弃上清。每管细胞样品中加入0.5mL PI染色液，用移液器轻轻混悬细胞，37℃避光孵育30min。用滤网过滤细胞悬液，使用流式细胞仪对细胞周期进行检测。细胞周期分析使用ModFit LT软件进行。
结果如图3所示，WACl显著诱导骨肉瘤细胞发生G2/M期周期阻滞，表明该化合物能导致HOS细胞有丝分裂紊乱。
实施例4：WACl在流式细胞术测定细胞内活性氧水平实验中能显著诱导HOS细胞中活性氧的累积
取对数生长期的人骨肉瘤细胞HOS细胞，经过铺板、不同浓度的WACl给药处理后，收集细胞。PBS清洗细胞沉淀后，向离心管中加入DCFH-DA探针稀释液(用无血清培养基按照1:5000稀释)，37℃避光孵育20min，每隔3～5min颠倒混匀一下使探针和细胞充分接触，3000rpm离心5min，弃上清。用无血清细胞培养液洗涤细胞3次，滤网过滤后使用流式细胞仪对细胞活性氧水平进行检测。
结果如图4所示，WACl能有效导致HOS细胞内活性氧的积累。
实施例5：WACl在流式细胞术测定细胞凋亡实验中能显著诱导HOS细胞凋亡
分别取对数生长期的HOS细胞，按照2.5×105每孔的细胞密度接种于6孔板中，用不同浓度的醉茄素衍生物A处理24小时后，收集细胞进行流式检测。具体操作如下：分别收集6孔板中的细胞培养基于离心管中，用预冷PBS溶液润洗细胞1～2次，加入1mL胰蛋白酶溶液对细胞充分消化。取等量离心管中的培养基终止消化，用移液器轻轻吹打细胞，收集细胞悬液置于上述离心管中，离心机在2500rpm转速下离心5min。吸弃上清后，分别加入1mL PBS溶液对细胞团进行重悬，并将其转移至1.5mL离心管中，2500rpm继续离心5min，吸弃上清。每管加入250μL 1x Annexin V Binding Solution重悬细胞，依次加入5μLAnnexin V-FITC和10μL Propidium Iodide(PI)Solution，用移液器轻轻混匀试剂，室温条件下避光孵育15min。继续补加400μL 1x Annexin V Binding Solution，混匀后用滤网过滤细胞悬液使细胞分散均匀，使用流式细胞仪对细胞凋亡情况进行检测。
结果如图5所示，WACl能有效诱导HOS细胞发生凋亡，证明WACl有效促进骨肉瘤细胞死亡，抑制骨肉瘤存活。
Claims (10)
1.一种具有如下结构的醉茄素A类化合物在制备治疗骨肉瘤的药物中的应用，
2.根据权利要求1所述的应用，其特征在于，所述药物为抑制骨肉瘤生长的药物。
3.根据权利要求1所述的应用，其特征在于，所述药物为促进骨肉瘤细胞死亡的药物。
4.根据权利要求1所述的应用，其特征在于，所述药物能够干扰骨肉瘤细胞的有丝分裂、阻滞G2/M期的周期、抑制骨肉瘤细胞的增殖。
5.根据权利要求1所述的应用，其特征在于，所述药物能够促进骨肉瘤细胞内活性氧的累积、诱导骨肉瘤细胞的凋亡。
6.根据权利要求1所述的应用，其特征在于，所述药物的给药剂量为1.0～4.0μM。
7.一种权利要求1所述的醉茄素A类化合物的药学上可接受的盐在制备治疗骨肉瘤的药物中的应用。
8.根据权利要求7所述的应用，其特征在于，所述药学上可接受的盐为所述醉茄素A类化合物与碱金属阳离子或碱土金属阳离子的无机碱形成的盐。
9.一种以权利要求1所述的醉茄素A类化合物或权利要求7所述的药学上可接受的盐作为活性成分的药物组合物在制备治疗骨肉瘤的药物中的应用。
10.根据权利要求9所述的应用，其特征在于，所述药物的制剂形式为胶囊剂、散剂、片剂、颗粒剂、丸剂、注射剂、糖浆剂、口服液、吸入剂、软膏剂、栓剂、贴剂。
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