CN113133999B - 蛇床子素及其衍生物在抑制醛酮还原酶中的应用 - Google Patents
蛇床子素及其衍生物在抑制醛酮还原酶中的应用 Download PDFInfo
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- CN113133999B CN113133999B CN202110464680.2A CN202110464680A CN113133999B CN 113133999 B CN113133999 B CN 113133999B CN 202110464680 A CN202110464680 A CN 202110464680A CN 113133999 B CN113133999 B CN 113133999B
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- aldehyde ketone
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Abstract
本发明属于医药技术领域,公开了蛇床子素及其衍生物在抑制醛酮还原酶中的应用。具体表现为蛇床子素及其衍生物或其药学上可接受的盐显著抑制醛酮还原酶的活性。所述的醛酮还原酶为AKR1C3。本发明的蛇床子素及其衍生物可选择性地抑制醛酮还原酶1C3的活性,且抑制效果显著。本发明还提供蛇床子素及其衍生物或其药学上可接受的盐在制备抑制醛酮还原酶1C3药物中的应用。本发明的蛇床子素及其衍生物通过抑制醛酮还原酶1C3的活性,抑制肿瘤细胞内雄激素产生的最终步骤,从而达到预防和治疗前列腺癌的效果。
Description
技术领域
本发明属于医药技术领域,特别涉及蛇床子素及其衍生物在抑制醛酮还原酶1C3中的应用。
背景技术
癌症(Cancer),亦称恶性肿瘤(Malignant neoplasm)是一种严重威胁人类健康的常见病和多发病。在男性恶性肿瘤中,前列腺癌的发病率位居首位(28%),致死率为10%,仅次于肺癌。现阶段,前列腺癌的治疗方法很多,包括随访观察、经尿道前列腺切除(TURP)、根治性前列腺切除(RP)、放射治疗、内分泌治疗、综合治疗等。由于雄激素和雄激素受体通路异常促使前列腺癌的发生和发展。因此,抑制雄激素的生物合成和阻断雄激素受体信号通路是前列腺癌的传统治疗方法,即雄激素剥夺疗法(Androgen deprivation therapy,ADT)。最初,ADT对晚期或转移性前列腺癌有效,但经过一段时间治疗后,大部分患者发展为致命性的去势前列腺癌(castrate resistant prostate cancer,CRPC)。目前用于治疗CRPC的药物有阿比特龙和恩杂鲁胺,然而阿比特龙会产生高血压的不良反应,需与强的松联合用药,且两者在治疗过程中均会观察到药物抵制作用。因此,研发作用于新靶点的治疗CRPC药物具有重大意义。
醛酮还原酶1C3(Aldehyde ketone reductase family 1member 3,AKR1C3)是醛酮还原酶家族的成员之一,是前列腺癌细胞自身合成睾酮与二氢睾酮的关键酶,在ADT后随肿瘤进展表达逐渐增高。研究发现,在CRPC中,AKR1C3基因表达能力增加了5.3倍,AKR1C3迅速上调,并参与雄激素的合成以应对雄激素水平的下降。AKR1C3还具有前列腺素PGF合成酶活性,能促进肿瘤细胞的生长;AKR1C3的过度表达与前列腺癌的发生、发展密切相关,已成为近几年研究治疗前列腺癌的新颖作用靶点。近几年研究AKR1C3抑制剂的报道较多,且化合物的结构多样,主要集中于以下几类药物及其类似物研究:①非甾体抗炎药及其类似物,如吲哚美辛和N-苯基邻氨基苯甲酸;②苯二氮卓类,如地西泮、艾司唑仑;③黄酮和肉桂酸,如槲皮素和鹰嘴豆素;④环戊烷衍生物,如贝美前列素等。
蛇床子素(Osthole),化学名为7-甲氧基-8-异戊烯基香豆素,又称为甲氧基欧芹酚、欧芹酚甲醚或喔斯脑,是从伞形科草本植物蛇床、独活等多种中草药提取得到的一种线型呋喃香豆素类化合物,因其在蛇床子干燥的果实中的含量最丰富,因此被称为蛇床子素。药理研究证明,蛇床子素具有多种生物活性,如抗过敏、保护心肌细胞、增强免疫功能、抗骨质疏松等。近年来,通过体内及体外实验证实,蛇床子素具有对抗多种肿瘤的作用,如乳腺癌、胆管癌、鼻咽癌、膀胱癌等,是一类非常重要的抗肿瘤药物分子。但关于蛇床子素类化合物作为AKR1C3抑制剂的应用尚未见报道。
发明内容
为了克服上述现有技术的缺点与不足,本发明的首要目的在于提供蛇床子素及其衍生物在抑制醛酮还原酶中的应用。
本发明的目的通过下述方案实现:
蛇床子素及其衍生物或其药学上可接受的盐在抑制醛酮还原酶中的应用,具体表现为蛇床子素及其衍生物或其药学上可接受的盐显著抑制醛酮还原酶的活性。
所述的醛酮还原酶为AKR1C3。
本发明的蛇床子素及其衍生物可选择性地抑制醛酮还原酶1C3的活性,且抑制效果显著。
所述的蛇床子素及其衍生物或其药学上可接受的盐,结构式如式(Ⅰ)或式(Ⅱ)所示:
其中,
R3为H或含1-6个碳原子的直链或支链烷基;
X为羰基或亚甲基;
Y为O或N;
R1、R2相同或不同的分别为H,羟基,C1-C8的直链烷基、支链烷基或环烷基,取代或未取代的芳基,取代或未取代的含N、O和S中的一种或一种以上的杂环基或杂环芳基;或R1、R2与Y成环为取代或未取代的含一个或一个以上的N、O或S的杂环基或杂环芳基。
上述C1-C8的直链烷基、支链烷基或环烷基,芳基,杂环基或杂环芳基中的一个或一个以上氢原子可被氟原子、氧原子、烯基、炔基、芳基、羟基、氨基、羰基、羧基、酯基、氰基、甲基、乙基、甲氧基、硝基取代。
当Y为O时,R1、R2为一个取代基。
本发明还提供上述蛇床子素及其衍生物在制备抑制醛酮还原酶1C3药物中的应用。
醛酮还原酶1C3在雄激素生物合成途径中起重要作用,在CRPC中过度表达,且在癌细胞对恩杂鲁胺产生耐药性及雄激素受体的选择性协同激活过程中起作用,本发明的蛇床子素及其衍生物可选择性地抑制醛酮还原酶1C3的活性、通过抑制肿瘤细胞内雄激素产生的最终步骤,从而实现抑制前列腺癌细胞增值的作用,达到预防和治疗前列腺癌的效果。
所述的药物可以制成任意药用剂型,这些剂型包括但不限于:片剂、糖衣片剂、薄膜衣片剂、肠溶衣片剂、胶囊剂、硬胶囊剂、软胶囊剂、口服液、口含剂、颗粒剂、冲剂、丸剂、丹剂、混悬剂、酒剂、酊剂、滴剂等。
所述的药物还含有一种或一种以上药学上可接受的载体和/或赋形剂。
所述的载体可包括如盐水、缓冲盐水、葡萄糖、水、甘油、乙醇及其组合。如果需要,还可以包含较小量的润湿剂或乳化剂,或pH缓冲剂。
本发明所述药物可以以非肠道方式给药或以腹腔内方式给药,其游离碱或其药学上可接受的盐形式的溶液或悬浮液能够在水中进行配制,并且适当混合以表面活性剂,例如羟丙基纤维素。也可以在甘油、液体聚乙二醇及其在油中的混合物中配制分散剂体,在通常的储存和使用条件下,所述制剂含有防腐剂以便抑制微生物的生长。
本发明适合于注射使用的药物组合物,其形式可包括无菌水溶液或分散液,以及用于即时配制注射溶液或分散液的无菌粉末。在所有情况下,所述形式必须是无菌的,并且必须是可流动的,达到了便于注射的程度,而且必须在生产和储存条件下是稳定的,并且针对微生物例如细菌和霉菌的污染作用必须是防腐的。载体可以是含有例如水、乙醇、多元醇(例如甘油、丙二醇或液体聚乙二醇)及其适当的混合物和植物油的溶剂或分散介质。
当给药用于治疗或抑制特定疾病或病症时,应该理解有效剂量可以根据使用的特定化合物、给药方式、疾病的状态和严重程度、治疗条件以及与被治疗个体有关的各种物理因素而变化。在治疗应用中,以足以治疗或至少部分改善疾病和其并发症的数量,将本发明化合物提供给已经患病的患者。该合适的数量被定义为“治疗有效量”。在特殊情况下治疗所使用的剂量必须客观地由治病的医生确定,涉及的变化包括患者的特殊状态、体重、年龄以及反应行为。将所需剂量水平提供给人类。所述剂量可以一次给药或分两次或多次给药。规定的日剂量可以随给药的方式变化。所述剂量能够以任何可用于将活性化合物导入接受者的血液中的方式给药,该方式包括口服、通过植入物、非肠道(包括静脉、腹膜内、关节内和皮下注射)、直肠、鼻内、表皮、眼内(眼滴剂)、阴道和经皮给药。
具体实施方式
下面结合实施例对本发明作进一步详细的描述,但本发明的实施方式不限于此。下列实施例中涉及的物料若无特殊说明均可从商业渠道获得。所述方法若无特别说明均为常规方法。所用各组分的量以摩尔体积份计,mol、L。
一实施方式,本发明提供一种蛇床子素及其衍生物或其药学上可接受的盐在抑制醛酮还原酶中的应用,具体表现为蛇床子素及其衍生物或其药学上可接受的盐显著抑制醛酮还原酶的活性。
一具体实施例中,所述的醛酮还原酶为AKR1C3。本发明的蛇床子素及其衍生物可选择性地抑制醛酮还原酶1C3的活性,且抑制效果显著。
另一实施方式,本发明提供上述蛇床子素及其衍生物在制备抑制醛酮还原酶1C3药物中的应用。
一具体实施例中,所述的蛇床子素及其衍生物或其药学上可接受的盐,结构式如式(Ⅰ)或式(Ⅱ)所示:
其中,
R3为H或含1-6个碳原子的直链或支链烷基;
X为羰基或亚甲基;
Y为O或N;
R1、R2相同或不同的分别为H,羟基,C1-C8的直链烷基、支链烷基或环烷基,取代或未取代的芳基,取代或未取代的含N、O和S中的一种或一种以上的杂环基或杂环芳基;或R1、R2与Y成环为取代或未取代的含一个或一个以上的N、O或S的杂环基或杂环芳基。
上述C1-C8的直链烷基、支链烷基或环烷基,芳基,杂环基或杂环芳基中的一个或一个以上氢原子可被氟原子、氧原子、烯基、炔基、芳基、羟基、氨基、羰基、羧基、酯基、氰基、甲基、乙基、甲氧基、硝基取代。
当Y为O时,R1、R2为一个取代基。
另一具体实施例中,本发明提供一种上述蛇床子素衍生物的制备方法,具体如下反应式所示:
反应式1:
反应式2:
反应式3:
反应式4:
反应式5:
其中,
反应式1中,先由蛇床子素经氧化得到化合物A,化合物A与烷基仲胺反应得到化合物B;其中,所述氧化采用的氧化剂可为二氧化硒等常规氧化剂;胺的反应可在氰基硼氰化钠等还原剂作用下进行。
反应式2中,化合物A经氧化得到化合物B;化合物B与N,N-二烷基胺反应得到化合物D;其中,所述氧化采用的氧化剂可为亚氯酸钠等常规氧化醛为酸的氧化剂,氧化反应在磷酸二氢钠的酸性环境下进行;胺的反应可在六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷(PyBOP)的作用下进行。
反应式3中,化合物C与烷基醇反应得到化合物E;反应可在浓硫酸脱水作用下进行。
反应式4中,化合物A经还原得到化合物F;化合物F与烷基取代苯酚脱水反应得到化合物G;其中,所述还原采用的还原剂可为氰基硼氢化钠/冰醋酸等常规还原体系;脱水反应可在三苯基磷/偶氮二甲酸二乙酯环境下进行。
反应式5中,化合物D脱甲基得到化合物H。所述脱甲基可在三溴化硼作用下进行。
本发明上述制备方法过程中的工艺为本领域常规工艺即可,本领域技术人员公知,工艺参数的调整并不影响反应的进行;因此对于本领域技术人员来说,在不脱离本发明构思的前提下,可根据本领域的基本知识确定合成的路线,对采用的反应物、催化剂、溶剂及温度等工艺参数进行若干改进,这些都属于本发明的保护范围。
一实施例,根据反应式1,将蛇床子素的乙醇溶液加入二氧化硒的N,N-二甲基甲酰胺溶液中,90℃回流反应10h,制备得到化合物A;将化合物A溶于四氢呋喃后与3-(4-氨基苯基)丙烯酸乙酯、冰乙酸室温反应2h,再加入氰基硼氢化钠继续反应24h,得到蛇床子素衍生物1。本领域技术人员根据公知常识可知,利用不同取代的氨基,可制备得到不同仲胺取代的蛇床子素衍生物。
另一实施例,根据反应式2,将化合物A溶于四氢呋喃后,加入2-甲基-2-丁烯、磷酸二氢钠缓冲液、亚氯酸钠冰浴反应5h,得到化合物C;将化合物C溶于四氢呋喃,依次加入正丙胺、缩合剂PyBOP、二异丙基乙基胺,室温反应3h,得到蛇床子素衍生物2。同理,采用不同R1、R2取代基的胺与化合物C反应可制备得到不同取代基的蛇床子素衍生物,如化合物3-16。本领域技术人员根据公知常识可知,利用不同取代的氨基,可制备得到不同取代基的蛇床子素衍生物。
再一实施例,根据反应式3,将化合物C与脂肪醇在浓硫酸的脱水作用下,反应生成蛇床子素衍生物17。本领域技术人员根据公知常识可知,利用不同脂肪醇,可制备得到不同取代基的蛇床子素衍生物。
再一实施例,根据反应式4,将化合物A溶于四氢呋喃后,加入冰乙酸、氰基硼氢化钠室温反应24h,得到化合物F;将化合物F溶于四氢呋喃后,与3,5-二甲基苯酚、三苯基磷、偶氮二甲酸二乙酯室温反应24h,得到蛇床子素衍生物18。本领域技术人员根据公知常识可知,利用不同取代的苯酚,可制备得到不同取代基的蛇床子素衍生物。
再一实施例,根据反应式5,将本发明的蛇床子素衍生物在三溴化硼作用下脱甲基,得到脱甲基化的蛇床子素衍生物19。本领域技术人员根据公知常识可知,本发明提供的蛇床子衍生物均可通过脱甲基,制备得到多种蛇床子素衍生物。
实施例1:蛇床子素及其衍生物对AKR1C3的影响
本发明提供根据上述制备方法得到的蛇床子素及其衍生物化合物1-化合物19,并对其抑制活性进行检测。
将蛇床子素及其衍生物与含有0.1M磷酸缓冲液(pH 6.0),8μM 9,10-菲醌以及0.15mM NADPH的混合溶液在30℃孵育10分钟后,加入重组AKR1C3蛋白(该重组蛋白的制备方法参见文献:Chemico-Biological Interactions,2015,240,310–315),然后以Flex 3多功能酶标仪检测化合物对辅酶NADPH消耗速率的影响,每组至少测量三次。对AKR1C3蛋白活性抑制的IC50值通过浓度测试及非线性回归,计算获得。从而获得蛇床子素及其衍生物对AKR1C1的抑制活性。
本发明化合物对AKR1C3酶的抑制活性测试数据如表1所示(同等条件下,阳性对照物甲氯酚那酸(Meclofenamic acid)对AKR1C3酶/AKR1C1酶的抑制活性IC50分别为0.52μM和0.74μM)。
表1蛇床子素及其衍生物对AKR1C3的抑制作用
由表1可见,本发明的蛇床子素及其衍生物可选择性地抑制醛酮还原酶1C3的活性,且抑制效果显著。其中,本发明的蛇床子素及其衍生物的IC50值比阳性对照物甲氯酚那酸还低,可显著抑制醛酮还原酶1C3活性,通过抑制肿瘤细胞内雄激素产生的最终步骤,从而达到预防和治疗前列腺癌的效果。
实施例2:蛇床子素及其衍生物对前列腺癌22Rv1细胞增值的影响
对本发明蛇床子素及其衍生物,采用CCK8法检测其对人前列腺癌细胞株22Rv1(该细胞购自中国科学院典型培养物包藏委员会细胞库/中国科学院上海生命科学研究院细胞资源中心,目录号SCSP-5022)体外培养的增殖抑制活性。将处于对数生长期的肿瘤细胞液接种于96孔板,细胞密度为1.5×104/孔,每个药物浓度设置3个复孔,用RPMI-1640培养基培养24h。加入不同浓度的待测化合物100μL,空白对照组加入RPMI-1640培养基100μL,细胞置于含5%CO2的37℃培养箱培养72h,按照CCK8法测试细胞活力,测试结果见表2。由表2可见,本发明蛇床子素及其衍生物对前列腺癌22Rv1细胞增值具有显著性抑制作用。
表2蛇床子素及其衍生物对前列腺癌22Rv1细胞的增殖抑制作用
注:氟芬那酸的IC50值源来参考文献[Eur.J.Med.Chem.2018,150,930–945.],恩杂鲁胺的IC50值源来参考文献[Eur.J.Med.Chem.2019,171,265–281.]。
化合物的相关数据如表3所示:
表3化合物的结构表征数据
上述实施例为本发明较佳的实施方式,但本发明的实施方式并不受上述实施例的限制,其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化,均应为等效的置换方式,都包含在本发明的保护范围之内。
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