CN115260260A - 具有kga抑制活性的含硒核糖类化合物及其合成方法的应用 - Google Patents
具有kga抑制活性的含硒核糖类化合物及其合成方法的应用 Download PDFInfo
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- CN115260260A CN115260260A CN202110476548.3A CN202110476548A CN115260260A CN 115260260 A CN115260260 A CN 115260260A CN 202110476548 A CN202110476548 A CN 202110476548A CN 115260260 A CN115260260 A CN 115260260A
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- ribose
- selenium
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- cancer
- mmol
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Abstract
本发明提供了具有KGA抑制活性的含硒核糖类化合物及其合成方法和应用,属于新药技术领域。本发明设计合成了一系列具有KGA抑制活性的核糖核酸类化合物,并进行各类生物活性筛选,旨在提高KGA抑制剂的化疗效果,增加核酸类化疗药物的半衰期,减少毒性,提高生物利用度和体内药效,抗肿瘤药效显著增长具有临床应用前景。
Description
技术领域
本发明涉及新药研发技术领域,尤其涉及具有KGA抑制活性的含硒核 糖类化合物及其合成方法的应用。
背景技术
肿瘤细胞基因突变,可造成葡萄糖有氧糖代谢途径的明显改变,即 Warburg效应:葡萄糖代谢增加200倍,但产物乳酸被排出体外,不能进入 线粒体三羧酸循环,因此谷氨酰胺成为肿瘤细胞线粒体产生能量所依赖的原 料,谷氨酰胺缺乏或谷氨酰胺酶的抑制均能抑制肿瘤细胞的生长。
谷氨酰胺酶是谷氨酰胺进入线粒体三羧酸循环必不可少的酶。尤其是在 癌细胞中。哺乳动物体内含有两个不同的基因编码谷氨酰胺酶:GLS1和 GLS2。二者的蛋白结构、动力学特征以及涉及的调节机制均不相同。GLS1 基因位于2号染色体,编码的是肾型同工酶。GLS2基因位于12号染色体, 编码的是肝型同工酶。现已发现3种GLS1变异体:典型的剪接变异体 1(KGA);被截去顶端、无催化作用的剪接变异体2;一个引申的剪接变异体 3(GAC)。GAC与KGA具有相同的N端,不同的C末端。GLS1的变异体 GAC在许多原发性肿瘤和肿瘤细胞系中都有强烈的表达,而GLS2在肿瘤细 胞中的表达则是相对有限的。因此,合成一种可以对上述的GLS1(KGA)抑 制但是对GLS2不抑制的化合物,将可以对相应的肿瘤细胞起到抑制作用, 并预期具有较小的生物毒性。KGA是抗肿瘤研究的靶标之一,目前尚未取 得突破性进展。
由于单一靶标的KGA抑制剂生物活性不够,如CB839临床因活性缺乏 失败,而我们早期研发的双靶标不对称己烷硒啉类化合物有很好的活性。此 类化合物存在溶解度小,生物利用度不高等问题。因此,进一步提高含硒 类KGA抑制剂的溶解度,生物利用度和体内药效,具有突破瓶颈的重要意 义。(脱氧)核糖核酸类化合物,如阿糖胞苷、吉西他滨和5-氟尿嘧啶,是 抗肿瘤代谢类化疗药物,用于晚期癌症病人的治疗。但此类化合物毒性较大, 代谢非常快,治疗窗窄,疗效持续时间短。
发明内容
本发明的目的在于提供具有KGA抑制活性的含硒核糖类化合物及其制 备方法的应用,本发明设计合成了一系列具有KGA抑制活性的核糖核酸类 化合物,并进行各类生物活性筛选,旨在提高KGA抑制剂的化疗效果,增 加核酸类化疗药物的半衰期,减少毒性,提高生物利用度和体内药效。
为了实现上述发明目的,本发明提供以下技术方案:
本发明提供了具有KGA抑制活性的含硒核糖类化合物,所述化合物的 结构通式包括:
系列A、B、C包括:
系列D、E、F包括:
R1包括氢、卤素、羟基和醚中的一种;
R2、R3、R4、R5分别独立地包括氢、羟基、卤素、醚、硅氧醚、硫醚、 苯醚、胺类、磷酸酯、磷酸酯衍生物、磺酸酯和亚砜类中的一种;
R6包括氢、氟、甲氧基和乙氧基中的一种;
其中,所述卤素为氟、氯、溴、碘中的一种;
所述醚为烷烃碳原子数≤5的烷氧基。
进一步的,所述含硒核糖类化合物的结构特征包括n=2的硒琳丙酸芳香 胺和/或n=5的硒琳已酸芳香胺的衍生物。
进一步的,R2、R3、R4、R5分别独立地包括氢、羟基、卤素、醚、磷酸 酯衍生物类中的一种。
进一步的,包括以下结构的化合物:
本发明提供了所述的含硒核糖类化合物的合成方法,A、B、C系列化 合物的合成步骤包含:
苯硒氯:将联硒酸、氯化亚砜于溶剂中反应,得到苯硒氯;
硒啉化:将上步得到的苯硒氯加入含氨基的核糖衍生物中,得到棕色油 状物;
硒啉胞嘧啶核糖:将上步得到的棕色油状物加入含四丁基氟化铵的四氢 呋喃溶液中进行反应,即得到目标产物。
本发明提供了所述的含硒核糖类化合物的合成方法,D、E、F系列化合 物的合成步骤包含:
苯硒氯:将联硒酸、氯化亚砜于溶剂中反应,得到苯硒氯;
硒啉酸化:将上步得到的苯硒氯、氨基酸于无水乙腈中反应得到苯硒酸;
硒啉酸胞嘧啶核糖:将上述得到的苯硒酸、溶剂、N-甲基吗啉、1-乙基 -3(3-二甲基丙胺)碳二亚胺、1-羟基苯并三唑与含氨基的核糖衍生物混合后反 应即得到目标产物。
进一步的,所述联硒酸、氯化亚砜和溶剂的摩尔体积比独立的为 12.0~13.0mmol:14~16ml:0.3~0.6ml。
进一步的,所述联硒酸和氯化亚砜的反应时间为3~5h,反应温度为 40~45℃。
进一步的,所述溶剂独立的包括二甲基甲酰胺、四氢呋喃、二氯甲烷和 甲醇中的一种或几种。
进一步的,所述苯硒氯与含氨基的核糖衍生物的摩尔比为1.0~1.4:1.0。
进一步的,所述棕色油状物与含四丁基氟化铵的四氢呋喃溶液的质量体 积比为510~530mg:3.0~4.0ml。
进一步的,所述苯硒氯、无水乙腈和氨基酸的摩尔体积比为 19.0~20.0mmol:14~16ml:59.0~60.0mmol。
进一步的,所述苯硒酸、溶剂、N-甲基吗啉、1-乙基-3(3-二甲基丙胺) 碳二亚胺、1-羟基苯并三唑与含氨基的核糖衍生物的摩尔体积比为 1.8~2.0mmol:4~6ml:5.0~6.0mmol:2.5~3.0mmol:3.5~4.0mmol:2.0~2.5mmol。
本发明提供了含硒核糖类化合物或其混合物形式或其可药用盐或药物 组合物在制备治疗癌症的药物中的应用,所述的癌症包括但不限于肝癌、肺 癌、白血病、胰腺癌、胃癌、乳腺癌、神经瘤、膀胱癌、前列腺癌、肉瘤、 黑色素瘤、肾癌、结肠癌和宫颈癌。
本发明的有益效果:
本发明针对现有技术中缺少具有高体内抗肿瘤活性的KGA抑制剂,以 及KGA抑制剂普遍具有溶解度低的缺点,提供了一种同时靶向肾型谷氨酰 胺和核酸代谢的双靶标抑制剂。嘌呤和嘧啶是核酸的母体是DNA和RNA的 重要组成部分,其衍生物比如吉西他滨、阿糖胞苷、5-氟尿嘧啶等能有效靶 向肿瘤的DNA和RNA合成,但是这类化疗药物的NH2-氨基极易被代谢失 活(半衰期5-10分钟)。因此我们利用这些化合物的作为片段,通过酰胺键, 合成新型的KGA双靶标抑制剂,使化合物有更显著的抗肿瘤活性和更好的 代谢稳定性。提高了化合物的溶解度,使化合物不仅能够起到显著的体内抑 制肿瘤的效果,且具有低毒或者无毒特点。
还具有以下优点:
具有KGA活性的核糖类药物偶联化合物具有抗肿瘤活性;
具有KGA活性的核糖类药物偶联化合物比母体核酸药物在肝微粒体中 的稳定性提高;
母体核糖类药物没有KGA活性,但是硒啉核糖类药物偶联化合物具有 明显的KGA活性IC500.5-5μM,具有很好的抗肿瘤细胞活性;
硒啉核糖类药物偶联化合物具有明显提高的溶解度;
动物模型(肝癌)显示明显提高的药效。
附图说明
图1为本申请化合物对的KGA酶的抑制活性实验数据图;
图2为本申请化合物对H22肿瘤细胞的抑制活性实验数据图;
图3为本申请化合物对A549肿瘤细胞的抑制活性实验数据图;
图4为本申请对动物模型(肝癌细胞)的药效活性实验数据图。
具体实施方式
本发明提供的具有KGA抑制活性的含硒核糖类化合物中,所述醚优选 为甲基醚、乙基醚、丙基醚、异丙基醚和丁基醚中的一种。
本发明提供了A、B、C系列化合物的合成方法。
在本发明中,所述联硒酸、氯化亚砜和溶剂的摩尔体积比为 12.0~13.0mmol:14~16ml:0.3~0.6ml,优选为12.5mmol:15ml:0.4~0.5ml。
在本发明中,苯硒氯步骤中,联硒酸和氯化亚砜的反应时间为3~5h,优 选为4h;反应温度为40~45℃,优选为41~44℃,进一步优选为43℃。
在本发明中,苯硒氯步骤中,还需要将生成物减压浓缩至蒸出液呈单滴 状,加溶剂继续减压浓缩得到黄色固体。
在本发明中,所述溶剂包括二甲基甲酰胺、四氢呋喃、二氯甲烷和甲醇 中的一种或几种,优选为四氢呋喃和甲醇。
在本发明中,硒啉化步骤中,所述苯硒氯与含氨基的核糖衍生物的摩尔 比为1.0~1.4:1.0,优选为1.2:1.0。
在本发明中,所述棕色油状物与含四丁基氟化铵的四氢呋喃溶液的质量 体积比为510~530mg:3.0~4.0ml,优选为515~525mg:3.2~3.8ml,进一步 优选为520mg:3.5ml。
在本发明中,硒啉化步骤中,苯硒氯和含氨基的核糖衍生物的反应的温 度为20~30℃,优选为22~27℃,优选为25℃;反应的时间为10~12h,优选 为11h。
在本发明中,硒啉化步骤中,还需要用饱和碳酸氢钠溶液洗涤一次,将 有机相加入到无水碳酸钠中干燥。
在本发明中,硒啉化步骤中,还需要将干燥后的产物在35~40℃下减压 浓缩除去溶剂,温度优选为37℃。
在本发明中,硒啉胞嘧啶核糖步骤中,反应的温度为20~30℃,优选为 22~27℃,进一步优选为25℃;反应的时间为0.5~1.5h,优选为1h。
在本发明中,硒啉胞嘧啶核糖步骤中,得到的浓缩物还需要通过柱层析 纯化,具体步骤为:将浓缩物中加入3~8ml的二氯甲烷溶解,加入100~200 目硅胶1.0~2.0g,浓缩,分别用二氯甲烷,体积比为30~50:1~3的二氯甲 烷、甲醇混合溶液洗脱杂质物,体积比为12~20:1~3的二氯甲烷、甲醇的 混合溶液洗脱产品,得到终产物。
在本发明中,硒啉胞嘧啶核糖步骤中,得到的浓缩物还需要通过柱层析 纯化,具体步骤优选为:将浓缩物中加入5ml的二氯甲烷溶解,加入150目 硅胶1.5g,浓缩,分别用二氯甲烷,体积比为40:1的二氯甲烷、甲醇混合 溶液洗脱杂质物,体积比为15:1的二氯甲烷、甲醇的混合溶液洗脱产品, 得到终产物。
本发明还提供了D、E、F系列化合物的合成方法,该合成方法中苯硒 氯的合成要求与上文相同,在此不再赘述。
在本发明中,硒啉酸化步骤中,所述苯硒氯、无水乙腈和氨基酸的摩尔 体积比为19.0~20.0mmol:14~16ml:59.0~60.0mmol,优选为19.1~19.7mmol: 15ml:59.1~59.5mmol。
在本发明中,硒啉酸化步骤中,苯硒氯、无水乙腈和氨基酸反应的温度 为20~30℃,优选为22~27℃,优选为25℃;反应的时间为10~12h,优选为 11h。
在本发明中,硒啉酸胞嘧啶核糖步骤中,所述苯硒酸、溶剂、N-甲基吗 啉、1-乙基-3(3-二甲基丙胺)碳二亚胺、1-羟基苯并三唑与含氨基的核糖衍生 物的摩尔体积比为1.8~2.0mmol:4~6ml:5.0~6.0mmol:2.5~3.0mmol: 3.5~4.0mmol:2.0~2.5mmol,优选为1.9mmol:5ml:5.6mmol:2.9mmol: 3.8mmol:2.1mmol。
在本发明中,所述溶剂独立的包括二甲基甲酰胺、四氢呋喃、二氯甲烷 和甲醇中的一种或几种,优选为四氢呋喃、二氯甲烷和甲醇。
在本发明中,硒啉酸胞嘧啶核糖步骤中,所述反应的温度为60~65℃, 优选为63℃;反应的时间为3.5~4.5h,优选为4h。
在本发明中,硒啉酸胞嘧啶核糖步骤中,原料反应至LC-MS监控至原 料≤2%。
在本发明中,硒啉酸胞嘧啶核糖步骤中,还需要将反应液冷却至0~10℃, 加入15~25ml的无水乙腈搅拌20~40min,优选为冷却至3~8℃,加入18~22ml 的无水乙腈搅拌25~35min,进一步优选为冷却至5℃,加入20ml的无水乙 腈搅拌30min,得到黄色固体。
在本发明中,硒啉酸胞嘧啶核糖步骤中,还需要对得到的黄色固体进行 硅胶柱层析纯化,具体步骤为:用10~20ml的二氯甲烷溶解黄色固体,加入 100~200目硅胶2.5~3.5g,用体积比为40~60:1~3的二氯甲烷、甲醇混合溶 液洗脱杂质物,用体积比为10~20:1~3的二氯甲烷、甲醇混合溶液洗脱产 品,得到终产物。
在本发明中,硒啉酸胞嘧啶核糖步骤中,还需要对得到的黄色固体进行 硅胶柱层析纯化,具体步骤优选为:用15ml的二氯甲烷溶解黄色固体,加 入150目硅胶3.0g,用体积比为50:1的二氯甲烷、甲醇混合溶液洗脱杂质 物,用体积比为15:1的二氯甲烷、甲醇混合溶液洗脱产品,得到终产物。
本发明提供了含硒核糖类化合物或其混合物形式或其可药用盐或药物 组合物在制备治疗癌症的药物中的应用,所述的癌症为肝癌和/或肺癌。
下面结合实施例对本发明提供的技术方案进行详细的说明,但是不能把 它们理解为对本发明保护范围的限定。
实施例
A、B、C系列化合物的合成路线为:
具体合成方法为:
苯硒氯:联硒酸,氯化亚砜和DMF(0.5ml)加入到茄形瓶中,回流反 应4小时,45℃减压浓缩至蒸出液呈单滴状,加入无水四氢呋喃(15ml)继续 45℃减压浓缩,得黄色固体。
硒啉化:将含氨基的核糖衍生物(1.0mmol)溶于2ml四氢呋喃,冷却 至5℃;将苯硒氯溶于四氢呋喃(2ml)溶液中并滴加至上述反应液中,保持内 温5℃,缓慢升至室温,搅拌过夜(12h)。
减压浓缩除去四氢呋喃,加入二氯甲烷(10ml)溶解。用饱和碳酸氢钠溶 液(5ml)洗涤,水(5ml)洗一次;有机相加入无水硫酸钠(1.0g)干燥,40℃减 压浓缩除去二氯甲烷,得棕色油状物投入下一步反应。
硒啉胞嘧啶核糖:将上一步棕色油状物加入四氢呋喃(3ml),室温搅拌, 加入含四丁基氟化铵的四氢呋喃溶液(1mol/L)室温搅拌1小时,减压浓缩除 去四氢呋喃,浓缩物通过柱层析纯化:油状物中加入二氯甲烷(5ml)溶解, 加入200目硅胶(1.5g),浓缩;分别用二氯甲烷,二氯甲烷:甲醇=40:1(v/v) 洗脱前杂,二氯甲烷:甲醇=15:1(v/v)洗脱产品,得终产品。
将A、B、C系列化合物的具体实施方法概括为表1中的实施例1~23。
表1(实施例1~23)
硒啉胞嘧啶二氟核糖(JNC201001)
MS m/z:[M+H]+=446
1H NMR(500MHz,DMSO)δ8.35(d,J=7.5Hz,1H),8.06(d,J=8.0Hz, 1H),7.92(d,J=7.8Hz,1H),7.79–7.71(m,2H),7.47(t,J=7.5Hz,1H),6.35 (d,J=6.5Hz,1H),6.20(t,J=7.3Hz,1H),5.35(t,J=5.4Hz,1H),4.29–4.14 (m,1H),3.92(dt,J=8.5,2.8Hz,1H),3.83(d,J=9.2Hz,2H).
硒啉胞嘧啶核糖(JNC201002)
MS m/z:[M+H]+=426
1H NMR(500MHz,DMSO)δ8.15(d,J=7.4Hz,1H),8.12(d,J=8.0Hz, 1H),7.90(dd,J=7.9,1.4Hz,1H),7.71(ddd,J=8.3,7.1,1.4Hz,1H),7.66(d,J =7.4Hz,1H),7.49–7.40(m,1H),6.08(d,J=3.9Hz,1H),4.09(dd,J=3.9,2.3 Hz,1H),3.94(t,J=2.6Hz,1H),3.85(td,J=8.3,5.6,2.9Hz,2H),3.63(d,J= 1.3Hz,2H),3.62(d,J=1.2Hz,2H).
间醚硒啉胞嘧啶二氟核糖(JNC201006)
MS m/z:[M+H]+=476
1H NMR(500MHz,DMSO)δ8.06(d,J=8.0Hz,1H),7.68(d,J=8.5Hz, 1H),7.57(d,J=1.5,1H),6.98(dd,J=8.5,1.5Hz,1H),6.32(d,J=8.0Hz,1H), 6.10(t,J=7.3Hz,1H),5.35(br,1H),4.64(br,1H),4.29–4.14(m,1H),3.91(m, 1H),3.85-3.60(m,5H).
邻醚硒啉氟嘌呤核糖(JNC202006)
MS m/z:[M+H]+=498
1H NMR(500MHz,DMSO)δ8.27(d,J=1.8Hz,1H),7.50-7.41(m,2H), 7.26(dd,J=7.2,1.5Hz,1H),6.31(dd,J=4.6,13.5Hz,1H),4.42-5.33(m,5H), 3.96-3.82(m,4H)3.63(m,2H)
对氟硒啉氮杂嘧啶2-脱氧核糖(JNC203008)
MS m/z:[M+H]+=429
1H NMR(500MHz,DMSO)δ8.45(s,1H),7.85–7.78(m,2H),7.26(td,J= 8.5,2.5Hz,1H),6.03(t,1H),5.2(d,1H),5.04(t,1H),4.25(m,1H),3.80(m,1H), 3.57(m,2H),2.17(m,2H)
D、E、F系列化合物的合成路线:
具体合成方法为:
苯硒氯:联硒酸,氯化亚砜和DMF(0.5ml)加入到茄形瓶中,升温至回 流反应4小时,44℃减压浓缩至蒸出液呈单滴状,加入无水四氢呋喃(15ml) 继续45℃减压浓缩,得黄色固体。
硒啉酸化:苯硒氯,无水乙腈(15ml)和氨基酸,室温搅拌过夜,过滤, 滤饼用水(5ml)洗涤后抽干,50℃鼓风干燥,得苯硒酸。
硒啉酸胞嘧啶核糖:苯硒酸加入DMF(5ml)搅拌溶解。依次加入N-甲基 吗啉(0.56g,5.6mmol),EDCI(1-乙基-3(3-二甲基丙胺)碳二亚胺)(0.55g, 2.9mmol),HOBt(1-羟基苯并三唑)(0.51g,3.8mmol)和含氨基的核糖衍 生物。升温至65℃反应4小时,LC-MS监控至原料≤2%。反应液冷却至10℃, 加入无水乙腈(20ml)搅拌30min,抽滤,得到的黄色固体硅胶柱层析纯化。 (用二氯甲烷(15ml)溶解固体,加入200目硅胶(3.0g)拌样,装柱硅胶(15.0 g)。用二氯甲烷:甲醇=50:1(v/v)洗脱前杂,用二氯甲烷:甲醇=15:1(v/v) 洗脱产物)。得到终产物。
将D、E、F系列化合物的具体实施方法概括为表2中的实施例24~61。
表2(实施例24~61)
硒啉丙酸胞嘧啶核糖(JNC204001)
MS m/z:[M+H]+=497
1H NMR(500MHz,DMSO)δ10.98(s,1H),8.09(d,J=7.5Hz,1H),8.01 (d,J=8.0Hz,1H),7.81(d,J=9.1Hz,1H),7.63–7.55(m,1H),7.41(t,J=7.5 Hz,1H),7.23(d,J=7.5Hz,1H),6.05(d,J=3.9Hz,1H),5.50(dd,J=10.6,4.8 Hz,2H),5.07(t,J=5.5Hz,1H),4.06(m,J=5.8Hz,1H),3.99(m,J=9.5,6.4 Hz,2H),3.93(s,1H),3.86–3.78(m,1H),3.62(t,J=5.4Hz,2H),2.79(t,J= 6.5Hz,2H).
硒啉丁酸胞嘧啶核糖(JNC204002)
MS m/z:[M+H]+=511
1H NMR(500MHz,DMSO)δ10.85(s,1H),8.36(d,J=7.7Hz,1H),8.06 (d,J=7.5Hz,1H),7.77(d,J=7.5Hz,1H),7.55(t,J=7.6Hz,1H),7.38(t,J= 7.4Hz,1H),7.20(d,J=7.5Hz,1H),6.05(d,J=3.9Hz,1H),5.55(dd,J=12.2, 4.6Hz,2H),5.16(t,J=5.3Hz,1H),4.05(m,J=5.7Hz,1H),3.93(dd,1H), 3.85–3.79(m,1H),3.70(t,J=7.0Hz,2H),3.61(t,J=5.3Hz,2H),2.45(t,J= 7.3Hz,2H),1.95–1.80(m,2H).
硒啉戊酸胞嘧啶核糖(JNC204003)
MS m/z:[M+H]+=525
1H NMR(500MHz,DMSO)δ10.83(s,1H),8.05(d,J=1.9Hz,1H),8.04 (d,J=2.6Hz,1H),7.80(dd,J=7.7,0.8Hz,1H),7.64–7.56(m,1H),7.47– 7.32(m,1H),7.20(d,J=7.5Hz,1H),6.05(d,J=3.9Hz,1H),5.48(d,J=5.0 Hz,2H),5.06(t,J=5.6Hz,1H),4.11–3.99(m,1H),3.92(dd,J=6.3,2.6Hz, 1H),3.82(td,J=2.8Hz,1H),3.73(t,J=6.7Hz,2H),3.61(t,J=5.5Hz,2H), 2.44(t,J=7.1Hz,2H),1.68–1.53(m,4H).
硒啉己酸胞嘧啶核糖(JNC204004)
MS m/z:[M+H]+=539
1H NMR(500MHz,DMSO)δ10.80(s,1H),8.04(dd,J=7.7,4.1Hz,2H), 7.79(d,J=7.0Hz,1H),7.63–7.57(m,1H),7.45–7.37(m,1H),7.19(d,J= 7.5Hz,1H),6.05(d,J=3.9Hz,1H),5.56–5.31(m,2H),5.06(t,J=5.6Hz, 1H),4.08–4.03(m,1H),3.94–3.89(m,1H),3.82(td,J=5.5,2.8Hz,1H),3.71 (t,J=7.1Hz,2H),3.61(t,J=5.5Hz,2H),2.39(t,J=7.4Hz,2H),1.69–1.52 (m,4H),1.31(m,J=15.2,8.2Hz,2H).
硒啉丙酸胞嘧啶二氟核糖(JNC204006)
MS m/z:[M+H]+=517
1H NMR(500MHz,DMSO)δ11.19(s,1H),8.30(d,J=7.6Hz,1H),8.03 (d,J=8.0Hz,1H),7.83(d,J=7.1Hz,1H),7.65–7.58(m,1H),7.43(dd,J= 11.4,4.3Hz,1H),7.31(d,J=7.6Hz,1H),6.35(d,J=6.5Hz,1H),6.19(t,J= 7.4Hz,1H),5.34(t,J=5.3Hz,1H),4.24(t,J=6.6Hz,1H),4.01(t,J=6.6Hz, 2H),3.91(dt,J=8.5,3.0Hz,1H),3.82(t,J=11.1Hz,1H),3.71–3.63(m,1H), 2.83(t,J=6.5Hz,2H).
硒啉戊酸胞嘧啶二氟核糖(JNC204007)
MS m/z:[M+H]+=545
1H NMR(500MHz,DMSO)δ11.01(s,1H),8.24(d,J=7.6Hz,1H),8.04 (d,J=8.0Hz,1H),7.80(d,J=7.2Hz,1H),7.64–7.53(m,1H),7.41(t,J=7.2 Hz,1H),7.27(d,J=7.6Hz,1H),6.32(d,J=6.5Hz,1H),6.16(t,J=7.4Hz, 1H),5.31(t,J=5.4Hz,1H),4.19(ddd,J=27.7,13.0,6.9Hz,1H),3.91–3.85 (m,1H),3.80(d,J=12.5Hz,1H),3.73(t,J=6.7Hz,2H),3.65(ddd,J=12.6, 5.7,3.6Hz,1H),2.46(t,J=7.1Hz,2H),1.70–1.51(m,4H).
硒啉丁酸胞嘧啶二氟核糖(JNC204008)
MS m/z:[M+H]+=531
1H NMR(500MHz,DMSO)δ11.02(s,1H),8.23(d,J=7.6Hz,1H),8.04 (d,J=8.0Hz,1H),7.80(d,J=7.7Hz,1H),7.64–7.54(m,1H),7.41(t,J=7.4 Hz,1H),7.26(d,J=7.6Hz,1H),6.32(d,J=6.5Hz,1H),6.16(t,J=7.4Hz, 1H),5.31(t,J=5.4Hz,1H),4.18(ddd,J=19.4,14.1,6.3Hz,1H),3.91–3.84 (m,1H),3.83–3.77(m,1H),3.74(t,J=6.9Hz,2H),3.65(ddd,J=12.7,5.7, 3.6Hz,1H),2.47(t,J=7.2Hz,2H),1.90(p,J=7.1Hz,2H).
硒啉己酸胞嘧啶二氟核糖(JNC204009)
MS m/z:[M+H]+=559
1H NMR(500MHz,DMSO)δ10.99(s,1H),8.23(d,J=7.6Hz,1H),8.03 (d,J=8.0Hz,1H),7.79(d,J=7.3Hz,1H),7.64–7.56(m,1H),7.41(t,J=7.2 Hz,1H),7.27(d,J=7.6Hz,1H),6.32(d,J=6.5Hz,1H),6.17(t,J=7.4Hz, 1H),5.31(t,J=5.4Hz,1H),4.26–4.12(m,1H),3.91–3.86(m,1H),3.80(d,J =10.4Hz,1H),3.71(t,J=7.0Hz,2H),3.65(ddd,J=12.6,5.7,3.6Hz,1H), 2.41(t,J=7.3Hz,2H),1.67–1.54(m,4H),1.36–1.24(m,2H).
间醚硒啉丙酸胞嘧啶二氟核糖(JNC204013)
MS m/z:[M+H]+=547
1H NMR(500MHz,DMSO)δ11.08(s,1H),8.30(d,J=7.6Hz,1H),8.03 (d,J=8.0Hz,1H),7.68(d,J=8.5Hz,1H),7.57(d,J=1.5,1H),6.98(dd,J= 8.5,1.5Hz,1H),6.35(d,J=6.5Hz,1H),6.19(t,J=7.4Hz,1H),5.34(t,J=5.3 Hz,1H),4.24(t,J=6.6Hz,1H),4.03(t,J=6.6Hz,2H),3.94-3.81(m,2H),3.73 –3.60(m,4H),2.83(t,J=6.5Hz,2H).
邻醚硒啉丙酸氯嘌呤2-氟核糖(JNC205010)
MS m/z:[M+H]+=587
1H NMR(500MHz,DMSO)δ8.27(d,J=1.8Hz,1H),7.50-7.41(m,2H), 7.26(dd,J=7.2,1.5Hz,1H),6.31(dd,J=4.6,13.5Hz,1H),4.42-5.33(m,5H), 3.92(s,3H),3.68-3.53(m,4H),2.79(t,J=6.5Hz,2H).
对氟硒啉丙酸氮杂嘧啶2-脱氧核糖(JNC206012)
MS m/z:[M+H]+=500
1H NMR(500MHz,DMSO)δ8.43(s,1H),7.86–7.76(m,2H),7.24(td,J =8.6,2.4Hz,1H),6.01(t,1H),5.22(d,1H),5.01(t,1H),4.23(m,1H),3.79(m, 1H),3.65-3.51(m,4H),2.79(t,J=6.5Hz,2H),2.17(m,2H).
实验例1
化合物的KGA活性(见表3,图1)
96孔板中每孔加药1μL,加入KGA酶终浓度20nM,其余用Hepe-缓 冲液A(50mMHepes、100mM NaCl、0.5mM EDTA、0.01%BSA、0.003% Brij-35、0.001%Tween20(pH 7.5)补足至最终体积为65ul/孔,室温共摇30min 后加入终浓度为150mM底物谷氨酰胺,用磷酸缓冲液B(65ul/孔),摇床 反应4小时;最后加入NADP+终浓度为400μM,EZMTT检测试剂和10nM E.Coli GDH(20μL)半小时后检测OD450的吸光度。结果显示母体阿糖胞 苷类衍生物没有KGA活性,但是硒啉阿糖胞苷类衍生物的化合物具有明显 的KGA活性IC500.5-5μM。
实验例2
硒啉阿糖胞苷类衍生物的化合物的抗肿瘤细胞活性(见表3,图2~3)
采用EZMTT考察本发明制得的化合物对人非小细胞肺癌A549细胞、 小鼠肝癌H22细胞生长抑制实验。方法是在96孔板中,加入硒啉阿糖胞苷 类衍生物的化合物(0-10uM终浓度),加入1000个细胞每孔,在RPMI,10% BFS,5%CO2条件下培养5天,再加入1XEZMTT指示剂,检测IC50,化合 物均有较好的抑制肿瘤能力。
表3硒啉核糖胞苷类衍生物的化合物的活性测试数据
实验例3
硒啉阿糖胞苷类衍生物具有明显提高的肝微粒体稳定性。(见表4)
设定反应体系终体积为100μL,包含1mg/mL的人肝微粒体溶液50μ L,测试药液10μL(0.5mM硒啉阿糖胞苷类衍生物的化合物),NADPH辅 酶的工作溶液40μL(在37℃预孵5min后再加入),经预孵育后加入2μL G6PDH启动反应,置于37℃恒温分别孵育5,30,90min,于各时间点下 各加入100μL DMSO终止反应,充分涡旋震荡,再将样品于9000r/min离 心5-10min,取上清液进行HPLC分析。每个测试药物以加入PBS和NADPH 辅助工作液为自身对照组,每个样品平行测定3次。硒啉阿糖胞苷类衍生物 的化合物比母体阿糖胞苷类衍生物的肝微粒体中的稳定性提高。
表4硒啉核糖苷类衍生物的化合物在血液和肝微粒体中的稳定性
化合物 | 5min(化合物%) | 30min(化合物%) |
阿糖胞苷 | 2.8±0.3 | ND |
JNC201002 | 16.3±1.2 | 14.5±0.8 |
JNC204002 | 26.3±0.7 | 23.5±0.5 |
JNC204004 | 34.9±0.2 | 30.6±0.4 |
JNC201001 | 30.2±5.2 | 9±3.4 |
JNC204006 | 36.7±1.6 | 15.6±3.3 |
JNC204007 | 52.3±1.0 | 30.4±1.4 |
JNC204008 | 30.2±0.2 | 9.5±0.1 |
Coumarin(对照) | 65.5±1.5 | 25.4±4.8 |
实验例4
硒啉阿糖胞苷类衍生物具有明显提高的溶解度(见表5)
均称取大约1mg硒啉阿糖胞苷类衍生物的化合物粉末于0.5mL离心管 中,分别加入100μL灭菌水或DMSO等溶剂,使粉末过量(存在大量固体 不完全溶解即可),超声30min,使其充分混合后,于25±1℃、100rpm振 摇24h,再于9000~10000rpm离心5min,取各溶剂中的上清液加甲醇稀释 合适的倍数。取20μL稀释液进样HPLC,根据tR所得的峰面积来计算化合物在各溶液中的溶解度。
表5硒啉核糖苷类衍生物化合物的溶解度
实验例5
表3中选取不同系列硒啉糖苷类衍生物的化合物的抗肿瘤细胞活性(见 表6)
采用EZMTT考察本发明制得的化合物对人源各类肿瘤细胞的生长抑制 实验。方法是在96孔板中,加入1000个细胞每孔,加入硒啉糖苷类衍生物 的化合物(0.1,1,10μM终浓度),在RPMI,10%BFS,5%CO2条件下培 养5天,再加入EZMTT指示剂,检测IC50,化合物均有较好的抑制肿瘤能 力。
表6硒啉核糖胞苷类衍生物对各类肿瘤细胞的抑制活性测试数据
实验例6(肿瘤动物模型)
利用小鼠皮下肿瘤模型观察含硒谷氨酰胺酶抑制剂聚合型胶束对ICR 小鼠皮下移植瘤的治疗效果,同时利用肿瘤重量来作为指示。(见图4)
取体重为20g左右的ICR小鼠10只每组,分别于小鼠右腋下侧的皮下接种 肝癌H22细胞,次日,以10mg/kg皮下注射,每天注射1次,连续注射10天, 每天记录体重和观察小鼠的状态。第11天,取小鼠的肿瘤,结果如图4显示, JNC204006,JNC204009系列化合物比索拉菲尼相比,瘤重比显著减小,说明药 物对肿瘤具有很好的治疗作用。
以上所述仅是本发明的优选实施方式,应当指出,对于本技术领域的普 通技术人员来说,在不脱离本发明原理的前提下,还可以做出若干改进和润 饰,这些改进和润饰也应视为本发明的保护范围。
Claims (10)
2.根据权利要求1所述的含硒核糖类化合物,其特征在于,所述含硒核糖类化合物的结构特征包括n=2的硒琳丙酸芳香胺和/或n=5的硒琳已酸芳香胺的衍生物。
3.根据权利要求2所述的含硒核糖类化合物,其特征在于,R2、R3、R4、R5分别独立地包括氢、羟基、卤素、醚、磷酸酯衍生物类中的一种。
5.权利要求1~4任一项所述的含硒核糖类化合物的合成方法,其特征在于,A、B、C系列化合物的合成步骤包含:
苯硒氯:将联硒酸、氯化亚砜于溶剂中反应,得到苯硒氯;
硒啉化:将上步得到的苯硒氯加入含氨基的核糖衍生物中,得到棕色油状物;
硒啉胞嘧啶核糖:将上步得到的棕色油状物加入含四丁基氟化铵的四氢呋喃溶液中进行反应,即得到目标产物。
6.权利要求1~4任一项所述的含硒核糖类化合物的合成方法,其特征在于,
D、E、F系列化合物的合成步骤包含:
苯硒氯:将联硒酸、氯化亚砜于溶剂中反应,得到苯硒氯;
硒啉酸化:将上步得到的苯硒氯、氨基酸于无水乙腈中反应得到苯硒酸;
硒啉酸胞嘧啶核糖:将上述得到的苯硒酸、溶剂、N-甲基吗啉、1-乙基-3(3-二甲基丙胺)碳二亚胺、1-羟基苯并三唑与含氨基的核糖衍生物混合后反应即得到目标产物。
7.根据权利要求5或6所述的合成方法,其特征在于,所述联硒酸、氯化亚砜和溶剂的摩尔体积比独立的为12.0~13.0mmol:14~16ml:0.3~0.6ml;
所述联硒酸和氯化亚砜的反应时间为3~5h,反应温度为40~45℃;
所述溶剂独立的包括二甲基甲酰胺、四氢呋喃、二氯甲烷和甲醇中的一种或几种。
8.根据权利要求5所述的合成方法,其特征在于,所述苯硒氯与含氨基的核糖衍生物的摩尔比为1.0~1.4:1.0;
所述棕色油状物与含四丁基氟化铵的四氢呋喃溶液的质量体积比为510~530mg:3.0~4.0ml。
9.根据权利要求6所述的合成方法,其特征在于,所述苯硒氯、无水乙腈和氨基酸的摩尔体积比为19.0~20.0mmol:14~16ml:59.0~60.0mmol;
所述苯硒酸、溶剂、N-甲基吗啉、1-乙基-3(3-二甲基丙胺)碳二亚胺、1-羟基苯并三唑与含氨基的核糖衍生物的摩尔体积比为1.8~2.0mmol:4~6ml:5.0~6.0mmol:2.5~3.0mmol:3.5~4.0mmol:2.0~2.5mmol。
10.权利要求1~4任一项所述的含硒核糖类化合物或权利要求5~9任一项所述的合成方法得到的化合物或其混合物形式或其可药用盐或药物组合物在制备治疗癌症的药物中的应用,其特征在于,所述的癌症包括但不限于肝癌、肺癌、白血病、胰腺癌、胃癌、乳腺癌、神经瘤、膀胱癌、前列腺癌、肉瘤、黑色素瘤、肾癌、结肠癌和宫颈癌。
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