CN106316930B - 3-甲基-2-吡啶-脱氢枞胺-希夫碱及其制备方法和应用 - Google Patents
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Abstract
本发明公开了一种3‑甲基‑2‑吡啶‑脱氢枞胺希夫碱及其制备方法和应用。本发明的3‑甲基‑2‑吡啶‑脱氢枞胺希夫碱拓展了脱氢枞胺基希夫碱化合物种类，为研究脱氢枞胺基希夫碱化合物结构与性能之间的关系创造条件。同时，该3‑甲基‑2‑吡啶‑脱氢枞胺希夫碱表现出良好的抗癌活性，并对正常细胞毒副作用小，为抗宫颈癌、乳腺癌新药物的开发提供依据。该3‑甲基‑2‑吡啶‑脱氢枞胺希夫碱的制备方法易操作，方法中所需物品毒性小，结合天然产物，具有很好的实用性。
Description
技术领域：
本发明涉及脱氢枞胺基化合物技术领域，具体涉及一种3-甲基-2-吡啶-脱氢枞胺希夫碱及其制备方法和应用。
背景技术
脱氢枞胺(如式I所示)是松香重要的改性产品之一，同时也是歧化松香胺的主要成分。原料丰富，价格相对便宜，脱氢枞胺具有一些独特理化性质，如有稳定的性质，良好的光学活性，较大的比旋光度等，这是其它松香衍生物不具备的。脱氢枞胺如今已经被用来大批地制备杀菌剂和防霉剂等，主要是因为它具备优良的生物活性。除此之外，脱氢枞胺类衍生物被作为金属缓蚀剂、润滑油添加剂、防腐剂等也很普遍。它在各个领域都有着广泛的应用，已经覆盖我们日常生活的各个方面。随着脱氢枞胺提取和纯化技术的进步，产品质量的提高，预计脱氢枞胺在医药、农药、金属加工、选矿、表面活性剂、染料、涂料、光化学拆分领域将得到更广泛的应用。
脱氢枞胺苯环改性可以引入不同的官能团，得到不同结构和性能的脱氢枞胺基化合物。Tsutsumi等以脱氢枞胺为原料，经氯甲基化、无机氰化物取代、雷尼镍还原等反应合成了脱氢枞胺衍生物，这些衍生物能用于尼龙和聚亚胺酯的改性，并有杀菌和防腐活性[Tsutsumi T,Sakata C.Novel phenanthlene der ivative and its production[P].JP02104565,1990]。同时，利用脱氢枞胺可生成很多N-C衍生物，这是目前对脱氢枞胺基化合物研究最多的结构。例如脱氢枞胺与氯乙酸在氢氧化钠存在下生成脱氢枞胺乙酸[宋湛谦,向凤仙,等.脱氢枞胺及其醋酸盐的合成和应用[J].林业科学,1981,(1):69-71]。
脱氢枞胺异氰是一种结构中含有N＝C＝O的脱氢枞胺的衍生物，它的合成方法多样，一种是以松香中的脱氢枞酸为母体，经过O＝C-Cl、叠氮化钠反应而得到的；一种是在氯化钯及CO下，脱氢枞胺能够直接合成脱氢枞胺异氰，但是这个反应的条件需要控制好，因为这反应的产率受到多方面影响，如反应温度、反应物浓度、反应溶剂等影响。除了上述两种方法外，脱氢枞胺与光气反应也可以得到上述产物。脱氢枞胺能够与含羰基的物质缩合生成席夫碱，席夫碱含有C＝N这个结构片段，研究此类化合物的报道很多，一般对脱氢枞胺的氨基改性都是从这个思路出发的。之所以对它的研究较多，是因为它本身有较强的抗肿瘤细胞活性且以它为配体合成的金属配合物的生活活性也特别优良。对肺腺癌细胞、人大细胞肺癌细胞和人结肠癌细胞都有很强的抑制作用。脱氢枞胺席夫碱化合物对金属有良好的缓释性能。
化学治疗一直被看作是治疗癌症的十分重要的手段之一，多年的研究表明，大部分希夫碱及其衍生物具有非常良好的杀菌抗癌活性。例如，在唐慧安[唐慧安,王哲民,朱巧军等.主族元素Sn的含硫希夫碱配合物的合成、表征、抗肿瘤活性[J].兰州大学学报(自然科学版),2001,37(1):121-122.]等的研究报道中，指出了某些希夫碱类配合物因含有硫原子而具有非常良好的抗肿瘤效果。
由于脱氢枞胺苯环上连接有异丙基和一六元环，整体空间较大，苯改性比较困难，所以在这方面的研究相对比较少。脱氢松香腈为原料，经氯甲基化和无机氰化物置换还原反应后，可以生成脱氢枞胺衍生物，尼龙可以利用这些衍生物来修饰，且可以做到有效杀菌和防腐。对脱氢枞胺芳环进行改性，发现它很容易发生磺化反应，且只发生在特定位置上，由此得到的磺化衍生物有很好的抗溃疡活性。硝基类芳环衍生物对裂褶菌、皱褶青霉都有一定的抑制效果，对一些菌种，如大肠杆菌、金黄色葡萄球菌等这些微生物具有优良的抑制活性，表现出抑菌性。我们研究的是N-C衍生物，目前没有对此类化合物的抗肝癌、抗卵巢癌、抗乳腺癌和人体静脉内皮细胞活性的研究。
发明内容
发明目的：针对现有技术中存在的不足，本发明的目的是提供一种3-甲基-2-吡啶-脱氢枞胺希夫碱，该化合物具有良好的抗癌活性。本发明的另一目的是提供一种上述3-甲基-2-吡啶-脱氢枞胺希夫碱的制备方法。本发明还有一目的是提供上述3-甲基-2-吡啶-脱氢枞胺希夫碱的应用。
技术方案：为了实现上述发明目的，本发明采用的技术方案为：
3-甲基-2-吡啶-脱氢枞胺希夫碱，结构式如下：
一种制备3-甲基-2-吡啶-脱氢枞胺希夫碱的方法：以6-甲基-2-吡啶甲醛和脱氢枞胺为原料，在冰醋酸和EtOH体系中，回流反应，由黄色变橙色，最后深墨绿色；反应停止，静置自然冷却，浓缩得褐色粘稠物，烘干，得产物3-甲基-2-吡啶脱氢枞胺-希夫碱。
所述的3-甲基-2-吡啶-脱氢枞胺希夫碱的制备方法：6-甲基-2-吡啶甲醛与脱氢枞胺的用量比例为1～1.2:1。
所述的3-甲基-2-吡啶-脱氢枞胺希夫碱在制备抗肿瘤药物中的应用。
有益效果：与现有技术相比，本发明的3-甲基-2-吡啶-脱氢枞胺希夫碱拓展了脱氢枞胺基希夫碱化合物种类，为研究脱氢枞胺基希夫碱化合物结构与性能之间的关系创造条件。同时，该3-甲基-2-吡啶-脱氢枞胺希夫碱表现出良好的抗癌活性，并对正常细胞毒副作用小，为抗宫颈癌、乳腺癌新药物的开发提供依据。该3-甲基-2-吡啶-脱氢枞胺希夫碱的制备方法易操作，方法中所需物品毒性小，结合天然产物，具有很好的实用性。
附图说明：
图1是3-甲基-2-吡啶-脱氢枞胺希夫碱的红外光谱图。
具体实施方式
下面结合具体实施例对本发明做进一步的说明。
在以下实施例中产物的表征中，红外光谱是在德国布鲁克公司VERTEX-80上采用KBr压片法测得的。MS谱在美国热电公司LTQ Orbitrap XL液相质谱联用仪上测得。1H-NMR、13C-NMR光谱在瑞士布鲁克拜厄斯宾公司AVANCEⅢ600MHz型核磁共振光谱仪上测定。
实施例1
在250mL的圆底烧瓶中加入10mmol 6-甲基-2-吡啶甲醛，10mmol脱氢枞胺，8滴冰醋酸，溶于100mL EtOH，回流，反应由黄色变橙色，最后深墨绿色；反应停止，静置自然冷却，无沉淀，完全浓缩，褐色粘稠物，烘干，得2.6852g产物，产率69.2％。
产物的IR谱图如图1所示：与脱氢枞胺对比，产物中3410cm-1处的的峰为单峰，说明伯胺已反应；2950cm-1处的峰为苯环上的C-H伸缩振动峰，2865cm-1处的的峰为为CH3-和-CH2-中的C-H伸缩振动峰，1450cm-1处的峰为H-C-H面内摇摆振动峰，1385cm-1处的峰为H-C-H对称的剪式振动单峰。与6-甲基-2-吡啶甲醛的红外相比较，1711cm-1处的-HC＝O特征吸收峰消失，1645cm-1处的峰是新的红外吸收峰，为-HC＝N-的特征吸收峰。表明了有-HC＝N-的生成。
产物的1H-NMR(CDCl3，δ/ppm，600MHz)：1.00(3H，s，H-26)；1.20～1.24(9H，t，H-24，25，27)；1.38～1.44(2H，m，H-10)；1.56～1.57(1H，m，H-12α)；1.60～1.67(2H，m，H-11)；1.71～1.81(1H，m，H-15)；1.89～1.92(1H，m，H-12β)；2.25～2.70(1H，m，H-14)；2.58(3H，s，H-7)；2.79～2.82(2H，m，H-16)；2.85～2.86(1H，m，H-23)；3.40，3.56(2H，dd，J＝96.6Hz，H-8)；6.86(1H，s，H-22)；6.97，6.99(1H，dd，H-20)；7.14(1H，d，J＝7.2Hz，H-19)；7.18(1H，d，J＝8.4Hz，H-2)；7.58(1H，m，H-3)；7.81(1H，d，J＝7.8Hz，H-1)；8.31(1H，s，H-6)。
产物的13C-NMR(CDCl3，δ/ppm，151MHz)：18.74,18.86,19.56,23.91,24.22,25.56,30.43,33.35,36.61,37.61,38.13,38.41,45.68,72.95,118.09,123.73,124.10,124.33,126.80,134.95,136.64,145.31,147.44,154.15,157.78,162.27。
产物的质谱：m/z：389.29[1+H]+。
可见产物为：3-甲基-2-吡啶-脱氢枞胺希夫碱，结构式如下：
实施例2
1)采用MTT法研究3-甲基-2-吡啶-脱氢枞胺希夫碱对Hela的抑制作用，结果IC50为8.23μmol/L。
MTT法具体操作如下：取对数生长期的待测试细胞，配制成105个/mL的单细胞悬液，在96孔培养板上接种，每孔100μL，于体积分数为5％的二氧化碳、饱和湿度、37℃培养箱中培养一天；之后，将100μL不同浓度的待测样品加入到培养板上，每种浓度均为2个复孔；继续培养24h后，每孔加20微升的MTT染色液，在培养箱中继续培养4h，小心去除上层清液，然后每孔加200μL THF，充分震荡半小时后，在酶标仪上595nm波长处测定OD样值，实验的空白组是用100μL无血清的DMEM培养液代替样品的，这时的吸光度值为OD空白值，通过以下公式计算样品对HepG2细胞抑制率：
m＝1-n＝1-OD样/OD空白。式中，m：抑制率，n：细胞存活率。
然后通过以下公式算出IC50：
lgIC50＝a-b(c-(3-d-e)/4)。式中，a：lg最大浓度；b：lg(最大浓度/相邻浓度)；c：抑制率总和；d：最大抑制率；e：最小抑制率。
2)采用MTT法研究3-甲基-2-吡啶-脱氢枞胺希夫碱对HepG2的抑制作用，方法同上，结果IC50为4.35μmol/L。
3)采用MTT法研究3-甲基-2-吡啶-脱氢枞胺希夫碱对Mcf-7的抑制作用，方法同上，结果IC50为4.33μmol/L。
4)采用MTT法研究3-甲基-2-吡啶-脱氢枞胺希夫碱对Huvec的抑制作用，方法同上，结果IC50为38.74μmol/L，3-甲基-2-吡啶-脱氢枞胺希夫碱的毒副作用较低。
实施例3
在250mL的圆底烧瓶中加入12mmol 6-甲基-2-吡啶甲醛，10mmol脱氢枞胺，8滴冰醋酸，溶于120mL EtOH，回流，反应由黄色变橙色，最后深墨绿色；反应停止，静置自然冷却，无沉淀，完全浓缩，褐色粘稠物，烘干，得2.5826g产物，产率66.5％。
改用甲醇作溶剂，设置反应温度为70℃，其他条件不变，得到相同产物。
Claims (4)
1.3-甲基-2-吡啶-脱氢枞胺希夫碱，其特征在于：结构式如下：
2.一种制备权利要求1所述的3-甲基-2-吡啶-脱氢枞胺-希夫碱的方法，其特征在于：以6-甲基-2-吡啶甲醛和脱氢枞胺为原料，在冰醋酸和EtOH体系中，回流反应，由黄色变橙色，最后深墨绿色；反应停止，静置自然冷却，浓缩得褐色粘稠物，烘干，得产物3-甲基-2-吡啶-脱氢枞胺-希夫碱。
3.根据权利要求2所述的制备3-甲基-2-吡啶-脱氢枞胺-希夫碱的方法，其特征在于：6-甲基-2-吡啶甲醛与脱氢枞胺的摩尔用量比为1～1.2:1。
4.权利要求1所述的3-甲基-2-吡啶-脱氢枞胺-希夫碱在制备抗肿瘤药物中的应用。
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