CN106316939B - N-2-吡啶酰基-脱氢枞胺及其制备方法和应用 - Google Patents
N-2-吡啶酰基-脱氢枞胺及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了N‑2‑吡啶酰基‑脱氢枞胺及其制备方法和应用。制备方法为：1)取2‑吡啶甲酸和HOBT，用乙酸乙酯溶解，0℃搅拌0.5h；加入DCC，0℃反应2.5h；2)取脱氢枞胺溶解于乙酸乙酯中，然后滴加至步骤1)反应体系，室温反应8h；冰浴搅拌半小时，使得DCU充分析出；3)过滤除去DCU，稀释滤液，用5％NaHCO3、10％柠檬酸分别洗涤2‑3遍，最后用饱和食盐水洗涤；乙酸乙酯层用无水硫酸钠干燥2h；3)过滤，滤液蒸除乙酸乙酯，得黄色固体产物。本发明的N‑2‑吡啶酰基‑脱氢枞胺，制备方法简单，产物纯度高，得率高，生物活性试验证实，对肿瘤细胞具有很好的抗毒活性，同时对正常细胞具有很低的毒性，在制备抗肿瘤药物中将具有广泛的应用。
Description
技术领域
本发明属于有机化合物技术领域，具体涉及N-2-吡啶酰基-脱氢枞胺及其制备方法和应用。
背景技术
脱氢枞胺，又名去氢枞胺，是一种松香的主要改性产物，同时也是歧化松香胺的主要成分。脱氢枞胺的性质非常稳定、旋光度较大，这都是其他松香衍生物不具有的物理化学性质。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。
脱氢枞胺N-C衍生物数量占脱氢枞胺改性化合物总量的比例最高。脱氢枞胺与内酯类化合物反应可得到脱氢枞胺丙酸，脱氢枞胺与氯乙酸在pH大于7的条件下下可生成脱氢枞胺乙酸，这些都是N-C衍生物。通过红外光谱法研究脱氢枞胺乙酸与金属离子的相互作用，发现脱氢枞胺乙酸与钒、铬和钼等金属阴离子在水溶液中可形成胶状物。脱氢枞胺的有机部分具有良好的亲油性，接上亲水基团后就可以用作表面活性剂。从歧化松香胺出发，分离获得了脱氢枞胺纯品，二甲基脱氢枞胺作为中间体，得到了两种新颖的，且同时具有阴、阳两种离子性质的甜菜碱类表面活性剂。脱氢枞胺酰胺类衍生物对杜氏利什曼原虫和克氏锥虫有良好的抑制活性。
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。
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、抗卵巢癌和人脐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N-2-吡啶酰基-脱氢枞胺，满足抗肿瘤药物的使用需求。本发明的另一目的是提供上述N-2-吡啶酰基-脱氢枞胺的制备方法。本发明还有一目的是提供上述N-2-吡啶酰基-脱氢枞胺的应用。
技术方案：为了实现上述发明，本发明采用的技术方案为：
N-2-吡啶酰基-脱氢枞胺，结构式如下：
一种合成所述的N-2-吡啶酰基-脱氢枞胺的方法，步骤如下：
1)取2-吡啶甲酸和1-羟基苯并三唑(HOBT)，用乙酸乙酯溶解，0～5℃搅拌0.5～1h；加入N,N’-二环己基碳二亚胺(DCC)，0～5℃反应2～3h；
2)取脱氢枞胺溶解于乙酸乙酯中，然后滴加至步骤1)反应体系，室温反应7～8h；冰浴搅拌0.5～1h，使得二环己基脲(DCU)充分析出；
3)过滤除去DCU，稀释滤液，用5％NaHCO3、10％柠檬酸分别洗涤2-3遍，最后用饱和食盐水洗涤；乙酸乙酯层用无水硫酸钠干燥2～4h；
4)过滤，滤液蒸除乙酸乙酯，得黄色固体产物。
所述的N-2-吡啶酰基-脱氢枞胺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N-2-吡啶酰基-脱氢枞胺，制备方法简单，产物纯度高，得率高，生物活性试验证实，对肿瘤细胞具有很好的抗毒活性，同时对正常细胞几乎无毒性，在制备抗肿瘤药物中将具有广泛的应用。
附图说明
图1是脱氢枞胺(a)、2-吡啶甲酸(b)和N-2-吡啶酰基-脱氢枞胺(c)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。
实施例1
N-2-吡啶酰基-脱氢枞胺，结构式如下：
一种合成N-2-吡啶酰基-脱氢枞胺的方法，步骤如下：
1)在100mL烧瓶中加入1.23g 2-吡啶甲酸，1.35g HOBT，用40mL乙酸乙酯溶解，0℃搅拌0.5h。加入2.06g DCC，0℃反应2.5h。2.85g脱氢枞胺溶解于10mL乙酸乙酯中，将此溶液滴加至反应体系，室温反应8h。最后，冰浴搅拌半小时，使得DCU充分析出。
2)过滤除去DCU，滤液稀释至200mL，分别用20mL 5％NaHCO3、20mL10％柠檬酸洗涤2-3遍，最后用20mL饱和食盐水洗涤。乙酸乙酯层用无水硫酸钠干燥2h。
3)过滤，滤液蒸除乙酸乙酯，得黄色固体3.58g，产率为91.79％。
对产物进行表征，脱氢枞胺、2-吡啶甲酸和N-2-吡啶酰基-脱氢枞胺的红外谱图如图1所示，脱氢枞胺氨基的吸收峰3400cm-1和2-吡啶甲酸羧基的吸收峰1716cm-1反应后均消失，说明已生成新物质；3392cm-1为酰胺基团中的N-H伸缩振动特征吸收峰；2926cm-1是甲基和亚甲基的反对称伸缩振动峰；1678cm-1为酰胺的C＝O特征吸收峰；1526cm-1为酰胺的N-H特征吸收峰。
该化合物的结构表征具体数据如下：1H NMR(CDCl3，600MHz)δ(ppm)：1.022(3H，s，H-19)，1.21～1.24(9H，m，H-16、17、20)，1.41～1.81(7H，m，H-1α、2、3、6)，2.03～2.05(1H，m，H-5)，2.28(1H，brd，J＝12Hz，H-1β)，2.81～2.91(3H，m，H-7、15)，3.28～3.50(2H，m，H-18)，6.89(1H，t，J＝6Hz，22-CONH)，6.99(1H，s，H-14)，7.17(1H，d，J＝8.4Hz，H-12)，7.40(1H，d，J＝12Hz，H-11)，7.81～8.52(4H，m，H-24、25、26、23)；13C NMR(CDCl3，151MHz)δ(ppm)：18.71，18.90，19.14，23.95，23.97，25.52，30.49,33.42，36.32，37.61，37.85，38.31，45.50，49.96，122.27，123.85，124.29，126.05，126.94，134.94，137.71，145.56，147.16，148.06，149.95，164.33；IR(KBr)：3392(N-H)，2926(-CH3，-CH2)，1678(0＝C-N)，1526(N-H)；MS(ESI)m/z：391.33[1+H]+，413.33[1+Na]+。
实施例2
1)采用MTT法检测N-2-吡啶酰基-脱氢枞胺对Hela的抑制作用
MTT法具体操作：取对数生长期的待测试Hela细胞，配制成105个/毫升的单细胞悬液，在96孔培养板上接种，每孔100微升，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100微升不同浓度的N-2-吡啶酰基-脱氢枞胺加入到培养板上，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200微升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100微升无血清的DMEM培养液代替样品的，这时的吸光度值为OD空白值，通过公式(1)计算样品对HepG2细胞抑制率：
m＝1-n＝1-OD样/OD空白 (1)
式中，m：抑制率；n：细胞存活率。
然后通过公式(2)，算出IC50：
lgIC50＝a-b(c-(3-d-e)/4) (2)
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。
结果显示，IC50为30.23μmol/L，抗癌活性强。
2)采用MTT法检测N-2-吡啶酰基-脱氢枞胺对HepG2的抑制作用
MTT法具体操作如下：取对数生长期的待测试HepG2细胞，配制成105个/毫升的单细胞悬液，在96孔培养板上接种，每孔100微升，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100微升不同浓度的N-2-吡啶酰基-脱氢枞胺加入到培养板上，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200微升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100微升无血清的DMEM培养液代替样品的，这时的吸光度值为OD空白值，通过公式(1)计算样品对HepG2细胞抑制率：
m＝1-n＝1-OD样/OD空白 (1)
式中，m：抑制率；n：细胞存活率。
然后通过公式(2)，算出IC50：
lgIC50＝a-b(c-(3-d-e)/4) (2)
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。
结果显示，IC50为24.53μmol/L，抗癌活性强。
3)采用MTT法检测N-2-吡啶酰基-脱氢枞胺对Huvec的毒副作用。
MTT法具体操作如下：取对数生长期的待测试Huvec细胞，配制成105个/毫升的单细胞悬液，在96孔培养板上接种，每孔100微升，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100微升不同浓度的N-2-吡啶酰基-脱氢枞胺加入到培养板上，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200微升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100微升无血清的DMEM培养液代替样品的，这时的吸光度值为OD空白值，通过公式(1)计算样品对HepG2细胞抑制率：
m＝1-n＝1-OD样/OD空白 (1)
式中，m：抑制率；n：细胞存活率。
然后通过公式(2)，算出IC50：
lgIC50＝a-b(c-(3-d-e)/4) (2)
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。
结果显示，IC50为40.09μmol/L，毒性小，对正常细胞几乎无毒害作用。
Claims (3)
1.N-2-吡啶酰基-脱氢枞胺，其特征在于，结构式如下：
2.一种合成权利要求1所述的N-2-吡啶酰基-脱氢枞胺的方法，其特征在于，步骤如下：
1)取2-吡啶甲酸和HOBT，用乙酸乙酯溶解，0～5℃搅拌0.5～1h；加入DCC，0～5℃反应2～3h；
2)取脱氢枞胺溶解于乙酸乙酯中，然后滴加至步骤1)反应体系，室温反应7～8h；冰浴搅拌0.5～1h，使得DCU充分析出；
3)过滤除去DCU，稀释滤液，用5％NaHCO3、10％柠檬酸分别洗涤2-3遍，最后用饱和食盐水洗涤；乙酸乙酯层用无水硫酸钠干燥2～4h；
4)过滤，滤液蒸除乙酸乙酯，得黄色固体产物。
3.权利要求1所述的N-2-吡啶酰基-脱氢枞胺在制备抗肿瘤药物中的应用。
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| WO2012078667A2 (en) * | 2010-12-06 | 2012-06-14 | The Penn State Research Foundation | Compositions and methods relating to proliferative diseases |
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| WO2012078667A2 (en) * | 2010-12-06 | 2012-06-14 | The Penn State Research Foundation | Compositions and methods relating to proliferative diseases |
Non-Patent Citations (3)
| Title |
|---|
| (+)-Dehydroabietylamine derivatives target triple-negative breast cancer;Taotao Ling等;《European Journal of Medicinal Chemistry》;20150723;第102卷(第18期);第9-13页 |
| N-Benzoyl-12-nitrodehydroabietylamine-7-one, a novel dehydroabietylamine derivative, induces apoptosis and inhibits proliferation in HepG2 cells;Ling-Ying Lin等;《Chemico-Biological Interactions》;20120625;第199卷(第2期);第67页图2，补充数据表S2化合物63 |
| 实用高效的酰胺键形成试剂;王哲清;《中国医药工业杂志》;20061231;第37卷(第12期);第855-858页 |
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