天然药物莪术醇的结构修饰
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摘要
莪术油是中药莪术的有效成分,具有抗肿瘤、抗病毒、抗炎等功用。莪术醇是莪术油的有效成分之一,是一种具有发展前途的抗肿瘤药物。迄今为止,采用有机化学方法对莪术醇进行结构修饰的报道较少。
本文研究了莪术醇在酸性条件下的芳构化反应,借鉴丙酮与莪术醇的芳构化反应,选择氢溴酸作催化剂,四氢呋喃作溶剂,选取不同的羰基化合物与莪术醇进行反应,制取了一系列的具有卓酮结构的化合物,收率在40.3-75.0%；基于反应中得到的中间体,提出芳构化的机理,并对3个卓酮化合物进行了X-ray单晶衍射分析。通过对机理的研究发现：羰基化合物的羰基在酸性条件下被活化生成碳正离子的稳定性及空间位阻是影响反应的主要因素,羰基活性较低及空间位阻较大的羰基化合物不能与莪术醇发生芳构化反应。
论文还通过氢化、重排、氧化、开环等反应对莪术醇进行结构修饰,制得氢化莪术醇(化合物11)、莪术醇开环产物(化合物13)、9,10环氧化物(化合物14),9位羟基化衍生物(化合物15)等,在结构修饰的过程中发现莪术醇在氢氧化钾催化下可以转化为双键迁移到环内的产物(化合物12),通过改进反应条件,收率可达到93.0%。对化合物12和15进行了X-ray单晶衍射分析,确定其立体构型。结合单晶数据分析,对环氧化反应、环氧环开环反应的机理和立体化学进行了深入探讨。
Curcuma oil is the active ingredient of curcuma which is a traditional Chinese medicine. It has anti-tumor, anti-virus, anti-inflammatory and other functions. Curcumol is one of the active ingredients of curcuma oil. It is a promising anticancer drug. Up to now, there are few reports on structural modification of curcumol by organic methods.
In this paper, we study the aromatization of curcumol under acidic conditions. Aromatization of curcumol with acetone is selected as the model reaction in this paper. Hydrobromide is selected as catalyst and tetrahydrofuran as solvent. Based on model reaction, a series of new trienone compounds have been prepared by curcumol reacting with different carbonyl compounds in the yield of 40.3-75.0%. And we proposed mechanism of aromatization. Three trienone compounds'X-ray diffraction data are analyzed. During the study of mechanism, we find that:the stability of carbonium generated from the carbonyl compounds and steric hindrance are the main factors affecting the aromatization. Carbonyl compounds with lower activity and larger steric can not have aromatization with curcumol.
In our study, the structural modification of curcumol is also carried out by hydrogenation, rearrangement, oxidation and ring opening reaction. We got hydrogenated curcumol (compound 11), open loop product of curcumol(compound 13),9,10-epoxide(compound 14) and 9-hydroxy derivatives(compound 15), etc. And in the process of structural modification of curcumol, we find that the double bond of curcumol can migrate into the ring under catalysis of potassium hydroxide. After improving the reaction conditions, we get a higher yield of 93.0%. Three-dimensional configuration of compound 12 and 15 is determined based on X-ray diffraction data analysis. We have a thorough discussion of the epoxidation and ring opening reaction mechanism and stereochemistry.
本文研究了莪术醇在酸性条件下的芳构化反应,借鉴丙酮与莪术醇的芳构化反应,选择氢溴酸作催化剂,四氢呋喃作溶剂,选取不同的羰基化合物与莪术醇进行反应,制取了一系列的具有卓酮结构的化合物,收率在40.3-75.0%；基于反应中得到的中间体,提出芳构化的机理,并对3个卓酮化合物进行了X-ray单晶衍射分析。通过对机理的研究发现：羰基化合物的羰基在酸性条件下被活化生成碳正离子的稳定性及空间位阻是影响反应的主要因素,羰基活性较低及空间位阻较大的羰基化合物不能与莪术醇发生芳构化反应。
论文还通过氢化、重排、氧化、开环等反应对莪术醇进行结构修饰,制得氢化莪术醇(化合物11)、莪术醇开环产物(化合物13)、9,10环氧化物(化合物14),9位羟基化衍生物(化合物15)等,在结构修饰的过程中发现莪术醇在氢氧化钾催化下可以转化为双键迁移到环内的产物(化合物12),通过改进反应条件,收率可达到93.0%。对化合物12和15进行了X-ray单晶衍射分析,确定其立体构型。结合单晶数据分析,对环氧化反应、环氧环开环反应的机理和立体化学进行了深入探讨。
Curcuma oil is the active ingredient of curcuma which is a traditional Chinese medicine. It has anti-tumor, anti-virus, anti-inflammatory and other functions. Curcumol is one of the active ingredients of curcuma oil. It is a promising anticancer drug. Up to now, there are few reports on structural modification of curcumol by organic methods.
In this paper, we study the aromatization of curcumol under acidic conditions. Aromatization of curcumol with acetone is selected as the model reaction in this paper. Hydrobromide is selected as catalyst and tetrahydrofuran as solvent. Based on model reaction, a series of new trienone compounds have been prepared by curcumol reacting with different carbonyl compounds in the yield of 40.3-75.0%. And we proposed mechanism of aromatization. Three trienone compounds'X-ray diffraction data are analyzed. During the study of mechanism, we find that:the stability of carbonium generated from the carbonyl compounds and steric hindrance are the main factors affecting the aromatization. Carbonyl compounds with lower activity and larger steric can not have aromatization with curcumol.
In our study, the structural modification of curcumol is also carried out by hydrogenation, rearrangement, oxidation and ring opening reaction. We got hydrogenated curcumol (compound 11), open loop product of curcumol(compound 13),9,10-epoxide(compound 14) and 9-hydroxy derivatives(compound 15), etc. And in the process of structural modification of curcumol, we find that the double bond of curcumol can migrate into the ring under catalysis of potassium hydroxide. After improving the reaction conditions, we get a higher yield of 93.0%. Three-dimensional configuration of compound 12 and 15 is determined based on X-ray diffraction data analysis. We have a thorough discussion of the epoxidation and ring opening reaction mechanism and stereochemistry.
引文
[1]Wang Y, Wang M Z. Study on the quality of Rhizoma curcumae[J].药学学报,2001,36(11):849.
[2]Hiroshi Flikino, Kanji Meguro, Yojiro Sakural, et al. Structure of Curcumol[J].Chem Pharm Bull,1965,13(12):484.
[3]Hiroshi Hikino, Kanji Meguro, Yojiro Sakural. Structure of Curcumol[J].Chem Pharm. Bull,1966,14(11):1241.
[4]黄可新,陶正明,张安将,等.温莪术化学成分的研究[J].中国中药杂志,2000,25(3)：163-165.
[5]汤敏燕,孙凌峰,汪洪武.中药莪术挥发油化学成分的研究[J].林产化学与工业,2000,20(3)：65-69.
[6]施广霞,于丽华,刘金友,等.β-榄香烯抗肿瘤作用的实验研究,Ⅰ：β-榄香烯体外对L615白血病细胞直接作用的实验研究[J].大连医学院学报,1994,16(2)：137.
[7]辽宁中医学院中医系肿瘤研究组,沈阳药学院中草药研究室,沈阳医学院电镜室.温我术有效成分抗肿瘤作用的研究[J].新医药学杂志,1978,19(2)：28.
[8]李传伟,徐英萍,苗芳,等.莪术油抗小鼠结肠癌效应的实验研究[J].泰山医学院学报,2005,26(2)：89.
[9]冯刚,黄涛,卢宏达,等.莪术油注射液对小鼠移植性S180肉瘤血管形成的抑制作用[J].肿瘤研究与临床,2005,17(4)：233.
[10]唐泽耀,宗成国,林原,等.莪术醇对大鼠血流变活性及对小鼠血凝时间的影响[J].中草药,2003,23(11)：646.
[11]李广勋.中药药理毒理与临床[M].天津科技翻译出版公司,1992,257-60.
[12]lnayama S, Gao J F, harimaya K. et al. The absolute stereostructure of curcumol isolated from cuecuma wenyujin[J]. Chem.Pharm. Bull,1984,32:3783-3786.
[13]浦天仇.莪术油与莪术醇的升白作用[J].温州医学院学报,1979,(1)：51.
[14]Strater N, Klabunde T, Tucker P, et al. [J]. Science,1995,268(J216):1489-1492.
[15]Kissinger C R, Parge H E, Knighton D R, et al. [J]. Nature,1995,678:641-644.
[16]尹炳柱,森章,竹下齐.多乙酰氧基烷基革酮和多羟基烷基卓酮的合成[J].有机化学,2000,20(4)：522—528.
[17]高文涛,刘俊龙,杨锦宗.卓酮和卓酚酮化合物合成新进展[J].合成化学,1999,7(2)：145-152.
[18]曹广智.硫氮卓酮合并用药的相互作用[J].中国医院药学杂志,1992,12(5)：205-206.
[19]邓嵘,陈济民,姚崇舜,等.莪术醇的研究进展[J].辽宁药物与临床,2001,4(1)：37.
[20]胡皆汉,韩秀文,杨振云.温莪术抗肿瘤有效成分的13CNMR谱及其人工改性衍生物化学结构的确定[J].波谱学杂志,1986,3(3)：241-248.
[21]郭永沺,杜晓鸣.11-氨甲基-2,6-二甲基-3,9-二异丙基三环(5.3.2.01,5)十二碳-5,9-二烯-8-醇的合成[J].药学学报,1989,24(9)：707-710.
[22]Fieser L F, et al. [J]. Am Chem Soc,62,228,1940.
[23]于润海,程蒲,张普民,聂秀范.温莪术抗肿瘤的研究[J].沈阳药学院学报,1992,10：25-27.
[24]Fieser, et al. [J]. Am Chem Soc,58,1348,1936.
[25]王树龙,郭殿武,孟昭珂.莪术醇的衍生物、含该衍生物的组合物及所述衍生物的制药用途：PCT/CN2006/000730[P].2005,05,26.
[2]Hiroshi Flikino, Kanji Meguro, Yojiro Sakural, et al. Structure of Curcumol[J].Chem Pharm Bull,1965,13(12):484.
[3]Hiroshi Hikino, Kanji Meguro, Yojiro Sakural. Structure of Curcumol[J].Chem Pharm. Bull,1966,14(11):1241.
[4]黄可新,陶正明,张安将,等.温莪术化学成分的研究[J].中国中药杂志,2000,25(3)：163-165.
[5]汤敏燕,孙凌峰,汪洪武.中药莪术挥发油化学成分的研究[J].林产化学与工业,2000,20(3)：65-69.
[6]施广霞,于丽华,刘金友,等.β-榄香烯抗肿瘤作用的实验研究,Ⅰ：β-榄香烯体外对L615白血病细胞直接作用的实验研究[J].大连医学院学报,1994,16(2)：137.
[7]辽宁中医学院中医系肿瘤研究组,沈阳药学院中草药研究室,沈阳医学院电镜室.温我术有效成分抗肿瘤作用的研究[J].新医药学杂志,1978,19(2)：28.
[8]李传伟,徐英萍,苗芳,等.莪术油抗小鼠结肠癌效应的实验研究[J].泰山医学院学报,2005,26(2)：89.
[9]冯刚,黄涛,卢宏达,等.莪术油注射液对小鼠移植性S180肉瘤血管形成的抑制作用[J].肿瘤研究与临床,2005,17(4)：233.
[10]唐泽耀,宗成国,林原,等.莪术醇对大鼠血流变活性及对小鼠血凝时间的影响[J].中草药,2003,23(11)：646.
[11]李广勋.中药药理毒理与临床[M].天津科技翻译出版公司,1992,257-60.
[12]lnayama S, Gao J F, harimaya K. et al. The absolute stereostructure of curcumol isolated from cuecuma wenyujin[J]. Chem.Pharm. Bull,1984,32:3783-3786.
[13]浦天仇.莪术油与莪术醇的升白作用[J].温州医学院学报,1979,(1)：51.
[14]Strater N, Klabunde T, Tucker P, et al. [J]. Science,1995,268(J216):1489-1492.
[15]Kissinger C R, Parge H E, Knighton D R, et al. [J]. Nature,1995,678:641-644.
[16]尹炳柱,森章,竹下齐.多乙酰氧基烷基革酮和多羟基烷基卓酮的合成[J].有机化学,2000,20(4)：522—528.
[17]高文涛,刘俊龙,杨锦宗.卓酮和卓酚酮化合物合成新进展[J].合成化学,1999,7(2)：145-152.
[18]曹广智.硫氮卓酮合并用药的相互作用[J].中国医院药学杂志,1992,12(5)：205-206.
[19]邓嵘,陈济民,姚崇舜,等.莪术醇的研究进展[J].辽宁药物与临床,2001,4(1)：37.
[20]胡皆汉,韩秀文,杨振云.温莪术抗肿瘤有效成分的13CNMR谱及其人工改性衍生物化学结构的确定[J].波谱学杂志,1986,3(3)：241-248.
[21]郭永沺,杜晓鸣.11-氨甲基-2,6-二甲基-3,9-二异丙基三环(5.3.2.01,5)十二碳-5,9-二烯-8-醇的合成[J].药学学报,1989,24(9)：707-710.
[22]Fieser L F, et al. [J]. Am Chem Soc,62,228,1940.
[23]于润海,程蒲,张普民,聂秀范.温莪术抗肿瘤的研究[J].沈阳药学院学报,1992,10：25-27.
[24]Fieser, et al. [J]. Am Chem Soc,58,1348,1936.
[25]王树龙,郭殿武,孟昭珂.莪术醇的衍生物、含该衍生物的组合物及所述衍生物的制药用途：PCT/CN2006/000730[P].2005,05,26.