姜黄素类似物的合成及抗肿瘤活性研究
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摘要
癌症是严重威胁人类健康的恶性疾病。征服癌症是人类的共同愿望,对于癌症的治疗,抗肿瘤药物正占据越来越重要的地位。开发高效、低毒的抗肿瘤药物是征服癌症的不可或缺的工作。
姜黄素是姜黄植物根茎提取物的主要活性成分,具有广泛的药理活性。众多细胞试验和动物试验证明姜黄素具有明确的抗肿瘤活性,姜黄素可以抑制多种肿瘤细胞的生长,抗癌谱广,毒副作用小,可作为抗突变剂以及抗促癌剂,对肿瘤的发生、发展多阶段均有明显的抑制效果,对同一肿瘤同时发挥多种效能。美国国立肿瘤研究所已将姜黄素列为第3代癌化学预防药。
但姜黄素本身难溶于水,其水溶液在中性至碱性条件下不稳定,姜黄素在体内的抗肿瘤活性偏低、体内吸收少、代谢过快、生物利用度低,极大地限制了它的应用。为了提高药物的稳定性及靶向性,增强其抗肿瘤活性,减少对正常组织的毒副作用,筛选低毒高效的抗癌新药,有必要对姜黄素进行相应的结构修饰或根据姜黄素结构特点合成姜黄素类似化合物。
本论文以姜黄素为先导化合物,合成了3个系列61个姜黄素类似物。对合成化合物进行体外肿瘤细胞增殖抑制试验,筛选出一批具有强抗肿瘤活性的姜黄素类似物,并研究了姜黄素类似物抗肿瘤活性与其结构之间的构效关系。
本论文采用15种芳香甲醛或取代芳香甲醛分别与6种酮(环己酮、环戊酮、丙酮、哌啶酮、四氢吡喃-4-酮、四氢噻哺-4-酮)反应,共合成3系列61个姜黄素类似物,其中11种合成物经SCI finder数据库检索为未见合成报道的化合物,分别为：E11、F4、F9、F10、F11、EN1、EN3、FN1、FN3、ES、FS。红外光谱测定、质谱分析、碳氢核磁共振分析、元素分析等结果表明,61种姜黄素类似物均具有姜黄素的官能团结构特点,所合成产物均为目标产物。
本论文应用MTT染色法体外检测所合成的61个姜黄素类似物对人前列腺癌细胞株Pc-3,人体胰腺癌细胞株Panc-1和人结肠癌细胞株HT-29的抗肿瘤活性。半数抑制浓度IC50值表明：61个姜黄素类似物中大部分对人前列腺癌细胞株PC-3,人体胰腺癌细胞株Panc-1和人结肠癌细胞株HT-29均有较强的抑制作用,肿瘤细胞株的增殖受到不同程度的抑制。其中35个姜黄素类似物的体外抗肿瘤活性比姜黄素强一倍以上,53个姜黄素类似物的体外抗肿瘤活性均比姜黄素强。化合物E9、F9、E10、F10、E11、F11、EN1、FN1、EN2、FN2、FN3等十多个姜黄素类似物具有显著的的强抗肿瘤活性,可望成为潜在的抗癌新药。其中化合物E10、F10对人前列腺癌细胞株PC-3的抑制活性是姜黄素的73倍。目前基于本研究结果进行的进一步研究正在美国Rutgers大学肿瘤研究所展开。
抗肿瘤活性构效关系研究发现：本论文合成的两侧芳香环为苯环(A-F系列)、吡啶环(N系列)、噻吩环(S系列)的姜黄素类似物大多数具有比姜黄素更强的抗肿瘤活性,芳香环为吡啶环的姜黄素类似物抗肿瘤活性较强。抗肿瘤活性强弱顺序为：
N系列>A-F系列>S系列。
中间单羰基连接桥结构能增强姜黄素类似物的抗肿瘤活性。本论文合成的61种化合物中间连接桥均为单羰基结构,其中90%的化合物抗肿瘤活性比姜黄素强,说明中间连接桥为单羰基结构的大部分姜黄素类似物抗肿瘤活性比姜黄素强,中间双羰基结构不是必须的。
中间单羰基结构影响姜黄素类似物抗肿瘤活性强弱。对于中间含4H-吡喃4-酮结构的E组(EN组、ES)、中间含4H-噻喃4-酮结构的F组(FN组、FS)、中间含哌啶酮结构的D组、中间含丙酮结构的C组、中间含环己酮结构的A组(AN组、AS)、中间含环戊酮结构的B组(BN组、BS),抗肿瘤活性强弱顺序为：
A-F系列；E组>F组>D组>C组>A组>B组
但N系列、S系列情况有所不同,可能由于杂环结构中N、S原子的影响。
N系列：FN组>EN组>AN组>BN组
S系列：FS> ES> AS> BS
此外,A-F系列中,两侧苯环3、4位同时有-OH、-OCH3或-OCH3、-OCH3取代基能显著提高姜黄素类似物的抗肿瘤活性,苯环上-OCH3增多抗肿瘤活性增强。
Cancer is a malignant disease threating human health seriously. It is the common aspiration of mankind to conquer cancer. Anticancer drugs are appearing an increasingly important position for the treatment of cancer. Development of efficient and low toxicity anticancer drugs is an indispensable work for conquering cancer.
Curcumin is the main active ingredient of extract from roots and stem of turmeric plant. It has wide range of pharmacological activity. It has been demonstrated that the curcumin has a clear anti-tumor activity by many in vitro and animal experiments. Curcumin can inhibit cell growth of many kinds tumor. It has a broad spectrum of anti-cancer activities, it has low toxic and side effects, it can be used as anti-mutagens and anti-tumor promotion agents. It has a significant inhibitory effect to multi-stage of tumor growth, such as occurrence and development stage of tumor. And it can play a variety of performance to one kind of tumor. Curcumin has been considered as a third-generation cancer chemopreventive drug by American National Cancer Institute.
However, curcumin itself is insoluble in water, its aqueous solution is instable at neutral to alkaline conditions. Its anti-tumor activity is low in vivo. Little absorb, rapid metabolism and low bioavailability have limited it's application. It is necessary to make the appropriate structural modification of curcumin and synthetic compounds similar to the structural characteristics of curcumin to improve the stability and targeting of drugs, to enhance its anti-tumor activity, to reduce normal tissue toxicity, to screen low toxicity and efficient anticancer drug.
With curcumin as the lead compound, research work in this thesis synthesized three series total 61 compounds of curcumin analogues. Many curcumin analogues with strong anti-tumor activity were found. The structure-activity relationship was studied.
Total three series, sixty-one curcumin analogues were obtained by the reaction of aromatic formaldehyde or replace aromatic formaldehyde with six ketones (cyclohexanone, cyclopentanone,acetone, piperidone,tetrahydro-4H-pyran-4-one, tetrahydrothiopyran-4-one). 11 compounds were synthesized firstly:E11, F4, F9, F10, F11, EN1, EN3, FN1, FN3, ES, FS. The molecular structure of 61 curcumin analogues were characterized and confirmed by elementary analysis. FT-IR, 13C NMR and 1H NMR, and the compound obtained was the objective products.
The antitumor activities in vitro were evaluated in Pc-3, Panc-1 and HT-29 cancer cells by MTT assay. The 50%inhibitory concentration (IC50) indicated that most of the curcumin analogues inhibited growth of human cancer cells such as Pc-3, Panc-1 and HT-29.35 curcumin analogues antitumor activity are several times stronger than curcumin,53 curcumin analogues had stronger antitumor activity than curcumin. The curcumin analogues E9、F9、E10、F10、E11、F11、EN1、FN1、EN2、FN2、FN3 had better antitumour activity, maybe some compounds will be new anticancer drugs. Especially the inhibitory activity of compounds E10 or F10 are 73 times stronger than curcumin to cancer cells PC-3. The advance research is being done in Susan Lehman Cullman Laboratory for Cancer Research of Rutgers University.
Analysis for the structure-activity relationship showed that the curcumin analogues of benzene series(A-F), pyridine series(N), thiophene series(S) had stronger anticancer efficacy than curcumin, especially the pyridine series. The order of anti-tumor activity is:
Series N> series A-F> series S.
Single carbonyl bridge among structure can enhance curcumin analogue anti-tumor activity. In this paper, the intermediate of connecting bridge of all curcumin analogues are single carbonyl structure,90%compounds have stronger antitumor activity than curcumin, which indicate that intermediate connecting bridge is not necessary for antitumor activity.
Single carbonyl structure influencing antitumor activity of curcumin analogues. The single carbonyl structure is tetrahydro-4H-pyran-4-one in every compound of group E (group EN, ES), the single carbonyl structure is tetrahydrothiopyran-4-one in every compound of group F (group FN, FS), the single carbonyl structure is piperidone in every compound of group D, the single carbonyl structure is acetone in every compound of group C, the single carbonyl structure is cyclohexanone in every compound of group A, the single carbonyl structure is cyclopentanone in every compound of group B. The order of antitumor activity is:
Series A-F:E>F>D>C>A>B
The situation is different for series N and series S, probably because there is one nitrogen or one sulfur atom in the heterocyclic structure. The order of antitumor activity is:
Series N:FN> EN> AN> BN
Series S:FS> ES> AS> BS
In addition, for series A-F, the group of-OH,-OCH3 or-OCH3,-OCH3 at 3,4 position of benzene ring can significantly improve the antitumor activity of curcumin analogues. More-OCH3 at position3 and 4 of benzene ring, stronger antitumor activity.
姜黄素是姜黄植物根茎提取物的主要活性成分,具有广泛的药理活性。众多细胞试验和动物试验证明姜黄素具有明确的抗肿瘤活性,姜黄素可以抑制多种肿瘤细胞的生长,抗癌谱广,毒副作用小,可作为抗突变剂以及抗促癌剂,对肿瘤的发生、发展多阶段均有明显的抑制效果,对同一肿瘤同时发挥多种效能。美国国立肿瘤研究所已将姜黄素列为第3代癌化学预防药。
但姜黄素本身难溶于水,其水溶液在中性至碱性条件下不稳定,姜黄素在体内的抗肿瘤活性偏低、体内吸收少、代谢过快、生物利用度低,极大地限制了它的应用。为了提高药物的稳定性及靶向性,增强其抗肿瘤活性,减少对正常组织的毒副作用,筛选低毒高效的抗癌新药,有必要对姜黄素进行相应的结构修饰或根据姜黄素结构特点合成姜黄素类似化合物。
本论文以姜黄素为先导化合物,合成了3个系列61个姜黄素类似物。对合成化合物进行体外肿瘤细胞增殖抑制试验,筛选出一批具有强抗肿瘤活性的姜黄素类似物,并研究了姜黄素类似物抗肿瘤活性与其结构之间的构效关系。
本论文采用15种芳香甲醛或取代芳香甲醛分别与6种酮(环己酮、环戊酮、丙酮、哌啶酮、四氢吡喃-4-酮、四氢噻哺-4-酮)反应,共合成3系列61个姜黄素类似物,其中11种合成物经SCI finder数据库检索为未见合成报道的化合物,分别为：E11、F4、F9、F10、F11、EN1、EN3、FN1、FN3、ES、FS。红外光谱测定、质谱分析、碳氢核磁共振分析、元素分析等结果表明,61种姜黄素类似物均具有姜黄素的官能团结构特点,所合成产物均为目标产物。
本论文应用MTT染色法体外检测所合成的61个姜黄素类似物对人前列腺癌细胞株Pc-3,人体胰腺癌细胞株Panc-1和人结肠癌细胞株HT-29的抗肿瘤活性。半数抑制浓度IC50值表明：61个姜黄素类似物中大部分对人前列腺癌细胞株PC-3,人体胰腺癌细胞株Panc-1和人结肠癌细胞株HT-29均有较强的抑制作用,肿瘤细胞株的增殖受到不同程度的抑制。其中35个姜黄素类似物的体外抗肿瘤活性比姜黄素强一倍以上,53个姜黄素类似物的体外抗肿瘤活性均比姜黄素强。化合物E9、F9、E10、F10、E11、F11、EN1、FN1、EN2、FN2、FN3等十多个姜黄素类似物具有显著的的强抗肿瘤活性,可望成为潜在的抗癌新药。其中化合物E10、F10对人前列腺癌细胞株PC-3的抑制活性是姜黄素的73倍。目前基于本研究结果进行的进一步研究正在美国Rutgers大学肿瘤研究所展开。
抗肿瘤活性构效关系研究发现：本论文合成的两侧芳香环为苯环(A-F系列)、吡啶环(N系列)、噻吩环(S系列)的姜黄素类似物大多数具有比姜黄素更强的抗肿瘤活性,芳香环为吡啶环的姜黄素类似物抗肿瘤活性较强。抗肿瘤活性强弱顺序为：
N系列>A-F系列>S系列。
中间单羰基连接桥结构能增强姜黄素类似物的抗肿瘤活性。本论文合成的61种化合物中间连接桥均为单羰基结构,其中90%的化合物抗肿瘤活性比姜黄素强,说明中间连接桥为单羰基结构的大部分姜黄素类似物抗肿瘤活性比姜黄素强,中间双羰基结构不是必须的。
中间单羰基结构影响姜黄素类似物抗肿瘤活性强弱。对于中间含4H-吡喃4-酮结构的E组(EN组、ES)、中间含4H-噻喃4-酮结构的F组(FN组、FS)、中间含哌啶酮结构的D组、中间含丙酮结构的C组、中间含环己酮结构的A组(AN组、AS)、中间含环戊酮结构的B组(BN组、BS),抗肿瘤活性强弱顺序为：
A-F系列；E组>F组>D组>C组>A组>B组
但N系列、S系列情况有所不同,可能由于杂环结构中N、S原子的影响。
N系列：FN组>EN组>AN组>BN组
S系列：FS> ES> AS> BS
此外,A-F系列中,两侧苯环3、4位同时有-OH、-OCH3或-OCH3、-OCH3取代基能显著提高姜黄素类似物的抗肿瘤活性,苯环上-OCH3增多抗肿瘤活性增强。
Cancer is a malignant disease threating human health seriously. It is the common aspiration of mankind to conquer cancer. Anticancer drugs are appearing an increasingly important position for the treatment of cancer. Development of efficient and low toxicity anticancer drugs is an indispensable work for conquering cancer.
Curcumin is the main active ingredient of extract from roots and stem of turmeric plant. It has wide range of pharmacological activity. It has been demonstrated that the curcumin has a clear anti-tumor activity by many in vitro and animal experiments. Curcumin can inhibit cell growth of many kinds tumor. It has a broad spectrum of anti-cancer activities, it has low toxic and side effects, it can be used as anti-mutagens and anti-tumor promotion agents. It has a significant inhibitory effect to multi-stage of tumor growth, such as occurrence and development stage of tumor. And it can play a variety of performance to one kind of tumor. Curcumin has been considered as a third-generation cancer chemopreventive drug by American National Cancer Institute.
However, curcumin itself is insoluble in water, its aqueous solution is instable at neutral to alkaline conditions. Its anti-tumor activity is low in vivo. Little absorb, rapid metabolism and low bioavailability have limited it's application. It is necessary to make the appropriate structural modification of curcumin and synthetic compounds similar to the structural characteristics of curcumin to improve the stability and targeting of drugs, to enhance its anti-tumor activity, to reduce normal tissue toxicity, to screen low toxicity and efficient anticancer drug.
With curcumin as the lead compound, research work in this thesis synthesized three series total 61 compounds of curcumin analogues. Many curcumin analogues with strong anti-tumor activity were found. The structure-activity relationship was studied.
Total three series, sixty-one curcumin analogues were obtained by the reaction of aromatic formaldehyde or replace aromatic formaldehyde with six ketones (cyclohexanone, cyclopentanone,acetone, piperidone,tetrahydro-4H-pyran-4-one, tetrahydrothiopyran-4-one). 11 compounds were synthesized firstly:E11, F4, F9, F10, F11, EN1, EN3, FN1, FN3, ES, FS. The molecular structure of 61 curcumin analogues were characterized and confirmed by elementary analysis. FT-IR, 13C NMR and 1H NMR, and the compound obtained was the objective products.
The antitumor activities in vitro were evaluated in Pc-3, Panc-1 and HT-29 cancer cells by MTT assay. The 50%inhibitory concentration (IC50) indicated that most of the curcumin analogues inhibited growth of human cancer cells such as Pc-3, Panc-1 and HT-29.35 curcumin analogues antitumor activity are several times stronger than curcumin,53 curcumin analogues had stronger antitumor activity than curcumin. The curcumin analogues E9、F9、E10、F10、E11、F11、EN1、FN1、EN2、FN2、FN3 had better antitumour activity, maybe some compounds will be new anticancer drugs. Especially the inhibitory activity of compounds E10 or F10 are 73 times stronger than curcumin to cancer cells PC-3. The advance research is being done in Susan Lehman Cullman Laboratory for Cancer Research of Rutgers University.
Analysis for the structure-activity relationship showed that the curcumin analogues of benzene series(A-F), pyridine series(N), thiophene series(S) had stronger anticancer efficacy than curcumin, especially the pyridine series. The order of anti-tumor activity is:
Series N> series A-F> series S.
Single carbonyl bridge among structure can enhance curcumin analogue anti-tumor activity. In this paper, the intermediate of connecting bridge of all curcumin analogues are single carbonyl structure,90%compounds have stronger antitumor activity than curcumin, which indicate that intermediate connecting bridge is not necessary for antitumor activity.
Single carbonyl structure influencing antitumor activity of curcumin analogues. The single carbonyl structure is tetrahydro-4H-pyran-4-one in every compound of group E (group EN, ES), the single carbonyl structure is tetrahydrothiopyran-4-one in every compound of group F (group FN, FS), the single carbonyl structure is piperidone in every compound of group D, the single carbonyl structure is acetone in every compound of group C, the single carbonyl structure is cyclohexanone in every compound of group A, the single carbonyl structure is cyclopentanone in every compound of group B. The order of antitumor activity is:
Series A-F:E>F>D>C>A>B
The situation is different for series N and series S, probably because there is one nitrogen or one sulfur atom in the heterocyclic structure. The order of antitumor activity is:
Series N:FN> EN> AN> BN
Series S:FS> ES> AS> BS
In addition, for series A-F, the group of-OH,-OCH3 or-OCH3,-OCH3 at 3,4 position of benzene ring can significantly improve the antitumor activity of curcumin analogues. More-OCH3 at position3 and 4 of benzene ring, stronger antitumor activity.
引文
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