联邻苯二酚结构的DNA交联剂的设计合成研究及其对黑素肿瘤细胞的选择性杀伤作用
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摘要
DNA作为生物体中遗传信息的主要载体在遗传信息的传递中车关重要,以DNA为靶目标的抗癌药物的设计一直是药物研究的热点之一。其中,许多临床上使用的抗肿瘤药物的作用机理涉及到DNA的交联。它们通过与DNA的共价结合作用将DNA双链交联,阻碍DNA双链的打开,使之不能进行遗传信息的复制和传递,从而导致细胞的死亡达到治疗癌症的目的。可诱导的DNA交联剂的引入,增强了药物的靶向性和选择性。
本论文设计合成了十二个含不同连接基团的联邻苯二酚结构的化合物,通过高碘酸钠或者酪氨酸酶的氧化诱导,研究了它们与DNA的交联活性。同时,鉴于恶性黑素瘤细胞中酪氨酸酶的含量高表达,我们建立了一种以联邻苯二酚结构的DNA交联剂选择性的杀伤黑素瘤细胞的方法。具体研究内容涵盖以下几点：
1.首先在体外实验中,我们用琼脂糖凝胶电泳实验检测了化合物与线性DNA交联的能力。在高碘酸钠的氧化诱导下,两个酚羟基在邻位的化合物7a-f都表现出了很强的DNA交联能力,而两个酚羟基在间位的化合物10a-f交联能力很差。在酪氨酸酶的氧化诱导下,所有的化合物均表现出DNA交联能力,两个酚羟基在间位的化合物10a-f比两个酚羟基在邻位的化合物7a-f的交联能力略好。并且,中间连有联苯结构的化合物10f交联活性最好。另外,我们通过3-甲基-2-苯并噻唑酮腙(MBTH)的颜色实验,捕捉到这类化合物在酪氨酸酶氧化诱导后有二醌的中间体的产生,初步提出了交联机理。
2.我们进一步对此类联邻苯二酚化合物的抗癌活性进行了研究。我们用MTT法对药物的细胞毒性进行了研究。细胞毒性实验表明此类联邻苯二酚化合物对酪氨酸酶高表达的恶性黑素瘤细胞的毒性非常明显,而对不含有酪氨酸酶的宫颈癌细胞Hela和正常卵巢细胞CHO毒性很弱。我们通过一系列的分了生物学的方法,包括在细胞内检测邻苯二酚结构的BODIPY荧光探针实验,单细胞凝胶电泳实验,γ-H2AX免疫荧光实验以及通过观测细胞核形态变化,验证了化合物对恶性黑素瘤细胞的选择性杀伤力主要是通过DNA损伤起作用。更重要的是,这些DNA损伤与DNA交联有关。联邻二苯酚的化合物是因为能与恶性黑色素瘤细胞的细胞核中的DNA发生交联,而导致了它具有高选择性的杀伤恶性黑色素瘤细胞的能力。
Because of the important role that the DNA plays in transferring genetic information, the research of antitumor drugs targeting DNA have always been one of the most attractive areas in durg design. Many anticancer drugs are involved in DNA cross-linking mechanism. They are able to cross-link DNA duplex with covalent bond and inhibit the release of the DNA duplex so that it cannot finish self-replication and the expression of genetic information, which will finally lead cells to death. Inducible DNA cross-linking agents is a novel strategy to increase the selectivity greatly of the drugs.
In this thesis, a series of bis(catechol) quaternary ammonium derivatives were designed and synthesized. We investigated their ability of cross-linking DNA which induced by NaIO4 and tyrosinase. For Tyrosinase is highly expressed in malignant tumors, we provide a possible chemotherapy for melanoma by using bis(catechol) quaternary ammonium derivatives that have notable cell selectivity in the tyrosinase-efficient melanoma cells. In summary, the main ideas of this thesis were as follows:
1. The DNA- DNA cross-linking ability of the tweleve bis(catechol) quaternary ammonium derivatives was investigated by denatured alkaline agarose gel electrophoresis. The 2,3-dihydroxy derivatives have good cross-linking results which induced by NaIO4 but the 3,4-dihydroxy derivatives not. When the compounds were induced by tyrosinase, the interstrand cross-linking was more efficacious for the 3,4-dihydroxy derivatives than for the 2,3-dihydroxy derivatives. And the 3,4-dihydroxy derivative with diphenol core (10f) is the most efficient crosslink agent. Then, we found that the o-quinone is key intermediate in the process by using the nucleophile 3-methyl-2-benzothiazolinone hydrazone (MBTH) in the tyrosinase assay and we proposed the mechanism of cross-linking DNA.
2. Their cytotoxicities to B16F1, Hela and CHO cells were tested by MTT assays. The specific and potent abilities to kill the tyrosinase-efficient melanoma cells have caught our interest in exploring the relationship between their abilities of cross-linking DNA and their selective cytotoxicities to cells. Through an integrated approach including intracellular imaging for detecting the dihydroxy phenol groups, alkaline comet assay andγ-H2AX immunofluorescence assay the speculation was confirmed. The bis(catechol) quaternary ammonium derivatives showed notable cell selectivity because they displayed cytotoxicities after being oxidized by tyrosinase and were able to efficiently target the DNA in the tyrosinase-efficient melanoma cells, where it forms both alkylated and cross-linked species.
本论文设计合成了十二个含不同连接基团的联邻苯二酚结构的化合物,通过高碘酸钠或者酪氨酸酶的氧化诱导,研究了它们与DNA的交联活性。同时,鉴于恶性黑素瘤细胞中酪氨酸酶的含量高表达,我们建立了一种以联邻苯二酚结构的DNA交联剂选择性的杀伤黑素瘤细胞的方法。具体研究内容涵盖以下几点：
1.首先在体外实验中,我们用琼脂糖凝胶电泳实验检测了化合物与线性DNA交联的能力。在高碘酸钠的氧化诱导下,两个酚羟基在邻位的化合物7a-f都表现出了很强的DNA交联能力,而两个酚羟基在间位的化合物10a-f交联能力很差。在酪氨酸酶的氧化诱导下,所有的化合物均表现出DNA交联能力,两个酚羟基在间位的化合物10a-f比两个酚羟基在邻位的化合物7a-f的交联能力略好。并且,中间连有联苯结构的化合物10f交联活性最好。另外,我们通过3-甲基-2-苯并噻唑酮腙(MBTH)的颜色实验,捕捉到这类化合物在酪氨酸酶氧化诱导后有二醌的中间体的产生,初步提出了交联机理。
2.我们进一步对此类联邻苯二酚化合物的抗癌活性进行了研究。我们用MTT法对药物的细胞毒性进行了研究。细胞毒性实验表明此类联邻苯二酚化合物对酪氨酸酶高表达的恶性黑素瘤细胞的毒性非常明显,而对不含有酪氨酸酶的宫颈癌细胞Hela和正常卵巢细胞CHO毒性很弱。我们通过一系列的分了生物学的方法,包括在细胞内检测邻苯二酚结构的BODIPY荧光探针实验,单细胞凝胶电泳实验,γ-H2AX免疫荧光实验以及通过观测细胞核形态变化,验证了化合物对恶性黑素瘤细胞的选择性杀伤力主要是通过DNA损伤起作用。更重要的是,这些DNA损伤与DNA交联有关。联邻二苯酚的化合物是因为能与恶性黑色素瘤细胞的细胞核中的DNA发生交联,而导致了它具有高选择性的杀伤恶性黑色素瘤细胞的能力。
Because of the important role that the DNA plays in transferring genetic information, the research of antitumor drugs targeting DNA have always been one of the most attractive areas in durg design. Many anticancer drugs are involved in DNA cross-linking mechanism. They are able to cross-link DNA duplex with covalent bond and inhibit the release of the DNA duplex so that it cannot finish self-replication and the expression of genetic information, which will finally lead cells to death. Inducible DNA cross-linking agents is a novel strategy to increase the selectivity greatly of the drugs.
In this thesis, a series of bis(catechol) quaternary ammonium derivatives were designed and synthesized. We investigated their ability of cross-linking DNA which induced by NaIO4 and tyrosinase. For Tyrosinase is highly expressed in malignant tumors, we provide a possible chemotherapy for melanoma by using bis(catechol) quaternary ammonium derivatives that have notable cell selectivity in the tyrosinase-efficient melanoma cells. In summary, the main ideas of this thesis were as follows:
1. The DNA- DNA cross-linking ability of the tweleve bis(catechol) quaternary ammonium derivatives was investigated by denatured alkaline agarose gel electrophoresis. The 2,3-dihydroxy derivatives have good cross-linking results which induced by NaIO4 but the 3,4-dihydroxy derivatives not. When the compounds were induced by tyrosinase, the interstrand cross-linking was more efficacious for the 3,4-dihydroxy derivatives than for the 2,3-dihydroxy derivatives. And the 3,4-dihydroxy derivative with diphenol core (10f) is the most efficient crosslink agent. Then, we found that the o-quinone is key intermediate in the process by using the nucleophile 3-methyl-2-benzothiazolinone hydrazone (MBTH) in the tyrosinase assay and we proposed the mechanism of cross-linking DNA.
2. Their cytotoxicities to B16F1, Hela and CHO cells were tested by MTT assays. The specific and potent abilities to kill the tyrosinase-efficient melanoma cells have caught our interest in exploring the relationship between their abilities of cross-linking DNA and their selective cytotoxicities to cells. Through an integrated approach including intracellular imaging for detecting the dihydroxy phenol groups, alkaline comet assay andγ-H2AX immunofluorescence assay the speculation was confirmed. The bis(catechol) quaternary ammonium derivatives showed notable cell selectivity because they displayed cytotoxicities after being oxidized by tyrosinase and were able to efficiently target the DNA in the tyrosinase-efficient melanoma cells, where it forms both alkylated and cross-linked species.
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