类型 基础研究 预答辩日期 2018-03-30
开始(开题)日期 2015-12-14 论文结束日期 2018-01-17
地点 新化工楼315 论文选题来源 国家自然科学基金项目     论文字数 6 (万字)
题目 功能型抗肿瘤铂(IV)前药的设计、合成及生物活性研究
主题词 铂(IV)前药,苯丁酸氮芥,汉黄芩素,雄激素受体,醌氧化还原酶
摘要 顺铂和奥沙利铂等经典铂(II)配合物是癌症化疗中最常见的药物。尽管其取得了巨大成功,然而铂(II)药物存在的诸如毒副作用大以及获得性耐药性等缺陷很大程度上限制了临床应用。为了克服这些问题,动力学惰性的铂(IV)配合物作为铂(II)配合物的前体,由于具有不同于二价铂药物的作用机制,开始进入人们的研究视野。 DNA自身修复是DNA损伤型抗癌药物产生耐药的重要原因之一。苯丁酸氮芥作为另外一种经典的DNA损伤药物,也被广泛用于临床治疗多种癌症。我们尝试将苯丁酸氮芥与铂类药物偶联,合成了一系列对DNA具有“联合作用”的铂(IV)配合物。该类新型铂(IV)配合物在正常生理条件下保持稳定且能够在抗坏血酸作用下还原释放出苯丁酸氮芥和对应的二价铂母体。通过对DNA的联合作用,该类铂(IV)配合物不仅表现出强效的抗肿瘤能力,能够显著诱导SGC7901和SGC7901/CDDP细胞发生凋亡,而且还能在一定程度上克服顺铂耐药。进一步研究发现,化合物2-19和2-21在SGC7901和SGC7901/CDDP细胞中均呈现比顺铂更强的DNA损伤能力,并且主要产生更为严重的DNA双链断裂,最终影响DNA自我复制,使得细胞周期发生阻滞。机制研究表明2-19克服耐药的原因不仅是增加癌细胞对铂的摄取与DNA和铂的结合,而且还包括配合物对PARP-1蛋白的抑制作用,抑制DNA自身修复。 癌症是一种发病机制很复杂的疾病,在肿瘤生长和转移过程中通常伴随着炎症反应的发生。汉黄芩素作为一种天然的抗肿瘤化合物,具有广泛的生物活性,现已处于临床I期研究阶段。我们通过一个连接基团将汉黄芩素嫁接到不同类型的铂(IV)轴向上,使合成的铂(IV)药物不仅具有铂类药物的DNA毒性,还兼有汉黄芩素的抗炎能力。进一步的机制研究表明该类配合物能够引起ROS富集,降低线粒体膜电位(ΔΨm),激活p53通路诱导细胞发生凋亡。其中,3-13和3-16不仅表现出显著的抗癌活性,而且还能够克服SGC7901/CDDP细胞的耐药性,降低对正常细胞(HUVEC)的毒性。体内实验表明3-16能够有效抑制肿瘤体积增长,且没有明显的毒性。 去势抵抗性前列腺癌(CRPC)是一种难以诊断和治愈的疾病,而高度表达的雄激素受体(AR)是其一个重要特征。我们以雄激素受体为靶点,设计合成了一系列以铂(IV)为基础结构的前药。研究表明该类前药均具有较好的AR结合能力。其中,一种同时包含有雄激素受体结合配体、香豆素衍生物和顺铂片段的“三合一”杂合体4-22,表现出强的AR结合能力,不仅选择性地聚集在LNCaP (+)细胞,在体外展示出优于顺铂的抗癌能力。化合物4-22能够将LNCaP细胞周期阻滞在S期,能够显著诱导细胞发生凋亡。通过该设计获得的前药,提高了顺铂选择性,而且为临床治疗去势抵抗性前列腺癌(CRPC)提供了一种有前景的方案。 醌氧化还原酶(NQO1)是一种能够提供双电子的具有细胞保护作用的特异性还原酶,现已发现其在多种癌细胞内过表达。我们将NQO1敏感的醌丙酸分子引入到铂(IV)配合物轴向,设计合成了一系列靶向NQO1的前药。研究表明,该类型的四价铂化合物不仅能够被抗坏血酸还原,还能够被NQO1特异性激活释放,具有针对癌细胞的双重响应能力。在此基础上将香豆素同时引入,合成了铂(IV)前药5-12,它们能够选择性地在NQO1过表达的A549细胞内聚集,经还原后释放出强烈的荧光,展示出很有前景的诊断治疗作用。由于其独特的联合作用能力,化合物5-11和5-12不仅在体内外试验中表现出高于顺铂的抗癌活性,而且还具有克服顺铂耐药的活性。该设计思路为构建靶向型的诊疗一体化药物提供了一种新颖的策略。
英文主题词 platinum(IV) prodrugs, chlorambucil, wogonin, androgen receptor, NQO1
英文摘要 Platinum(II)-based complexes like cisplatin and oxaliplatin are well known the mainstay of chemotherapy regimens on clinic. Although a huge success has been achieved by platinum(II) drugs, several defects such as severe side effects and drug resistance restrict their applications. To overcome these drawbacks, platinum(IV) complexes, exhibiting kinetic inertness compared with their platinum(II) counterparts, have been investigated for the antitumor application due to their unique mechanisms. Repair of lesions in DNA is an established mechanism of resistance to antitumor DNA-damaging drugs. As one of the classic DNA alkylating agents, chlorambucil has been mainly used to treat many types of tumors. Herein we designed and synthesized a series of platinum(IV) complexes with a “joint action” to damage DNA by conjugation of chlorambucil with platinum-based drugs. This new type of platinum(IV) complexes were stable under the physiological condition and could be easily reduced to their platinum(II) equivalents and release chlorambucil in the presence of ascorbic acid. By taking a joint action to enhance the damage of DNA, the conjugates displayed potent antitumor activity against all the tested cancer cell lines, and notably could overcome cisplatin resistance at certain degree, thereby induced cell apoptosis significantly in both SGC7901 and SGC7901/CDDP cells. Further investigation indicated that 2-19 and 2-21 possessed stronger ability to damage DNA by causing DNA double-strand breaks, which consequently inhibited DNA replication and arrested the cell cycle. Mechanism researches revealed that 2-19 suppressed the drug resistance by the improvement of the platinum uptake in cancer cells and DNA platination as well as generating the inhibition of PARP-1 protein which could suppress the DNA repair. Cancer is a disease with complicated pathogenesis, and cancer-associated inflammation often occurrs along with the tumor growth and metastatic progression. Wogonin, a natural product that possesses wide biological activities, is now in phase I clinical test as an anticancer agent in China. Herein we reported a series of novel platinum(IV) conjugates by tethering wogonin to the axial position of platinum(IV) complexes to via a linker group. Novel platinum(IV) conjugates not only inherited the genotoxicity from cisplatin, but also obtained the COX inhibitory property from wogonin. Further mechanistic investigation revealed that the wogonin-Pt conjugates caused the accumulation of ROS, decreased the mitochondrial membrane potential (ΔΨm), activated the p53 pathway and then induced apoptosis. Thus, 3-13 and 3-16 not only displayed excellent anticancer activity, but also overcame the resistance in SGC7901/CDDP cells and attenuated the toxicity to HUVEC cells. Moreover, in vivo studies revealed that 3-16 could inhibit the tumor growth and exhibit nearly no toxic effect. High expression level of androgen receptor (AR) is a major characteristic of castration-resistant prostate cancer (CRPC), which is difficult to diagnose and cure. Taking the high level AR of CRPC as the target, we firstly reported three Pt(IV)-based prodrugs targeting AR. Competitive experiments showed that AR-Pt(IV) conjugates all displayed decent AR binding affinity and antagonist activity against androgen receptor. Among them, 4-22 is a three-in-one hybrid containing an AR binding ligand, a cisplatin unit and a coumarin moiety. Based on the decent AR binding affinity, 4-22 selectively accumulated more in LNCaP (AR+) cells than in PC-3 (AR-) cells, thereby exhibited excellent anticancer activity superior to cisplatin. Further mechanistic research revealed that 4-22 could arrest the cell cycle at S phase and increase the apoptosis dramaticlly. In brief, the AR-targeted theranostic agent successfully improved AR-overpressed tumor selectivity of cisplatin and offered a promising strategy to treat CRPC. Human NAD(P)H:quinone oxidoreductase isozyme I (NQO1), a cytoprotective 2-electron-specific reductase was found at unusually high activity levels in cancer cells. Here we described a series of NQO1 targeting platinum(IV) prodrugs by conjugating a quinone propionic acid. Researches showed that this kind of platinum(IV) complexes had potential to be dual stimuli-activatable prodrugs due to the reported reducing capacity by VC and stimuli-activated characteristic by NQO1 which was over-expressed in numerous cancer cells. Besides, we synthesized a theranostic prodrug 5-12 by tethering a coumarin motiety. Prodrug 5-12 could selectively accumulate in NQO1-overexpressed cancer cells and exhibit strong fluorescence after reduction, showing a promising theranostic effect. Due to their unique combined action mechanism, prodrugs 5-11 and 5-12 not only possessed potent and selective anticancer activities superior to cisplatin both in vitro and in vivo, but also overcame the resistance. Thus, this work may offer a new stratagy for the construction of targeting theranostic anticancer agents.
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Novel platinum(IV) complexes conjugated with a wogonin derivative
Conjugation of platinum(IV) complexes with chlorambucil to
冯煦 正高 博导 中国科学院植物研究所
孙宏斌 正高 教授 博导 中国药科大学
刘红科 正高 教授 博导 南京师范大学
孙岳明 正高 教授 博导 东南大学
廖志新 正高 教授 博导 东南大学
房雷 副高 副教授 东南大学