新型组蛋白去乙酰化酶抑制剂的设计、合成及抗肿瘤活性研究
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摘要
本研究论文是以在生物表观遗传学研究过程中发现的与肿瘤发生、发展和转移以及肿瘤组织新生血管生成密切相关的生物靶标组蛋白去乙酰化酶(HDACs)为作用靶点,设计合成了三个系列共计109个具有全新骨架结构的HDACs抑制剂,并对其进行了体内外生物活性评价和构效关系讨论。全文共分为五个部分进行分章论述。
一.研究背景
肿瘤(tumor)是仅次于心脑血管疾病的严重威胁人类生命健康的第二大杀手。目前,我国恶性肿瘤的发病率以每年2.5%的速度增长,死亡率每年递增约1.3%。
组蛋白去乙酰化酶(HDACs)是一类催化各种底物(如核小体组蛋白)赖氨酸残基末端的乙酰基水解的蛋白酶家族。目前发现的人源HDACs包括4个亚族共18个亚型。
研究发现,许多HDACs家族成员的表达和活性在多种肿瘤病例中都有上调的表现,这表明HDACs与肿瘤的发生发展密切相关。近来,越来越多的研究表明,HDACs通过使组蛋白末端的赖氨酸残基去乙酰化来抑制基因转录,并通过去乙酰化多种非组蛋白而影响蛋白质的稳定性和定位、蛋白质-DNA相互作用及蛋白质-蛋白质相互作用,这其中很多效应都会促进肿瘤的发生和发展。HDACs在肿瘤的发生发展过程中主要起以下几方面的作用：1.促进肿瘤细胞增殖和侵袭迁移；2.促进肿瘤组织新生血管生成；3.增强肿瘤细胞对放疗化疗药物的耐药性；4.抑制肿瘤细胞分化和凋亡等。
随着HDACs与肿瘤密切关系的逐步阐明,越来越多的HDACs抑制剂显示出了高效的体内外抗肿瘤活性和多重的抗肿瘤作用机制,如：诱导肿瘤细胞凋亡和自噬、引起肿瘤细胞周期阻滞、抑制肿瘤细胞血管生成、降低肿瘤细胞的运动性和迁移能力、增强肿瘤细胞对放疗和化疗的敏感性、降低肿瘤细胞DNA的自我修复能力等。迄今为止,已有两个HDACs抑制剂(SAHA和FK228)被美国食品药品监督管理局(FDA)批准用于治疗皮肤T细胞淋巴瘤。此外,目前还有十余种HDACs抑制剂进入了临床研究,用于淋巴瘤,实体瘤和其它血液系统肿瘤的治疗。因此,寻找高效、低毒的小分子HDACs抑制剂已成为当前国内外抗癌领域的研究热点。
虽然已知的HDACs抑制剂的结构类型丰富多样,但绝大部分抑制剂都符合一个通用的药效团模型,该药效团模型主要分为三部分：分别位于两端的锌离子螯合基团(ZBG)和酶表面识别区域(Surface Recognition Domain),以及将以上两部分连接起来的适当长度的疏水性长链(Linker)。本论文根据已知的HDACs抑制剂的药效团模型和酶活性位点结构信息,合理设计、定向合成具有全新结构的HDACs抑制剂,从中筛选、优化得到具有体内外抗肿瘤活性的先导化合物,为进一步开发具有我国自主知识产权的创新性抗肿瘤药物奠定基础。
二.以四氢异喹啉-3-羧酸为骨架结构的异羟肟酸类组蛋白去乙酰化酶抑制剂的设计、合成及抗肿瘤活性研究
针对HDACs抑制剂药效团模型的三个部分进行结构改造是获得HDACs抑制剂的有效策略之一。本部分将构象限定这一经典策略用于HDACs抑制剂疏水性长链(Linker)的结构改造当中。通过对化合物进行构象限定,一方面可以获得化合物的药效构象,提高化合物对其作用靶点的分子识别作用,降低由于化合物脱靶而引起的毒副作用；另一方面可以一定程度上提高化合物的代谢稳定性。这都有利于获得高效、低毒、代谢稳定的HDACs抑制剂。
通过文献调研,我们发现1,2,3,4-四氢异喹啉-3-羧酸(简称Tic)是一种具有独特几何构象和生物活性的非天然α-氨基酸。Tic的结构片段被用于许多活性化合物的设计与合成。本部分创新性地将Tic片段引入HDACs抑制剂药效团结构中的Linker部分,结合计算机辅助药物设计手段,经过几轮的活性评价筛选(体外抑酶活性筛选、体外抗肿瘤细胞增殖活性筛选和动物体内抑瘤活性筛选)和结构优化改造,共设计合成66个四氢异喹啉-3-羧酸系列的HDACs抑制剂,化学结构经过1HNMR、HRMS和IR确证,活性优秀的化合物的纯度经HPLC测试大于等于95%。经查阅文献证实,所合成的目标化合物均为新型化合物,未见文献或专利报道。
考虑到各种Zn2+依赖性HDACs亚型的活性位点具有高度的保守性,而HDAC8的活性位点晶体结构已知,我们首先采用HDAC8作为酶源对目标化合物进行筛选,对抑酶活性较好的化合物进一步进行体外抗肿瘤细胞增殖活性筛选和动物体内抑瘤活性筛选。绝大多数目标化合物的体外抑酶活性优于已上市的阳性对照药SAHA,部分目标化合物对多株肿瘤细胞具有显著的抗增殖活性,其中化合物13e,22a和22c显示出与阳性对照药SAHA相当甚至更强的裸鼠体内抗人乳腺癌细胞(MDA-MB-231)、抗人结肠癌细胞(HCT116)增殖活性和杂种鼠体内抗肝癌细胞(H22)肺转移活性。本系列活性最强的化合物22c,由于其明显优于SAHA的体内外抗肿瘤活性,已被作为抗癌候选药物进行临床前研究与开发。
三.以酪氨酸为骨架结构的异羟肟酸类组蛋白去乙酰化酶抑制剂的设计、合成及抗肿瘤活性研究
上述系列中设计得到的四氢异喹啉-3-羧酸系列HDACs抑制剂有效的HDACs抑酶活性和体内外抗肿瘤活性激发了我们对其进行进一步结构改造和优化的热情。为了考察分子柔性对活性的影响,本章采用相对柔性的酪氨酸结构片段代替四氢异喹啉-3-羧酸系列HDACs抑制剂骨架结构中的刚性四氢异喹啉-3-羧酸结构片段。设计合成的13个酪氨酸系列化合物结构经过1HNMR和HRMS确证。经查阅文献证实,所合成的目标化合物均为新型化合物,未见文献或专利报道。
我们首先对目标化合物进行了HDAC8的抑酶活性筛选和体外人乳腺癌细胞(MDA-MB-231)、肺癌细胞(A549)和结肠癌细胞(HCT116)的抗增直活性筛选,结果表明酪氨酸系列化合物与四氢异喹啉-3-羧酸系列化合物相比,有较强的HDAC8抑酶活性和较弱的抗肿瘤细胞增殖活性。其中,目标化合物Q1、Q2、Q3和Q4的HDAC8抑酶活性比SAHA强10倍以上。进一步的以HeLa细胞核提取物为酶源(主要含HDAC1和HDAC2)的测试结果表明,化合物Q1-Q4的活性明显差于SAHA,这可能是该系列化合物抗肿瘤细胞增殖活性较差的原因,因为研究表明HDAC1和HDAC2的活性与肿瘤细胞增殖密切相关。这些结果提示我们酪氨酸衍生物类HDACs抑制剂具有一定的HDAC8亚型选择性,有希望进一步设计改造成为高选择性的HDAC8选择性抑制剂。
四.以1,4-二硫-7-氮杂螺[4,4]壬烷-8-羧酸为骨架结构的直链异羟肟酸类组蛋白去乙酰化酶抑制剂的设计、合成及抗肿瘤活性研究
根据已知的HDACs抑制剂的药效团模型,结合经典的类肽化合物作为酶抑制剂的设计策略,我们设计了一系列直链类异羟肟酸化合物。我们将1,4-二硫-7-氮杂螺[4,4]壬烷-8-羧酸活性片段引入HDACs抑制剂药效团模型的酶表面识别区域(Surface Recognition Domain),以考察该部分对化合物活性和选择性的影响。合成得到的30个1,4-二硫-7-氮杂螺[4,4]壬烷-8-羧酸系列化合物结构均经过1HNMR和HRMS确证,部分代表性化合物结构经过13CNMR确证。经查阅文献证实,所合成的目标化合物均为新型化合物,未见文献或专利报道。
我们首先对目标化合物进行了HDAC8的抑酶活性筛选,结果表明该系列化合物普遍具有较强的HDAC8抑制活性。值得指出的是,目标化合物33f、331、341、33k、33m和33n的HDAC8抑酶活性明显优于上市药物SAHA,其中化合物331和33k的半数抑制浓度(IC50)分别达到0.021±0.004mmol和0.035±0.007mmol,然而该系列化合物的抗肿瘤细胞增殖活性(人乳腺癌细胞MDA-MB-231、MCF-7和人前列腺癌细胞PC-3)却远不及SAHA。后续的HDAC1抑酶活性测试结果提示我们,化合物331和33k具有一定的HDAC8亚型选择性,可以作为先导化合物用来设计得到全新的具有亚型选择性的HDACs抑制剂。
五.全文总结与展望
本课题综合运用药物化学、化学生物学、计算机化学等前沿学科的交叉,以当前抗肿瘤研究领域的热点组蛋白去乙酰化酶HDACs为靶标,合理设计、定向合成了三个系列共109个具有全新骨架结构的HDACs抑制剂。对所有目标化合物进行了分子水平的抑酶活性筛选,从中选取活性较好的化合物逐层进行细胞水平、动物水平的抗肿瘤活性测试,利用得到的构效关系信息对表现优异的化合物进行进一步的结构改造、修饰和优化。结果表明：四氢异喹啉-3-羧酸衍生物骨架结构可以用来设计、合成具有体内外抗肿瘤活性的广谱HDACs抑制剂,目前得到的化合物22c的体内外抗肿瘤活性明显优于上市药物SAHA,对22c的进一步临床前评价和研究正在深入进行当中；而酪氨酸衍生物和1,4-二硫-7-氮杂螺[4,4]壬烷-8-羧酸衍生物骨架结构有望进一步开发得到具有亚型选择性的HDACs抑制剂,用于治疗与某些或某个HDACs亚型相关的疾病,如炎症、神经退行性疾病等。
Ⅰ. Research background
Tumor is the secondary killer of human life next to cardiovascular and cerebrovascular diseases. In current China, the growth rate of malignant tumor incidence and mortality is as high as2.5%and1.3%, respectively.
Histone deacetylases (HDACs) are enzymes responsible for deacetylation of lysine residues in various proteinaceous substrates such as nucleosomal histones. The human HDACs family consists of18isoforms, which can be divided into4classes.
Many experiments revealed that expression and activity of HDACs are upregulated in many tumor types. The hydrolysis of the acetyl group from the histones results in condensation of chromosomal DNA and transcriptional repression. Besides, aberrant deacetylation of other non-histone proteins can influence protein stability and localization, protein-DNA interaction and protein-protein interaction, many of which can promote tumorigenesis and development. The effects of HDACs in tumor mainly contain:1. promoting tumor cell proliferation and invasion;2. promoting tumor angiogenesis;3. enhancing resistance to chemotherapy and radiotherapy;4. prohibiting tumor cell differentiation and apoptosis, etc.
Given the pleiotropic functions of HDACs in tumorigenesis and development, the diverse antitumor mechanisms of HDACs inhibitors are slowly unfolding: inducing tumor cell apoptosis and autophagy, causing tumor cell cycle arrest, anti-angiogenesis, reducing DNA damage repair, enhancing chemotherapy and radiotherapy, reducing tumor cell invation and motility, etc. Currently, over ten HDACs inhibitors are in clinical trials as antitumor agents and two of them, SAHA and FK228, have been approved by the FDA for the treatment of cutaneous T-cell lymphoma (CTCL). Therefore, pursuing potent HDACs inhibitors with low toxicity has become the hot topic in the field of antitumor research.
Despite the variety of structural characteristics, most HDACs inhibitors can be broadly described by a common pharmacophore, which mainly contains3parts:a zinc ion binding group (ZBG) and a surface recognition domain, joined by a linker domain with proper length. In this study, according to the analysis of the HDACs active site structure and known HDACs inhibitors pharmacophore, we rationally designed and synthesized series of HDACs inhibitors with novel chemical scaffolds. Through several rounds of evaluation, SAR analysis and structural optimization, we would like to find some lead compounds with promising in vitro and in vivo antitumor activity, which could lay a solid foundation for the research and development of novel antitumor drugs with our own intellectual property.
Ⅱ. Design, synthesis and antitumor activity study of tetrahydroisoquinoline-3-carboxylic acid-based hydroxamic acid derivatives as HDACs inhibitors
One effective strategy in novel HDACs inhibitors design is introducing diverse chemical scaffolds to any part of the common pharmacopore. In this study, we applied classical conformational restriction strategy to design HDACs inhibitors with rigid linker. Increasing selectivity and reducing toxicity of lead compounds is the principal advantage of conformational restriction. Moreover, another intriguing advantage is that rigid compounds tend to have higher bioavailability and stability.
Based on our literatures investigation, we found that Tic, short for1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, is an unnatural a-amino acid with distinct geometrical conformation and varied biological activity. The structure of Tic has been contained in many active compounds. In this part, we introduced the rigid Tic fragment to the linker part of HDACs inhibitors and the rationality of our design was confirmed by compouter aided drug design (CADD) system. We totally synthesized66compounds, which were evaluated in enzyme inhibitin assay, MTT assay and in nude mouse models. All target compounds are novel without any report before us and their structures were confirmed by1HNMR, HRMS and IR. Part compounds with good activity are≥95%pure by HPLC analysis.
On the basis that all Zn2+dependent HDACs are highly conserved in their active sites and the crystal structure of HDACS active site is now available, we firstly used HDAC8as the enzyme source to screen our target compounds. Most tetrahydrpisoquinoline-based hydroximic acid derivatives exhibited more potent HDAC8inhibition than the positive control SAHA. Compounds with good enzyme inhibition were further evaluated in MTT assay and in nude mouse xenograft models. Among these analogues, compounds13e,22a and22c exhibited comparable even more potent in vivo antitumor activities in a human breast carcinoma (MDA-MB-231) xenograft model, a human colon tumor (HCT116) xenograft model and a mouse hepatoma-22(H22) pulmonary metastasis model. The most potent compound22c has been chosen as the antitumor candidate for further preclinical research and development due to its superior antitumor potency compared with SAHA.
Ⅲ. Design, synthesis and antitumor activity study of tyrosine-based hydroxamic acid derivatives as HDACs inhibitors
The promising antitumor activity of tetrahydroisoquinoline-based HDACs inhibitors inspired us to make some modifications and optimizations on this scaffold. In order to investigate the influence of molecular flexibility on HDACs inhibitory activity, the tetrahydroisoquinoline scaffold was simplified to the more flexible tyrosine scaffold. In this part, total13compounds were designed and synthesized with their structures confirmed by1HNMR and HRMS. All these compounds are novel without any report before us.
Enzyme inhibition assay revealed that tyrosine-based derivatives exhibited more potent HDAC8inhibitory activities relative to their corresponding tetrahydroisoquinoline analogues and SAHA. Among these new derivatives, compounds Q1, Q2, Q3and Q4were over10-fold more potent against HDAC8than SAHA. However, their antiproliferative activities against human breast carcinoma (MDA-MB-231), human lung carcinoma (A549) and human colon tumor (HCT116) were disappointing. Further enzyme inhibition assay against HeLa cell nuclear extract (mainly HDAC1and HDAC2) indicated that Q1-Q4were much less potent than SAHA, which might explain why their antiproliferative activities were poor because HDAC1and HDAC2were reported to be closely related to tumor cell proliferation. These results gave us the information that the tyrosine-based hydroxamic acid scaffold was HDAC8isoform selective to some degree, which could be further derivatized to give rise to HDAC8selective inhibitors.
Ⅳ. Design, synthesis and antitumor activity study of linear l,4-Dithia-7-azaspiro[4,4]nonane-8-carboxylic acid-based hydroxamic acid derivatives as HDACs inhibitors
In this part, a novel series of peptidomimetics HDACs inhibitors with linear linker was designed and synthesized based on the common HDACs inhibitors pharmacophore. In order to probe its influence on activity and selectivity, the unnatural amino acid1,4-Dithia-7-azaspiro[4,4]nonane-8-carboxylic acid was introduced into the surface recognition domain of our HDACs inhibitors. Newly synthesized30compounds are all novel without any report before us with their structures confirmed by'HNMR and HRMS. Some representative compounds were analyzed by13CNMR.
Enzyme inhibition assay revealed that most of these derivatives were very potent against HDAC8. It was notable that compounds33f,331,341,33k,33m and33n were more potent against HDAC8than SAHA, with the IC50of331and33k being as low as0.021±0.004mmol and0.035±0.007mmol, respectively. However, their antiproliferative acitivities against human breast carcinoma (MCF-7, MDA-MB-231) and prostate carcinoma (PC-3) were not satisfactory. The following enzyme inhibition assay against HDAC1showed that compounds331and33k were more prefer to HDAC8rather than HDAC1. So these two compounds could be used as the lead to design HDACs isoform selective inhibitors.
Ⅴ. Conclusion and perspective
In conclusion, based on the combination of medicinal chemistry, chemical biology and computational chemistry, we rationally designed and synthesized109novel HDACs inhibitors, which could be divided into3series according to their scaffolds. All the target compounds were tested in HDACs enzyme inhibition assay and compounds with good activities were progressed to in vitro antiproliferative assays and in vivo experiments. Our research revealed that tetrahydroisoquinoline scaffold could be used to obtain pan-HDACs inhibitors with potent in vitro and in vivo antitumor activities. Among these tetrahydroisoquinoline-based hydroxamic acid derivatives, compound22c exhibited more potent in vitro and in vivo antitumor potency than approved drug SAHA, and further research and development are underway. While the tyrosine scaffold and the1,4-Dithia-7-azaspiro[4,4]nonane-8-carboxylic acid scaffold are promising in developing HDACs isoform selective inhibitors, which could be very useful in treating diseases (such as inflammation, neurodegenerative disease, etc) caused by disorder of some specific HDACs isoform.
一.研究背景
肿瘤(tumor)是仅次于心脑血管疾病的严重威胁人类生命健康的第二大杀手。目前,我国恶性肿瘤的发病率以每年2.5%的速度增长,死亡率每年递增约1.3%。
组蛋白去乙酰化酶(HDACs)是一类催化各种底物(如核小体组蛋白)赖氨酸残基末端的乙酰基水解的蛋白酶家族。目前发现的人源HDACs包括4个亚族共18个亚型。
研究发现,许多HDACs家族成员的表达和活性在多种肿瘤病例中都有上调的表现,这表明HDACs与肿瘤的发生发展密切相关。近来,越来越多的研究表明,HDACs通过使组蛋白末端的赖氨酸残基去乙酰化来抑制基因转录,并通过去乙酰化多种非组蛋白而影响蛋白质的稳定性和定位、蛋白质-DNA相互作用及蛋白质-蛋白质相互作用,这其中很多效应都会促进肿瘤的发生和发展。HDACs在肿瘤的发生发展过程中主要起以下几方面的作用：1.促进肿瘤细胞增殖和侵袭迁移；2.促进肿瘤组织新生血管生成；3.增强肿瘤细胞对放疗化疗药物的耐药性；4.抑制肿瘤细胞分化和凋亡等。
随着HDACs与肿瘤密切关系的逐步阐明,越来越多的HDACs抑制剂显示出了高效的体内外抗肿瘤活性和多重的抗肿瘤作用机制,如：诱导肿瘤细胞凋亡和自噬、引起肿瘤细胞周期阻滞、抑制肿瘤细胞血管生成、降低肿瘤细胞的运动性和迁移能力、增强肿瘤细胞对放疗和化疗的敏感性、降低肿瘤细胞DNA的自我修复能力等。迄今为止,已有两个HDACs抑制剂(SAHA和FK228)被美国食品药品监督管理局(FDA)批准用于治疗皮肤T细胞淋巴瘤。此外,目前还有十余种HDACs抑制剂进入了临床研究,用于淋巴瘤,实体瘤和其它血液系统肿瘤的治疗。因此,寻找高效、低毒的小分子HDACs抑制剂已成为当前国内外抗癌领域的研究热点。
虽然已知的HDACs抑制剂的结构类型丰富多样,但绝大部分抑制剂都符合一个通用的药效团模型,该药效团模型主要分为三部分：分别位于两端的锌离子螯合基团(ZBG)和酶表面识别区域(Surface Recognition Domain),以及将以上两部分连接起来的适当长度的疏水性长链(Linker)。本论文根据已知的HDACs抑制剂的药效团模型和酶活性位点结构信息,合理设计、定向合成具有全新结构的HDACs抑制剂,从中筛选、优化得到具有体内外抗肿瘤活性的先导化合物,为进一步开发具有我国自主知识产权的创新性抗肿瘤药物奠定基础。
二.以四氢异喹啉-3-羧酸为骨架结构的异羟肟酸类组蛋白去乙酰化酶抑制剂的设计、合成及抗肿瘤活性研究
针对HDACs抑制剂药效团模型的三个部分进行结构改造是获得HDACs抑制剂的有效策略之一。本部分将构象限定这一经典策略用于HDACs抑制剂疏水性长链(Linker)的结构改造当中。通过对化合物进行构象限定,一方面可以获得化合物的药效构象,提高化合物对其作用靶点的分子识别作用,降低由于化合物脱靶而引起的毒副作用；另一方面可以一定程度上提高化合物的代谢稳定性。这都有利于获得高效、低毒、代谢稳定的HDACs抑制剂。
通过文献调研,我们发现1,2,3,4-四氢异喹啉-3-羧酸(简称Tic)是一种具有独特几何构象和生物活性的非天然α-氨基酸。Tic的结构片段被用于许多活性化合物的设计与合成。本部分创新性地将Tic片段引入HDACs抑制剂药效团结构中的Linker部分,结合计算机辅助药物设计手段,经过几轮的活性评价筛选(体外抑酶活性筛选、体外抗肿瘤细胞增殖活性筛选和动物体内抑瘤活性筛选)和结构优化改造,共设计合成66个四氢异喹啉-3-羧酸系列的HDACs抑制剂,化学结构经过1HNMR、HRMS和IR确证,活性优秀的化合物的纯度经HPLC测试大于等于95%。经查阅文献证实,所合成的目标化合物均为新型化合物,未见文献或专利报道。
考虑到各种Zn2+依赖性HDACs亚型的活性位点具有高度的保守性,而HDAC8的活性位点晶体结构已知,我们首先采用HDAC8作为酶源对目标化合物进行筛选,对抑酶活性较好的化合物进一步进行体外抗肿瘤细胞增殖活性筛选和动物体内抑瘤活性筛选。绝大多数目标化合物的体外抑酶活性优于已上市的阳性对照药SAHA,部分目标化合物对多株肿瘤细胞具有显著的抗增殖活性,其中化合物13e,22a和22c显示出与阳性对照药SAHA相当甚至更强的裸鼠体内抗人乳腺癌细胞(MDA-MB-231)、抗人结肠癌细胞(HCT116)增殖活性和杂种鼠体内抗肝癌细胞(H22)肺转移活性。本系列活性最强的化合物22c,由于其明显优于SAHA的体内外抗肿瘤活性,已被作为抗癌候选药物进行临床前研究与开发。
三.以酪氨酸为骨架结构的异羟肟酸类组蛋白去乙酰化酶抑制剂的设计、合成及抗肿瘤活性研究
上述系列中设计得到的四氢异喹啉-3-羧酸系列HDACs抑制剂有效的HDACs抑酶活性和体内外抗肿瘤活性激发了我们对其进行进一步结构改造和优化的热情。为了考察分子柔性对活性的影响,本章采用相对柔性的酪氨酸结构片段代替四氢异喹啉-3-羧酸系列HDACs抑制剂骨架结构中的刚性四氢异喹啉-3-羧酸结构片段。设计合成的13个酪氨酸系列化合物结构经过1HNMR和HRMS确证。经查阅文献证实,所合成的目标化合物均为新型化合物,未见文献或专利报道。
我们首先对目标化合物进行了HDAC8的抑酶活性筛选和体外人乳腺癌细胞(MDA-MB-231)、肺癌细胞(A549)和结肠癌细胞(HCT116)的抗增直活性筛选,结果表明酪氨酸系列化合物与四氢异喹啉-3-羧酸系列化合物相比,有较强的HDAC8抑酶活性和较弱的抗肿瘤细胞增殖活性。其中,目标化合物Q1、Q2、Q3和Q4的HDAC8抑酶活性比SAHA强10倍以上。进一步的以HeLa细胞核提取物为酶源(主要含HDAC1和HDAC2)的测试结果表明,化合物Q1-Q4的活性明显差于SAHA,这可能是该系列化合物抗肿瘤细胞增殖活性较差的原因,因为研究表明HDAC1和HDAC2的活性与肿瘤细胞增殖密切相关。这些结果提示我们酪氨酸衍生物类HDACs抑制剂具有一定的HDAC8亚型选择性,有希望进一步设计改造成为高选择性的HDAC8选择性抑制剂。
四.以1,4-二硫-7-氮杂螺[4,4]壬烷-8-羧酸为骨架结构的直链异羟肟酸类组蛋白去乙酰化酶抑制剂的设计、合成及抗肿瘤活性研究
根据已知的HDACs抑制剂的药效团模型,结合经典的类肽化合物作为酶抑制剂的设计策略,我们设计了一系列直链类异羟肟酸化合物。我们将1,4-二硫-7-氮杂螺[4,4]壬烷-8-羧酸活性片段引入HDACs抑制剂药效团模型的酶表面识别区域(Surface Recognition Domain),以考察该部分对化合物活性和选择性的影响。合成得到的30个1,4-二硫-7-氮杂螺[4,4]壬烷-8-羧酸系列化合物结构均经过1HNMR和HRMS确证,部分代表性化合物结构经过13CNMR确证。经查阅文献证实,所合成的目标化合物均为新型化合物,未见文献或专利报道。
我们首先对目标化合物进行了HDAC8的抑酶活性筛选,结果表明该系列化合物普遍具有较强的HDAC8抑制活性。值得指出的是,目标化合物33f、331、341、33k、33m和33n的HDAC8抑酶活性明显优于上市药物SAHA,其中化合物331和33k的半数抑制浓度(IC50)分别达到0.021±0.004mmol和0.035±0.007mmol,然而该系列化合物的抗肿瘤细胞增殖活性(人乳腺癌细胞MDA-MB-231、MCF-7和人前列腺癌细胞PC-3)却远不及SAHA。后续的HDAC1抑酶活性测试结果提示我们,化合物331和33k具有一定的HDAC8亚型选择性,可以作为先导化合物用来设计得到全新的具有亚型选择性的HDACs抑制剂。
五.全文总结与展望
本课题综合运用药物化学、化学生物学、计算机化学等前沿学科的交叉,以当前抗肿瘤研究领域的热点组蛋白去乙酰化酶HDACs为靶标,合理设计、定向合成了三个系列共109个具有全新骨架结构的HDACs抑制剂。对所有目标化合物进行了分子水平的抑酶活性筛选,从中选取活性较好的化合物逐层进行细胞水平、动物水平的抗肿瘤活性测试,利用得到的构效关系信息对表现优异的化合物进行进一步的结构改造、修饰和优化。结果表明：四氢异喹啉-3-羧酸衍生物骨架结构可以用来设计、合成具有体内外抗肿瘤活性的广谱HDACs抑制剂,目前得到的化合物22c的体内外抗肿瘤活性明显优于上市药物SAHA,对22c的进一步临床前评价和研究正在深入进行当中；而酪氨酸衍生物和1,4-二硫-7-氮杂螺[4,4]壬烷-8-羧酸衍生物骨架结构有望进一步开发得到具有亚型选择性的HDACs抑制剂,用于治疗与某些或某个HDACs亚型相关的疾病,如炎症、神经退行性疾病等。
Ⅰ. Research background
Tumor is the secondary killer of human life next to cardiovascular and cerebrovascular diseases. In current China, the growth rate of malignant tumor incidence and mortality is as high as2.5%and1.3%, respectively.
Histone deacetylases (HDACs) are enzymes responsible for deacetylation of lysine residues in various proteinaceous substrates such as nucleosomal histones. The human HDACs family consists of18isoforms, which can be divided into4classes.
Many experiments revealed that expression and activity of HDACs are upregulated in many tumor types. The hydrolysis of the acetyl group from the histones results in condensation of chromosomal DNA and transcriptional repression. Besides, aberrant deacetylation of other non-histone proteins can influence protein stability and localization, protein-DNA interaction and protein-protein interaction, many of which can promote tumorigenesis and development. The effects of HDACs in tumor mainly contain:1. promoting tumor cell proliferation and invasion;2. promoting tumor angiogenesis;3. enhancing resistance to chemotherapy and radiotherapy;4. prohibiting tumor cell differentiation and apoptosis, etc.
Given the pleiotropic functions of HDACs in tumorigenesis and development, the diverse antitumor mechanisms of HDACs inhibitors are slowly unfolding: inducing tumor cell apoptosis and autophagy, causing tumor cell cycle arrest, anti-angiogenesis, reducing DNA damage repair, enhancing chemotherapy and radiotherapy, reducing tumor cell invation and motility, etc. Currently, over ten HDACs inhibitors are in clinical trials as antitumor agents and two of them, SAHA and FK228, have been approved by the FDA for the treatment of cutaneous T-cell lymphoma (CTCL). Therefore, pursuing potent HDACs inhibitors with low toxicity has become the hot topic in the field of antitumor research.
Despite the variety of structural characteristics, most HDACs inhibitors can be broadly described by a common pharmacophore, which mainly contains3parts:a zinc ion binding group (ZBG) and a surface recognition domain, joined by a linker domain with proper length. In this study, according to the analysis of the HDACs active site structure and known HDACs inhibitors pharmacophore, we rationally designed and synthesized series of HDACs inhibitors with novel chemical scaffolds. Through several rounds of evaluation, SAR analysis and structural optimization, we would like to find some lead compounds with promising in vitro and in vivo antitumor activity, which could lay a solid foundation for the research and development of novel antitumor drugs with our own intellectual property.
Ⅱ. Design, synthesis and antitumor activity study of tetrahydroisoquinoline-3-carboxylic acid-based hydroxamic acid derivatives as HDACs inhibitors
One effective strategy in novel HDACs inhibitors design is introducing diverse chemical scaffolds to any part of the common pharmacopore. In this study, we applied classical conformational restriction strategy to design HDACs inhibitors with rigid linker. Increasing selectivity and reducing toxicity of lead compounds is the principal advantage of conformational restriction. Moreover, another intriguing advantage is that rigid compounds tend to have higher bioavailability and stability.
Based on our literatures investigation, we found that Tic, short for1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, is an unnatural a-amino acid with distinct geometrical conformation and varied biological activity. The structure of Tic has been contained in many active compounds. In this part, we introduced the rigid Tic fragment to the linker part of HDACs inhibitors and the rationality of our design was confirmed by compouter aided drug design (CADD) system. We totally synthesized66compounds, which were evaluated in enzyme inhibitin assay, MTT assay and in nude mouse models. All target compounds are novel without any report before us and their structures were confirmed by1HNMR, HRMS and IR. Part compounds with good activity are≥95%pure by HPLC analysis.
On the basis that all Zn2+dependent HDACs are highly conserved in their active sites and the crystal structure of HDACS active site is now available, we firstly used HDAC8as the enzyme source to screen our target compounds. Most tetrahydrpisoquinoline-based hydroximic acid derivatives exhibited more potent HDAC8inhibition than the positive control SAHA. Compounds with good enzyme inhibition were further evaluated in MTT assay and in nude mouse xenograft models. Among these analogues, compounds13e,22a and22c exhibited comparable even more potent in vivo antitumor activities in a human breast carcinoma (MDA-MB-231) xenograft model, a human colon tumor (HCT116) xenograft model and a mouse hepatoma-22(H22) pulmonary metastasis model. The most potent compound22c has been chosen as the antitumor candidate for further preclinical research and development due to its superior antitumor potency compared with SAHA.
Ⅲ. Design, synthesis and antitumor activity study of tyrosine-based hydroxamic acid derivatives as HDACs inhibitors
The promising antitumor activity of tetrahydroisoquinoline-based HDACs inhibitors inspired us to make some modifications and optimizations on this scaffold. In order to investigate the influence of molecular flexibility on HDACs inhibitory activity, the tetrahydroisoquinoline scaffold was simplified to the more flexible tyrosine scaffold. In this part, total13compounds were designed and synthesized with their structures confirmed by1HNMR and HRMS. All these compounds are novel without any report before us.
Enzyme inhibition assay revealed that tyrosine-based derivatives exhibited more potent HDAC8inhibitory activities relative to their corresponding tetrahydroisoquinoline analogues and SAHA. Among these new derivatives, compounds Q1, Q2, Q3and Q4were over10-fold more potent against HDAC8than SAHA. However, their antiproliferative activities against human breast carcinoma (MDA-MB-231), human lung carcinoma (A549) and human colon tumor (HCT116) were disappointing. Further enzyme inhibition assay against HeLa cell nuclear extract (mainly HDAC1and HDAC2) indicated that Q1-Q4were much less potent than SAHA, which might explain why their antiproliferative activities were poor because HDAC1and HDAC2were reported to be closely related to tumor cell proliferation. These results gave us the information that the tyrosine-based hydroxamic acid scaffold was HDAC8isoform selective to some degree, which could be further derivatized to give rise to HDAC8selective inhibitors.
Ⅳ. Design, synthesis and antitumor activity study of linear l,4-Dithia-7-azaspiro[4,4]nonane-8-carboxylic acid-based hydroxamic acid derivatives as HDACs inhibitors
In this part, a novel series of peptidomimetics HDACs inhibitors with linear linker was designed and synthesized based on the common HDACs inhibitors pharmacophore. In order to probe its influence on activity and selectivity, the unnatural amino acid1,4-Dithia-7-azaspiro[4,4]nonane-8-carboxylic acid was introduced into the surface recognition domain of our HDACs inhibitors. Newly synthesized30compounds are all novel without any report before us with their structures confirmed by'HNMR and HRMS. Some representative compounds were analyzed by13CNMR.
Enzyme inhibition assay revealed that most of these derivatives were very potent against HDAC8. It was notable that compounds33f,331,341,33k,33m and33n were more potent against HDAC8than SAHA, with the IC50of331and33k being as low as0.021±0.004mmol and0.035±0.007mmol, respectively. However, their antiproliferative acitivities against human breast carcinoma (MCF-7, MDA-MB-231) and prostate carcinoma (PC-3) were not satisfactory. The following enzyme inhibition assay against HDAC1showed that compounds331and33k were more prefer to HDAC8rather than HDAC1. So these two compounds could be used as the lead to design HDACs isoform selective inhibitors.
Ⅴ. Conclusion and perspective
In conclusion, based on the combination of medicinal chemistry, chemical biology and computational chemistry, we rationally designed and synthesized109novel HDACs inhibitors, which could be divided into3series according to their scaffolds. All the target compounds were tested in HDACs enzyme inhibition assay and compounds with good activities were progressed to in vitro antiproliferative assays and in vivo experiments. Our research revealed that tetrahydroisoquinoline scaffold could be used to obtain pan-HDACs inhibitors with potent in vitro and in vivo antitumor activities. Among these tetrahydroisoquinoline-based hydroxamic acid derivatives, compound22c exhibited more potent in vitro and in vivo antitumor potency than approved drug SAHA, and further research and development are underway. While the tyrosine scaffold and the1,4-Dithia-7-azaspiro[4,4]nonane-8-carboxylic acid scaffold are promising in developing HDACs isoform selective inhibitors, which could be very useful in treating diseases (such as inflammation, neurodegenerative disease, etc) caused by disorder of some specific HDACs isoform.
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