HDAC Inhibitors Inspired by Natural Products

消化器官如胃、结肠和肾脏的癌症是普遍存在的，并且可能非常严重。 难以治疗，因此为寻求针对这些类型的新药物提供了令人信服的理由。 恶性肿瘤已经引起相当大兴趣的新兴靶标是组蛋白脱乙酰酶（HDAC）， 一个参与染色质重塑和表观遗传事件的酶家族。已经有 在这一领域的大量工作，主要集中在羟肟酸类，其中第一个已经获得 批准用于治疗皮肤T细胞淋巴瘤。HDAC同工酶之间的选择性差， 被认为是与当前HDAC抑制剂的临床使用相关的许多毒性的基础。新 具有上级活性的HDAC抑制剂可以显著影响该靶标在癌症中的功效。 我们有兴趣开发一种全新的HDAC抑制剂， 选择性这些新的抑制剂是基于天然产物的化学型，环庚三烯酚酮系统。为 几个世纪以来，台湾扁柏（Chamaanoparis taiwanesis）和日本扁柏的木材和提取物 （Chamaaparis obtuse）在日本和中国都很珍贵。树的提取物（扁柏油）已被 具有抗菌和抗增殖活性，目前用于许多局部药物， 化妆品这些提取物的成分在20世纪40年代初进行了研究，导致了一种 一种不寻常的热带植物，称为扁柏酚（也称为thujaplicin），被证明是负责大部分的 生物活性。天然存在的托酚酮如thujaplicin已被公认为具有 通过螯合羟基酮与金属离子相互作用，可以形成一个多功能的平台， 发现特异性靶向结合金属离子的试剂，如金属酶中的那些。其实我们 已经证明了托酚酮类似物能够抑制HDAC-2。在这个R21应用程序中，我们的目标是 研究这种非苯型芳香族化合物作为发现的良好先导化合物的潜力 HDAC的新抑制剂我们的初步分析表明，这一类别的独特结构特征 提供机会，以纳入高水平的效力和选择性。 我们的目标是使用R21机制来确定开发基于托酚酮的铅系列的可行性 作为HDAC抑制剂。第一个具体目标将描述多种差异取代的 酚酮，总共约40种，将在第二个目标中使用酶和细胞- 基于分析。还将对前五种抑制剂进行初步代谢稳定性研究。在 第三个目的是试图使HDAC与铅抑制剂复合结晶。这些研究将 最终支持基于结构的药物设计工作，因为我们正在进行先导优化。实现 R21应用中概述的目标将使我们对关键合成物进行高水平的控制， 结构和生物化学方面对进一步的化合物开发至关重要。

Cancers of the digestive organs such as the stomach, colon and the kidney are prevalent and can be very difficult to treat, thus providing a compelling rationale for the pursuit of new agents that target these types of malignancies. Emerging targets that have generated considerable interest are histone deacetylases (HDACs), a family of enzymes that is involved in chromatin remodeling and epigenetic events. There has already been considerable work in this area, largely focusing on the hydroxamate class, the first of which has gained approval for the treatment of cutaneous T-cell lymphoma. Poor selectivity between HDAC isozymes is believed to underlie much of the toxicity associated with the clinical use of current HDAC inhibitors. New HDAC inhibitors with superior activities could significantly impact the efficacy of this target in cancer. We are interested in developing a completely novel class of HDAC inhibitors with enhanced levels of selectivity. These new inhibitors are based on a natural product chemotype, the tropolone system. For centuries, the wood and extracts from taiwanhinoki (Chamaecyparis taiwanesis) and Japanese hinoki (Chamaecyparis obtuse) have been prized in Japan and China. The extracts of the tree (hinoki oil) have been valued for antibacterial and antiproliferative activity and are currently used in numerous topical agents and cosmetics. The composition of these extracts was studied in the early 1940s, leading to the identification of an unusual tropolonoid termed hinokitiol (also known as thujaplicin) that was shown to be responsible for much of the biological activity. Naturally occurring tropolones such as thujaplicin have been recognized for their ability to interact with metal ions through chelation of the ¿-hydroxy ketone and could form a versatile platform for the discovery of agents that specifically target bound metal ions such as those in metalloenzymes. In fact, we have already demonstrated that tropolone analogs are capable of inhibiting HDAC-2. In this R21 application, we aim to investigate the potential of this non-benzenoid aromatic to serve as a good lead compound for the discovery of new inhibitors of HDAC. Our preliminary analysis suggests that the unique structural features of this class offer opportunities to incorporate high levels of potency and selectivity. It is our aim to use the R21 mechanism to establish the feasibility of developing a tropolone-based lead series as HDAC inhibitors. The first specific aim will describe the synthesis of a variety of differentially substituted tropolones, approximately 40 in total, which will be evaluated in the second aim using enzymatic and cell- based assays. Preliminary metabolic stability studies will also be conducted on the top five inhibitors. In the third aim, attempts will be made to crystallize HDAC in complex with a lead inhibitor. These studies will ultimately support a structure-based drug design effort as we move forward with lead optimization. Realization of the goals outlined in this R21 application would position us with high levels of control over the key synthetic, structural and biochemical facets critical for further compound development.