Novel Indenoisoquinoline Topoisomerase I Inhibitors

新型茚并异喹啉拓扑异构酶 I 抑制剂

• 批准号: 7495704
• 负责人: MARK S CUSHMAN
• 金额: $ 23.67万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-10 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7495704
• 关键词: Affinity; Amino Acids; Animal Model; Animals; Antineoplastic Agents; Base Pairing; Binding; Biochemical; Biological; Biological Assay; Biological Availability; Biological Models; Camptothecin; Carbohydrates; Cell Line; Charge; Chemicals; Class; Clinical; Collaborations; Complex; DNA; DNA Structure; DNA analysis; DNA strand break; Detection; Development; Drug Kinetics; Electrons; Electrostatics; Enzyme Inhibition; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Evaluation; Excision; Fiber; Folate; Future; Goals; Human; Hydrogen Bonding; In Vitro; Intravenous infusion procedures; Kinetics; Knowledge; Lactones; London; Mediating; Metabolic; Modeling; Modification; Molecular; Monitor; Nitrogen; Numbers; Object Attachment; Oxidants; Pattern; Pharmaceutical Preparations; Property; Relative (related person); Relaxation; Research; Research Project Grants; Resistance; Role; Series; Solubility; Structure; Surface; System; Systems Analysis; Testing; Therapeutic; Topoisomerase I inhibition; Topoisomerase-I Inhibitor; Type I DNA Topoisomerases; Xenograft procedure; anticancer activity; base; cancer cell; cancer therapy; charge transfer complex; chemotherapeutic agent; chemotherapy; clinical application; cytotoxicity; design; drug structure; human TOP1 protein; in vivo; inhibitor/antagonist; intercalation; member; mutant; novel; programs; protein structure; reaction rate; success; van der Waals force

DESCRIPTION (provided by applicant): Topoisomerase I is an important target for the development of new chemotherapeutic agents for the treatment of cancer in humans. Although some members of the camptothecin class of topoisomerase I inhibitors are presently in clinical use as anticancer agents, the camptothecins suffer from a number of inherent limitations, including chemical and metabolic instability due to lactone ring opening, and rapid reversibility of topoisomerase I inhibition upon drug removal. Because of these limitations, effective chemotherapy with the camptothecins requires long I.V. infusions and prolonged and continuous exposure. Recent studies in our research group, in collaboration with others, have resulted in the synthesis of a new class of topoisomerase I inhibitors, the indenoisoquinolines. A combination of enzyme inhibition studies, in vitro cytotoxicity results in human cancer cell cultures, and in vivo animal studies have provided compelling evidence that the indenoisoquinolines will overcome some of the limitations of the camptothecins. One of the main goals of the presently proposed research program will be to design and synthesize more effective indenoisoquinolines as topoisomerase I inhibitors with potential clinical application in the treatment of cancer in humans. It can be assumed that the efficacy of the indenoisoquinoline topoisomerase I inhibitors can be maximized by taking advantage of the various chemical forces that are involved in stabilization of the ternary complexes formed from DNA, the enzyme, and the inhibitors. The forces responsible for the bonding of the drug to DNA bases in the ternary complex include charge-transfer complex formation, electrostatic attraction, and London dispersion forces. In addition to these forces, the ternary complexes are also stabilized through hydrogen bonding of the indenoisoquinolines to some of the nearby amino acid residues of the enzyme. One of the main goals of this research project will be to maximize each of these various forces in an array of new drug molecules using our knowledge of the crystal structures of the drug-enzyme-DNA ternary complexes. We presently have determined the crystal structures of complexes formed from two indenoisoquinolines, and we expect that additional crystal structures will become available through future efforts. The structures of the indenoisoquinolines will also be manipulated in order to target them to cancer cells, maximize favorable solubility properties, and increase their bioavailabilities. The new compounds prepared in this study will be evaluated in a number of biochemical and biological assays. These will include analysis of DNA cleavage patterns induced by topoisomerase I in the presence of the inhibitors, analysis of the stabilities of the ternary complexes, DNA unwinding studies to detect intercalation, inhibition of topoisomerase I-mediated DNA relaxation, detection of DNA strand breaks in cellular systems, and analysis of enzyme-inhibitory activities in camptothecin resistant mutant cell lines. The cytotoxicities of the indenoisoquinolines in cancer cell cultures will be determined, and promising candidates will be investigated for anticancer activity in a variety of animal model systems. The mechanism of action of the indenoisoquinolines will be studied in detail, and the information will be used to maximize their therapeutic potential as anticancer agents.

描述（由申请人提供）： 拓扑异构酶I是开发用于治疗人类癌症的新化学治疗剂的重要靶标。尽管拓扑异构酶I抑制剂的喜树碱类的一些成员目前在临床上用作抗癌剂，但喜树碱具有许多固有的局限性，包括由于内酯开环引起的化学和代谢不稳定性，以及在药物去除后拓扑异构酶I抑制的快速可逆性。由于这些局限性，有效的喜树碱化疗需要长时间的静脉输注和长期持续的暴露。 我们的研究小组最近的研究，与他人合作，导致一类新的拓扑异构酶I抑制剂，茚并异喹啉的合成。酶抑制研究、人癌细胞培养物中的体外细胞毒性结果和体内动物研究的组合提供了令人信服的证据，表明茚并异喹啉将克服喜树碱的一些局限性。目前提出的研究计划的主要目标之一将是设计和合成更有效的茚并异喹啉作为拓扑异构酶I抑制剂，具有潜在的临床应用于治疗人类癌症。 可以假设，茚并异喹啉拓扑异构酶I抑制剂的功效可以通过利用参与稳定由DNA、酶和抑制剂形成的三元复合物的各种化学力而最大化。在三元复合物中负责药物与DNA碱基键合的力包括电荷转移复合物形成、静电吸引和伦敦分散力。除了这些力之外，三元复合物还通过茚并异喹啉与酶的一些附近氨基酸残基的氢键合而稳定。该研究项目的主要目标之一是利用我们对药物-酶-DNA三元复合物晶体结构的了解，最大限度地发挥新药分子阵列中的各种作用力。我们目前已经确定了从两个茚并异喹啉形成的复合物的晶体结构，我们希望通过未来的努力，更多的晶体结构将变得可用。茚并异喹啉的结构也将被操纵，以使它们靶向癌细胞，最大化有利的溶解性，并增加它们的生物利用度。 本研究中制备的新化合物将在许多生化和生物测定中进行评价。这些将包括拓扑异构酶I诱导的抑制剂存在下的DNA裂解模式的分析，三元复合物的稳定性分析，DNA解旋的研究，以检测嵌入，抑制拓扑异构酶I介导的DNA松弛，检测DNA链断裂的细胞系统中，喜树碱抗性突变细胞系的酶抑制活性的分析。将确定茚并异喹啉类化合物在癌细胞培养物中的细胞毒性，并将在各种动物模型系统中研究有希望的候选物的抗癌活性。将详细研究茚并异喹啉的作用机制，这些信息将用于最大限度地发挥其作为抗癌剂的治疗潜力。