SYNTHESIS/KINETICS/DNA METAL INTERACTION AND BIOLOGICAL ACTIVITY OF TITANOCENE

二茂钛的合成/动力学/DNA 金属相互作用和生物活性

• 批准号: 6107150
• 负责人: ENRIQUE MELENDEX
• 金额: $ 5.66万
• 依托单位: UNIVERSITY OF PUERTO RICO MAYAGUEZ
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-01 至 2000-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6107150
• 关键词: 6 thioguanine; X ray crystallography; allopurinol; animal genetic material tag; antineoplastics; chemical substitution; cytosine analog; drug design /synthesis /production; drug screening /evaluation; electron spin resonance spectroscopy; fluorouracil; metal complex; nuclear magnetic resonance spectroscopy; organometallic compounds; pharmacokinetics; polynucleotides; synthetic nucleic acid; thermodynamics; thiouracil; titanium; ultraviolet spectrometry

The proposed research is aimed at the understanding of the structure- activity relationship of metallocene anti-tumor agents The long term objective is using the structure-activity relationship, to synthesize active ligands (L). The initial study is focused on the synthesis, physico-chemical characterization and biological activity profile of CP2TiCIL and CP2TiL2 derivatives containing antimetabolites as ligands. The parent compound CP2TiCI2 is active against colorectal, lung and beast carcinomas therefore, the new derivatives may have similar have similar anti-tumor activity. However, their activity will be determined by mean of the biological activity study. The specific objectives of this study are: 1) Synthesis and characterization of new titanocene complexes containing modified DNA and RNA bases. This will be accomplished by replacing CI- for 6-thioguanine, 6-thiopurine, 2- thuouracil, 2-thiocytosine, allopurinol and 5-fluorouracil as ligands. Due to synergism, the proposed complexes are expected to be highly active anti-tumor agents, since they contain two antitumor agents in one unit compound. 2) Kinetics of ligand hydrolysis (CP and L). This will be monitored by conductance measurements and UV-VIS and 1H NMR spectroscopies. This objective provides vital information regarding to the stability and decomposition pattern of these complexes in aqueous solution. 3) DNA-Metallocene interaction studies will be pursued in order to gain insights with regard to the mechanism of action, binding constants and related thermodynamic parameters. The purpose of this drug binding study is to determine the affinity of the new synthesized complexes to DNA and to explore how this affinity changes as we change the structure (ligands) of the complexes. 4) Biological screening of new titanocene complexes. Biological screening of new synthesized titanocene complexes will be performed at the National Cancer Institute. The screening efforts are intended to find titanocene complexes with potential therapeutic uses. This research will afford valuable information to the understanding of chemical for the rational design of new organometallic antineoplastic agents. This proposal was originally submitted a part of the MBRS program at the InterAmerican University of Puerto Rico but the PI was relocated to UPRM.

本研究旨在了解茂金属抗肿瘤剂的构效关系，长期目标是利用构效关系合成活性配体（L）。 初步研究重点是含有抗代谢物作为配体的 CP2TiCIL 和 CP2TiL2 衍生物的合成、物理化学表征和生物活性概况。母体化合物CP2TiCl2具有抗结直肠癌、肺癌和兽癌活性，因此新衍生物可能具有类似的抗肿瘤活性。然而，它们的活性将通过生物活性研究来确定。本研究的具体目标是： 1) 含有修饰的 DNA 和 RNA 碱基的新型二茂钛复合物的合成和表征。这将通过将 CI- 替换为 6-硫鸟嘌呤、6-硫嘌呤、2-硫尿嘧啶、2-硫胞嘧啶、别嘌呤醇和 5-氟尿嘧啶作为配体来实现。由于协同作用，所提出的复合物有望成为高活性的抗肿瘤剂，因为它们在一个单元化合物中含有两种抗肿瘤剂。 2) 配体水解动力学（CP 和 L）。这将通过电导测量以及 UV-VIS 和 1H NMR 光谱进行监测。该目标提供了有关这些复合物在水溶液中的稳定性和分解模式的重要信息。 3) 将进行DNA-茂金属相互作用研究，以获得有关作用机制、结合常数和相关热力学参数的见解。这项药物结合研究的目的是确定新合成的复合物与 DNA 的亲和力，并探索当我们改变复合物的结构（配体）时这种亲和力如何变化。 4)新型二茂钛配合物的生物学筛选。新合成的二茂钛复合物的生物学筛选将在国家癌症研究所进行。筛选工作旨在寻找具有潜在治疗用途的二茂钛配合物。这项研究将为理解化学、合理设计新型有机金属抗肿瘤药物提供有价值的信息。该提案最初是作为波多黎各美洲大学 MBRS 项目的一部分提交的，但 PI 被转移到 UPRM。