Design of Metallocene Complexes with Antitumor Properties

该研究旨在了解金属的结构-活性关系， 抗肿瘤剂。化疗是治疗这种危及生命的疾病和金属的替代方案之一 复合体在该领域具有重要作用。因此，长期目标是，利用结构-活性 关系，设计具有所需抗肿瘤活性的新型金属配合物，并了解其抗肿瘤活性。 分子水平的作用机制。研究主要集中在合成、化学和生物化学方面 官能化的环戊二烯（M = Ti（IV）， V（IV）和Mo（IV））衍生物。的 母体化合物Cp 2 TiCl 2对结肠直肠癌、肺癌和乳腺癌有活性，因此，新的 衍生物可能具有相似的抗肿瘤活性特征。然而，它们的活性将由平均值决定。 生物活性的研究。本课题的具体目标是：1）合成与表征 含有氨基酸的新的R-Cp 2 MX 2（M = Ti（IV）、V（IV）和Mo（IV），R =烷氧羰基）配合物， 亲水基团作为辅助配体。由于官能化Cp环赋予的水解稳定性， 和由亲水配体赋予的水溶性，预期这些络合物与 在生理条件下，同时保持作为pH值的函数的不稳定特性，能够释放 溶液中的金属离子2)配体水解（Cp和L）。这将通过UV-VIS和1H NMR进行监测 光谱学该目标提供了关于稳定性和分解的重要信息 这些复合物在水溶液中的模式。3)金属-生物分子（DNA、寡核苷酸、谷胱甘肽） 将进行相互作用研究，以深入了解作用机制、结合机制、 常数和结合特异性/选择性以及可能的转运和/或失活机制。四、 新的Ti（IV）、V（IV）和Mo（IV）络合物的生物筛选将在生物测试实验室进行， UPR-Mayaguez。筛选工作旨在发现Ti（IV）、V（IV）和Mo（IV）的络合物， 潜在的治疗用途。这一研究将为认识和理解这一现象提供有价值的信息。 抗肿瘤金属化合物构效关系同时也为合理设计 新的有机金属络合剂。

The proposed research is aimed at the understanding of the structure-activity relationship of metallic antitumor agents. Chemotherapy is one of the alternatives to treat this life-threatening disease and metal complexes have an important role in the area. Thus, the long term objective is, using the structure-activity relationship, to design novel metal complexes with the desired antitumor activity and to understand the mechanism of action at molecular levels. The study is focused on the synthesis, chemical and biochemical characterization and biological activity profile of functionalized Cyclopentadienyl metallocenes (M = Ti(IV), V(IV) and Mo(IV)) derivatives containing amino acids and hydrophilic groups as ancillary ligands. The parent compound, Cp2TiCI2 is active against colorectal, lung and breast carcinomas therefore, the new derivatives may have similar antitumor activity profile. However, their activity will be determined by mean of the biological activity study. The specific objectives of this project are: 1) Synthesis and characterization of new R-Cp2MX2 (M = Ti(IV), V(IV) and Mo(IV), R = carboalkoxy) complexes containing amino acids and hydrophilic groups as ancillary ligands. Due to the hydrolytic stability imparted by functionalized Cp ring and water solubility imparted by the hydrophilic ligands, these complexes are expected to be compatible to physiological conditions while retaining the labile character as function of pH, being able to release the metal ion in solution. 2) Ligand hydrolysis (Cp and L). This will be monitored by 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) Metal-Biomolecule (DNA, oligonucleotide, glutathione) interaction studies will be pursued in order to gain insights with regard to the mechanism of action, binding constants and binding specificity/selectivity and possible mechanism of transport and/or deactivation. 4) Biological screening of new Ti(IV), V(IV) and Mo(IV) complexes will be performed at the Biotesting Lab, UPR-Mayaguez. The screening efforts are intended to find Ti(IV), V(IV) and Mo(IV) complexes with potential therapeutic uses. This research will afford valuable information to the understanding of the structure-activity relationship of antitumor metallic species. Also it lays grounds for the rational design of new organometallic antineoplastic agents.