Design of Metallocene Complexes with Antitumor Properties

拟议的研究旨在了解金属的结构-活性关系。 抗肿瘤药物。化疗是治疗这种危及生命的疾病和金属的替代方法之一。 建筑群在该地区发挥着重要作用。因此，长期目标是，使用结构-活动 关系，设计具有预期抗肿瘤活性的新型金属配合物，并了解 分子水平上的作用机制。重点研究了该化合物的合成、化学和生物化学。 官能化环戊二烯基茂金属化合物(M=Ti(IV)， V(IV)和Mo(IV))衍生物，含有氨基酸和亲水性基团作为辅助配体。这个 母体化合物Cp2TiCl2对结直肠癌、肺癌和乳腺癌具有活性，因此，新的 衍生物可能具有类似的抗肿瘤活性。然而，他们的活动将由手段决定 生物活性研究的一部分。本项目的具体目标是：1)合成和表征 新的含氨基酸的R-Cp2MX2(M=Ti(IV)，V(IV)和Mo(IV)，R=碳烷氧基)配合物 作为辅助配体的亲水性基团。由于官能化CP环所赋予的水解性 和亲水配体赋予的水溶解性，这些配合物有望与 生理条件，同时保持不稳定的性质作为pH的函数，能够释放 溶液中的金属离子。2)配基水解(CP和L)。这将通过UV-Vis和1H核磁共振进行监测 分光镜。这一目标提供了关于稳定性和分解的重要信息 这些络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) 将继续进行相互作用研究，以获得关于作用、约束的机制的见解 常数和结合的特异性/选择性以及运输和/或失活的可能机制。4) 新的钛(IV)、钒(IV)和钼(IV)配合物的生物筛选将在生物测试实验室进行， UPR-Mayaguez。筛选工作旨在寻找钛(IV)、V(IV)和Mo(IV)的配合物 潜在的治疗用途。这项研究将为我们理解和理解这一现象提供宝贵的信息。 抗肿瘤金属物种的构效关系。同时也为合理的设计奠定了基础。 新型有机金属抗肿瘤药物。

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.