Receptor and Carriers for Coupled Ion Transport

耦合离子传输的受体和载体

• 批准号: 9030218
• 负责人: Jonathan L Sessler
• 金额: $ 29.82万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-10 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9030218
• 关键词: A549; Address; Animals; Anions; Antineoplastic Agents; Apoptosis; Area; Bicarbonates; Binding; Biological; Cancer cell line; Cations; Cell Death; Cell Line; Cells; Cellular Membrane; Chemotherapy-Oncologic Procedure; Chloride Ion; Chloride-Bicarbonate Antiporters; Chlorides; Collaborations; Coupled; Crown Ethers; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; DNA Sequence Alteration; Data; Diamide; Disease; Disease Management; Disease-Free Survival; Dose; Drug Kinetics; Electrophysiology (science); Environment; Epithelial Cells; Female; Formulation; Functional disorder; Gadolinium; Generations; Goals; Hand; Health; Hela Cells; HepG2; Hereditary Disease; Human; In Vitro; Injection of therapeutic agent; International; Ion Channel; Ion Transport; Ions; Lead; Link; Liposomes; Lung diseases; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Membrane; Mind; Modeling; Monitor; Movement; Mus; Necrosis; New Agents; Nose; Oral; Organism; PC3 cell line; Play; Positioning Attribute; Potassium; Potassium Chloride; Preparation; Process; Prodigiosin; Property; Role; System; Testing; Texaphyrin; Therapeutic Agents; Thinking; Toxic effect; Transmembrane Transport; Variant; Work; Xenograft Model; aqueous; base; cancer cell; cell transformation; design; drug development; effective therapy; experience; follow-up; gadolinium oxide; improved; in vitro activity; in vitro testing; in vivo; membrane model; mutant; novel; novel strategies; novel therapeutics; potency testing; protein aminoacid sequence; pyridine; receptor; repaired; research clinical testing; small molecule; symporter; systemic toxicity; trait; tumor; tumor xenograft

 DESCRIPTION (provided by applicant): This project is focused on the synthesis and study of synthetic carriers that can be used to mediate the coupled flow of anions and anion-cation ion pairs across cellular membranes. It is now appreciated that the controlled movement of anions across cellular membranes is an absolute requirement for the disease-free survival of all higher biological organisms. Malfunctions in these processes are correlated with a number of debilitating disorders, of which cystic fibrosis (CF) is the most widely recognized. Repairing deficiencies in anion flow could thus provide new treatments. We thus propose to make small molecule carriers that can be used to promote the trans-membrane exchange of Cl and HCO3 , the into-cell delivery of Cl and Na , and the controlled out-of- -- -+ cell egress of Cl- and K+. These systems are expected to promote apoptosis and thus provide a new approach to cancer chemotherapy. They also offer a solution to CF that in due course is expected to give rise to novel treatments that are safe and effective. Good progress has already been made towards realizing these objectives. For instance, a calixarene crown ether-calixpyrrole ion pair receptor has been prepared that binds KCl but rejects NaCl in mixed aqueous- organic environments. This system, but not its controls, displays low micromolar antiproliferative activity in vitro agaist the A549 human lung cancer cell line. A first generation pyridine diamide strapped calixpyrrole has also been prepared that likewise shows low micromolar antiproliferative activity against a variety of cancer cell lines, including the A549 cell line. This is the first synthetic carrier sysem for which a causal link between chloride transport and apoptosis activity has been demonstrated. This pyridine diamide strapped calixpyrrole is able to differentiate between wild type and mutant cystic fibrosis cell lines. We thus feel we are now well positioned to attain our ultimate project goals of developing new therapeutic agents based on synthetic anion carriers. With such an objective in mind, we have set four specific aims; these involve briefly: 1) The synthetic optimization of existing systems, 2) the preparation of new carriers for targeted pairs o ions, 3) in vitro analyses of efficacy using both cancer and CF cell lines, and 4) in vivo studies (toxicity and efficacy) of the most promising systems. This project will benefit from collaboration with Profs. Philip A. Gale (transport studies) and Injae Shin (cell studies). The experience of the co-PI, Dr. Alan Watts, in the area of pulmonary disease and the management of animal studies is considered to be an additional strength.

 描述（由申请人提供）：该项目专注于可用于介导阴离子和阴离子-阳离子对穿过细胞膜的耦合流动的合成载体的合成和研究。现在人们认识到阴离子穿过细胞膜的受控运动。细胞膜是所有高等生物有机体无病生存的绝对必要条件。这些过程的故障与许多使人衰弱的疾病相关，其中囊性纤维化（CF）是最广泛认识的。因此，阴离子流的缺陷可以提供新的治疗方法，因此我们建议制造可用于促进 Cl 和 HCO3 的跨膜交换、Cl 和 Na 的细胞内输送以及受控的流出的小分子载体。 - -- -+ 细胞的 Cl- 和 K+ 排出预计会促进细胞凋亡，从而提供一种新的癌症化疗方法，预计在适当的时候会产生新的治疗方法。很安全例如，已制备出杯芳烃冠醚-杯吡咯离子对受体，该受体在混合水-有机环境中结合 KCl，但排斥 NaCl，但其对照则不然。体外对 A549 人肺癌细胞系表现出低微摩尔抗增殖活性 还制备了第一代吡啶二酰胺束缚的杯吡咯，其同样表现出低微摩尔活性。对多种癌细胞系（包括 A549 细胞系）具有抗增殖活性。这是第一个已证明氯离子转运与细胞凋亡活性之间存在因果关系的合成载体系统，能够区分野生型。因此，我们认为我们现在已经准备好实现基于合成阴离子载体开发新治疗剂的最终项目目标，我们设定了四个目标。具体目标；这些简要涉及：1）现有系统的综合优化，2）为目标离子对制备新载体，3）使用癌症和CF细胞系进行体外功效分析，以及4）体内研究（毒性和功效）最有前途的系统将受益于与 Philip A. Gale 教授（运输研究）和 Injae Shin（细胞研究）的合作。 联合首席研究员 Alan Watts 博士在肺部疾病和动物研究管理领域被认为是额外的优势。