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）：本项目的重点是合成和研究合成载体，可用于介导阴离子和阴-阳离子对跨细胞膜的耦合流动。现在认识到，阴离子穿过细胞膜的受控运动是所有高等生物有机体无病生存的绝对要求。这些过程中的功能障碍与许多衰弱性疾病相关，其中囊性纤维化（CF）是最广泛认识的。因此，修复阴离子流的缺陷可以提供新的治疗方法。因此，我们建议，使小分子载体，可用于促进跨膜交换的Cl和HCO 3，进入细胞交付的Cl和Na，和控制出-+细胞出口的Cl-和K+。这些系统有望促进细胞凋亡，从而为癌症化疗提供新的途径。它们还提供了CF的解决方案，预计在适当的时候会产生安全有效的新型治疗方法。在实现这些目标方面已经取得了良好进展。例如，已经制备了杯芳烃冠醚-杯吡咯离子对受体，其在混合的水性-有机环境中结合KCl但排斥NaCl。该系统，而不是其对照，显示低微摩尔体外抗增殖活性对A549人肺癌细胞系。还制备了第一代吡啶二酰胺束缚的杯吡咯，其同样显示出对多种癌细胞系（包括A549细胞系）的低微摩尔抗增殖活性。这是第一个合成载体系统，其中氯离子转运和细胞凋亡活性之间的因果关系已被证明。这种吡啶二酰胺束缚的杯吡咯能够区分野生型和突变型囊性纤维化细胞系。因此，我们认为，我们现在处于有利地位，以实现我们的最终项目目标，开发新的治疗剂的基础上合成阴离子载体。考虑到这样的目标，我们设定了四个具体目标;这些目标简要地涉及：1）现有系统的合成优化，2）靶向离子对的新载体的制备，3）使用癌症和CF细胞系的功效的体外分析，以及4）最有希望的系统的体内研究（毒性和功效）。该项目将受益于与教授的合作。Philip A. Gale（运输研究）和Injae Shin（细胞研究）。的经验 共同PI，Alan Watts博士，在肺部疾病和动物研究管理领域被认为是一个额外的优势。