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.
This project involves the synthesis and study of small molecules that can be used to carry pairs of ions into and out of cells. In due course, this work is expected to produce inherently safe and effective treatments for cystic fibrosis and other anion transport diseases. It also provides a new approach to cancer drug development.
