Design and development of a polyhedral borane drug delivery system for the small-molecule antimetabolite 5-fluorouracil

Abstract

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Polyhedral boranes represent a unique class of molecules that have been exploited for a variety of applications. Their unique bonding provides a novel scaffold for polyfunctionalized and dendrimer-like drug delivery vehicles. In particular, the closed-cage icosahedral closo-B12H122- has been the interest of extensive study and a multitude of applications. The 12-vertexes on the closo-B12H22- structure and its established chemistry for functionalization have allowed the development of more complex and higher molecular weight multimeric species. These 12-fold substituted polyhedral boranes, known as closomers, have been studied with respect to their chemistry and properties and are now being exploited for their use in medicinal applications. With the previously reported high-yielding synthesis of the perhydroxylated species [closo-B12(OH)12]2-, a plethora of complexes have been prepared through the exploitation of the similar reactivity of the B-OH and C-OH bond. Through the use of ester, ether, carbonate, carbamate, and Huisgen [3+2] dipolar cycloaddition reactions, a well-established library of closomers has been prepared and has established the chemistry needed for the development of medically applicable systems. The use of these established methods has been expanded upon herein to create vertex-differentiated and 12-fold homofunctionlaized closomer compounds. Furthermore, as a requisite to building higher-order closomers, an extensive library of heterofunctionalized poly(ethylene glycol) compounds have been prepared. In the work reported herein, the homo- and heterofunctionalization of closomers is discussed leading to the synthesis of a 12-fold 5-fluorouracil loaded and glucosamine targeted closomer drug delivery system.