Studies and synthetic methodology of Nampt inhibition

Abstract

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] The purpose of this research is to study and synthesize an array of a highly potent pharmaceuticals that can selectively cause apoptosis in various cancer cells and to synthesize click chemistry components to be used in drug delivery systems. Utilizing hydrophobic properties of carboranes, an array of drug derivatives were synthesized as potential Nampt inhibitors. These drugs selectively bind to nicotinamide Phosphoribosyl transferase (Nampt), preventing cancer cells from replenishing nicotinamide adenine dinucleotide (NAD) through the salvage pathway which leads to apoptosis. The association constants of unsubstituted o-, m-, and p-carborane, adamantane, and their derivatives with [beta]-cyclodextrin ([beta]-CD) are reported for the first time using displacement binding in an aqueous solution. Although hydrophobicity plays a major role in the association with [beta]-CD, unsubstituted o-carborane which is the least hydrophobic carborane derivative, exhibits the highest Ka' of 2690 M[subscript -1]. The Ka' values for the m-, and p-carborane isomers decrease with decreasing dipole moment (1830 M-1 and 1560 M[subscript -1] respectively). Adamantane exhibits a Ka' value lower than each of the three carborane isomers at 1410 M[subscript -1]. These studies indicate that cyclodextrin inclusion complexes could be well suited as a drug delivery vehicle for our carborane containing drug derivatives. Click chemistry linkers functionalized with azide or alkyne functional groups were synthesized for use in a peptide drug conjugate. These linkers also utilized an amine reactive functional group to allow for reaction with amines found in peptides.