Development of cancer targeted Nampt inhibitors
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The purpose of this research is the discovery of a highly potent pharmaceutical that can selectively cause apoptosis in various cancer cells. To utilize hydrophobic properties of carboranes, 1,7-dicarba-closo-dodecaborane (m-CB) has been selected as a template to synthesize new targeted antitumor agent. These drugs selectively bind to nicotinamide phosphoribosyltransferase (Nampt), preventing cancer cells from replenishing nicotinamide adenine dinucleotide (NAD+) through their recycle pathway, leading to apoptosis. Previously, our group reported a family of potent small molecule inhibitors of Nampt. Herein an improved, gram-scale synthesis of our most potent agent: 1-(4'-(trans-3''-(3'''-pyridyl) acrylamide)butyl)-1,7-dicarba-closo-dodecaborane (MC4-PPEA), as well as several other derivatives is reported. Additionally, the carborane moiety of the molecule has been modified with a hydroxymethyl functional group to allow for its covalent attachment to targeted prodrugs. This new molecule exhibits nanomolar potencies against human breast cancer cell lines in vitro. In this dissertation, several linker models capable of reacting with drug molecules containing primary alcohols are also proposed. These molecules are covalently linked through different hydrolytically or enzymatically cleavable moieties, each bearing an azide at its distal end. Using click chemistry, these prodrugs can be readily attached to protein or peptide targeting vectors, imaging agents, or other therapeutic delivery vehicles in high yield. The association constants (Ka') 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. The limitations of this technique are also explored. 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-1. The Ka' values for the m-, and p-carborane isomers decrease with decreasing dipole moment (1830 M-1 and 1560 M-1 respectively). Adamantane exhibits a Ka' value lower than each of the three carborane isomers at 1410 M-1. Our carborane containing drug MC4-PPEA exhibited Ka' of 2606 M-1 which could lead to the possible use of beta-CDs as delivery vehicles for our CB containing drugs.