New methods and approaches toward lead optimization and drug discovery

The generation of small-molecule libraries has become a major focus in the development of medicinal agents. Libraries of small molecules have been prepared both for the identification of lead compounds and for the optimization of lead compounds that have been identified through either library screening efforts or alternative methods. Small-molecule combinatorial libraries are based on common structural motifs or core structures. One previously explored approach toward the identification of new receptor agonists and antagonists has been to generate large collections or libraries of compounds based on "privileged structures". However, most privileged structure libraries have relied on the display of predominantly hydrocarbon functionality from the privileged scaffold. To achieve a higher level of success in identifying lead compounds, a strategy toward the rapid generation of highly functionalized compounds is desired. Chapter one discusses our efforts toward designing a synthetic strategy that would enable the display of high degree of functionality off of a rigid steroid scaffold through functional group orthogonal chemistry thereby obviating the need for protecting groups. Methodology to prepare this class of compounds employing chemoselective reactions such as Suzuki coupling, conjugated thiol addition and oxime formation was optimized and the generality was investigated. This type of strategy can be applied toward the synthesis of libraries where large numbers of highly functionalized compounds can be efficiently prepared.; Chapter two of this dissertation describes a novel approach toward the identification of lead compounds called "pharmacophore recombination". This strategy utilizes the principle of fragment assembly to pre-select binding pharmacophore fragments from a given library of "monomer units", followed by linking these binding monomers in a possible dimer combinations followed by a second screen to identify potent low molecular weight compounds. These pharmacophore units are tethered together through a chemoselective oxime linkage between an O,O'-diaminoalkanediol linker and aldehyde building blocks. The principle of pharmacophore recombination was demonstrated on two targets where low molecular weight small molecules were identified that blocked the protein-protein interactions of CD4/gp120 and Fc/Z-domain.; O-Alkyl oximes have become increasingly important in chemical biology and medicinal chemistry research. Chemoselective ligation to provide the oxime linkage is the key step in the synthesis of numerous semisynthetic biopolymers and biomolecules, and the O-alkyl oxime functionality is present in greater than 2300 drugs and drug candidates. The significance of the O-alkyl hydroxylamines is demonstrated in our own work described in the first two chapters. Thus, chapter three of this dissertation describes methodology toward the synthesis of alkoxylamines via alcohol aminations employing a new electrophilic aminating agent, 3,3'-di-tert-butyl oxaziridine. This practical, high-yielding, single-step procedure for the preparation of alkoxylamines illustrates the direct electrophilic amination of alkoxide nucleophiles. Because this reported method relies upon a completely different disconnection than prior methods, previously inaccessible alkoxylamines can now readily be prepared in high yields. We further report use of this method for the high-yielding, one-pot preparation of O-alkyl oximes from alcohols.