STRUCTURAL ANALYSIS AND SYNTHETIC PROGRESS TOWARDS SMALL MOLECULES AS MODULATORS OF ANGIOGENESIS AT THE CELLULAR AND TRANSCRIPTIONAL LEVELS

Abstract

Progress towards the design and the application of small molecules as inhibitors of angiogenesis is reported. First, the regulation of hypoxia inducible transcription with epipolythiodioxopiperazine (ETP) natural products is discussed, beginning with the exploration of the physical and chemical properties of ETP skeletal analogs, xylylene-linked bis-diketopiperazines (1,4-piperazine-2,5-diones, DKPs).The design, synthesis and solid-state structures of a new class of xylylene-linked bis(1,4-piperazine-2,5-diones) are reported in an effort to extend the molecular framework of piperazine-2,5-diones. These compounds were derived from piperazine-2,5-dione as the core structure, synthesized via a new efficient route, and their crystal structures were determined. We examined the effects of side chain substitution on conformations of the linked bis-DKPs in the solid state. The results suggested that the interplay between the attractive intermolecular interactions and repulsive steric interactions of the substituents at the C6 and C6' positions of the diketopiperazine rings is important in determining the solid-state conformations of xylylene-linked bis(piperazine-2,5-diones).Asymmetric alpha-sulfenylation reactions were designed and performed as a potential route to the synthesis of epipolythiodioxopiperazine natural products. First, a chiral auxiliary approach is reported, sulfenylating chiral azomethines of alpha-amino acids as epipolythiodiketopiperazine precursors in yields of 55% with de as high as 74%. Asymmetric organocatalytic alpha-sulfenylation of substituted piperazine-2,5-diones is also reported, with chiral cinchona alkaloids as bases and benzyl-substituted electrophilic sulfur transfer reagents. The reaction was investigated with varied catalyst loading, type of sulfenylating agent, temperature and solvent. The effects of ring substitution and type of catalyst on yield and enantioselectivity of the reaction are reported. The synthetic utility of the asymmetric alpha-sulfenylation in context of the synthesis of epipolythiodioxopiperazine fungal metabolites is discussed.Finally, chemical approach towards the inhibition of angiogenesis by targeting alpha v beta 3 integrin antagonists with synthetic multifunctional boron neutron capture therapy (BNCT) integrin ligands is presented. The novel synthesis of an alpha v beta 3 integrin antagonist containing a free amine group for peripheral modification is reported, along with the preparation of a bifunctional BNCT integrin ligand and a trifunctional BNCT integrin ligand containing a fluorescent dye. Synthetic challenges and potential therapeutic applications of these ligands are discussed.