I. Helical templating of oligopeptides by cyclodextrin-based receptors. II. Cracking the histone code: Oligopeptides as selective agents in histone deacetylase inhibition

Chapter 1. β-cyclodextrin-based receptors were synthesized and tested for their ability to induce a helical fold in peptides bearing hydrophobic amino acid residues in the i, i + 11 or i, i + 14 positions. Circular dichroism experiments revealed that a dimeric β-cyclodextrin receptor synthesized from a [1,1′-biphenyl]-4,4 ′-dithiol core demonstrated an ability to fold a designed peptide bearing the artificial amino acid L-p-t-butylphenylalanine in the i, i + 11 positions, while other dimeric and monomeric receptors failed to do so. Titration studies were performed using both circular dichroism and calorimetry, the analysis of which yielded an apparent K_a on the order of 104–105 M−1. However, no evidence could be obtained for helical folding with a peptide carrying tryptophan residues in place of the p-t-butylphenylalanine units. Our studies suggest that receptors of this type may be useful in molecular recognition of hydrophobic, already α-helical peptides in aqueous solution.; Chapter 2. Small-molecule inhibitors of human histone deacetylase (HDAC) enzymes were designed and synthesized. Using the lead cytodifferentiating agent suberoyl anilide hydroxamic acid (SAHA) as a template, efforts were undertaken to rigidify inhibitors via incorporation of phenyl units into the linkers. These compounds were indeed active, although of reduced potency relative to SAHA. Several non-hydroxamic acid based compounds were constructed, including an ortho-amino anilide compound, which was active at micromolar concentrations. These studies confirmed that hydroxamic acids were by far the most potent compounds studied.; Multiple techniques were developed to synthesize peptide-based hydroxamic acids. An orthogonally-protected building block proved to be the most versatile method for this purpose. A series of pentamers and nonamers corresponding to actual histone sequences was synthesized and evaluated for activity in both HDAC inhibition and cellular proliferation assays. These studies revealed that in some cases nonameric inhibitors demonstrated specificity for HDAC1/2, while pentameric inhibitors were more active and able to penetrate intact cells. An approach to evaluation of the “histone code” was developed, via efforts to incorporate other post-translational modifications into inhibitor sequences.