Abstract Anginex, a synthetic 33mer β-sheet-forming peptide, is a potent inhibitor of angiogenesis in vitro and in vivo. Previous studies demonstrate that Anginex, through binding to one of the hydrophobic faces of human galectin-1 (hGal-1), prevents endothelial cell adhesion to the extracellular matrix, induces apoptosis in angiogenically-activated endothelial cells (ECs), and suppresses tumor growth in animal models. Since small molecules have several pharmacologic advantages over therapeutic peptides, we sought to design a small molecule peptidomimetic of anginex. Calix[4]arene was chosen as the basic scaffold to mimic the approximate molecular dimensions, amphipathicity, and cationic topology of Anginex. Chemical modification of the hydrophobic (upper rim) and hydrophilic (lower rim) faces of calix[4]arene resulted in the discovery of a lead compound, 0118, possessing in vitro and in vivo activities similar to that of anginex. These studies reveal that small hydrophobic groups on the upper rim and dimethylaminoethylacetamide (DMAEA) moieties on the lower rim of 0118 are important for its biologic activity. Until now, structure-activity relationship (SAR) development of calixarene has focused on modifications of its hydrophobic and hydrophilic surfaces. Since the hGal-1-Anginex binding site is a hydrophobic surface, we hypothesize that a larger hydrophobic calixarene surface area will translate into enhanced bioactivity. We have chosen calix[6]arene and tetrathiacalix[4]arene as tools to explore the core-expanded SAR of our lead compound. A calix[6]arene analog of 0118 not only has a larger hydrophobic footprint, but also a greater intra-annular topoisomerization rate which should allow for greater conformational space sampling and, therefore, better inducible fit within its molecular receptor. The tetrathiacalix[4]arene derivative, with its longer C-S bonds (relative to the methylene bonds of calix[4]arene and calix[6]arene), should allow for a hydrophobic footprint larger than the parent 0118 but smaller than that of the calix[6]arene analog. The current studies focus on the synthesis and biologic activity of these 0118 core-expanded derivatives. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A141.