The ability to synthesize molecules is of fundamental importance and at the core of advances in every technological field. We seek to advance the synthetic art and to solve chemical problems in areas such as materials science and biology. Current focus areas include:

Engineering organic crystals. Non-covalent interactions govern intermolecular contacts, which are of universal importance in chemistry, materials science, and biology. Using a family of piperazinedione-containing molecules, we have demonstrated that the three-dimensional order of an organic crystal can be controlled by incorporation of three linearly independent molecular recognition elements (Figure 1). In this way we have produced bulk materials (e.g., compound 1) that exhibit useful liquid crystal properties. We have also designed and synthesized piperazinedione-containing molecules that exhibit non-linear optical properties (e.g., compound 2). We are currently examining the effects of larger dipoles and alterations of molecular topography on crystal packing and bulk properties.

Figure 1. Design of a piperazinedione for liquid crystal applications.

Development of Multivalent Ligand Constructs. In collaboration with Drs. Robert Gillies and Victor Hruby, we are developing multivalent ligand constructs, which will find application in cancer imaging and therapy. We have to date synthesized dimeric constructs of variants of melanocyte stimulating hormone (MSH), including compounds 3-5. Presently we are preparing constructs with higher multimerization.

• L. J. Williams, B. Jagadish, R. A. Kloster, S. R. Lyon, M. D. Carducci, and E. A. Mash, "Organic Crystal Engineering with Piperazine-2,5-diones. 1. Crystal Packing of Piperazinediones Derived from Substituted 2-Aminoindan-2-carboxylic Acids," Tetrahedron 1999, 55, 14281-14300.

• L. J. Williams, B. Jagadish, M. G. Lansdown, M. D. Carducci, and E. A. Mash, "Organic Crystal Engineering with Piperazine-2,5-diones. 2. Crystal Packing of Weakly Dipolar Piperazinediones Derived from 2-Amino-4-bromo-7-methoxyindan-2-carboxylic Acid," Tetrahedron 1999, 55, 14301-14322.

• B. Jagadish, L. J. Williams, M. D. Carducci, C. Bosshard, and E. A. Mash, "The Crystal Packing of a Strongly Dipolar Piperazinedione," Tetrahedron Lett. 2000, 41, 9483-9487.

• B. Jagadish, M. D. Carducci, C. Bosshard, P. Günter, J. I. Margolis, L. J. Williams, and E. A. Mash, "Organic Crystal Engineering with Piperazine-2,5-diones. 4. Crystal Packing of Piperazinediones Derived from 2-Amino-7-cyano-4-methoxyindan-2-carboxylic Acid," Crystal Growth & Design 2003, 3, 811-821.

• R. A. Kloster, M. D. Carducci, and E. A. Mash, "Crystal Engineering of a Liquid Crystalline Piperazinedione," Org. Lett. 2003, 5, 3683-3686.

• R. A. Weatherhead-Kloster, H. D. Selby, W. B. Miller III, and E. A. Mash, "Organic Crystal Engineering with 1,4-Piperazine-2,5-diones. 6. Studies of the Hydrogen Bond Association of Cyclo[(2-Methylamino-4,7-dimethoxyindan-2-carboxylic Acid)(2-Amino-4,7-dimethoxyindan-2-carboxylic Acid)]," J. Org. Chem. 2005, 70, 8693-8702.

• H. L. Handl, J. Vagner, H. Han, E. Mash, V. J. Hruby, R. J. Gillies, "Hitting Multiple Targets with Multimeric Ligands," Expert Opinion on Therapeutic Targets 2004, 8, 565-586.

• Y. Monguchi, J. Vagner, H. L. Handl, U. Jana, L. J. Begay, V. J. Hruby, R. J. Gillies, and E. A. Mash, "Design, Synthesis, and Validation of Rigid Linkers for Bioactive Peptides," Tetrahedron Lett. 2005, 46, 7589-7592.

• J. Vagner, H. L. Handl, Y. Monguchi, U. Jana, L. J. Begay, E. A. Mash, V. J. Hruby, R. J. Gillies, "Rigid Linkers for Bioactive Peptides," Bioconjugate Chem. 2006, 17, 1545-1550.

• M. E. Bowen, Y. Monguchi, R. Sankaranarayanan, J. Vagner, L. J. Begay, L. Xu, B. Jagadish, V. J. Hruby, R. J. Gillies, and E. A. Mash, "Design, Synthesis, and Validation of a Branched Flexible Linker for Bioactive Peptides," J. Org. Chem. 2007, 72, 1675-1680.

• B. Jagadish, R. Sankaranarayanan, L. Xu, R. Richards, J. Vagner, V. J. Hruby, R. J. Gillies, and E. A. Mash, "Squalene-derived Flexible Linkers for Bioactive Peptides," Bioorg. Med. Chem. Lett. 2007, 17, 3310-3313.

• H. L. Handl, R. Sankaranarayanan, J. S. Josan, J. Vagner, E. A. Mash, R. J. Gillies, and V. J. Hruby, "Synthesis and Evaluation of Bivalent NDP-α-MSH(7) Peptide Ligands for Binding to the Human Melanocortin Receptor 4 (hMC4R)," Bioconjugate Chem. 2007, 18, 1101-1109.