The structure and function of the cell are determined by its genetic information and are modulated by external stimuli. The chemically-mediated internal and external fluxes of information collide at the level of membrane, remodeling both entities – the unit (cell) and the system (organism). The dynamic equilibrium and its position are essential for both homeostasis and evolution; their dramatic shift is associated with diseases and death. We are interested in designing and developing new chemical entities, concepts, methods and systems to assess, control and correct the status of this dual flux of information with compounds/systems active at these boundaries, aiming at both diagnostic and therapeutic applications.

In our small molecule approach to chemical flux modulation across the membrane boundary we design and synthesize selective inhibitors and activators for membrane-bound proteins (e.g. carbonic anhydrases, matrix metalloproteinases) by embedding in their structure moieties that will dramatically affect their pharmacokinetics, making these compounds salt-like and therefore membrane-impermeant, or highly lipophilic. We were successful in generating nanomolar-active carbonic anhydrase (CA) inhibitors and activators with selectivity against membrane-bound isozymes (some over-expressed in tumors), as well as highly lipophilic CA inhibitors active at the level of the brain CA isozymes. We are currently developing various classes of CA inhibitors and activators with isozyme selectivity for diagnostic purposes as well as useful tools for physiology studies.

Selective publications
M.A. Ilies and M.D. Banciu, “Non-sulfonamide carbonic anhydrase inhibitors” in “Carbonic Anhydrase, Its Inhibitors and Activators”, C.T. Supuran, A. Scozzafava, J. Conway Eds., CRC Press, Boca Raton, 2004, pp. 207-239.

M.A. Ilies, B. Masereel, S. Rolin, A. Scozzafava, G. Câmpeanu, V. Cîmpeanu, C.T. Supuran, “Carbonic anhydrase inhibitors: Aromatic and heterocyclic sulfonamides incorporating adamantyl moieties with strong anticonvulsant activity”, Bioorg. Med. Chem., 12, 2717-2726 (2004)

M.A. Ilies, D. Vullo, J. Pastorek, A. Scozzafava, M. Ilies, M.T. Caproiu, S. Pastorekova and C.T. Supuran, “Carbonic anhydrase inhibitors. Inhibition of tumor-associated isozyme IX by halogenosulfanilamide and halogeno-aminobenzolamide derivatives”, J. Med. Chem., 46, 2187-2196 (2003).

A. Scozzafava, F. Briganti, M.A. Ilies, C.T. Supuran, “Carbonic anhydrase inhibitors: Synthesis of membrane-impermeant low molecular weight sulfonamides possessing in vivo selectivity for the membrane-bound versus the cytosolic isozymes”, J. Med. Chem, 43, 292-300 (2000).

A second research direction of our group involves a supra-molecular approach to modulate the chemical flux of material/information across external and internal cell boundaries. We combine groups/moieties of extreme properties (e.g. highly polar and non-polar moieties) in the design of various amphiphiles (lipids, amphiphilic block copolymers, etc) used for drug and gene (DNA, siRNA, oligonucleotides) delivery systems. Besides the synthetic effort, our group is actively involved in the formulation, characterization (size, shape, zeta potential, etc) and biological evaluation (drug delivery, transfection) of self-assembled systems generated from these amphiphilic building blocks. This inter-disciplinary research combines medicinal chemistry, supra-molecular chemistry, physical chemistry and physical pharmacy, biochemistry and molecular biology to generate efficient, biologically-active nanoparticles for treatment of various forms of cancer.

Selective publications
M.A. Ilies, W.A. Seitz, B.H. Johnson, E.L. Ezell, A.L. Miller, E.B. Thompson, A.T. Balaban, “Lipophilic Pyrylium Salts in the Synthesis of Efficient Pyridinium-Based Cationic Lipids, Gemini Surfactants, and Lipophilic Oligomers for Gene Delivery”, J. Med. Chem., 49, 3872-3887 (2006).

M.A. Ilies, B.H. Johnson, F. Makori, A. Miller, W.A. Seitz, E.B. Thompson, A.T. Balaban, “Pyridinium cationic lipids in gene delivery: An in vitro and in vivo comparison of transfection efficiency versus a tetraalkylammonium congener”, Arch. Biochem. Biophys., 435, 217-226 (2005).

M.A. Ilies, W.A. Seitz, I. Ghiviriga, B.H. Johnson, A. Miller, E.B. Thompson, A.T. Balaban, “Pyridinium cationic lipids in gene delivery: a structure-activity correlation study”, J. Med. Chem., 47, 3744-3754 (2004).