Marc Ilies, Ph.D.
3307 N. Broad Street
Philadelphia, PA 19140
office Room 517
phone (215) 707-1749
Research interests and current projects
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 (signals) collide at the level of membrane, remodeling both entities - the unit (cell) and the system (tissue, organ, or parent 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 combining medicinal chemistry, materials sciences and pharmaceutical sciences towards the design and development of novel chemical entities, concepts, methods and systems for assessing, controlling and correcting the status of this dual flux of information, aiming at both diagnostic and therapeutic applications. A recurrent theme of our research is exploiting the special properties of pyridinium salts for achieving these goals.
“Chemical solutions to delivery problems”
- Bio-organic and medicinal chemistry, chemical biology at membrane interfaces: selective enzyme inhibitors and activators, drug design, drug targeting/retargeting, cellular and molecular markers; imaging and early diagnostic compounds
- Pyridinium derivatives: synthesis, physicochemical, and biological properties;
- Materials sciences: synthesis, self-assembling, physicochemical and biological properties of amphiphilic molecules of different molecular weights and packing parameters: surfactants, gemini surfactants, lipophilic oligomeric surfactants, lipids, dendrons, polymers
- Drug and gene delivery systems with emphasis on synthetic interfacial manipulation for controlling main physicochemical and biological properties; nanotechnology.
In our medicinal chemistry concentration we are modulating the hydrophilic/lipophilic ballance of known pharmacophores in order to induce specific PK profiles and/or isozyme/receptor selectivity.
We are using pyridinium salts to design and synthesize membrane-impermeant compounds used as selective inhibitors and activators for membrane-bound proteins (e.g. carbonic anhydrases, matrix metalloproteinases).
We were successful in generating nanomolar-active carbonic anhydrase (CA) inhibitors and activators with selectivity against membrane-bound isozymes (some over-expressed in tumors). We are currently developing various classes of CA inhibitors and activators with isozyme selectivity for diagnostic/therapeutic (theranostic) purposes and for physiology studies.
Another direction involves the decoration of known pharmacophores with lipophilic moieties in order to allow their topical delivery or to induce isozyme selectivity and/or a specific PK profile.
We synthesized new antiglaucoma CA inhibitors, highly lipophilic CA inhibitors active at the level of the brain CA isozymes, as well as matrix metalloproteinase inhibitors with selectivity for the deep pocket izozymes.
K. Dave, A. Scozzafava, D. Vullo, C. T. Supuran and M. A. Ilies “Pyridinium derivatives of histamine are potent activators of cytosolic carbonic anhydrase isoforms I, II and VII: solution and crystallographic studies”, Org. Biomol. Chem., 9, 2790-2800 (2011).
K. Dave, M. A. Ilies, A. Scozzafava, C. Temperini, D. Vullo, C. T. Supuran “An inhibitor-like binding mode of a carbonic anhydrase activator within the active site of isoform II”, Bioorg. Med. Chem. Lett., 21, 2764-2768 (2011). (Cover article)
M.A. Ilies “Metal complexes as dual carbonic anhydrase inhibitors” in Drug Design of Zinc-Enzyme Inhibitors: Functional, Structural, and Disease Applications (Binghe Wang Series in Drug Discovery and Development), C. T. Supuran, J. Y. Winum Eds., Wiley, 2009, 439-472.
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. Campeanu, V. Cimpeanu, 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).
M. Ilies, M.D. Banciu, A. Scozzafava, M.A. Ilies, M.T. Caproiu, and C.T. Supuran, “Protease inhibitors: Synthesis of bacterial collagenase and matrix metalloproteinase inhibitors incorporating arylsulfonylureido and 5-dibenzo-suberenyl/suberyl moieties”, Bioorg. Med. Chem., 11, 2227-2239 (2003).
M. Ilies, M.D. Banciu, M.A. Ilies, A. Scozzafava, M.T. Caproiu and C.T. Supuran, “Carbonic anhydrase activators: Design of high affinity isozymes I, II and IV activators, incorporating tri-/tetrasubstituted-pyridinium-azole moieties”, J. Med. Chem., 45 (2), 504-510 (2002).
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).
In our materials sciences concentration we combine groups/moieties of extreme properties (e.g. highly polar pyridinium and non-polar moieties) in the design of various amphiphiles (pyridinium surfactants, gemini-, trimeric- and tetrameric surfactants, pyridinium lipids, dendrons, amphiphilic block copolymers, etc).
Their supra-molecular assemblies are exploited towards the design of novel drug and genetic material delivery systems, either alone or in combination with other amphiphiles.
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 (nanoparticles) generated from these amphiphilic building blocks.
V. D. Sharma, M. A. Ilies, "Heterocyclic Cationic Gemini Surfactants: A Comparative Overview of their Synthesis, Self-assembling, Physicochemical and Biological Properties", Medicinal Research Reviews, 2012, in press (published online doi: 10.1002/med.21272).
B. Tangeysh, M. Fryd, M. A. Ilies, B. B. Wayland, “Palladium Metal Nanoparticle Size Control through Ion Paired Structures of [PdCl4]-2 with Protonated PDMAEMA”, Chem. Commun. 48, 8955-8957 (2012).
X. Zhu, M. Fryd, B. D. Tran, M. A. Ilies, B. Wayland, “Modifying the Hydrophilic-Hydrophobic Interface of PEG-b-PCL to Increase Micelle Stability: Preparation of PEG-b-PBO-b-PCL Triblock Copolymers, Micelle Formation and Hydrolysis Kinetics”, Macromolecules, 45, 660-665 (2012).
M. A. Ilies, T. V. Sommers, L. C. He, A. Kizewski, V. D. Sharma “Pyridinium Amphiphiles in Gene Delivery - Present and Perspectives” in “Amphiphiles: Molecular Assembly and Applications”, R. Nagarajan Ed., ACS Books, 2011, 23-38.
V. V. Shuvaev, M. A. Ilies, E. Simone, S. Zaitsev, Y. Kim, S. Cai, A. Mahmud, T. Dziubla, S. Muro, D. E. Discher, V. R. Muzykantov “Endothelial targeting of antibody-decorated polymeric filomicelles”, ACS Nano, 5, 6991-6999 (2011).
S. Savarala, F. Monson, M. A. Ilies, S. L. Wunder, “Supported Lipid Bilayer Systems Stabilization by Undulatory-Protrusion Forces, and Destabilization by Lipid Bridging”, Langmuir, 27, 5850-5861 (2011).
S. Savarala, S. Ahmed, M. A. Ilies, S. L. Wunder “Stabilization of soft lipid colloids: competing effects of nanoparticle decoration and supported lipid bilayer formation”, ACS Nano, 5, 2619-2628 (2011).
A. T. Balaban, M. A. Ilies, A. Eichhofer, T. S. Balaban, “Molecular and crystal structure of a self-assembling pyridinium cationic lipid”, J. Mol. Struct., 984, 228-231 (2010).
S. Savarala, S. Ahmed, M. A. Ilies, S. L. Wunder, “Formation and Colloidal Stability of DMPC Supported Lipid Bilayers on SiO2 Nanobeads”, Langmuir, 26, 12081-12088 (2010).
V. Percec, M. Peterca, M.J. Sienkowska, M.A. Ilies, E. Aqad, J. Smidrkal, P.A. Heiney, “Synthesis and Retrostructural Analysis of Libraries of AB3 and Constitutional Isomeric AB2 Phenylpropyl Ether-Based Supramolecular Dendrimers”, J. Am. Chem. Soc., 128, 3324-3334 (2006).
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).
M.A. Ilies, W.A. Seitz, M.T. Caproiu, M. Wentz, R.E. Garfield and A.T. Balaban, “Pyridinium-Based Cationic Lipids as Gene Transfer Agents”, Eur. J. Org. Chem., 14, 2645-2655 (2003).
M.A. Ilies, W.A. Seitz and A.T. Balaban, “Cationic lipids in gene delivery: principles, vector design and therapeutical applications”, Curr. Pharm. Des., 8 (27), 2441-2473 (2002).
M.A. Ilies and A.T. Balaban, “Recent developments in cationic lipid-mediated gene delivery and gene therapy”, Expert Opin. Ther. Patents, 11 (11), 1729-1752 (2001).
This inter-disciplinary research combines concepts from medicinal chemistry, supra-molecular chemistry, physical chemistry and physical pharmacy, biochemistry and molecular biology to generate efficient entities for the detection and treatment of various forms of cancer and for other biological applications.