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Vladimir Sidorov

Assistant professor Organic chemistry (804) 828-7507 vasidorov@vcu.edu

Education

M.S., Magna Cum Laude, Kazan State University, 1993
Ph.D., Prague Institute of Chemical Technology, 1998
Postdoctoral scholar, Georgetown University 1998-1999
University of Maryland, College Park, 1999-2002
Research Chemist, University of California, San Francisco 2002-2003

Research Interests

Active Delivery of Substrates by Ditopic Ligands.

The idea of active substrate transport into the cytosol utilizes the K+/Na+ transmembrane gradient maintained in living cells. We are working on the synthesis and study of a series of ditopic ligands that are able to bind a target substrate and Na+ cooperatively. The complexes formed from a ligand, Na+ and a substrate will be able to diffuse through the cell membrane and fall apart in the cytosol upon interaction with intracellular K+, thus releasing a target substrate. A substrate-free ligand will then diffuse back into extracellular medium, where it will rebind Na+ and another substrate molecule. In this way the transport becomes a part of the K+/Na+ ATPase rectification cycle and mimics such naturally occurring process as Na+-glucose cotransport. As the transport driving force is the Na+/K+ gradient across the membrane, significant quantities of the substrate can be accumulated in the cell cytosol (inwardly directed drug pump) compared to passive diffusion. Whereas passive diffusion, whether mediated or not, ultimately equilibrates the intracellular and extracellular concentrations of a substrate, active transport can provide significantly higher intracellular over extracellular concentrations. As the result, lower doses of a drug could be administered in the presence of an active delivery system. Active drug delivery has also promise in combatting certain multidrug-resistant tumors. This multidrug resistance (MDR) is due to the rectifying function of overexpressed P glycoprotein (PgP). PgP acts in cells as an outwardly directed non-specific pump that transports substances out of cytosol faster than they can diffuse in. Our ditopic ligands may help overcoming this problem by accelerating the inwardly directed transport of a drug to the rate that is higher than the rate of outwardly directed transport maintained by PgP. Our target substrates cover a wide class of organic and inorganic compounds, ranging from simple anions such as chloride to complex anticancer chemotherapeutics such as doxorubicin.

Nanodevices based on triggerable liposomes

We are developing several systems that can serve as nanoreactors or vessels for the targeted drug delivery. Liposomes, the spherical assemblies of lipids of submicron size have a confined aqueous interior separated from the bulk solution by a bilayer membrane. This aqueous interior can be utilized as a vessel for a drug or as a space for the reaction sensitive to the environment. The challenging task however is to trigger the release of the drug at a desired time or to initiate the reaction. We are using the low molecular weight ionophores as external stimuli for such purposes. When applied to liposomal systems, these ionophores change the ionic compositions inside the liposomes causing the change in intravesicular pH or transmembrane potential. This initial change is followed by a cascade of events promoted by other system components resulting in a controlled burst of liposomes, or their controlled fusion or initiation of enzymatic reaction within liposomal interior.

Functional receptors for biomembrane assays

The last two decades were characterized by an increasing interest in synthetic membrane-active compounds exhibiting pharmacological properties through the function more typical for natural proteins and peptides. Thus, the synthetic ionophores have shown activity against vancomycin-resistant bacteria and found applications as artificial enzymes, therapeutics for genetic diseases and biological sensors. Likewise, many common drugs, in particular local anesthetics, interact with cell membranes similarly to the membrane-attached proteins, causing endocytosis, changes in shape, affecting membrane fluidity and occasionally causing membrane disruption. Therefore, development of methods allowing a rapid assessment of the membrane activity of new compounds under near physiological conditions in model membranes (liposomes) becomes a crucial part of the ongoing research. This project addresses the need for the development of functional receptors capable of strong binding of anionic water-soluble fluorescent dyes under near-physiological conditions. These receptors interact with the dye only under specific conditions across lipid bilayers and therefore allow the detection and monitoring of events in biological membranes.

In our team, we are working in a highly interdisciplinary environment. The individual projects cover a wide variety of disciplines and methods of study, ranging from wet organic synthesis to state-of-the-art electrophysiological assays. Our students have an opportunity to learn numerous spectroscopical techniques applicable to all aspects of modern chemistry. Students (graduate and undergraduate) interested in work in our group are always welcome to contact me by e-mail or in person.

Selected Publications

1. C.A. Winschel, A. Kalidindi, I. Zgani, J.L. Magruder, V. Sidorov. Receptor for Anionic Pyrene Derivatives Provides the Basis for New Biomembrane Assays. J. Am. Chem. Soc. 2005, 127, 14704-14713

2. F.W. Kotch, V. Sidorov, Y-F. Lam, K.J. Kayser, M. Koucher, J.T. Davis. Water-Mediated Association Provides an Ion Pair Receptor. J. Am. Chem. Soc. 2003, 125, 15140-15150.

3. V. Sidorov, F.W. Kotch, J.L. Kuebler, Y-F. Lam, J.T. Davis. Chloride Transport Across Lipid Bilayers and Transmembrane Potential Induction by an Oligophenoxyacetamide. J. Am. Chem. Soc. 2003, 125, 2840-2841.

4. V. Sidorov, F.W. Kotch, G. Abdrakhmanova, R. Mizani, J.C. Fettinger, J.T. Davis. Ion Channel Formed from a Calix[4]arene-Amide that Binds HCl. J. Am. Chem. Soc. 2002, 124, 2267-2278.

5. V. Sidorov, F.W. Kotch, M. El-Kouedi, J.T. Davis. Toward Artificial Ion Channels: Self-Assembled Nanotubes from Calix[4]arene-Guanosine Conjugates. Chem. Commun. 2000, 2369-2370.

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