NIU Department of
Chemistry & Biochemistry
Where the study of matter...matters!
Assistant Professor
Office: Faraday Hall 343
Phone: (815) 753-8427
dkadnikov@niu.edu
Postdoctoral Fellow, University of California, San Francisco, 2002-2006
Ph.D., Iowa State University, 2002
Diplomate, Higher Chemical College of the Russian Academy of Sciences, 1997
Organic synthesis; molecular pharmacology; nuclear receptors; 
-helix mimetics, inhibition of protein-protein interactions.
Synthesis of 2-quinolones via palladium-catalyzed carbonylative annulations of internal alkynes by N-substituted o-iodoanilines. Kadnikov, D. V.; Larock, R. C. (2004) J. Org. Chem., 69: 6772-6780.
Palladium-catalyzed carbonylative annulation of terminal alkynes: Synthesis of coumarins and 2-quinolones. Kadnikov, D. V.; Larock, R. C. (2003) J. Organomet. Chem., 687: 425-435.
Palladium-catalyzed carbonylative annulation of internal alkynes by o-iodophenols: Synthesis of 3,4-disubstituted coumarins. Kadnikov, D. V.; Larock, R. C. (2003) J. Org. Chem., 68: 9423-9432.
Synthesis of coumarins via palladium-catalyzed carbonylative annulations of internal alkynes by o-iodophenols. Kadnikov, D. V.; Larock, R. C. (2000) Org. Lett., 2: 3643-3646.
The focus of my research group is the design and synthesis of novel small molecules capable of interacting with biological targets, and utilizing these synthetic agents to study cellular and physiological processes. We are interested in understanding the molecular basis of biological processes, but since we approach these problems with a synthetic organic chemist's "toolbox," our major efforts are concentrated on the design of new molecules, development of new and efficient synthetic routes to these targets, and execution of these syntheses.
In the design of such molecules, we aim to develop synthetic agents which can be prepared rapidly and efficiently, but which also possess a wide variety of diverse structural elements. In studying the effects of our compounds on their cellular targets, we are trying to gain an understanding of a variety of phenomena: what structural elements of the small molecule and its target are responsible for their interaction, and how these interactions translate into the observed biological responses; the pharmacology of activation and inactivation of the cellular target; and what physiological response it causes.
One of our main interests is in the development of small-molecule regulators of gene transcription. Only a small fraction of the 30,000 genes in the human genome is transcribed at any given moment, while transcription of most genes is switched on or off in response to internal and external stimuli. Malfunction or misregulation of gene transcription gives rise to a variety of diseases. Thus, the ability to regulate gene transcription with small molecules will afford us the tools to study the molecular basis of physiological processes and, it is hoped, provide leads to new therapeutic agents. To achieve this goal, we target a superfamily of proteins known as nuclear receptors, which activate the transcription of genes in response to the binding of a small-molecule ligand.
Figure 1. Complex of a small-molecule ligand with a ligand-binding
domain of the nuclear receptor LXR
.
The physiological effects of well-known hormones--such as testosterone or estrogen, thyroid hormone, or retinoic acid--are all mediated by nuclear receptors. Nuclear receptors are thus involved in regulating all major life processes, from development, maturation, and reproduction to metabolism and the response to stress or inflammation.
We are targeting nuclear receptors that are involved in the regulation of cholesterol metabolism and of xenobiotic metabolism (the protection of an organism from foreign agents). We aim to develop small molecules that will, upon binding to the nuclear receptor, start or stop gene transcription. Our goal is not only to mimic the function of endogenous ligands, but also to design synthetic ligands with unique biological properties: a ligand, for example, that would turn on gene transcription in the liver but not in other tissues, or a ligand that will activate transcription of only one subset of nuclear receptor target genes, but inhibit the transcription of others. Our ultimate goal is to develop a set of molecules with varying pharmacological profiles.
We are also exploring the possibility of using small molecules as inhibitors of protein-protein interactions. Most cellular processes involve the formation of complexes of two or more proteins. Consequently, the ability to disrupt these complexes is a powerful tool for the study of biological pathways. Inhibition of the formation of protein-protein complexes also represents a novel class of therapeutic targets. We are particularly interested in protein-protein interfaces involving -helices. While -helices are uibiquitous elements of protein structure, very few non-peptide mimics of -helices have been developed to date.
We are exploring a modular approach to the design of such molecules, where the mimics of the -helix core and of the amino acid side chains are designed independently and the final structure is assembled in combinatorial fashion. Initially, we are targeting several well-understood protein-protein complexes involved in the progression of cancer. Developing small-molecule -helix mimetics for these complexes would give us insights into the general principles of designing such mimetics. We would then attempt to develop libraries of small-molecule mimetics with which we could probe a variety of protein-protein complexes that have -helices at their interfaces.
Figure 2. -Helical peptide of the p53 protein bound to the N-terminal domain of the MDM2 oncoprotein.