 |
Bogdan Z. OlenyukAssistant Professor of Chemistry olenyuk at email.arizona.edu Old Chemistry 309 Phone: (520) 626-0754 Fax: (520) 621-8407 |
Honors
|
Education and Appointments
|
Research Interests
|
Research Summary | |
Synthetic Organic Chemistry, Chemical Biology, Chemical Genetics Regulation of gene expression through disruption of transcription factor-coactivator interactions Chemical control of cell adhesion and migration Asymmetric synthesis of epipolythiodiketopiperazines Development of enantioselective organocatalytic transformations Control of protein function through targeted degradationDevelopment of Enantioselective Organocatalytic Transformations Organocatalytic asymmetric heterofunctionalization of carbonyl compounds has recently emerged as a powerful synthetic methodology due to its efficiency, simplicity and low catalyst costs. While synthetic methods for the asymmetric α-heterofunctionalization of aldehydes, ketones, lactones and β-dicarbonyl compounds have been developed, direct organocatalytic methods for the asymmetric α-sulfenylation of less reactive β-amido esters and substituted piperazine-2,5-diones have not been explored. We are actively investigating asymmetric α-heterofunctionalization of the piperazine-2,5-dione ring system in an effort to develop an efficient route to sporidesmins – an intriguing class of biologically active secondary metabolites produced by the filamentous fungi Chaetomium and Pithomyces sp. Asymmetric Synthesis of Epipolythiodiketopiperazine Fungal Metabolites Sporidesmins are a class of natural products containing one or two disulfide-bridged epipolythiodiketopiperazine (ETP) fragments and displaying a broad spectrum of biological activity. Under physiological conditions, the bridged disulfide moiety can exist either in oxidized or reduced forms and is thought to be essential for biological activity of this class of natural products. Recent studies have indicated that several members of the sporidesmins family may have anticancer activity. Only a few syntheses of sporidesmins have been reported to date. With the exception of (+)-11,11'-Dideoxyverticillin A, all syntheses produced racemic compounds. We are pursing asymmetric synthesis of sporidesmins within the framework of our newly developed synthetic methodology of stereoselective construction of the epipolythiodiketopiperazine ring system. Regulation of Gene Expression through Disruption of Transcription Factor-Coactivator Interactions The ability to predictably and specifically control function of a single gene or a cluster of genes in the context of a complex regulatory network is an important problem, as it creates a foundation for rational design of new therapeutics. Because tight control of such function is critical for cellular existence, with aberrant genes often regarded as a cause in development of diseases, the goal of primary importance in the biomedial field has been to develop methods of altering gene expression in malignant cells while leaving normal cells unaffected. We conduct fundamental studies aimed at the development of unique, highly specific small molecule-based gene regulators capable of exploiting differences in cellular microenvironment or transcriptional machinery composition. Our goal is to design potent and specific inhibitors of a contact between cysteine-histidine rich domains of the coactivator proteins and transactivation domains of transcription factors. At present, we have succeeded in developing of small molecules that disrupt a contact between the C-terminal transactivation domain of the α subunit of hypoxia-inducible factor 1 (HIF-1) and CH1 domain of the coactivator protein p300/CBP. We have shown that disruption of this interaction results in rapid downregulation of important in cancer progression hypoxia-inducible genes. HIF-1 is an essential activator responsible for oxygen-dependent gene regulation. The HIF-1 based transcriptional system senses changes in oxygen levels and translates these into pathophysiological responses that govern angiogenesis, erythropoiesis, control of vasomotor tone and energy metabolism. The mechanistic details of this mode of regulation are being explored at the molecular level with the goal of creating a foundation for development of mechanism-based anticancer drugs. Chemical Control of Cellular Adhesion and Migration Our second federally funded project is focused on development of modular multivalent antagonists targeting adhesion receptors in vascular endothelial cells. Specifically, we design "theranostics": multifunctional receptor antagonists carrying a diagnostic and a therapeutic functionality. Our aim is to inhibit the angiogenic process that accompanies tumor growth and metastasis.  Integrins are heterodimeric transmembrane receptors that mediate the interactions between cells and the extracellular matrix. They are involved in a large number of important intracellular processes, such as differentiation, cell-matrix adhesion, apoptosis and stress response. This diverse family of glycoproteins consists of at least 18 α and 8 β subunits that can dimerize in more than 24 different combinations to yield surface receptors capable of recognizing one or several components of extracellular matrix. Structural reorganization of the integrin heterodimers upon binding and the resulting intracellular signaling thought to control cell survival, proliferation, and migration.  Our interest in modulation of integrin function is twofold: (1) we are developing modular dendritic integrin antagonists incorporating cell surface receptor targeting moieties coupled to binary therapeutic agents, such as carborane-containing dendrimers for neutron capture, and (2) we are creating cell-targeting nanomaterials through the use of cell receptor targeting moiety deposited of the surface of a nanoparticles, such as silica microspheres.  In collaboration with Prof. Ilya Zharov from the University of Utah, we are evaluating the binding properties of our newly synthesized integrin antagonists toward their cognate receptors and conducting the necessary structural optimizations. The goal is to enhance the affinity and specificity of designed integrin antagonists, potentially affording new tools in cancer imaging and new antiangiogenic agents. Beyond suppression of angiogenesis, our project is aimed to address fundamental questions regarding molecular mechanisms of cell adhesion and migration. Ultimately, we seek to understand which key interactions between integrin receptors and various extracellular matrix components result in the perpetuation of growth factor signaling in cancers.  Modulation of Protein Levels through Targeted Degradation The interference with protein expression or with protein function in vivo may be carried out on three levels: DNA, mRNA, and post-translational modification. Genetic knockouts disrupt protein function at the DNA level by directly interfering with transcriptional machinery of the gene responsible for a given protein product. On the mRNA level, downregulation of a protein of interest may be accomplished by RNA interference (RNAi), which causes degradation of the mRNA within the cell. The least explored of all three is an approach that involves interference with gene products at the post-translational level. This involves modification and /or degradation of the protein after it has been completely expressed. Our goal is to design small molecules which induce the destruction (rather than inhibition) of a targeted protein using protein degradation machinery of a living cell. Development of such an approach would provide a chemical genetic alternative to the traditional ways of interfering with protein function, resulting in loss of function, or "knockouts". Importantly, a small molecule capable of inducing this process should do so without any manipulation with the genetic content of an organism, thus allowing one to target proteins that are not readily targeted by traditional genetic means. Even more important is to achieve accurate temporal control over the protein degradation, thus allowing targeted destruction to proceed only within the specific time window during cell cycle. We plan to develop a general strategy for the design and synthesis of molecules capable of inducing degradation of the selected proteins at the specific time point during cell cycle. Our approach relies on heterobifunctional molecules which contain a ligand for the target protein, a linker moiety, and a recognition sequence for the APCCDH1 ubiquitin ligase.  Temporally-controlled protein degradation may offer a general strategy to create conditional knockouts. Such knockout of a protein could be used to control a desired cellular phenotype via the induced degradation of a critical regulatory transcription factor which is difficult to target by genetic or biochemical means.
| |
Selected Publications | |
|
