Danzhu Wang

Hypoxia inducible factor pathway inhibitors as anticancer therapeutics

Hypoxia is a significant feature of solid tumor cancers. Hypoxia leads to a more malignant phenotype that is resistant to chemotherapy and radiation, is more invasive and has greater metastatic potential. Hypoxia activates the hypoxia inducible factor (HIF) pathway, which mediates the biological effects of hypoxia in tissues. The HIF complex acts as a transcription factor for many genes that increase tumor survival and proliferation. To date, many HIF pathway inhibitors indirectly affect HIF but there have been no clinically approved direct HIF inhibitors. This can be attributed to the complexity of the HIF pathway, as well as to the challenges of inhibiting protein-protein interactions.

3,6-Substituted-1,2,4,5-tetrazines: tuning reaction rates for staged labeling applications

Cycloaddition reactions involving tetrazines have proven to be powerful bioorthogonal tools for various applications. Conceivably, sequential and selective labeling using tetrazine-based reactions can be achieved by tuning the reaction rate. By varying the substituents on tetrazines, cycloaddition rate variations of over 200 fold have been achieved with the same dienophile. Upon coupling with different dienophiles, such as norbornene, the reaction rate difference can be over 14,000 fold. These substituted tetrazines can be very useful for selective labeling under different conditions.

Fluorescent conjugate of sLex-selective bisboronic acid for imaging application

Carbohydrate-based biomarkers such as sialyl Lewis X are known to correlate with cancer formation and progression. By targeting sialyl Lewis X, we have developed a boronolectin-fluorophore conjugate, which was able to selectively label and image xenograft (sc) tumor. This represents the very first example that a small molecule capable of recognizing a carbohydrate biomarker was used for optical imaging application.

Binding Model for the Interaction of Anticancer Arylsulfonamides with the p300 Transcription Cofactor

Hypoxia inducible factors (HIFs) are transcription factors that activate expression of multiple gene products and promote tumor adaptation to a hypoxic environment. To become transcriptionally active, HIFs associate with cofactors p300 or CBP. Previously, we found that arylsulfonamides can antagonize HIF transcription in a bioassay, block the p300/HIF-1α interaction, and exert potent anticancer activity in several animal models. In the present work, KCN1-bead affinity pull down, (14)C-labeled KCN1 binding, and KCN1-surface plasmon resonance measurements provide initial support for a mechanism in which KCN1 can bind to the CH1 domain of p300 and likely prevent the p300/HIF-1α assembly. Using a previously reported NMR structure of the p300/HIF-1α complex, we have identified potential binding sites in the p300-CH1 domain. A two-site binding model coupled with IC50 values has allowed establishment of a modest ROC-based enrichment and creation of a guide for future analogue synthesis.

The Future of Boron in Medicinal Chemistry: Therapeutic and Diagnostic Applications

Because of its unique electronic structure, boron has special properties useful in designing new diagnostic and therapeutic agents. Specifically, boron’s strong Lewis acidity and ability to undergo fission under neutron bombardment form the foundation for boron-containing compounds to be developed as inhibitors of hydrolytic enzymes, chemosensors and artificial receptors for carbohydrates and other Lewis bases, and boron neutron capture agents. A number of boron-containing compounds have been evaluated in animal and human studies for diagnostics and therapeutic applications. One compound in particular, Velcade, has been approved as an anticancer agent. This chapter highlights some of the most significant contributions in the field.

Chapter 5:Synthetic Receptors for Carbohydrates

The chapter summarizes the design and development of synthetic receptors that can selectively target various types of carbohydrate structures, including monosaccharides, oligosaccharides, and glycoconjugates. Biological carbohydrate receptors are called lectins and X-ray crystal structures of their binding pockets show that effective receptor/carbohydrate association is achieved by a synergistic network of polar and nonpolar interactions. The different categories of synthetic carbohydrate receptors are described (boronic acids, organic macrocycle and cleft-shaped molecules, and metal coordination complexes), along with their binding properties and how they can be utilized for diagnostic or therapeutic applications. Examples include efforts to create solution-state chemosensors for mono- and disaccharides. Also described is recent work to detect cell surface glycoconjugates, which are often disease-specific biomarkers and thus valuable molecular targets for biomedical imaging or drug targeting. The chapter concludes with a summary of current challenges and likely future directions.

Fluorescent Probes for Gaseous Biological Signaling Agents

Gasotransmitters, nitric oxide, carbon monoxide, and hydrogen sulfide are common biological signaling agents in mammals. Despite the tremendous progress made so far in the understanding of their critical roles in mammalian physiology and disease, there is much more that we do not know. Critical to this field is the availability of tools that allow for the rapid, sensitive, and selective detection of these gasotransmitters. This article attempts to capture recent development in this area, especially in the development of probes that allow for intracellular detection.

A general and efficient entry to asymmetric tetrazines for click chemistry applications

Abstract The importance of click chemistry is widely recognized. Among all the known click reactions, those involving tetrazines represent the fastest click reactions reported and are generating a great deal of interest. However, there is no efficient entry to asymmetric tetrazines and those with strong electron withdrawing groups, which limits the development of this field. Herein, we report a general and efficient entry to asymmetric tetrazines with strongly electron withdrawing groups.