Alexander Draganov

The first chemical synthesis of boronic acid-modified DNA through a copper-free click reaction

The first chemical incorporation of the boronic acid group into DNA using a copper-free click reagent was reported. Compared with the PCR-based method, this approach allows for site-specific incorporation and synthesis on a larger scale.

A novel metal-free synthesis of 6H-isoindolo[2,1-alpha]indol-6-one

Abstract 6H-Isoindolo[2,1-α]indol-6-one, a core structure for a number of biologically active compounds, was synthesized in four steps. The approach is metal-free and uses a Beckmann rearrangement followed by an intramolecular cyclization.

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.

Inhibition of MDM2 by a rhein-derived compound AQ-101 suppresses cancer development in SCID mice

A novel small-molecule anthraquinone (AQ) analogue, AQ-101, which was synthesized through chemical modification of the core structures of rhein, exhibited potent anticancer activity. In the present study, we evaluated the cancer-inhibiting mechanism of AQ-101 and tested the therapeutic potential of this compound for treating cancer in mice. We found that AQ-101 was able to induce MDM2 protein degradation through a self-ubiquitination and proteasome-mediated mechanism. This AQ-101–induced MDM2 downregulation led to activation of p53, which contributed to apoptosis of acute lymphoblastic leukemia (ALL), especially those with a wild-type p53 phenotype and MDM2 expression in vitro and in vivo. When given for a period of 2 weeks (20 mg/kg/day, 3×/week), AQ-101 inhibited development of ALL in nude or SCID mice with a human ALL xenograft and achieved cure by the end of the 5-month experiment. Importantly, AQ-101 showed minimal or no inhibitory effect on normal human hematopoiesis in vitro and was well tolerated in vivo in animal models. Given that MDM2-overexpressing cancers are commonly refractory to current treatment options, our study results suggest that further development of AQ-101 is warranted, as it represents a potentially new, safe anticancer drug with a novel strategy for targeting MDM2. Mol Cancer Ther; 17(2); 497–507. ©2017 AACR.