Combinatorial Chemistry and Drug Discovery
Torrey Pines Institute for Molecular Studies
Port Saint Lucie, FL 34987
The last two decades has witnessed major breakthroughs in the identification of genes, gene products, metabolic pathways, and signaling pathways, as well as progress in miniaturization and robotics, enabling the development of high-throughput mechanism-based biological assays. One of the central objectives of organic and medicinal chemistry is the design, synthesis, and production of molecules having value as human therapeutic agents. Our research group is interested in the design, synthesis, analysis, conformations, dynamics and structure-biological activity relationships of diverse nitrogen heterocycles of different ring sizes. Diaza- and triaza-cyclic compounds with different substitution patterns and embedded in various molecular frameworks constitute important structure classes in the search for bioactivity. The compounds are designed to follow known drug-likeness rules including “Lipinski’s Rule of Five”. Examples of the synthesis and identifiaction of highly active compounds from mixture based libraries in different assays will be presnted.
Strain-release functionalization as an enabling strategy in medicinal chemistry and drug discovery.
Justin M. Lopchuk
Department of Drug Discovery, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612
Driven by the ever-increasing pace of drug discovery and the need to push the boundaries of unexplored chemical space, medicinal chemists are routinely turning to unusual strained bioisosteres such as bicyclo[1.1.1]pentane, azetidine, and cyclobutane to modify their lead compounds. Too often, however, the difficulty of installing these fragments surpasses the challenges posed even by the construction of the parent drug scaffold. This talk will describe the development and application of a general strategy where spring-loaded, strained C–C and C–N bonds react with amines to allow for the “any-stage” installation of small, strained ring systems. In addition to the functionalization of small building blocks and late-stage intermediates, the methodology has been applied to bioconjugation and peptide labeling. The most recent version of our strain-release methodology, stereospecific strain-release heteroatom functionalization, enables the stereospecific “cyclopentylation” of amines, alcohols, thiols, carboxylic acids, and other heteroatoms. The development, synthesis, scope of reaction, bioconjugation, and synthetic comparisons of four new chiral “cyclopentylation” reagents will be discussed.
Discovery of Selective Inhibitors for the Beta-catenin/B-cell lymphoma 9 Protein–Protein Interaction.Discovery of Selective Inhibitors for the Beta-catenin/B-cell lymphoma 9 Protein–Protein Interaction.
Logan R. Hoggard, John A. Wisniewski, Yongqiang Zhang, Min Zhang, Haitao (Mark) Ji*
Drug Discovery Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
Small-molecule α-helix proteomimetics, such as terphenyl, tris-benzamide, and derivatives, use rigid or pre-organized scaffolds to overlap with the backbones of α-helices and position three substituents to the area where the side chains of α-helical hot spots i, i + 3/4, and i + 7 are located. While the substituents on these designed proteomimetics are critical for biological activities, the scaffolds themselves are not involved in binding. α-Helical hot spots at positions i, i + 3/4, and i + 7 are the primary driving force for many α-helix mediated PPIs. The installation of functional groups to trigger inhibitor selectivity and maintain druglike properties has not been an easy task for small-molecule α-helix proteomimetics. In this study, a new generic scaffold that itself can mimic the binding mode of hydrophobic side chains of α-helical hot spots at positions i, i + 3, and i + 7 was designed. Compared to small-molecule α-helix proteomimetics, this generic scaffold has a much lower molecular weight and a higher ligand efficiency. Decoration of this generic scaffold can lead to small-molecule inhibitors that selectively disrupt α-helix mediated PPIs. Based on this scaffold, new potent inhibitors selective for the β-catenin/B-cell lymphoma 9 interaction were designed and synthesized. The biochemical and cell-based studies demonstrated that this new class of inhibitors can selectively inhibit canonical Wnt signaling, downregulate Wnt target genes, and suppress the growth of Wnt/β-catenin-dependent cancer cells.
- Hoggard, L. R.; Zhang, Y.; Zhang, M.; Panic, V.; Wisniewski, J. A.; Ji, H.* Rational design of selective small-molecule inhibitors for β-catenin/B-cell lymphoma 9 protein–protein interactions. Am. Chem. Soc. 2015, 137 (38), 12249–12260.
- Wisniewski, J. A.; Yin, J.; Teuscher, K. B.; Zhang, M.; Ji, H. Structure-based design of 1,4-dibenzoylpiperazines as β-catenin/B-cell lymphoma 9 protein-protein interaction inhibitors. ACS Med. Chem. Lett. 2016, 7 (5), 508–513. PMCID: PMC4867476.
- Teuscher, K. B.; Zhang, M.; Ji, H. A versatile method to determine the cellular bioavailability of small-molecule inhibitors. Med. Chem. 2017, 60 (1), 157–169.
Natural Product Inspired Synthetic Medicinal Chemistry: Functional and Complexity Driven Discoveries
Robert W. Huigens III
University of Florida
Various natural products, such as taxol, morphine and vancomycin, play a prominent role in medicine due to their ability to modulate biological targets critical to human disease. Our lab has two natural product inspired synthetic medicinal chemistry programs, driven by the function of phenazine antibiotics and the structural complexity of select indole alkaloids. Each program aims to address major biomedical problems, including: (1) the discovery of therapeutically relevant small molecules capable of eradicating surface-attached bacterial biofilms and (2) enhancing the chemical diversity of screening libraries used to drive drug discovery in high throughput screening campaigns. Our first program aims to target bacterial biofilms, which contain specialized persister cells that are metabolically dormant and demonstrate high antibiotic tolerance towards every class of conventional antibiotic. These biofilms are the underlying cause of chronic and recurring bacterial infections. We have discovered that the marine phenazine antibiotic 2-bromo-1-hydroxyphenazine is a tunable molecular scaffold that provides access to highly potent antibacterial agents that are able to eradicate drug-resistant and antibiotic-tolerant bacterial biofilms. Our second program is aimed at the rapid generation of highly diverse and complex small molecules, which we access through short synthetic sequences motivated by the dramatic alteration of the inherent complex ring system of various indole alkaloids. We recently reported a new tryptoline ring distortion approach from yohimbine, an indole alkaloid with a complex fused ring system. From these and other efforts, we have generated a library of >180 complex and diverse small molecules, which are producing an array of interesting hit compounds in diverse disease areas that will be presented.
AApeptides as a scaffold for the discovery of bioactive molecules
Department of Chemistry, CHE 205, University of South Florida, 4202 E. Fowler Ave, Tampa, FL 33647
The identification and development of sequence-specific peptidomimetics is of significance in bioorganic chemistry and chemical biology. A new class of peptidomimetics termed "AApeptides" was recently developed by our group. The synthesis of AApeptides can be conveniently achieved on the solid phase. Similar to other peptidomimetics, AApeptides are resistant to proteolytic degradation, and possess limitless potential to introduce chemically diverse functional groups. Moreover, they are able to fold into well-defined secondary and tertiary structures. The functions of AApeptides have also been recently explored, including rational design of AApeptides for the mimicry of the primary and secondary structure of bioactive peptides, and combinatorial library for the discovery of potential molecular probes and drug leads.
Peptide N-Amination: A versatile backbone modification for proteomimetic constraint
- Juan R. Del Valle
Department of Chemistry, University of South Florida, Tampa, FL 33620
Backbone amide substitution has a profound impact on the conformation, bioactivity, and proteolytic stability of parent peptides. Although N-alkylation has been extensively employed in peptide SAR campaigns, heteroatomic amide substituents have received far less attention. Here, we describe a novel series of N-amino peptide (NAP) derivatives that mimic β-sheet-like secondary structure and exhibit enhanced resistance to aggregation and proteolysis. Tetrahydropyridazinedione (tpd)-constrained peptides feature a cyclic Ni-Cαi+1 constraint leading to stabilization of extended backbone conformation by NMR and X-ray diffraction. ‘Stitched’β-strand foldamers based on oligomeric tpd constraints thus represent a new class of β-strand mimics readily accessible by conventional SPPS. We have subsequently investigated the impact of simple NAP modifications on β-sheet stability and β-strand recognition by a variety of biophysical methods. Our results demonstrate, for the first time, that peptide N-amination supports β-sheet conformation despite the presence of a tertiary amide. This non-covalent stabilization is attributed to increased torsional strain, cis amide lone pair repulsion, and intraresidue C6 H-bonding. Development of an efficient electrophilic amination approach toward enantiopure α-hydrazino acids corresponding to each of the primary proteinaceous amino acids further enables rapid ‘NAP scanning’ of lead sequences.