ABSTRACT
Over the past decade, DNA-encoded libraries (DELs) have emerged as a leading platform for small molecule drug discovery among pharmaceutical companies, biotech companies and academic drug hunters alike. This revolutionary technology has tremendous potential that is yet to be fully realized, as the exploration of therapeutically relevant chemical space is fueled by the ever-expanding repertoire of DNA-compatible reactions used to construct the libraries. Advances in direct coupling reactions, like photo-catalytic cross couplings, unique cyclizations such as the formation of 1,2,4-oxadiazoles, and new functional group transformations are valuable contributions to the DEL reaction toolkit, and indicate where future reaction development efforts should focus in order to maximize the productivity of DELs.
Subject(s)
DNA/chemistry , Small Molecule Libraries/chemistry , Combinatorial Chemistry Techniques , Molecular Structure , Small Molecule Libraries/chemical synthesisABSTRACT
A dense hydrogen-bond network is responsible for the mechanical and structural properties of polysaccharides. Random derivatization alters the properties of the bulk material by disrupting the hydrogen bonds, but obstructs detailed structure-function correlations. We have prepared well-defined unnatural oligosaccharides including methylated, deoxygenated, deoxyfluorinated, as well as carboxymethylated cellulose and chitin analogues with full control over the degree and pattern of substitution. Molecular dynamics simulations and crystallographic analysis show how distinct hydrogen-bond modifications drastically affect the solubility, aggregation behavior, and crystallinity of carbohydrate materials. This systematic approach to establishing detailed structure-property correlations will guide the synthesis of novel, tailor-made carbohydrate materials.
ABSTRACT
Lactotetraosyl (Lc4) and neo-lactotetraosyl (nLc4) are backbones that are common to many glycans. Using automated glycan assembly, these common core structures were constructed and elaborated to access synthetically challenging glycans of biological relevance. The incorporation of α-fucoses is demonstrated for H-type I and II; α(1,3)-galactose epitopes were prepared, and the pentasaccharide HNK-1 required incorporation of a 3-O-sulfate. In addition to preparing the target structures, essential insights were gained regarding the relationships of glycosylating agents and nucleophiles as well as the linker stability.
Subject(s)
Blood Group Antigens/chemistry , Glycosylation , Oligosaccharides/chemistry , Polysaccharides/chemistry , Chemistry, Organic , Chromatography, High Pressure Liquid , Epitopes/chemistry , Fucose/chemistry , Humans , Thioglycosides/chemistryABSTRACT
A synthetic strategy combining automated solid-phase chemical synthesis and enzymatic sialylation was developed to access α(2,3)-sialylated glycans.
Subject(s)
N-Acetylneuraminic Acid/metabolism , Polysaccharides/biosynthesis , Sialyltransferases/metabolism , Solid-Phase Synthesis Techniques , Automation , Carbohydrate Conformation , Molecular Sequence Data , N-Acetylneuraminic Acid/chemistry , Polysaccharides/chemistry , Sialyltransferases/chemistryABSTRACT
Dangerous, antibiotic resistant bacteria have been observed with increasing frequency over the past several decades. In this review the factors that have been linked to this phenomenon are addressed. Profiles of bacterial species that are deemed to be particularly concerning at the present time are illustrated. Factors including economic impact, intrinsic and acquired drug resistance, morbidity and mortality rates, and means of infection are taken into account. Synchronously with the waxing of bacterial resistance there has been waning antibiotic development. The approaches that scientists are employing in the pursuit of new antibacterial agents are briefly described. The standings of established antibiotic classes as well as potentially emerging classes are assessed with an emphasis on molecules that have been clinically approved or are in advanced stages of development. Historical perspectives, mechanisms of action and resistance, spectrum of activity, and preeminent members of each class are discussed.
ABSTRACT
Semisynthetic derivatives of the clinically useful aminoglycosides tobramycin and amikacin were prepared by selectively modifying their 6'' positions with a variety of hydrogen bond donors and acceptors. Their binding to the rRNA A-site was probed using an in vitro FRET-based assay, and their antibacterial activities against several resistant strains (e.g., Pseudomonas aeruginosa, Klebsiella pneumonia, MRSA) were quantified by determining minimum inhibitory concentrations (MICs). The most potent derivatives were evaluated for their eukaryotic cytotoxicity. Most analogues displayed higher affinity for the bacterial A-site than the parent compounds. Although most tobramycin analogues exhibited no improvement in antibacterial activity, several amikacin analogues showed potent and broad-spectrum antibacterial activity against resistant bacteria. Derivatives tested for eukaryotic cytotoxicity exhibited minimal toxicity, similar to the parent compounds.
Subject(s)
Amikacin/analogs & derivatives , Amikacin/chemical synthesis , Anti-Bacterial Agents/chemical synthesis , Bacteria/drug effects , Drug Resistance, Bacterial/drug effects , RNA, Ribosomal, 16S/drug effects , Tobramycin/analogs & derivatives , Tobramycin/chemical synthesis , Amikacin/pharmacology , Anti-Bacterial Agents/pharmacology , Antibiotics, Antineoplastic/chemical synthesis , Antibiotics, Antineoplastic/pharmacology , Binding Sites , Cell Survival/drug effects , Models, Molecular , Molecular Conformation , Tobramycin/pharmacologyABSTRACT
The emergence of virulent, drug-resistant bacterial strains coupled with a minimal output of new pharmaceutical agents to combat them makes this a critical time for antibacterial research. Aminoglycosides are a well-studied, highly potent class of naturally occurring antibiotics with scaffolds amenable to modification, and therefore, they provide an excellent starting point for the development of semisynthetic, next-generation compounds. To explore the potential of this approach, we synthesized a small library of aminoglycoside derivatives selectively and minimally modified at one or two positions with a guanidine group replacing the corresponding amine or hydroxy functionality. Most guanidino-aminoglycosides showed increased affinity for the ribosomal decoding rRNA site, the cognate biological target of the natural products, when compared with their parent antibiotics, as measured by an in vitro fluorescence resonance energy transfer (FRET) A-site binding assay. Additionally, certain analogues showed improved minimum inhibitory concentration (MIC) values against resistant bacterial strains, including methicillin-resistant Staphylococcus aureus (MRSA). An amikacin derivative holds particular promise with activity greater than or equal to the parent antibiotic in the majority of bacterial strains tested.
