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The World Health Organization (WHO) describes antimicrobial resistance (AMR) as one of the three greatest threats to human health. Yet, the current global antibiotic pipeline is scarce, and new resources to combat bacterial pathogens that have become resistant to available antibiotics are few and far between. Therefore, the development of new antibiotics is urgently needed to address the ongoing “antibiotic crisis”. In that regard, thiopeptide antibiotics appear to be good potential sources of new antibacterials. They are potent inhibitors of bacterial protein synthesis and their mode of action is reasonably well understood. Yet, little effort has been made to clinically leverage these natural products. In part, this may be due to the fact that there existed no viable synthetic methods to conduct medicinal chemistry work on these substances. This dissertation presents the first total synthesis of micrococcin P2, a D-series, 26-membered antibiotic, by a synthetic route that incorporates a number of refinements relative to past approaches, and that provides access to large quantities of end product. The synthesis demonstrates economical, concise, efficient, convergent, and diversity-oriented protocols that facilitate medicinal chemistry ventures to a considerable extent. This has enabled an extensive biological evaluation of micrococcin P2 and congeners against Clostridioides difficile, Mycobacterium tuberculosis and non-tuberculous Mycobacterium (NTM). A parallel effort demonstrates the application of the new methodology in a synthetic study toward lactocillin, a metabolite of the human symbiotic bacterium, Lactobacillus gasseri. The work presented herein outlines a route to the most advanced synthetic precursor of lactocillin described to date.

Objective: Microdecompression has come to be more commonly used in a number of ways for the treatment of lumbar spine stenosis (LSS). But, despite the many advantages, the risk of reoperation higher than the fusion surgery is our main concern for microdecompression. Little is known regarding the risk[for full text, please go to the a.m. URL], 67. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), 1. Joint Meeting mit der Koreanischen Gesellschaft für Neurochirurgie (KNS)

Estrogen-related receptor gamma (ERRγ) has recently been recognized as an attractive target for treating inflammation, cancer, and metabolic disorders. Herein, we discovered and demonstrated the in vitro pharmacology as well as the absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of chemical entities that could act as highly selective inverse agonists for ERRγ. The results were comparable to those for GSK5182 (4), a leading ERRγ inverse agonist ligand. Briefly, the half-maximal inhibitory concentration (IC50) range of the synthesized compounds for ERRγ was 0.1–10 μM. Impressively, compound 24e exhibited potency comparable to 4 but was more selective for ERRγ over three other subtypes: ERRα, ERRβ, and estrogen receptor α. Furthermore, compound 24e exhibited a superior in vitro ADMET profile compared to the other compounds. Thus, the newly synthesized class of ERRγ inverse agonists could be lead candidates for developing clinical therapies for ERRγ-related disorders.

This thesis described here aims to achieve the total synthesis of nosiheptide, a representative member of the so-called E-series of thiopeptide antibiotic. Our group has established various techniques for the assembly of their complex molecular framework, and demonstrated the total syntheses of two D-series thiopeptide antibiotics. However, there is no precedent total synthesis of compound belonging to E-series. The part of the reason is that the presence of an additional 3-OH substituent not only adds significant synthetic complications, but also bars the use of the previously established technology. The present work details the assembly of the pyridine-thiazole cluster of E-series thiopeptide substance through a modified Hantzsch reaction that delivers the complete pyridine segment in a triply convergent fashion. Optimization studies related to this pyridine formation have further enhanced the conciseness and simplicity of the method. This chemistry thus developed can be applied to medicinal chemistry investigations in thiopeptide antibiotic field; an endeavor that will possibly unveil valuable new antibiotics.