Development of a total synthesis of Myxovalargin A and derivatives ̶ investigations on transformations with polymer-supported Bisazidoiodate (I)

The first part of this dissertation deals with the chemical total synthesis of peptide natural product Myxovalargin A, which was isolated from a culture supernatant of the myxobacterial strain Myxococcus fulvus, Mx f65, and first mentioned by name as early as 1981. It exhibits antibiotic activity against a wide range of GRAM-positive and GRAM-negative bacteria. However, the amino acid sequence with corresponding configurations obtained from feeding experiments at that time contrasts with the results of a recent gene cluster analysis. For this reason, both variants of myxovalargin were synthesized in this work by a combination of solid-phase and liquid-phase peptide chemistry. Mass spectrometric comparisons of the two synthesized myxovalargins with the natural product isolated from the bacterial supernatant confirmed unequivocally the stereochemistry postulated by the gene cluster analysis. Moreover, a synthetic approach for structurally simplified myxovalargin derivatives was investigated. The second part of this dissertation deals with chemical studies on polymer-bound bisazidoiodate (I), which exhibits the same chemical properties as iodoazide, but not its explosive character. Of particular importance here is the photochemically induced homolytic cleavage of iodine azide to release azide radicals, which provide the reactive species for the chemoselective oxidation of secondary alcohols in the presence of primary alcohols. In addition, a new reactivity of iodine azide toward phenols and ketones was explored, with the intermediate formation of hypoiodite being the key step in the oxidative azidation of phenols and ketones

Oxidative azidations of phenols and ketones using iodine azide after release from an ion exchange resin

The oxidative oligoazidation of phenols and ketones using iodine azide (IN3) provided by its release from an ion exchange resin is reported. Preliminary mechanistic studies indicate a previously unknown reactivity of iodine azide toward phenols and ketones. © The Royal Society of Chemistry 2021

Photochemical Transformations with Iodine Azide after Release from an Ion-Exchange Resin

This report discloses the photochemical homolytic cleavage of iodine azide after its formation following release from polymer-bound bisazido iodate(I) anions. A series of radical reactions are reported including the 1,2-functionlization of alkenes and the unprecedented chemoselective oxidation of secondary alcohols in the presence of primary alcohols

The Myxobacterial Antibiotic Myxovalargin: Biosynthesis, Structural Revision, Total Synthesis, and Molecular Characterization of Ribosomal Inhibition

Resistance of bacterial pathogens against antibiotics is declared by WHO as a major global health threat. As novel antibacterial agents are urgently needed, we re-assessed the broad-spectrum myxobacterial antibiotic myxovalargin and found it to be extremely potent against Mycobacterium tuberculosis. To ensure compound supply for further development, we studied myxovalargin biosynthesis in detail enabling production via fermentation of a native producer. Feeding experiments as well as functional genomics analysis suggested a structural revision, which was eventually corroborated by the development of a concise total synthesis. The ribosome was identified as the molecular target based on resistant mutant sequencing, and a cryo-EM structure revealed that myxovalargin binds within and completely occludes the exit tunnel, consistent with a mode of action to arrest translation during a late stage of translation initiation. These studies open avenues for structure-based scaffold improvement toward development as an antibacterial agent

Multiparameter Kinetic Analysis for Covalent Fragment Optimization by Using Quantitative Irreversible Tethering (qIT).

Chemical probes that covalently modify cysteine residues in a protein-specific manner are valuable tools for biological investigations. Covalent fragments are increasingly implemented as probe starting points, but the complex relationship between fragment structure and binding kinetics makes covalent fragment optimization uniquely challenging. We describe a new technique in covalent probe discovery that enables data-driven optimization of covalent fragment potency and selectivity. This platform extends beyond the existing repertoire of methods for identifying covalent fragment hits by facilitating rapid multiparameter kinetic analysis of covalent structure-activity relationships through the simultaneous determination of Ki , kinact and intrinsic reactivity. By applying this approach to develop novel probes against electrophile-sensitive kinases, we showcase the utility of the platform in hit identification and highlight how multiparameter kinetic analysis enabled a successful fragment-merging strategy

The myxobacterial antibiotic myxovalargin: Biosynthesis, structural revision, total synthesis and molecular characterization of ribosomal inhibition

Resistance of bacterial pathogens against antibiotics is declared by WHO as a major global health threat. As novel antibacterial agents are urgently needed, we re-assessed the broad-spectrum myxobacterial antibiotic myxovalargin and found it to be extremely potent against Mycobacterium tuberculosis. To ensure compound supply for further development we studied myxovalargin biosynthesis in detail enabling production via fermentation of a native producer. Feeding experiments as well as functional genomics analysis suggested a structural revision, which was eventually corroborated by development of a concise total synthesis. The ribosome was identified as the molecular target based on resistant mutant sequencing and a cryo-EM structure revealed that myxovalargin binds within and completely occludes the exit tunnel, consistent with a mode of action to arrest translation during a late stage of translation initiation. Pharmacokinetic and initial in vivo efficacy studies indicated that myxovalargin and analogues show potential for development as an antibacterial agent