Recent Developments in the Biosynthesis of Aziridines.

Only 0.016 % of all known natural products contain an aziridine ring, but this unique structural feature imparts high reactivity and cytotoxicity to the compounds in which it is found. Until 2021, no naturally occurring aziridine-forming enzymes had been identified. Since 2021, the biosynthetic enzymes for ~10 % of known aziridine containing natural products have been identified and characterized. This article describes the recent advances in our understanding of enzyme-catalyzed aziridine formation in the context of historical methods for aziridine formation through synthetic chemistry.

The l-Alanosine Gene Cluster Encodes a Pathway for Diazeniumdiolate Biosynthesis.

N-Nitroso-containing natural products are bioactive metabolites with antibacterial and anticancer properties. In particular, compounds containing the diazeniumdiolate (N-nitrosohydroxylamine) group display a wide range of bioactivities ranging from cytotoxicity to metal chelation. Despite the importance of this structural motif, knowledge of its biosynthesis is limited. Herein we describe the discovery of a biosynthetic gene cluster in Streptomyces alanosinicus ATCC 15710 responsible for producing the diazeniumdiolate natural product l-alanosine. Gene disruption and stable isotope feeding experiments identified essential biosynthetic genes and revealed the source of the N-nitroso group. Additional biochemical characterization of the biosynthetic enzymes revealed that the non-proteinogenic amino acid l-2,3-diaminopropionic acid (l-Dap) is synthesized and loaded onto a free-standing peptidyl carrier protein (PCP) domain in l-alanosine biosynthesis, which we propose may be a mechanism of handling unstable intermediates generated en route to the diazeniumdiolate. These discoveries will facilitate efforts to determine the biochemistry of diazeniumdiolate formation.

Synthetic studies toward citrinadin A: construction of the pentacyclic core.

This manuscript describes the preparation of an advanced intermediate toward the total synthesis of citrinadin A, featuring a [3+2] cycloaddition employing in situ generation of the dipole.

Collaborative Total Synthesis: Routes to (±)-Hippolachnin A Enabled by Quadricyclane Cycloaddition and Late-Stage C-H Oxidation.

Described herein are synthetic efforts toward the synthesis of hippolachnin A. Two independently devised routes from the Brown and Wood groups allowed for the synthesis of hippolachnin A from the unusual starting material, quadricyclane, by harnessing the power of late-stage C-H oxidation. Collaborative union of the best features of the two routes allowed for preparation of the molecule with improved efficiency.

Synthetic studies toward the citrinadins: enantioselective preparation of an advanced spirooxindole intermediate.

This manuscript describes the enantioselective preparation of a spirooxindole that is suited for advancedment to either Citrinadin A or B.

An enantioselective total synthesis and stereochemical revision of (+)-citrinadin B.

This manuscript describes an enantioselective synthesis of the naturally occurring alkaloid citrinadin B. The synthetic effort revealed an anomaly in the original structural assignment that has led to the proposal of a stereochemical revision. This revision is consistent with the structures previously reported for a closely related family of alkaloids, PF1270A-C. The synthesis is convergent and employs a stereoselective intermolecular nitrone cyloaddition reaction as a key step.

Synthetic polymer nanoparticle-polysaccharide interactions: a systematic study.

The interaction between synthetic polymer nanoparticles (NPs) and biomacromolecules (e.g., proteins, lipids, and polysaccharides) can profoundly influence the NPs fate and function. Polysaccharides (e.g., heparin/heparin sulfate) are a key component of cell surfaces and the extracelluar matrix and play critical roles in many biological processes. We report a systematic investigation of the interaction between synthetic polymer nanoparticles and polysaccharides by ITC, SPR, and an anticoagulant assay to provide guidelines to engineer nanoparticles for biomedical applications. The interaction between acrylamide nanoparticles (~30 nm) and heparin is mainly enthalpy driven with submicromolar affinity. Hydrogen bonding, ionic interactions, and dehydration of polar groups are identified to be key contributions to the affinity. It has been found that high charge density and cross-linking of the NP can contribute to high affinity. The affinity and binding capacity of heparin can be significantly diminished by an increase in salt concentration while only slightly decreased with an increase of temperature. A striking difference in binding thermodynamics has been observed when the main component of a polymer nanoparticle is changed from acrylamide (enthalpy driven) to N-isopropylacryalmide (entropy driven). This change in thermodynamics leads to different responses of these two types of polymer NPs to salt concentration and temperature. Select synthetic polymer nanoparticles have also been shown to inhibit protein-heparin interactions and thus offer the potential for therapeutic applications.