Hünlich Base: (Re)Discovery, Synthesis, and Structure Elucidation after a Century

After almost 100 years, the structure of the product of the reaction between 2,4-diaminotoluene and formaldehyde was elucidated: derivative <b>3</b>, which we call the Hünlich base, was synthesized on a multigram scale and its enantiomers were easily separated in preparative amounts. Furthermore, transformation of the NH₂ groups to the corresponding bis-iodides and bis-azides is presented. The latter was also used for desymmetrization by click chemistry

Hünlich Base: (Re)Discovery, Synthesis, and Structure Elucidation after a Century

After almost 100 years, the structure of the product of the reaction between 2,4-diaminotoluene and formaldehyde was elucidated: derivative <b>3</b>, which we call the Hünlich base, was synthesized on a multigram scale and its enantiomers were easily separated in preparative amounts. Furthermore, transformation of the NH₂ groups to the corresponding bis-iodides and bis-azides is presented. The latter was also used for desymmetrization by click chemistry

Experimental Evolution of Diverse Strains as a Method for the Determination of Biochemical Mechanisms of Action for Novel Pyrrolizidinone Antibiotics

The continuing rise of multidrug resistant pathogens has made it clear that in the absence of new antibiotics we are moving toward a “postantibiotic” world, in which even routine infections will become increasingly untreatable. There is a clear need for the development of new antibiotics with truly novel mechanisms of action to combat multidrug resistant pathogens. Experimental evolution to resistance can be a useful tactic for the characterization of the biochemical mechanism of action for antibiotics of interest. Herein, we demonstrate that the use of a diverse panel of strains with well-annotated reference genomes improves the success of using experimental evolution to characterize the mechanism of action of a novel pyrrolizidinone antibiotic analog. Importantly, we used experimental evolution under conditions that favor strongly polymorphic populations to adapt a panel of three substantially different Gram-positive species (lab strain <i>Bacillus subtilis</i> and clinical strains methicillin-resistant <i>Staphylococcus aureus</i> MRSA131 and <i>Enterococcus faecalis</i> S613) to produce a sufficiently diverse set of evolutionary outcomes. Comparative whole genome sequencing (WGS) between the susceptible starting strain and the resistant strains was then used to identify the genetic changes within each species in response to the pyrrolizidinone. Taken together, the adaptive response across a range of organisms allowed us to develop a readily testable hypothesis for the mechanism of action of the CJ-16 264 analog. In conjunction with mitochondrial inhibition studies, we were able to elucidate that this novel pyrrolizidinone antibiotic is an electron transport chain (ETC) inhibitor. By studying evolution to resistance in a panel of different species of bacteria, we have developed an enhanced method for the characterization of new lead compounds for the discovery of new mechanisms of action

Enantioselective Total Synthesis of Antibiotic CJ-16,264, Synthesis and Biological Evaluation of Designed Analogues, and Discovery of Highly Potent and Simpler Antibacterial Agents

An improved and enantioselective total synthesis of antibiotic CJ-16,264 through a practical kinetic resolution and an iodolactonization reaction to form the iodo pyrrolizidinone fragment of the molecule is described. A series of racemic and enantiopure analogues of CJ-16,264 was designed and synthesized through the developed synthetic technologies and tested against drug-resistant bacterial strains. These studies led to interesting structure–activity relationships and the identification of a number of simpler, and yet equipotent, or even more potent, antibacterial agents than the natural product, thereby setting the foundation for further investigations in the quest for new anti-infective drugs

Streamlined Total Synthesis of Trioxa­carcins and Its Application to the Design, Synthesis, and Biological Evaluation of Analogues Thereof. Discovery of Simpler Designed and Potent Trioxa­carcin Analogues

A streamlined total synthesis of the naturally occurring antitumor agents trioxa­carcins is described, along with its application to the construction of a series of designed analogues of these complex natural products. Biological evaluation of the synthesized compounds revealed a number of highly potent, and yet structurally simpler, compounds that are effective against certain cancer cell lines, including a drug-resistant line. A novel one-step synthesis of anthra­quinones and chloro anthra­quinones from simple ketone precursors and phenyl­selenyl chloride is also described. The reported work, featuring novel chemistry and cascade reactions, has potential applications in cancer therapy, including targeted approaches as in antibody–drug conjugates

Synthesis and Biological Investigation of Δ¹²-Prostaglandin J₃ (Δ¹²-PGJ₃) Analogues and Related Compounds

A series of Δ¹²-prostaglandin J₃ (Δ¹²-PGJ₃) analogues and derivatives were synthesized employing an array of synthetic strategies developed specifically to render them readily available for biological investigations. The synthesized compounds were evaluated for their cytotoxicity against a number of cancer cell lines, revealing nanomolar potencies for a number of them against certain cancer cell lines. Four analogues (<b>2</b>, <b>11</b>, <b>21</b>, and <b>27</b>) demonstrated inhibition of nuclear export through a covalent addition at Cys528 of the export receptor Crm1. One of these compounds (i.e., <b>11</b>) is currently under evaluation as a potential drug candidate for the treatment of certain types of cancer. These studies culminated in useful and path-pointing structure–activity relationships (SARs) that provide guidance for further improvements in the biological/pharmacological profiles of compounds within this class