Toxicology study of a tissue anchoring paclitaxel prodrug.

Background: Local drug presentation made possible by drug-eluting depots provides benefits for a vast array of diseases, including cancer, microbial infection, and wound healing. Drug-eluting depots provide sustained drug release of therapeutics directly at disease sites with tunable kinetics, remove the need for drugs to access disease sites from circulation, and reduce the side effects associated with systemic therapy. Recently, we introduced an entirely novel approach to local drug presentation named Tissue-Reactive Anchoring Pharmaceuticals (TRAPs).

Pyrrolidine-2,3-diones: heterocyclic scaffolds that inhibit and eradicate biofilms.

The absence of novel antibiotic classes, coupled with the rising threat of antibiotic persistence and resistance, is pushing the world perilously close to a new pre-antibiotic era. Over 35 000 people die every year in the US as a consequence of antimicrobial-resistant infections. Bacterial biofilms further complicate this scenario, as they are inherently more resistant to antibiotic treatments.

Synthesis of Spiropyrrolines One-Pot TfO-Mediated Amide Activation/Formal [3 + 2]-Cycloaddition of α-Formylamino Ketones.

An efficient method for the synthesis of spiropyrrolines from readily accessible α-formylamino ketones is reported. The method involves amide activation using TfO, followed by a formal [3 + 2]-cycloaddition of the resulting enolic nitrilium intermediate with Michael acceptors, ultimately affording spiropyrrolines. Mechanistic insights were gained through NMR studies, elucidating the precise role of the base additive and suggesting the formation of an enolic nitrilium intermediate.

An enantioselective formal synthesis of thienamycin.

Thienamycin is a carbapenem antibiotic with potent activity against gram-negative and gram-positive bacteria. Due to its promising activity but lack of chemical stability, thienamycin serves as inspiration for new synthetic antibiotic scaffolds. In this study, we report a nine-step enantioselective formal synthesis of thienamycin.

Fighting fibrin with fibrin: Vancomycin delivery into coagulase-mediated Staphylococcus aureus biofilms via fibrin-based nanoparticle binding.

Staphylococcus aureus skin and soft tissue infection is a common ailment placing a large burden upon global healthcare infrastructure. These bacteria are growing increasingly recalcitrant to frontline antimicrobial therapeutics like vancomycin due to the prevalence of variant populations such as methicillin-resistant and vancomycin-resistant strains, and there is currently a dearth of novel antibiotics in production. Additionally, S.

Total Synthesis and Microbiological Evaluation of Leopolic Acid A and Analogues.

New antimicrobial scaffolds are scarce, and there is a great need for the development of novel therapeutics. In this study, we report a convergent 9-step synthesis of leopolic acid A and a series of targeted analogues. The designed compounds allowed for incorporation of non-natural ureido dipeptide moieties and 4- and 5-position substituents around the 2,3-pyrrolidinedione of leopolic acid A.

Expanded library of novel 2,3-pyrrolidinedione analogues exhibit anti-biofilm activity.

Herein we report a new library of 2,3-pyrrolidinedione analogues that expands on our previous report on the antimicrobial studies of this heterocyclic scaffold. The novel 2,3-pyrrolidinediones reported herein have been evaluated against S. aureus and methicillin-resistant S.

Photoredox Catalyzed C(sp)-C(sp) Coupling of α-Bromoesters and Triethylamine.

We report a photoredox methodology for C(sp)-C(sp) coupling between α-bromoesters and triethylamine capable of accessing building blocks with handles for further functionalization. Mechanistic studies indicate the presence of a carbon centered radical. The achiral substrates obtained with this method have the potential to be elaborated to access enantioenriched scaffolds with increased molecular complexity.

Integrated genomic analysis reveals aberrations in WNT signaling in germ cell tumors of childhood and adolescence.

Germ cell tumors (GCTs) are neoplasms of the testis, ovary and extragonadal sites that occur in infants, children, adolescents and adults. Post-pubertal (type II) malignant GCTs may present as seminoma, non-seminoma or mixed histologies. In contrast, pre-pubertal (type I) GCTs are limited to (benign) teratoma and (malignant) yolk sac tumor (YST).

Total Synthesis of Bipolamine I.

Indolizidine alkaloids have been the target of chemical and biological studies for decades, most recently highlighted by the isolation of the curvulamine and bipolamine polypyrrole-containing subclass. Herein we report a stereoselective 15-step synthesis of bipolamine I, a distinct member of the broader family, and through this work develop an intermediate that will serve to access other polypyrrole natural products and key analogues going forward.

Stereoselective Synthesis of the Spirocyclic γ-Lactam Core of the Ansalactams.

Ansalactam A is an ansa macrolide natural product that contains a densely functionalized spiro-γ-lactam core containing three contiguous stereocenters. This unusual motif distinguishes it from other members of this family and represents a significant synthetic challenge. Herein, we report the development of a stereoselective formal [3+2] cycloaddition reaction for the construction of this key spiro-γ-lactam motif for the first time, thereby enabling access to the northern domain of ansalactam A.

Nasal Reconstruction after Mohs Cancer Resection: Lessons Learned from 2553 Consecutive Cases.

Background: Nasal defects following Mohs resection are a reconstructive challenge, demanding aesthetic and functional considerations. Many reconstructive modalities are available, each with varying utility and efficacy. The goal of this study was to provide an algorithmic approach to nasal reconstruction and illustrate lessons learned from decades of reconstructing Mohs defects.

Rapid synthesis of the core scaffold of crinane and haemanthamine through a multi-component approach.

A rapid synthesis of the core structures of crinane and haemanthamine has been developed, enabled by a multicomponent approach. This work constitutes a formal synthesis of crinane and sets the stage for access to both families of natural products and key analogues. A key highlight of the approach is the modularity of the core synthesis, overcoming existing challenges for these scaffolds and providing a path to explore site-selective oxidation to expand the scope of molecules accessible from common intermediates.

Leveraging Marine Natural Products as a Platform to Tackle Bacterial Resistance and Persistence.

Antimicrobial resistance to existing antibiotics represents one of the greatest threats to human health and is growing at an alarming rate. To further complicate treatment of bacterial infections, many chronic infections are the result of bacterial biofilms that are tolerant to treatment with antibiotics because of the presence of metabolically dormant persister cell populations. Together these threats are creating an increasing burden on the healthcare system, and a "preantibiotic" age is on the horizon if significant action is not taken by the scientific and medical communities.

Design, synthesis, and evaluation of substrate - analogue inhibitors of Trypanosoma cruzi ribose 5-phosphate isomerase type B.

Ribose 5-phosphate isomerase type B (RPI-B) is a key enzyme of the pentose phosphate pathway that catalyzes the isomerization of ribose 5-phosphate (R5P) and ribulose 5-phosphate (Ru5P). Trypanosoma cruzi RPI-B (TcRPI-B) appears to be a suitable drug-target mainly due to: (i) its essentiality (as previously shown in other trypanosomatids), (ii) it does not present a homologue in mammalian genomes sequenced thus far, and (iii) it participates in the production of NADPH and nucleotide/nucleic acid synthesis that are critical for parasite cell survival. In this survey, we report on the competitive inhibition of TcRPI-B by a substrate - analogue inhibitor, Compound B (K = 5.

Stereoselective, Multicomponent Approach to Quaternary Substituted Hydroindole Scaffolds.

The Amaryllidaceae alkaloids have been a target of synthesis for decades due to their complex architectures and biological activity. A central feature of these natural product cores is a quaternary substituted hydroindole heterocycle. Building off the foundation of our previous multicomponent approach to highly functionalized pyrrolidinones, herein we report a highly convergent, diastereoselective, multicomponent approach to access the hydroindole cores present within crinine, haemanthamine, pretazettine, and various other bioactive alkaloids.

Gender-specific participation and outcomes among jail diversion clients with co-occurring substance use and mental health disorders.

Men and women with co-occurring substance use disorders and mental illness are at relatively high risk for becoming involved in the criminal justice system. Programs, such as post-booking jail diversion, aim to connect these individuals to community-based treatment services in lieu of pursuing criminal prosecution. Gender appears to have an important influence on risk factors and pathways through the criminal justice system, which in turn may influence how interventions like jail diversion work to engage men and women in treatment services and reduce recidivism.

Concise Synthesis and Antimicrobial Evaluation of the Guanidinium Alkaloid Batzelladine D: Development of a Stereodivergent Strategy.

Herein, we describe a stereodivergent route to (±)-batzelladine D (), (+)-batzelladine D (), (-)-batzelladine D (), and a series of stereochemical analogues and explore their antimicrobial activity for the first time. The concise synthetic approach enables access to the natural products in a sequence of 8-12 steps from readily available building blocks. Highlights of the synthetic strategy include gram-scale preparation of a late stage intermediate, pinpoint stereocontrol around the tricyclic skeleton, and a modular strategy that enables analogue generation.

In Vitro Evaluation of a Novel Synthetic Bilirubin Analog as an Antioxidant and Cytoprotective Agent for Pancreatic Islet Transplantation.

Bilirubin is a natural cytoprotective agent and physiologic doses have proven to be beneficial in various models of organ and cellular transplantation. Recently, we showed that bilirubin has protective effects in models of pancreatic islet transplantation, preventing cell death associated with islet stress and suppressing the release of damage-associated molecular patterns. Despite these promising therapeutic attributes, the natural bilirubin used in these research studies is animal-derived (porcine), making it unsuitable for clinical application.

Dynamic nuclear polarization enhanced neutron crystallography: Amplifying hydrogen in biological crystals.

Dynamic nuclear polarization (DNP) can provide a powerful means to amplify neutron diffraction from biological crystals by 10-100-fold, while simultaneously enhancing the visibility of hydrogen by an order of magnitude. Polarizing the neutron beam and aligning the proton spins in a polarized sample modulates the coherent and incoherent neutron scattering cross-sections of hydrogen, in ideal cases amplifying the coherent scattering by almost an order of magnitude and suppressing the incoherent background to zero. This chapter describes current efforts to develop and apply DNP techniques for spin polarized neutron protein crystallography, highlighting concepts, experimental design, labeling strategies and recent results, as well as considering new strategies for data collection and analysis that these techniques could enable.

Stereocontrolled Synthesis of (±)-Melokhanine E via an Intramolecular Formal [3 + 2] Cycloaddition.

A convergent sequence to access the indole alkaloid (±)-melokhanine E in 12-steps (8-step longest linear sequence) and an 11% overall yield is reported. The approach utilizes two cyclopropane moieties as reactive precursors to a 1,3-dipole and imine species to enable stereoselective construction of the core scaffold through a formal [3 + 2] cycloaddition. The natural product was evaluated for its antimicrobial activity based on isolation reports; however, no activity was observed.

5-Benzylidene-4-Oxazolidinones Are Synergistic with Antibiotics for the Treatment of Staphylococcus aureus Biofilms.

The failure of frontline antibiotics in the clinic is one of the most serious threats to human health and requires a multitude of novel therapeutics and innovative approaches to treatment so as to curtail the growing crisis. In addition to traditional resistance mechanisms resulting in the lack of efficacy of many antibiotics, most chronic and recurring infections are further made tolerant to antibiotic action by the presence of biofilms. Herein, we report an expanded set of 5-benzylidene-4-oxazolidinones that are able to inhibit the formation of Staphylococcus aureus biofilms, disperse preformed biofilms, and, in combination with common antibiotics, are able to significantly reduce the bacterial load in a robust collagen-matrix model of biofilm infection.