Syntheses of Minutuminolate and Related Coumarin Natural Products and Evaluation of Their TNF-α Inhibitory Activities.

The concise syntheses of the coumarin natural product, minutuminolate (), and its related natural products, 7-methoxy-8-(2-acetoxy-3-methyl-1-oxobut-2-enyl) coumarin () and muralatin I (), were accomplished for the first time in 4-5 steps from the commercially available umbelliferone. The key step involves a palladium-catalyzed oxidative rearrangement reaction to assemble the α-acyloxyenone moiety in and . The incorporation of this functionality enables the successful synthesis of coumarin through an acidic hydrolysis reaction.

Degradation of MK2 with natural compound andrographolide: A new modality for anti-inflammatory therapy.

The p38-MK2 signaling axis functions as an initiator of inflammation. Targeting the p38-MK2 signaling axis represents a direct therapeutic intervention of inflammatory diseases. We described here a novel role of andrographolide (AG), a small-molecule ent-labdane natural compound, as an inhibitor of p38-MK2 axis via MK2 degradation.

Impact of Preoperative Echocardiograms on In-Hospital Outcomes of Patients Undergoing Surgical Hip Fracture Repair and Their Clinical Appropriateness.

Objectives: Preoperative transthoracic echocardiograms (TTE) before hip fracture repairs are controversial. This study aimed to quantify the frequency of ordering TTE, the appropriateness of testing based on current guidelines, and the impact of TTE on in-hospital morbidity and mortality outcomes.

Methods: This retrospective chart review of adult patients admitted with hip fracture compared the length of stay (LOS), time to surgery, in-hospital mortality, and postoperative complications between TTE and non-TTE groups.

Calcaratarin D, a labdane diterpenoid, attenuates mouse asthma via modulating alveolar macrophage function.

Background And Purpose: Alveolar macrophages (AMs) contribute to airway inflammation and remodelling in allergic asthma. Calcaratarin D (CalD), a labdane diterpenoid from rhizomes of the medicinal plant Alpinia calcarata, has recently been shown to possess anti-inflammatory properties. The present study evaluated protective effects of CalD in a house dust mite (HDM)-induced asthma mouse model.

Small-molecule enhancers of CRISPR-induced homology-directed repair in gene therapy: A medicinal chemist's perspective.

CRISPR technologies are increasingly being investigated and utilized for the treatment of human genetic diseases via genome editing. CRISPR-Cas9 first generates a targeted DNA double-stranded break, and a functional gene can then be introduced to replace the defective copy in a precise manner by templated repair via the homology-directed repair (HDR) pathway. However, this is challenging owing to the relatively low efficiency of the HDR pathway compared with a rival random repair pathway known as non-homologous end joining (NHEJ).

COVID-19 and the promise of small molecule therapeutics: Are there lessons to be learnt?

The coronavirus disease 2019 (COVID-19) pandemic had grounded the world to a standstill. As the disease continues to rage two years on, it is apparent that effective therapeutics are critical for a successful endemic living with COVID-19. A dearth in suitable antivirals has prompted researchers and healthcare professionals to investigate existing and developmental drugs against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Promoting GAINs (Give Attention to Limitations in Assays) over PAINs Alerts: no PAINS, more GAINs.

Many concepts and guidelines in medicinal chemistry have been introduced to aid in successful drug discovery and development. An example is the concept of Pan-Assay Interference Compounds (PAINS) and the elimination of such nuisance compounds from high-throughput screening (HTS) libraries. PAINs, along with other guidelines in medicinal chemistry, are like double-edged swords.

Discovery and development of labdane-oxindole hybrids as small-molecule inhibitors against chikungunya virus infection.

Chikungunya virus (CHIKV) infection, a febrile illness caused by a mosquito-transmitted alphavirus, has afflicted millions of people worldwide. There is currently no approved effective antiviral treatment for CHIKV infection. In this study, we report a new class of small-molecule CHIKV inhibitors, the oxindole-labdanes, that potently block the replication of CHIKV with good selectivity.

Candida-Induced Emphysematous Gastritis in a Multiple Myeloma Patient: Conservative Management With Favorable Outcome.

Emphysematous gastritis is a rare, and often fatal, infection with unclear recommendations on management. We report the first documented case of emphysematous gastritis caused by  species in a patient on chemotherapy for multiple myeloma. Our patient, who presented with gastrointestinal symptoms was found to have gas in the stomach wall, peri-gastric, and portal veins on CT scan.

Evaluation of 2-Bromoisobutyryl Catechol Derivatives for Atom Transfer Radical Polymerization-Functionalized Polydopamine Coatings.

The use of α-bromoisobutyryl-functionalized polydopamine (PDA), derived from an mixture with dopamine (DA) and α-bromoisobutyryl bromide, enables surface-initiated atom transfer radical polymerization (SI-ATRP) of a broad range of methacrylate monomers for surface functionalization. Although the putative intermediate 2-bromo--(3,4-dihydroxyphenethyl)-2-methylpropanamide has been proposed to account for the SI-ATRP activity of α-bromoisobutyryl-functionalized PDA, there has not been a systematic investigation on the efficacy of other catechol-derived 2-bromoisobutyryl derivatives for SI-ATRP. In this work, a number of catechol-derived ATRP initiators containing the 2-bromoisobutyryl moiety were designed and synthesized, in an effort to investigate the effect of changes in structure on initiator immobilization, and subsequent ATRP performance.

Gold(I)-Catalyzed Intramolecular Hydroarylation of Phenol-Derived Propiolates and Certain Related Ethers as a Route to Selectively Functionalized Coumarins and 2-Chromenes.

Methods are reported for the efficient assembly of a series of phenol-derived propiolates, including the parent system , and their Au(I)-catalyzed cyclization (intramolecular hydroarylation) to give the corresponding coumarins (e.g., ).

Polypharmacology of andrographolide: beyond one molecule one target.

Covering: 1951 to 2020Andrographolide is one of the most widely studied plant secondary metabolites, known to display diverse pharmacological actions. Current literature has documented a sizeable list of pharmacological targets for andrographolide, suggesting its multi-targeting nature. Many of these targets are central to the pathophysiology of highly prevalent diseases such as cardiovascular diseases, neurodegenerative disorders, autoimmunity, and even cancer.

From irreversible to reversible covalent inhibitors: Harnessing the andrographolide scaffold for anti-inflammatory action.

Covalent drugs with prolonged actions often show superior potency, yet integrated strategies for optimizing their structural and electronic features are lacking. Herein, we present our effort directed towards understanding the contribution of chemical reactivity to biological potency to rationally design new covalent inhibitors based on the ent-ladane andrographolide scaffold for anti-inflammatory action. Specifically, a series of andrographolide derivatives comprising various Michael acceptors was developed and their thiol reactivity was assayed under various chemical and biological conditions.

Slow-, Tight-Binding Inhibition of CYP17A1 by Abiraterone Redefines Its Kinetic Selectivity and Dosing Regimen.

Substantial evidence underscores the clinical efficacy of inhibiting CYP17A1-mediated androgen biosynthesis by abiraterone for treatment of prostate oncology. Previous structural analysis and in vitro assays revealed inconsistencies surrounding the nature and potency of CYP17A1 inhibition by abiraterone. Here, we establish that abiraterone is a slow-, tight-binding inhibitor of CYP17A1, with initial weak binding preceding the subsequent slow isomerization to a high-affinity CYP17A1-abiraterone complex.

The Chemistry of Bioinspired Catechol(amine)-Based Coatings.

Surface coatings are widely used for the protection of underlying materials from erosion or contamination by the external environment, with biomimetic organic coatings based on catecholamine chemistry gaining prominence in recent years. Such coatings have found use in the biomedical field, e.g.

A fluorescence-displacement assay using molecularly imprinted polymers for the visual, rapid, and sensitive detection of the algal metabolites, geosmin and 2-methylisoborneol.

A visual, rapid, and sensitive method for the detection of two algal metabolites, geosmin (GSM) and 2-methylisoborneol (2-MIB) using a competitive displacement technique based on molecular imprinted polymers (MIPs) and fluorescent tags was developed. In this method, fluorescent tags that bind to synthetic receptor sites of MIPs were designed and synthesised. In the presence of target analytes (geosmin and 2-methylisoborneol respectively), the tags are displaced leading to fluorescence signals.

The identification of naturally occurring labdane diterpenoid calcaratarin D as a potential anti-inflammatory agent.

In this study we report, for the first time, the synthesis of the natural product calcaratarin D via a stereo- and regio-selective aldol condensation with (S)-β-hydroxy-γ-butyrolactone as key steps. A concise synthetic route (under 10 steps) to a series of structurally related normal-labdane diterpenes was also developed and their anti-inflammatory activities were evaluated in an in vitro model of inflammation. The structure-activity relationships (SARs) pertaining to the labdane scaffold were elucidated and results suggest that an α-alkylidene-β-hydroxy-γ-butyrolactone system is necessary for potent activity in the labdanes.

A synthetic approach to chrysophaentin F.

The chrysophaentins are a newly discovered natural product family displaying promising anti-infective activity. Herein we describe an approach to chrysophaentin F that uses an array of metal catalysed coupling reactions (Cu, Ni, Pd, W, Mo) to form key bonds.

Direct Evidence for the Critical Role of 5,6-Dihydroxyindole in Polydopamine Deposition and Aggregation.

The definitive role of the intermediate 5,6-dihydroxyindole (DHI) in the formation of polydopamine (PDA) coatings from aqueous dopamine (DA) has not been clearly elucidated and remains highly controversial. Our foray into this debate as reported in this study agrees with some reported assertions that DHI-based coatings are not synonymous with PDA coatings. Our conclusion arises from a systematic comparison of the components and properties of DHI-based coatings and PDA coatings.

insights into the nanoscale deposition of 5,6-dihydroxyindole-based coatings and the implications on the underwater adhesion mechanism of polydopamine coatings.

The biomimetic coating polydopamine (PDA) has emerged as a promising coating material for various applications. However, the mechanism of PDA deposition onto surfaces is not fully understood, and the coating components of PDA and its relation to the putative intermediate 5,6-dihydroxyindole (DHI) are still controversial. This investigation discloses the deposition mechanisms of dopamine (DA)-based coatings and DHI-based coatings onto silicon surfaces by monitoring the nanoscale deposition of both coatings using high-precision ellipsometry.

Influencing the Fate of Cardiac and Neural Stem Cell Differentiation Using Small Molecule Inhibitors of ALK5.

In this study, 50 tri-substituted imidazoles (TIs), which are analogs of the small molecules TA-01 and SB203580, were synthesized and screened for cardiomyogenic activities. Several TIs displayed cardiomyogenic activities when applied during the differentiation from days 3-5. The TIs did not affect the Wnt/β-catenin pathway during cardiomyogenesis and the likely mechanism of action is through the inhibition of ALK5 of the TGFβ pathway.

Unraveling the Inconsistencies of Cardiac Differentiation Efficiency Induced by the GSK3β Inhibitor CHIR99021 in Human Pluripotent Stem Cells.

Cardiac differentiation efficiency is hampered by inconsistencies and low reproducibility. We analyzed the differentiation process of multiple human pluripotent stem cell (hPSC) lines in response to dynamic GSK3β inhibition under varying cell culture conditions. hPSCs showed strong differences in cell-cycle profiles with varying culture confluency.

The polypharmacology of natural products.

The once-popular approach of using natural products as a prime source for medicinal chemistry and drug discovery has waned considerably in the past two decades due to the advent of high-throughput screening of small molecule mega libraries. However, the growing appreciation of network pharmacology as the next drug-discovery paradigm suggests that natural products and their unique polypharmacology offer significant advantages for finding novel therapeutics particularly for the treatment of complex and multifactorial diseases. Drug discovery process is awaiting the revitalization of interest in natural products and their derivatives.

A Multidisciplinary Discharge Timeout Checklist Improves Patient Education and Captures Discharge Process Errors.

Objective: To design and implement a discharge timeout checklist, and to assess its effects on patients' understanding as well as the potential impact on preventable medical errors surrounding hospital discharges to home.

Methods: Based on the structure successfully used for surgical procedures and using the Model for Improvement framework, we designed a discharge checklist to review and assess patients' understanding of discharge medications, catheters, home care plans, follow-up, symptoms, and who to call with problems after discharge. In parallel, we developed a process of integrating the checklist into the discharge process after routine discharge procedures were completed.