Leveraging Pyrazolium Ylide Reactivity to Access Indolizine and 1,2-Dihydropyrimidine Derivatives.

N-Heterocyclic ylides are important synthetic precursors to rapidly build molecular complexity. Pyrazolium ylides have largely been unexplored, and we demonstrate their diverse utility in this report. We show that these readily accessible building blocks can be used to construct different heterocyclic skeletons by varying the coupling partner. Indolizines can be formed via an N-deletion type mechanism when reacting pyrazolium salts with electron deficient alkynes. 1,2-Dihydropyrimidines can be formed via a rearrangement mechanism when reacting pyrazolium ylides with isocyanates. These reactions enable access to valuable heteroarenes without the need for transition metal catalysis, high temperatures, or strong bases.

Late-onset prosthetic aortic valve stenosis caused by pannus formation.

Transcatheter aortic valve replacement (TAVR) is a less invasive alternative to an open surgical aortic valve replacement (SAVR) for treating severe symptomatic aortic stenosis. Despite gaining widespread acceptance and approval for use in patients with high, moderate, and low surgical risk, the increasing use of TAVR has raised concerns about potential short- and long-term complications. We present the case of a 69-year-old female who underwent TAVR and subsequently presented to our outpatient cardiology clinic with progressively worsening dyspnea, orthopnea, and paroxysmal nocturnal dyspnea two years after the procedure. Echocardiography and stress testing revealed a recurrence of aortic stenosis, leading to a diagnosis of structural valve deterioration. The patient was subsequently scheduled for SAVR, which revealed commissural fusion, scarring, and unusual pannus formation that significantly narrowed the effective valve area, necessitating valve replacement. Despite requiring SAVR, two years after TAVR, the patient had a favorable postoperative course and outcome on follow-up. This case underscores the importance of continued surveillance and evaluation of patients who undergo TAVR, as they remain at risk for long-term complications such as structural valve deterioration. Proper management, including timely diagnosis and intervention, can lead to successful outcomes in such patients. Learning objective: This case underscores the importance of continued surveillance and evaluation of patients who undergo transcatheter aortic valve replacement, as they remain at risk for long-term complications such as structural valve deterioration. Proper management, including timely diagnosis and intervention, can lead to successful outcomes in such patients.

Regioselective Synthesis of C3-Hydroxyarylated Pyrazoles.

Pyrazoles are ubiquitous structures in medicinal chemistry. We report the first regioselective route to C3-hydroxyarylated pyrazoles obtained through reaction of pyrazole N-oxides with arynes using mild conditions. Importantly, this method does not require the C4 and C5 positions of the pyrazole to be functionalized to observe regioselectivity. Using this method, we completed the synthesis of a recently reported JAK 1/2 inhibitor. Our synthesis produces the desired product in 4 steps from commercially available starting materials.

Design, synthesis and biological evaluation studies of novel small molecule ENPP1 inhibitors for cancer immunotherapy.

Ecto-nucleotide pyrophosphatase/phosphodiesterases 1 (ENPP1 or NPP1), is an attractive therapeutic target for various diseases, primarily cancer and mineralization disorders. The ecto-enzyme is located on the cell surface and has been implicated in the control of extracellular levels of nucleotide, nucleoside and (di) phosphate. Recently, it has emerged as a critical phosphodiesterase that hydrolyzes cyclic 2'3'- cGAMP, the endogenous ligand for STING (STimulator of INterferon Genes). STING plays an important role in innate immunity by activating type I interferon in response to cytosolic 2'3'-cGAMP. ENPP1 negatively regulates the STING pathway and hence its inhibition makes it an attractive therapeutic target for cancer immunotherapy. Herein, we describe the design, optimization and biological evaluation studies of a series of novel non-nucleotidic thioguanine based small molecule inhibitors of ENPP1. The lead compound 43 has shown good in vitro potency, stability in SGF/SIF/PBS, selectivity, ADME properties and pharmacokinetic profile and finally potent anti-tumor response in vivo. These compounds are a good starting point for the development of potentially effective cancer immunotherapy agents.

A prospective longitudinal study to evaluate bone health, implication of FRAX tool and impact on quality of life (FACT-P) in advanced prostate cancer patients.

BACKGROUND: Androgen-deprivation therapy (ADT) as a treatment modality in advanced prostate cancer has deleterious effect on bone mineral density (BMD) and quality of life (QOL). Using FRAX (Fracture Risk Assessment) model, candidates at high risk of fractures can be predicted and appropriate treatment can be initiated at early step to prevent skeletal-related events. Objectives of the present study were to evaluate bone health, implication of FRAX tool in advanced prostate cancer and to see the impact of ADT and Bone-directed therapy (BDT) on FRAX and FACT-P QOL scores. MATERIAL & METHOD: We conducted a prospective longitudinal study of 83 localized and metastatic prostate cancer patients from March 2017 to Dec 2020. FRAX tool using BMD femoral neck (GE-Lunar) was used to compute the probability of 10-year Major osteoporotic fracture (MOF) and hip fracture risk %. Patients who received monthly Zolendronic acid with or without Vitamin-D/calcium supplementation were classified as BDT group. FRAX and FACT-P were measured at baseline and 12 months follow-up and compared between different therapeutic modalities to see the impact on clinical outcomes. RESULTS: Majority of patients had skeletal metastasis (78.3%) and high-grade disease at presentation. Secondary osteoporosis was the most commonly (82.05%) observed clinical risk factor (CRF) followed by smoking (19.23%). Hip fracture risk ≥3% accounted for larger proportion of patients than did MOF risk ≥20% (21.2% and 2.5%, respectively). Statistically significant reduction was observed in both MOF and hip fracture risk in BDT group, while worsening on ADT. ADT duration correlated positively with both MOF and hip fracture risk (R2=0.148, P<0.001 and R2=0.164, P<0.001, respectively). FRAX score accurately predict future fracture events in majority (80%) of high-risk patients. Statistically and clinically significant worsening in PWB, EWB, PCS, FACT-P Total, FACT-P TOI and FAPSI scores were observed in patients on ADT. Statistically and clinically significant improvement was noted in physical well-being in BDT group. However, other QOL domains and FACT-P total scores remained stable. CONCLUSIONS: ADT caused duration depended worsening of FRAX and FACT-P score in these patients while improvements of FRAX were seen on BDT. FRAX tool is advantageous in identifying the patients who require early intervention or therapy to decrease skeletal-related events.

Possible competitive modes of decarboxylation in the annulation reactions of ortho-substituted anilines and arylglyoxylates.

Annulation reactions of ortho-substituted anilines and arylglyoxylates in the presence of K2S2O8 at 80 °C under metal-free neutral conditions have been investigated, which extended a platform for the tandem synthesis of nitrogen heterocycles. While arylglyoxylic acids are known to undergo decarboxylation to form an acyl radical in the presence of K2S2O8 and used in the Minisci acylation of electron-deficient (hetero)aromatics, their reactions with electron-rich ortho-substituted anilines to form nitrogen heterocycles have recently been studied. Depending upon the experimental conditions used in the reactions, the mechanism of the formation of heterocycles involving reactions of an acyl radical or aryl iminocarboxylic acids has been postulated. Given the subtle understanding of the mechanisms of annulation reactions of 2-substituted anilines and arylglyoxylates in the presence of K2S2O8, an extensive mechanistic investigation was undertaken. In the current study, the various mechanistic pathways including the generation of acyl, imidoyl, aminal, and N,O-hemiketal radicals have been postulated based on different possible decarboxylation modes. Some of the proposed intermediates are supported based on the available analytical data. The protocol uses a single, inexpensive reagent K2S2O8, which offers not only transition-metal-free conditions but also serves as the reagent for the key decarboxylation step. Taken together, this study complements the current development of the annulation reactions of 2-substituted anilines and arylglyoxylates in terms of synthesis and mechanistic understanding.

Identification and structure-activity relationship studies of small molecule inhibitors of the human cathepsin D.

Cathepsin D, an aspartyl protease, is an attractive therapeutic target for various diseases, primarily cancer and osteoarthritis. However, despite several small molecule cathepsin D inhibitors being developed, that are highly potent, most of them show poor microsomal stability, which in turn limits their clinical translation. Herein, we describe the design, optimization and evaluation of a series of novel non-peptidic acylguanidine based small molecule inhibitors of cathepsin D. Optimization of our hit compound 1a (IC50 = 29 nM) led to the highly potent mono sulphonamide analogue 4b (IC50 = 4 nM), however with poor microsomal stability (HLM: 177 and MLM: 177 µl/min/mg). To further improve the microsomal stability while retaining the potency, we carried out an extensive structure-activity relationship screen which led to the identification of our optimised lead 24e (IC50 = 45 nM), with an improved microsomal stability (HLM: 59.1 and MLM: 86.8 µl/min/mg). Our efforts reveal that 24e could be a good starting point or potential candidate for further preclinical studies against diseases where Cathepsin D plays an important role.

Homoarginine Supplementation Prevents Left Ventricular Dilatation and Preserves Systolic Function in a Model of Coronary Artery Disease.

Background Homoarginine ( hA rg) has been shown to be cardioprotective in a model of ischemic heart failure; however, the mechanism remains unknown. hA rg can inhibit tissue-nonspecific alkaline phosphatase ( TNAP ), an enzyme that promotes vascular calcification. We hypothesized that hA rg will exert beneficial effects by reducing calcification in a mouse model of coronary artery disease associated with TNAP overexpression and hypercholesterolemia. Methods and Results TNAP was overexpressed in the endothelium in mice homozygous for a low-density lipoprotein receptor mutation (wicked high cholesterol [ WHC ] allele). WHC and WHC -endothelial TNAP mice received placebo or hA rg supplementation (14 mg/L in drinking water) starting at 6 weeks of age simultaneously with an atherogenic diet. Outcomes were compared between the groups after 4 to 5 weeks on treatment. Experiments were performed in males, which presented a study limitation. As expected, WHC -endothelial TNAP mice on the placebo had increased mortality (median survival 27 days, P<0.0001), increased coronary calcium and lipids ( P<0.01), increased left ventricular end-diastolic diameter ( P<0.0001), reduced ejection fraction ( P<0.05), and increased myocardial fibrosis ( P<0.0001) compared with WHC mice. Contrary to our hypothesis, hA rg neither inhibited TNAP activity in vivo nor reduced coronary artery calcification and atherosclerosis in WHC -endothelial TNAP mice; however, compared with the placebo, hA rg prevented left ventricular dilatation ( P<0.01), preserved ejection fraction ( P<0.05), and reduced myocardial fibrosis ( P<0.001). Conclusions The beneficial effect of hA rg supplementation in the setting of calcified coronary artery disease is likely due to its direct protective actions on the myocardial response to the ischemic injury and not to the inhibition of TNAP activity and calcification.

Palladium-Catalyzed Serendipitous Synthesis of Arylglyoxylic Amides from Arylglyoxylates and N,N-Dialkylamides in the Presence of Halopyridines.

A palladium-catalyzed synthesis of arylglyoxylic amides by the reaction of arylglyoxylates and N,N-dialkylamides in the presence of a 2,3-dihalopyridine has been realized for the first time. An anticipated 2,3-diaroylpyridine did not form in this reaction. The current study unveils an unprecedented role of 2,3-dihalopyridine toward this amidation. Our mechanistic study reveals that the arylglyoxylate could react with halopyridine to form a traceless activated pyridyl ester of arylglyoxylic acid, which upon subsequent reaction with amino surrogate, N,N-dialkylamides could form the arylglyoxylic amides.

EUS-guided fine-needle core liver biopsy sampling using a novel 19-gauge needle with modified 1-pass, 1 actuation wet suction technique.

BACKGROUND AND AIMS: EUS-guided fine-needle core biopsy sampling is a safe and effective technique for diagnosis of focal liver lesions. However, data are limited in its role in parenchymal disease. We evaluated the utility of EUS-guided parenchymal liver biopsy sampling with a modified 1-pass wet suction technique (EUS-modified liver biopsy sampling [EUS-MLB]) in patients with unexplained increase in liver-associated tests. METHODS: We retrospectively evaluated the safety and efficacy of EUS-MLB in patients referred for EUS to evaluate for biliary obstruction and pancreatic disorders but with associated unexplained liver tests. EUS-MLB was performed during the same session after biliary obstruction was excluded. RESULTS: One hundred sixty-five consecutive patients underwent EUS-MLB. The median age was 52 years (interquartile range [IQR], 42-65). Sixty-eight patients (41%) were men. The median of the maximum intact core tissue length was 2.4 cm (IQR, 1.8-3.5). The median total specimen length (TSL) was 6 cm (IQR, 4.3-8). The median number of complete portal tracts (CPTs) per TSL was 18 (IQR, 13- 24). The mean number of CPTs per sample length was 7.5 cm. Adverse events were uncommon (1.8%) and included abdominal pain and self-limited hematoma. CONCLUSIONS: EUS-guided fine-needle biopsy sampling using a novel 19-gauge core needle with a modified 1-pass 1 actuation wet suction technique (EUS-MLB) is a safe and effective way to evaluate patients with unexplained liver tests abnormalities who are undergoing EUS for exclusion of biliary obstruction.

Intramolecular Minisci acylation under silver-free neutral conditions for the synthesis of azafluorenones and fluorenones.

Despite its synthetic potential, intramolecular acylation by the Minisci reaction remains unexplored. The development of a new intramolecular Minisci acylation under silver-free neutral conditions providing access to azafluorenones and fluorenones is described. Distinct from the current literature known approaches for Minisci acylation, the report described herein features a method that: (a) avoids the use of silver that is invariably used in Minisci acylation, (b) does not require any acidic conditions for the activation of pyridines, and

Palladium-Catalyzed Decarboxylative Ortho-Acylation of Tertiary Benzamides with Arylglyoxylic Acids.

A palladium-catalyzed ortho-acylation of tertiary benzamides using arylglyoxylic acids has been described. Unlike the palladium insertion reported to occur in the distorted N-C(O) amide bond of tertiary benzamides, the current study unveils ortho C-H palladation in acylic or cyclic N,N-dialkylbenzamides affording ortho-acylated tertiary benzamides in good to excellent yields. Our experimental study on the mechanism provides information on the tendency of the amide nitrogen toward weak coordination with palladium as opposed to oxygen. However, density functional theory calculations suggest coordination of amide oxygen to palladium, which makes the mechanism especially interesting. A Pd(II)/Pd(III) catalytic cycle and nucleophilic attack by the acyl radical rather than arylglyoxylate anion are supported by mechanistic studies.

Intramolecular Acylation of Unactivated Pyridines or Arenes via Multiple C-H Functionalizations: Synthesis of All Four Azafluorenones and Fluorenones.

An unprecedented intramolecular acylation of unactivated pyridines via multiple C(sp3/sp2)-H functionalizations of a methyl, hydroxymethyl, or aldehyde group has been developed providing a general access to all four azafluorenones. The application of this protocol is further demonstrated to the synthesis of azafluorenone related fused nitrogen heterocycles and fluorenones. In addition, design and synthesis of a novel fluorene based organic emitter for potential use in organic light emitting devices (OLEDs) is also reported.

Formation of amides, their intramolecular reactions for the synthesis of N-heterocycles, and preparation of a marketed drug, sildenafil: a comprehensive coverage.

A unified approach to the tandem preparation of diverse nitrogen heterocycles via decarboxylative acylation of ortho-substituted amines with α-oxocarboxylic acids and subsequent intramolecular cyclizations has been developed. The key features of this work include: the first example of transition-metal-free decarboxylative amidation of α-oxocarboxylic acids with ortho-substituted amines, realization of intramolecular cyclization of amides employing nucleophiles that have previously been unexplored, mechanistic investigation of an unprecedented K2S2O8 promoted amide formation and its subsequent intramolecular cyclizations, and application to the synthesis of a best-selling marketed drug.

Palladium-catalyzed regiocontrolled domino synthesis of N-sulfonyl dihydrophenanthridines and dihydrodibenzo[c,e]azepines: control over the formation of biaryl sultams in the intramolecular direct arylation.

A palladium-catalyzed domino N-benzylation/intramolecular direct arylation involving sulfonanilides and 2-bromobenzyl bromides has been developed for the first time, providing a workable access to N-sulfonyl dihydrophenanthridines in good to excellent yields. Under the optimized conditions, the formation of 5,6-dihydrophenanthridines was largely controlled over the formation of biaryl sultams containing a seven member ring. The optimized condition was found extendable to the regiocontrolled domino formation of N-sulfonyl-6,7-dihydro-5H-dibenzo[c,e]azepines over the biaryl sultam formation. Using an appropriate substrate, a biaryl sultam has been obtained exclusively.

Metachronous bilateral segmental testicular infarction: multi-parametric ultrasound imaging with grey-scale ultrasound, Doppler ultrasound, contrast-enhanced ultrasound (CEUS) and real-time tissue elastography (RTE).

Segmental testicular infarction is a rare cause of acute scrotal pain. The appearances on grey-scale sonography are often indistinguishable from that of a testicular tumour, resulting in unnecessary orchiectomy. We report a case of acute bilateral testicular infarction, of unknown etiology, which was conservatively managed to resolution following a confident diagnosis achieved with the aid of contrast-enhanced ultrasound (CEUS) and real-time tissue elastography (RTE) along with conventional grey-scale and Doppler sonography. The evolving appearances on each of the sonographic modalities are described. We discuss the importance of complementing conventional sonography with CEUS and RTE in order to make a confident diagnosis and avoid unnecessary surgical intervention.

Transient auditory dysfunction: a description and study of prevalence.

Transient auditory dysfunction (TAD) is a previously undescribed symptom complex of unknown cause. It is characterized by short-lasting sensorineural hearing loss (unilateral or bilateral), it is associated with tinnitus, it resolves completely within minutes, and it is not accompanied by vestibular symptoms. We conducted a cross-sectional prospective study to define TAD, find its prevalence, and discuss its significance. Two hundred healthy subjects between the ages of 16 and 49 years were surveyed using a questionnaire. Of these subjects, 41 (20.5%) reported experiencing symptoms of TAD. The mean number of episodes was 5.9 times per month, the mean duration was 41 seconds, and 80% experienced concomitant tinnitus. We conclude that TAD is a common finding in a healthy population. This may have implications for the pathogenesis of sudden-onset sensorineural hearing loss. Further longitudinal studies and detailed audiologic evaluation of patients with TAD are required to ascertain the significance, etiology, and pathophysiology of this condition.

Formulation of niosomal gel for enhanced transdermal lopinavir delivery and its comparative evaluation with ethosomal gel.

The aim was to develop niosomal gel as a transdermal nanocarrier for improved systemic availability of lopinavir. Niosomes were prepared using thin-film hydration method and optimized for molar quantities of Span 40 and cholesterol to impart desirable characteristics. Comparative evaluation with ethosomes was performed using ex vivo skin permeation, fluorescence microscopy, and histopathology studies. Clinical utility via transdermal route was acknowledged using in vivo bioavailability study in male Wistar rats. The niosomal formulation containing lopinavir, Span 40, and cholesterol in a molar ratio of 1:0.9:0.6 possessed optimally high percentage of drug entrapment with minimum mean vesicular diameter. Ex vivo skin permeation studies of lopinavir as well as fluorescent probe coumarin revealed a better deposition of ethosomal carriers but a better release with niosomal carriers. Histopathological studies indicated the better safety profile of niosomes over ethosomes. In vivo bioavailability study in male Wistar rats showed a significantly higher extent of absorption (AUC(0→∞), 72.87 h × µg/ml) of lopinavir via transdermally applied niosomal gel as compared with its oral suspension. Taken together, these findings suggested that niosomal gel holds a great potential of being utilized as novel, nanosized drug delivery vehicle for transdermal lopinavir delivery.

Features of testicular epidermoid cysts on contrast-enhanced sonography and real-time tissue elastography.

A series of 7 testicular epidermoid cysts were imaged by contrast-enhanced sonography to assess internal vascularity and by real-time tissue elastography to grade stiffness by a visual and strain ratio quantification scoring system. No internal vascular enhancement was seen on contrast-enhanced sonography; the 3 largest lesions showed rim enhancement. On the real-time elastographic color display, all lesions were predominantly blue ("hard"), and the lesions analyzed for the strain ratio had a mean value of 43.57. Contrast-enhanced sonography depicts the absence of vascular flow, and real-time elastography shows that the epidermoid cysts are hard. This combination of information will help further characterize these lesions.