Two-component symmetrical diarylation of ynamides.

The present study describes a method for the dicarbofunctionalization of ynamide via a palladium-catalyzed two-component diarylation with aryl boronic acids. The reaction involves a consecutive transmetalation of the aryl boronic acids with a Pd(II)-complex making the transformation stereoselective. Importantly, the reaction proceeds under mild conditions and tolerates a broad range of functional groups. Control experiments validate the role of the oxidant (useful for catalyst regeneration) in the reaction mechanism.

Three Component syn-1,2-Arylmethylation of Internal Alkynes.

A Pd-catalyzed three-component syn-1,2-arylmethylation of internal alkynes (ynamides/yne-acetates/alkynes) is described. The readily available and bench stable coupling partners iodo-arenes, and methyl boronic acid are successfully used in this coupling strategy to access the methyl-containing tetra-substituted olefins; the scope is broad showing excellent functional-group tolerance. Notably, the transformation is regio- as well as stereoselective. The biologically relevant motifs (BRM) bearing iodo-arenes and ynamides are also used for the late-stage syn-1,2-arylmethylation of alkynes. Aryl-alkylation, aryl-trideuteriomethylation, alkynyl-methylation, and alkenyl-methylation of ynamides are also presented. The Me-substituted alkenes are further transformed into synthetically important ß-amino-indenones and α-fluoro-α'-methyl ketones.

Regioselective Difunctionalization and Annulation of Ynamide.

The use of ynamides in organic synthesis has gained significant attention due to their ability to provide access to complex molecular structures through transformations such as 1,2-difunctionalization and annulation reactions. These reactions enable the formation of highly functionalized N-bearing olefins and unusual N-bearing heterocycles. In this minireview, we present a systematic overview of the regioselective difunctionalization and annulation reactions of ynamides. We discuss the multi-component reactions, and radical-triggered functionalizations across the ynamides carbon-carbon multiple bonds and the use of bifunctional reagents in annulation of ynamides, highlighting their potential in expanding the substrate scope. Furthermore, we provide insights into the mechanistic breakthroughs that have been achieved in recent years in the development of these reactions. Finally, we emphasize the promising future prospects of ynamides as versatile building blocks for the synthesis of complex molecular architectures.

Pathogenesis of Viral Infections and Male Reproductive Health: An Evidence-Based Study.

Viruses, being intracellular obligate parasites, can cause several congenital and sexually transmitted diseases. Depending on the site of infection, viruses can adopt various pathogenic mechanisms for their survival and to escape the host immune response. The male reproductive system is one of the attainable targets of many viruses including immunodeficiency virus (HIV), Zika virus (ZIKV), adenovirus, cytomegalovirus (CMV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and infection with such viruses may cause serious health issues. Leydig cells and seminiferous tubules are the prime sites of mammalian testis for viral infection. The azoospermic condition is a common symptom of viral infection, wherein the hypothalamic-pituitary-testicular (HPT) axis can be disrupted, leading to decreased levels of luteinizing hormone (LH). Furthermore, oxidative stress (OS) is a major contributing factor to viral infection-associated male infertility. The likelihood of direct and indirect infection, as well as sex-based variability in the vulnerability pattern to viral infections, has been observed. However, there appears to be a long-term impact of viral infection on male reproductive performance due to testicular tissue pathogenicity - a process that requires thorough investigation. The present study aimed to explore how the viruses affect the male reproductive system, including their distribution in tissues and body fluids, possible targets as well as the effects on the endocrine system. We used the major electronic databases such as MEDLINE and SCOPUS. Google Scholar was also consulted for additional literature search related to the topic. Obtained literatures were sorted based on the content. The articles that reported the pathogenesis of viruses on male reproductive health and were published in the English language were included in the present study.

Gold-Catalyzed Transformation of Ynamides.

Ynamide, a unique species with inherited polarization of nitrogen lone pair electron to triple bond, has been largely used for the developement of novel synthetic methods and the construction of unusual N-bearing heterocycles. The reaction versatility of ynamide on umpolung reactivity, radical reactions and asymmetric synthesis have been recently reviewed. This review provides an overall scenic view into the gold catalyzed transformation of ynamides. The ynamides reactivity towards nitrogen-transfer reagents, such as azides, nitrogen ylides, isoxazoles, and anthranils; oxygen atom-transfer reagents, like nitrones, sulfoxides, and pyridine N-oxides; and carbon nucleophiles under gold catalysis are herein uncovered. The scope as well the mechanistic insights of each reaction is also briefed.

TRIP6 inhibits Hippo signaling in response to tension at adherens junctions.

The transcriptional co-activator YAP controls cell proliferation, survival, and tissue regeneration in response to changes in the mechanical environment. It is not known how mechanical stimuli such as tension are sensed and how the signal is transduced to control YAP activity. Here, we show that the LIM domain protein TRIP6 acts as part of a mechanotransduction pathway at adherens junctions to promote YAP activity by inhibiting the LATS1/2 kinases. Previous studies showed that vinculin at adherens junctions becomes activated by mechanical tension. We show that vinculin inhibits Hippo signaling by recruiting TRIP6 to adherens junctions and stimulating its binding to and inhibition of LATS1/2 in response to tension. TRIP6 competes with MOB1 for binding to LATS1/2 thereby blocking MOB1 from recruiting the LATS1/2 activating kinases MST1/2. Together, these findings reveal a novel pathway that responds to tension at adherens junctions to control Hippo pathway signaling.

Keteniminium-Driven Umpolung Difunctionalization of Ynamides.

A three-component Pd-catalyzed coupling of ynamides, aryl diazonium salts, and aryl boronic acids for the synthesis of novel triaryl-substituted enamides is described. This transformation represents the first example of an umpolung regioselective unsymmetrical syn-1,2-diarylation/aryl-olefination of ynamides. The aryl moieties of the diazonium salt (electrophile) and boronic acid (nucleophile) are explicitly incorporated in the electrophilic α- and nucleophilic ß-position, respectively, of the ynamide, resulting in a single isomer of the N-bearing tetrasubstituted olefin. The scope is broad (68 examples), showing excellent functional-group tolerance. DFT calculations substantiate the rationale of the mechanistic cycle and the regioselectivity. The chemoselectivity and synthetic potential of the enamide products were also studied.

Thioarylative Radical Cyclization of Yne-Dienone.

We herein demonstrated a N-hydroxyphthalimide (NHPI)-mediated chemo- and regioselective radical cyclization of yne-dienone with thiols to construct 3-thioaryl bearing [6,6]-fused dihydrochromenone derivatives. This transformation tolerates common functional groups and has broad scope. The reaction proceeds via the attack of a thioaryl radical to alkyne over the activated Michael acceptor. The TEMPO quenching experiment suggests the involvement of a radical intermediate. Synthetic versatility of 3-thioaryldihydrochromenones is also showcased.

Alkyne Versus Ynamide Reactivity: Regioselective Radical Cyclization of Yne-Ynamides.

Ynamides are typically more reactive than simple alkynes and olefins. However, a serendipitous observation revealed a rare case where the reactivity of simple alkynes exceeds that of ynamides. This led to the development of a unique sulfur-radical-triggered cyclization of yne-tethered ynamides, which involves attack of the alkyne by a thiyl radical followed by cyclization with the ynamide. A wide range of novel 4-thioaryl pyrroles that could tolerate common functional moieties and N-protecting groups were expediently constructed by this strategy. The current method contrasts with the typical cyclization of yne-ynamides, which involves the attack of the alkyne moiety by the ynamide core. Control experiments and DFT calculations supported the participation of the sulfur radical in the reaction and the regioselective cyclization. The synthetic potential of the substituted pyrroles is also discussed.

Regioselective Twofold Annulation of Propargyl Acetates.

The regioselective annulation of unsymmetrical alkynes has always been a focused research topic. A Pd-catalyzed double annulation of unsymmetrical alkynes (i.e., yne-acetates) with aryl diazonium salts for the synthesis of substituted naphthalene derivatives is developed. The process addresses intrinsic regioselectivity challenges in the annulations of unsymmetrical alkynes. Mechanistic investigations shed light on the crucial role of the acetate-directing groups in determining the regiochemical reaction outcome.

Influence of SGLT2 Inhibitors in Remodeling, Substrate and Ion Metabolism of Myocardium to Prevent Cardiovascular Risks: Recent Work and Advancement.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of drugs that lower blood glucose levels while decreasing blood pressure, volume loss, and weight loss. SGLT2 inhibitors were studied to determine their effectiveness in treating cardiovascular disease and their side effects. Study outcomes related to cardiovascular and metabolic outcomes were examined in patients on SGLT2 inhibitors by searching PubMed, Embase, Cochrane, and SCOPUS. Articles related to clinical trials, reviews, and meta-analyses were considered. A review of SGLT2 inhibitors' mechanisms of action in preventing cardiovascular (CVS) disease progression was described. We then reviewed the possible effects of SGLT2 inhibitors on CVS dysfunction development, composition, and stability. In the following, we discussed the impact of SGLT2 inhibitors on CVD events, such as ischemic strokes and myocardial infarctions, and their role in treating congestive heart failure and cardiovascular mortality.

A comprehensive review on the risks assessment and treatment options for Sarcopenia in people with diabetes.

Objectives: This comprehensive review aims to examine the reciprocal interplay between Type 2 diabetes mellitus (T2DM) and sarcopenia, identify prevailing research gaps, and discuss therapeutic approaches and measures to enhance healthcare practices within hospital settings. Methods: A thorough literature review was conducted to gather relevant studies and articles on the relationship between T2DM and sarcopenia. Various databases were searched, including Google Scholar, PubMed, Scopus, and Science Direct databases. The search terms included T2DM, sarcopenia, inflammation, insulin resistance, advanced glycation end products, oxidative stress, muscle dimensions, muscle strength, muscle performance, aging, nutrition, hormone levels, and physical activity. The collected articles were critically analysed to extract key findings and identify gaps in current research. Results: The prevalence and incidence of metabolic and musculoskeletal disorders, notably T2DM and sarcopenia, have surged in recent years. T2DM is marked by inflammation, insulin resistance, accumulation of advanced glycation end products, and oxidative stress, while sarcopenia involves a progressive decline in skeletal muscle mass and function. The review underscores the age-related correlation between sarcopenia and adverse outcomes like fractures, falls, and mortality. Research gaps regarding optimal nutritional interventions for individuals with T2DM and sarcopenia are identified, emphasizing the necessity for further investigation in this area. Conclusions: The reciprocal interplay between T2DM and sarcopenia holds significant importance. Further research is warranted to address knowledge gaps, particularly in utilizing precise measurement tools during clinical trials. Lifestyle modifications appear beneficial for individuals with T2DM and sarcopenia. Additionally, practical nutritional interventions require investigation to optimize healthcare practices in hospital settings. Supplementary Information: The online version contains supplementary material available at 10.1007/s40200-023-01262-w.

Translocation of heme oxygenase-1 to mitochondria is a novel cytoprotective mechanism against non-steroidal anti-inflammatory drug-induced mitochondrial oxidative stress, apoptosis, and gastric mucosal injury.

The mechanism of action of heme oxygenase-1 (HO-1) in mitochondrial oxidative stress (MOS)-mediated apoptotic tissue injury was investigated. MOS-mediated gastric mucosal apoptosis and injury were introduced in rat by indomethacin, a non-steroidal anti-inflammatory drug. Here, we report that HO-1 was not only induced but also translocated to mitochondria during gastric mucosal injury to favor repair mechanisms. Furthermore, mitochondrial translocation of HO-1 resulted in the prevention of MOS and mitochondrial pathology as evident from the restoration of the complex I-driven mitochondrial respiratory control ratio and transmembrane potential. Mitochondrial translocation of HO-1 also resulted in time-dependent inhibition of apoptosis. We searched for the plausible mechanisms responsible for HO-1 induction and mitochondrial localization. Free heme, the substrate for HO-1, was increased inside mitochondria during gastric injury, and mitochondrial entry of HO-1 decreased intramitochondrial free heme content, suggesting that a purpose of mitochondrial translocation of HO-1 is to detoxify accumulated heme. Heme may activate nuclear translocation of NF-E2-related factor 2 to induce HO-1 through reactive oxygen species generation. Electrophoretic mobility shift assay and chromatin immunoprecipitation studies indicated nuclear translocation of NF-E2-related factor 2 and its binding to HO-1 promoter to induce HO-1 expression during gastric injury. Inhibition of HO-1 by zinc protoporphyrin aggravated the mucosal injury and delayed healing. Zinc protoporphyrin further reduced the respiratory control ratio and transmembrane potential and enhanced MOS and apoptosis. In contrast, induction of HO-1 by cobalt protoporphyrin reduced MOS, corrected mitochondrial dysfunctions, and prevented apoptosis and gastric injury. Thus, induction and mitochondrial localization of HO-1 are a novel cytoprotective mechanism against MOS-mediated apoptotic tissue injury.

Palladium-Catalyzed Regioselective Arylalkenylation of Ynamides.

A cationic palladium-catalyzed arylalkenylation of ynamides is presented. The putative keteniminium arylpalladium intermediate likely dictates the regioselective carbopalladation of the ynamide to form a vinylpalladium species. The capture of this complex by the olefin yields linear conjugated ß-alkenyl aminodienes (especially with trans selectivity). The transformation features a broad scope with labile functional group tolerance and makes 42 unusual molecular scaffolds with structural diversity. DFT studies provide valuable insights into the reaction mechanism.

A 6-endo-dig Thiolative Cyclization of Yne-Ynamides: Access to Thiodihydropyridin-2-ones.

A straightforward regioselective intramolecular 6-endo-dig cyclization of yne-tethered ynamide is herein developed. The reaction involves an intramolecular enolate attack of ketene-N,O-acetals, generated in situ from yne-ynamide and methanesulfonic acid, to the alkyne moiety activated by a sulfonium cation. The transformation enables access to structurally diverse 5-(arylthio)-3,6-dihydropyridin-2(3H)-ones with broad functional group compatibility. The recovery of S-protecting groups and synthetic applications of the products make the transformation useful.

Cationic-palladium catalyzed regio- and stereoselective syn-1,2-dicarbofunctionalization of unsymmetrical internal alkynes.

π-Extended tetrasubstituted olefins are widely found motifs in natural products, leading drugs, and agrochemicals. Thus, development of modular strategies for the synthesis of complex all-carbon-substituted olefins always draws attention. The difunctionalization of unsymmetrical alkynes is an attractive approach but it has remained faced with regioselectivity issues. Here we report the discovery of a regio- and stereoselective syn-1,2-dicarbofunctionalization of unsymmetrical internal alkynes. A cationic Pd-catalyzed three-component coupling of aryl diazonium salts, aryl boronic acids (or olefins) and yne-acetates enables access to all-carbon substituted unsymmetrical olefins. The transformation features broad scope with labile functional group tolerance, building broad chemical space of structural diversity (94 molecules). The value of this synthetic method is demonstrated by the direct transformation of natural products and drug candidates containing yne-acetates, to enable highly substituted structurally complex allyl acetate analogues of biologically important compounds. Synthetic versatility of the carboxylate bearing highly substituted olefins is also presented. The reaction outcome is attributed to the in situ formation of stabilized cationic aryl-Pd species, which regulates regioselective aryl-palladation of unsymmetrical yne-acetates. Control experiments reveal the synergy between the carboxylate protecting group and the cationic Pd-intermediate in the regioselectivity and reaction productivity; density functional theory (DFT) studies rationalize the selectivity of the reaction.

Emerging Trends in Immunotherapy for Cancer.

Recent advances in cancer immunology have enabled the discovery of promising immunotherapies for various malignancies that have shifted the cancer treatment paradigm. The innovative research and clinical advancements of immunotherapy approaches have prolonged the survival of patients with relapsed or refractory metastatic cancers. Since the U.S. FDA approved the first immune checkpoint inhibitor in 2011, the field of cancer immunotherapy has grown exponentially. Multiple therapeutic approaches or agents to manipulate different aspects of the immune system are currently in development. These include cancer vaccines, adoptive cell therapies (such as CAR-T or NK cell therapy), monoclonal antibodies, cytokine therapies, oncolytic viruses, and inhibitors targeting immune checkpoints that have demonstrated promising clinical efficacy. Multiple immunotherapeutic approaches have been approved for specific cancer treatments, while others are currently in preclinical and clinical trial stages. Given the success of immunotherapy, there has been a tremendous thrust to improve the clinical efficacy of various agents and strategies implemented so far. Here, we present a comprehensive overview of the development and clinical implementation of various immunotherapy approaches currently being used to treat cancer. We also highlight the latest developments, emerging trends, limitations, and future promises of cancer immunotherapy.

Yb(iii)-catalysed syn-thioallylation of ynamides.

Reported herein is a syn-thioallylation of ynamides incorporating a sulfide moiety at the α-position and an allyl group at the ß-position of the ynamide. The transformation is successful under ytterbium(iii)-catalysis, providing access to highly substituted thioamino-skipped-dienes with broad substrate scope. Thus, tetrasubstituted olefins (with four different functional groups: amide, phenyl, thioaryl/alkyl, and allyl on the carbon centers) are made in a single step from readily accessible ynamides, preserving complete atom economy. The reaction can be extended to the synthesis of selenoamino dienes by ynamide syn-selenoallylation. DFT studies and control experiments provide insight into the reaction mechanism.

Ring Expansion and 1,2-Migration Cascade of Benzisoxazoles with Ynamides: Experimental and Theoretical Studies.

Demonstrated herein is an AuI -catalyzed annulation of sulfonyl-protected ynamides with substituted 1,2-benzisoxazoles for the synthesis of E-benzo[e][1,3]oxazine derivatives. The transformation involves the addition of benzisoxazole to the gold-activated ynamide, ring expansion of the benzisoxazole fragment to provide an α-imino vinylic gold intermediate, and 1,2-migration of the sulfonamide motif to the masked carbene center to deliver the respective ring-expanded benzo[e][1,3]oxazine of predominant E configuration. A trapping experiment justifies the participation of the α-imino masked gold carbene. DFT computations also support the hypothesized mechanism and rationalize the product stereoselectivity.