Synthesis of Quinoline and Dihydroquinoline Embelin Derivatives as Cardioprotective Agents.

A set of new dihydroquinoline embelin derivatives was obtained from the reaction of the natural benzoquinone embelin (1) with anilines and aromatic aldehydes in the presence of AgOTf. The synthesis of these compounds involves the formation of a Knoevenagel adduct, followed by nucleophilic addition of aniline and subsequent electrocyclic ring closure. The scope of the reaction regarding the aldehydes and anilines was determined. Quinoline derivatives were also obtained from the corresponding dihydroquinolines under oxidation with DDQ. The cardioprotective activity of the synthesized compounds was screened using a doxorubicin-induced cardiotoxicity model in H9c2 cardiomyocytes. Some structure-activity relationships were outlined, and the best activities were achieved with quinoline-embelin derivatives having a 4-nitrophenyl group attached at the pyridine ring. The obtained results indicated that embelin derivatives 4i, 6a, 6d, 6k, and 6m could have potential as cardioprotective agents, as they attenuated a DOX-induced cardiotoxicity effect acting on oxidative stress and apoptosis.

A Qualitative Exploration of Maternal Anxiety: Implications for Helping Professionals.

OBJECTIVES: To gain insight into the nature of maternal anxiety among mothers from diverse cultures through exploring the components of maternal anxiety and ways mothers cope with it in order to assist helping professionals in providing psychoeducation and counseling to mothers who experience intense anxiety regarding their children. METHODS: In this qualitative study, 17 mothers participated in cognitive interviews conducted as a part of the maternal anxiety scale development. Data from semi-structured interviews was explored using thematic analysis. RESULTS: Four themes related to mothers' experiences of anxiety emerged from the data: (1) maternal insecurities and social comparison, (2) coping with anxiety, (3) dependence versus autonomy, (4) cultural considerations. CONCLUSIONS FOR PRACTICE: The results of this study can be used by helping professionals working with mothers by implementing emotion regulation skills for maternal anxiety that are described in the implications section of the paper.

Influence of the degree of adherence to the mediterranean diet and its components on cardiometabolic risk during pregnancy. The GESTAFIT project.

BACKGROUND AND AIMS: Studies regarding dietary patterns and cardiometabolic risk markers during pregnancy are scarce. The aim of the present study was to analyse whether different degrees of adherence to the Mediterranean diet (MD) and the MD components were associated with cardiometabolic markers and a clustered cardiometabolic risk during pregnancy. METHODS AND RESULTS: This study comprised 119 pregnant women from the GEStation and FITness (GESTAFIT) project. Dietary habits were assessed with a food frequency questionnaire at the 16th and 34th gestational weeks (g.w.). The Mediterranean Diet Score was employed to assess MD adherence. The following cardiometabolic markers were assessed: pre-pregnancy body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting glucose, triglycerides and high-density lipoprotein cholesterol (HDL-C). A greater MD adherence was associated with a better cardiometabolic status in cross-sectional (16th g.w. and 34th g.w.) and prospective analyses (MD adherence at the 16th g.w. and cardiometabolic markers at the 34th g.w.; SBP, DBP and HDL-C; all, p < 0.05). Participants with the highest MD adherence (Tertile 3) had a lower clustered cardiometabolic risk than those with the lowest MD adherence (Tertile 1) at the 16th and 34th g.w. (both, p < 0.05). A higher intake of fruits, vegetables and fish and a lower intake of refined cereals and red meat and subproducts were associated with a lower cardiometabolic risk during pregnancy (all, p < 0.05). CONCLUSION: A higher MD adherence, a greater intake of fruits, vegetables and fish and a lower intake of refined cereals and red meat and subproducts showed a cardioprotective effect throughout gestation.

Kinetically guided radical-based synthesis of C(sp3)-C(sp3) linkages on DNA.

DNA-encoded libraries (DEL)-based discovery platforms have recently been widely adopted in the pharmaceutical industry, mainly due to their powerful diversity and incredible number of molecules. In the two decades since their disclosure, great strides have been made to expand the toolbox of reaction modes that are compatible with the idiosyncratic aqueous, dilute, and DNA-sensitive parameters of this system. However, construction of highly important C(sp3)-C(sp3) linkages on DNA through cross-coupling remains unexplored. In this article, we describe a systematic approach to translating standard organic reactions to a DEL setting through the tactical combination of kinetic analysis and empirical screening with information captured from data mining. To exemplify this model, implementation of the Giese addition to forge high value C-C bonds on DNA was studied, which represents a radical-based synthesis in DEL.

Mechanistic insights into the activation of ester prodrugs of 666-15.

cAMP-response element binding protein (CREB) is an oncogenic transcription factor implicated in many different types of cancer. We previously reported the discovery of 666-15 as a potent inhibitor of CREB-mediated gene transcription. In an effort to improve the aqueous solubility of 666-15, amino ester prodrugs 1 and 4 were designed and synthesized. Detailed chemical and biological studies of 1 and 4 revealed that a small portion of the prodrugs were converted into 666-15 through intermediate 3 instead of a long-range O,N-acyl transfer reaction that was initially proposed. These results provide unique insights into the activation of these ester prodrugs.

Design, synthesis and biological evaluation of new embelin derivatives as CK2 inhibitors.

A new series of furan embelin derivatives was synthesized and characterized as ATP-competitive CK2 inhibitors. The new compounds were efficiently synthesized using a multicomponent approach from embelin (1), aldehydes and isonitriles through a Knoevenagel condensation/Michael addition/heterocyclization. Several compounds with inhibitory activities in the low micromolar or even submicromolar were identified. The most active derivative was compound 4l (2-(tert-butylamino)-3-(furan-3-yl)-5-hydroxy-6-undecylbenzofuran-4,7-dione) with an IC50 value of 0.63 µM. It turned out to be an ATP competitive CK2 inhibitor with a Ki value determined to be 0.48 µM. Docking studies allowed the identification of key ligand-CK2 interactions, which could help to further optimize this family of compounds as CK2 inhibitors.

Efficient Multicomponent Synthesis of Diverse Antibacterial Embelin-Privileged Structure Conjugates.

A library of embelin derivatives has been synthesized through a multicomponent reaction from embelin (1), aldehydes and privileged structures such as 4-hydroxycoumarin, 4-hydroxy-2H-pyran-2-one and 2-naphthol, in the presence of InCl3 as catalyst. This multicomponent reaction implies Knoevenagel condensation, Michael addition, intramolecular cyclization and dehydration. Many of the synthesized compounds were active and selective against Gram-positive bacteria, including one important multiresistant Staphylococcus aureus clinical isolate. It was found how the conjugation of diverse privileged substructure with embelin led to adducts having enhanced antibacterial activities.

5-Ethynylarylnaphthalimides as antitumor agents: Synthesis and biological evaluation.

A set of 5-ethynylarylnaphthalimides was synthesized by Sonogashira cross-coupling reactions and evaluated for antiproliferative and antitopoisomerase II in vitro activities. Furthermore docking studies of these molecules as DNA-intercalators were carried out and the in vivo DNA-damaging activity was also determined with the model organism Saccharomyces cerevisiae. From the obtained results three naphthalimides 6, 13 and 14 showed strong topoisomerase II inhibitory activity. These three molecules also presented good docking scores as DNA-intercalators using a self-complementary oligodeoxynucleotide d(ATGCAT)2 as a model, and compounds 13 and 14 were among the most cytotoxic in the in vivo DNA-damaging activity.

Microwave-Assisted Organocatalytic Intramolecular Knoevenagel/Hetero Diels-Alder Reaction with O-(Arylpropynyloxy)-Salicylaldehydes: Synthesis of Polycyclic Embelin Derivatives.

A highly efficient and regioselective approach to new polycyclic embelin derivatives through a domino Knoevenagel condensation/intramolecular hetero Diels-Alder reaction using O-(arylpropynyloxy)-salicylaldehydes in the presence of ethylenediamine diacetate (EDDA) is reported. This organocatalyzed protocol is compatible toward a wide range of aryl-substituted alkynyl ethers with electron-donating and electron-withdrawing groups. When other active methylene compounds were subjected to this domino reaction the corresponding adducts were obtained in high yield.

Toxic Hepatitis Associated With the Use of Contraceptives: A Diagnosis to Bear in Mind.

Drug-induced liver injury (DILI) is a rare condition with a high burden of morbidity and risk of severe complications that may even require liver transplantation to survive. There are no pathognomonic diagnostic tests for this condition, thus being a challenge it is considered a diagnosis of exclusion. We present the case of a patient who, after starting intramuscular contraceptives, presented with acute alteration of liver function that requires the ruling out of multiple pathologies that could be the cause of the biochemical findings. With the pharmacological suspension and initiation of support measures, full recovery was achieved.

Tunable Redox Mediators for Li-O2 Batteries Based on Interhalide Complexes.

Li-O2 batteries can provide significantly higher gravimetric energy density than Li-ion batteries, but their practical use is limited by a number of fundamental issues associated with oxidizing discharge products such as Li2O2 and LiOH during charging. Soluble inorganic redox mediators (RMs) like LiI and LiBr have been shown to enhance round-trip efficiency where different solvents can greatly shift the redox potential of the RMs, significantly altering the overpotential during charging, as well as their oxidizing power against the discharge product. Unfortunately, other design requirements like (electro)chemical stability with the electrode as well as reactive discharge products greatly constrain the selection of solvent, making it impractical to additionally design the solvent to provide optimal RM performance. In this work, we demonstrate that interhalide RMs based on LiI/LiBr and LiI/LiCl mixtures can enable tuning of the oxidizing power of the RM in a given solvent. I-Br interhalides I2Br- to IBr2- showed increasing chemical oxidizing power toward Li2O2 and LiOH with increasing Br, and DEMS measurements during charging of Li-O2 cells demonstrated that these I-Br interhalide RMs led to increased O2 evolution with respect to LiI and reduced charging potential and CO2 evolution with respect to LiBr.

A clickable photoaffinity probe of betulinic acid identifies tropomyosin as a target.

Target identification of bioactive compounds is important for understanding their mechanisms of action and provides critical insights into their therapeutic utility. While it remains a challenge, unbiased chemoproteomics strategy using clickable photoaffinity probes is a useful and validated approach for target identification. One major limitation of this approach is the efficient synthesis of appropriately substituted clickable photoaffinity probes. Herein, we describe an efficient and consistent method to prepare such probes. We further employed this method to prepare a highly stereo-congested probe based on naturally occurring triterpenoid betulinic acid. With this photoaffinity probe, we identified tropomyosin as a novel target for betulinic acid that can account for the unique biological phenotype on cellular cytoskeleton induced by betulinic acid.

Colon injury and gastrocolocutaneous fistula complication of percutaneous endoscopic gastrostomy.

Percutaneous endoscopic gastrostomy (PEG) insertion is an effective endoscopic procedure for enteral feeding in patients with difficulty swallowing. Many postprocedural complications have been reported after the PEG procedure. The displacement of the transverse colon over the anterior gastric wall can predispose the patient to colonic injury and fistulae during PEG placement. Gastrocolonic fistulas represent a serious but rare complication post PEG placement. We report a 90 year old man with a background of multiple comorbidities and high preoperative risk who developed a gastrocolocutaneous fistula post PEG placement due to a colonic injury. He was successfully treated with nonoperative management.

Prediction of ACE-I Inhibitory Peptides Derived from Chickpea (Cicer arietinum L.): In Silico Assessments Using Simulated Enzymatic Hydrolysis, Molecular Docking and ADMET Evaluation.

Chickpea (Cicer arietinum L.) peptides have shown in vitro potential to inhibit the angiotensin I-converting enzyme (ACE-I). However, the potential molecular interactions between chickpea peptides (CP) and ACE-I as well as their ADMET (absorption/distribution/metabolism/excretion/toxicity) characteristics remain unknown. Thus, our aim was to study the in silico interactions of CP with ACE-I and the CP ADMET characteristics. Legumin and provicilin sequences were submitted to in silico analysis to search for ACE-I inhibitory peptides. Simulated enzymatic hydrolysis was performed using the BIOPEP-UWM database, and the ACE-I inhibitory peptides generated (EC50 ≤ 200 µM) were selected to perform molecular docking and ADMET analysis. After hydrolysis, 59 out of 381 peptides with ACE-I inhibitory potential were released. Based on A and B parameters, the legumin peptides showed better ACE-I inhibitory potential than the provicilin ones. CP mainly interact with residues from pocket S1 (Ala354/Glu384) and S2 (His353/His513) through hydrogen bonds (distances < 3.0 Å) and hydrophobic interactions (binding energy from −5.7 to −9.2 kcal/mol). Through ADMET analysis, CP showed optimal values for inhibiting ACE-I in vivo. ACE-I inhibitory peptides from legumin and provicilin can bind strongly and tightly to the active site of ACE-I. Further studies to evaluate in vivo the antihypertensive effects of CP are warranted.

Prevalence of Chronic Infection by Hepatitis C Virus in Asymptomatic Population With Risk Factors in Cartagena, Colombia.

Introduction: Infection by the hepatitis C virus (HCV) is an important cause of chronic liver disease, considered a public health problem worldwide with high morbidity and mortality due to limited access to diagnostic tests in developing countries. Only a small percentage know their infection status and receive timely treatment. It is critical to make diagnostic tests for HCV infection accessible and to provide timely treatment, which not only reduces the spread of infection but also stops the progression of HCV disease without symptoms. Objective: To determine the prevalence of chronic infection by HCV in patients with risk factors by using rapid tests in Cartagena, Colombia, and describe their epidemiological characteristics. Methodology: A cross-sectional descriptive observational study was carried out on asymptomatic adults with risk factors for HCV infection in the city of Cartagena between December 2017 and November 2019. A rapid immunochromatographic test was performed to detect antibodies, characterizing the population. Results: In total, 1,023 patients were identified who met the inclusion criteria, 58.5% women and 41.4% men, obtaining nine positive results, confirming chronic infection with viral load for HCV, finding seven cases of genotype 1b and two genotype 1a. Conclusion: In our study, a prevalence of hepatitis C infection of 0.9% was found in asymptomatic individuals with risk factors, which allows us to deduce that the active search for cases in risk groups constitutes a pillar for the identification of the disease, the initiation of antiviral therapy, and decreased morbidity and mortality.

PROTACs to address the challenges facing small molecule inhibitors.

Small molecule inhibitors of proteins represent important medicines and critical chemical tools to investigate the biology of the target proteins. Advances in various -omics technologies have fueled the pace of discovery of disease-relevant proteins. Translating these discoveries into human benefits requires us to develop specific chemicals to inhibit the proteins. However, traditional small molecule inhibitors binding to orthosteric or allosteric sites face significant challenges. These challenges include drug selectivity, therapy resistance as well as drugging undruggable proteins and multi-domain proteins. To address these challenges, PROteolysis TArgeting Chimera (PROTAC) has been proposed. PROTACs are heterobifunctional molecules containing a binding ligand for a protein of interest and E3 ligase-recruiting ligand that are connected through a chemical linker. Binding of a PROTAC to its target protein will bring a E3 ligase in close proximity to initiate polyubiquitination of the target protein ensuing its proteasome-mediated degradation. Unlike small molecule inhibitors, PROTACs achieve target protein degradation in its entirety in a catalytical fashion. In this review, we analyze recent advances in PROTAC design to discuss how PROTACs can address the challenges facing small molecule inhibitors to potentially deliver next-generation medicines and chemical tools with high selectivity and efficacy. We also offer our perspectives on the future promise and potential limitations facing PROTACs. Investigations to overcome these limitations of PROTACs will further help realize the promise of PROTACs for human benefits.

Modular Synthesis and Antiproliferative Activity of New Dihydro-1H-pyrazolo[1,3-b]pyridine Embelin Derivatives.

A set of new dihydro-1H-pyrazolo[1,3-b]pyridine and pyrazolo[1,3-b]pyridine embelin derivatives was synthesized through a multicomponent reaction from natural embelin, 3-substituted-5-aminopyrazoles and aldehydes. The synthesized compounds were evaluated against three hematologic tumor cell lines, HEL (acute erythroid leukemia), K-562 (chronic myeloid leukemia) and HL-60 (acute myeloid leukemia), and five breast cancer cell lines (SKBR3, MCF-7, MDA-MB-231, BT-549, HS-578T). The primate non-malignant kidney Vero cell line was used as the control of cytotoxicity. From the obtained results, some structure-activity relationships were outlined. Furthermore, in silico prediction of physicochemical properties and ADME parameters were determined for the derivatives with the best antiproliferative values.

JKST6, a novel multikinase modulator of the BCR-ABL1/STAT5 signaling pathway that potentiates direct BCR-ABL1 inhibition and overcomes imatinib resistance in chronic myelogenous leukemia.

Chronic myelogenous leukemia (CML) is a hematological malignancy that highly depends on the BCR-ABL1/STAT5 signaling pathway for cell survival. First-line treatments for CML consist of tyrosine kinase inhibitors that efficiently target BCR-ABL1 activity. However, drug resistance and intolerance are still therapeutic limitations in Ph+ cells. Therefore, the development of new anti-CML drugs that exhibit alternative mechanisms to overcome these limitations is a desirable goal. In this work, the antitumoral activity of JKST6, a naphthoquinone-pyrone hybrid, was assessed in imatinib-sensitive and imatinib-resistant human CML cells. Live-cell imaging analysis revealed JKST6 potent antiproliferative activity in 2D and 3D CML cultures. JKST6 provoked cell increase in the subG1 phase along with a reduction in the G0/G1 phase and altered the expression of key proteins involved in the control of mitosis and DNA damage. Rapid increases in Annexin V staining and activation/cleavage of caspases 8, 9 and 3 were observed after JKST6 treatment in CML cells. Of interest, JKST6 inhibited BCR-ABL1/STAT5 signaling through oncokinase downregulation that was preceded by rapid polyubiquitination. In addition, JKST6 caused a transient increase in JNK and AKT phosphorylation, whereas the phosphorylation of P38-MAPK and Src was reduced. Combinatory treatment unveiled synergistic effects between imatinib and JKST6. Notably, JKST6 maintained its antitumor efficacy in BCR-ABL1-T315I-positive cells and CML cells that overexpress BCR-ABL and even restored imatinib efficacy after a short exposure time. These findings, together with the observed low toxicity of JKST6, reveal a novel multikinase modulator that might overcome the limitations of BCR-ABL1 inhibitors in CML therapy.

Leupeptin-based inhibitors do not improve the mdx phenotype.

Calpain activation has been implicated in the disease pathology of Duchenne muscular dystrophy. Inhibition of calpain has been proposed as a promising therapeutic target, which could lessen the protein degradation and prevent progressive fibrosis. At the same time, there are conflicting reports as to whether elevation of calpastatin, an endogenous calpain inhibitor, alters pathology. We compared the effects of pharmacological calpain inhibition in the mdx mouse using leupeptin and a proprietary compound (C101) that linked the inhibitory portion of leupeptin to carnitine (to increase uptake into muscle). Administration of C101 for 4 wk did not improve muscle histology, function, or serum creatine kinase levels in mdx mice. Mdx mice injected daily with leupeptin (36 mg/kg) for 6 mo also failed to show improved muscle function, histology, or creatine kinase levels. Biochemical analysis revealed that leupeptin administration caused an increase in m-calpain autolysis and proteasome activity, yet calpastatin levels were similar between treated and untreated mdx mice. These data demonstrate that pharmacological inhibition of calpain is not a promising intervention for the treatment of Duchenne muscular dystrophy due to the ability of skeletal muscle to counter calpain inhibitors by increasing multiple degradative pathways.

[Stability: a factor to consider in antibiotic-lock solutions]. / La estabilidad como factor para considerar en las soluciones de sellado antibiótico.

Antibiotic-lock therapy (ALT) has been related to a reduction in the need for catheter withdrawal in patients with catheter-related infection. The stability of the antimicrobial solutions used in ALT has not been sufficiently investigated. A systematic literature review was performed to identify articles including studies on the stability of ALT solutions. Nine studies fulfilled the inclusion criteria requiring specific drug determination techniques, and no apparent drug alterations were observed. The main microorganisms studied were Staphylococcus spp., Pseudomonas aeruginosa, and Klebsiella pneumoniae. The antibiotics included cefazolin, ceftazidime, ciprofloxacin, colistin, gentamicin, ticarcillin/clavulanate, and vancomycin in solution, administered alone or in combinations, with or without heparin. All solutions were fairly stable except for ciprofloxacin at a concentration of 10mg/mL. Few studies applied strict criteria to assess the stability of antibiotic solutions used in ALT; hence, the currently available data are limited. Therefore, it seems advisable to include appropriate stability studies in further research on the use of ALT.