Total Syntheses of Polyhydroxylated Steroids by an Unsaturation-Functionalization Strategy.

Highly oxygenated cardiotonic steroids, such as ouabain, possess a wide spectrum of biological functions and remain significant synthetic challenges. Herein, we have applied an unsaturation-functionalization strategy and developed a synthetic method in addressing the C19-hydroxylation issue for efficient synthesis of polyhydroxylated steroids. An effective asymmetric dearomative cyclization allowed the construction of the C19-hydroxy unsaturated steroidal skeleton in only four steps from the Hajos-Parrish ketone ketal 7. The synthetic sequence featured C3-OH-directed hydrogenation/epoxidation, m-CPBA-triggered epoxidation/SN 2' nucleophilic substitution, Birch reduction of an enone, and regioselective LiAlH4 reduction to furnish the polyhydroxy functionalities on the steroid skeleton with high stereochemical control and efficiency. This approach ultimately enabled the total synthesis of 19-hydroxysarmentogenin and ouabagenin in 18 and 19 steps, respectively, overall. The synthesis of these polyhydroxylated steroids offers synthetic versatility and practicality in the search for new therapeutic agents.

Design, Synthesis, Antiviral Evaluation, and Molecular Dynamics Simulation Studies of New Spirocyclic Thiopyrimidinones as Anti HCoV-229E.

The current pandemic threat presented by viral pathogens like SARS-CoV-2 (COVID-19) suggests that virus emergence and dissemination are not geographically confined. As a result, the quest for antiviral agents has become critical to control this pandemic. In the current study, we provide a novel family of spirocyclic thiopyrimidinone derivatives whose cytotoxicity and antiviral efficacy were investigated against human coronavirus 229E (HCoV-229E) as a model for the Coronaviridae family. We utilized MTT and cytopathic effect (CPE) inhibitory tests on green monkey kidney (vero-E6) cell lines. The new molecules showed varied degrees of antiviral activity against the vero-E6 cell lines with minimal cytotoxicity. With a high level of a selective index (SI=14.8), compound 9 showed outstanding inhibitory ability and could effectively suppress the human coronavirus 229E. Molecular dynamics simulation (MD) studies were performed to measure the interaction and stability of the protein-ligand complex in motion. The MD results for the most active compound 9 explored remarkable interactions with the binding pockets of the main protease (Mpro) of SARS-CoV-2 enzyme confirming the results gained from in vitro experiments. ADMET properties were also predicted for all the tested compounds. All these results demonstrated that the novel spirocyclic thiopyrimidinone derivatives would have the potential to be safe, low-cost chemical compounds that might be used as a novel therapeutic option for Coronaviridae viruses like COVID-19.

Enantioselective formation of quaternary carbon stereocenters in natural product synthesis: a recent update.

Covering: 2013-2018 Natural products bearing quaternary carbon stereocenters have attracted tremendous interest from the synthetic community due to their diverse biological activities and fascinating molecular architectures. However, the construction of these molecules in an enantioselective fashion remains a long-standing challenge because of the lack of efficient asymmetric catalytic methods for installing these motifs. The rapid progress in the development of new-generation efficient chiral catalysts has opened the door for several asymmetric reactions, such as Michael addition, dearomative cyclization, polyene cyclization, α-arylation, cycloaddition, allylation, for the construction of quaternary carbon stereocenters in a highly enantioselective fashion. These asymmetric catalytic methods have greatly facilitated the synthesis of complex natural products with improved output and overall efficiency. In this concise review, we highlight the progress in the last six years in complex natural product synthesis, in which at least one quaternary carbon stereocenter has been constructed via asymmetric catalytic technologies, with particular emphasis on the analysis of the stereochemical model of each enantioselective transformation.

Cooperative 5- and 10-membered ring interactions in the 10-helix folding of oxetin homo-oligomers.

Homo-oligomers of the natural product oxetin (cis-3-amino-2-oxetanecarboxylic acid) were prepared and their conformational behaviour studied in solution and solid state and by molecular modelling. The predominant secondary structure was a 10-helix, propiciously stabilized by a network of 5-membered ring H-bonds implicating ring oxygens and neighboring amide hydrogen atoms.

Synthetic Access to All Four Stereoisomers of Oxetin.

A short synthesis of all four stereoisomers of 3-amino-2-oxetanecarboxylic acid (oxetin) is described. The oxetane core is built using a Paternò-Büchi photochemical [2 + 2] cycloaddition; from the key intermediates, complementary resolution protocols provide access to enantiomerically pure oxetin and epi-oxetin on gram-scale.

Synthesis and biological evaluation of novel pyrimidines derived from 6-aryl-5-cyano-2-thiouracil.

Starting from 6-aryl-5-cyano-2-thiouracil derivative 1a-f, a series of novel thiazolo[3,2-a]pyrimidines 4a-f were synthesized. The mechanism and the regioselectivity of the studied reactions are discussed. In addition, a series of tetrahydro-4-H-pyrimido[2,1-b][1,3]thiazines 7a-e and 2-((ethoxymethyl)thio)-4-aryl-1,6-dihydropyrimidines 9b,c,e were synthesized. The anti-microbial activities of some of the prepared compounds were screened, and the results revealed that compounds 3c and 4c were more active than the standard (Ampicillin) against gram positive bacteria (Pseudomonas aeruginosa). Moreover, compounds 4b,e and 3f were found to be good antifungal agents against the studied fungal strains.

Synthesis and antiproliferative activity of novel polynuclear heterocyclic compounds derived from 2,3-diaminophenazine.

2,3-Diaminophenazine 1 was used as a precursor for the preparation of some novel phenazine derivatives such as imidazo[4,5-b]phenazine-2-thione 2, its methylthio 3, ethyl 1-aryl-3H-[1,2,4]triazolo[2,3-a]imidazo[4,5-b]phenazines 8a-c, ethyl (2Z)-[3-aminophenazin-2-yl)amino](phenylhydrazono)ethanoate 9, pyrazino[2,3-b]phenazine derivatives 10, 12, 15-17, [1,4]diazepino[2,3-b]phenazine derivatives 13, 14, 2,3-dibenzoylaminophenazine 18, 1H-Imidazo[4,5-b]phenazine derivatives 20, 23a-c, 24, 25 and 4-[(E)-(3-amino phenazin-2-yl)diazenyl] derivatives 27-29. All compounds were tested as inhibitors of the proliferation of human lung carcinoma and colorectal cancer cell lines through inhibition of Tyrosine Kinases. Most of compounds exert good activity against the two cancer cell lines. Five compounds (1, 2, 3, 25 and 28) were found to possess the same activity as the standard drug Cisplatin.

The reliability of the standard for clinicians' interview in psychiatry (SCIP): a clinician-administered tool with categorical, dimensional and numeric output.

BACKGROUND: Existing standardized diagnostic interviews are not used by psychiatrists in clinical settings. There is an urgent need for a clinician-administered tool for assessment of adult psychopathology that produces dimensional measures, in addition to categorical diagnoses. METHODS: The Standard for Clinicians' Interview in Psychiatry (SCIP) was designed to be used in clinical settings and generates dimensional measures. The reliability of the SCIP was tested at six sites: one hospital and two clinics in USA, two hospitals in Egypt and one clinic in Canada. Participants were adult patients who were admitted for inpatient psychiatric treatment or came for regular office visits in the outpatient clinic. Refusal rate was <1%. Missing data were <1.1%. Patients with dementia, mental retardation or serious medical conditions were excluded. A total of 1,004 subjects were interviewed between 2000 and 2012. RESULTS: Inter-rater reliability (Kappa) was measured for 150 SCIP items: 116 items (77.3%) had good reliability (Kappa>0.7), 28 items (18.7%) had fair reliability (Kappa ranges from 0.5 to 0.7) and six items (4%) had poor reliability (Kappa<0.5). Cronbach's alpha for internal consistency was measured for the SCIP dimensions: anxiety, posttraumatic stress, depression, mania, hallucinations, Schneider first-rank symptoms, delusions, disorganized thoughts, disorganized behavior, negative symptoms, alcohol addiction, drug addiction, attention and hyperactivity. All of the SCIP dimensions had substantial Cronbach's alpha values (>0.7) with the exception of disorganized thoughts (Cronbach's alpha=0.375). CONCLUSIONS: The SCIP is a reliable tool for assessing psychological symptoms, signs and dimensions of the main psychiatric diagnoses.

Reduced hippocampal N-acetyl-aspartate (NAA) as a biomarker for overweight.

OBJECTIVE: We previously demonstrated an inverse relationship between both dentate gyrus neurogenesis - a form of neuroplasticity - and expression of the antiapoptotic gene marker, BCL-2 and adult macaque body weight. We therefore explored whether a similar inverse correlation existed in humans between body mass index (BMI) and hippocampal N-acetyl-aspartate (NAA), a marker of neuronal integrity and putatively, neuroplasticity. We also studied the relationship of a potentially neurotoxic process, worry, to hippocampal NAA in patients with generalized anxiety disorder (GAD) and control subjects (CS). METHODS: We combined two previously studied cohorts of GAD and control subjects. Using proton magnetic resonance spectroscopy imaging ((1)H MRSI) in medication-free patients with GAD (n = 29) and a matched healthy control group (n = 22), we determined hippocampal concentrations of (1) NAA (2) choline containing compounds (CHO), and (3) Creatine + phosphocreatine (CR). Data were combined from 1.5 T and 3 T scans by converting values from each cohort to z-scores. Overweight and GAD diagnosis were used as categorical variables while the Penn State Worry Questionnaire (PSWQ) and Anxiety Sensitivity Index (ASI) were used as dependent variables. RESULTS: Overweight subjects (BMI ≥ 25) exhibited lower NAA levels in the hippocampus than normal-weight subjects (BMI < 25) (partial Eta-squared = 0.14) controlling for age, sex and psychiatric diagnosis, and the effect was significant for the right hippocampus in both GAD patients and control subjects. An inverse linear correlation was noted in all subjects between right hippocampal NAA and BMI. High scores on the PSWQ predicted low hippocampal NAA and CR. Both BMI and worry were independent inverse predictors of hippocampal NAA. CONCLUSION: Overweight was associated with reduced NAA concentrations in the hippocampus with a strong effect size. Future mechanistic studies are warranted.

Fluorescence photoactivation by ligand exchange around the boron center of a BODIPY chromophore.

Chelation of the boron center of the borondipyrromethene (BODIPY) platform by a catecholate ligand results in effective fluorescence suppression. Electron transfer from the chelating unit to the adjacent chromophore upon excitation is responsible for fluorescence quenching. Under the influence of a photoacid generator, the catecholate chelator can be exchanged with a pair of methoxide ligands. This photoinduced transformation prevents electron transfer and efficiently activates the fluorescence of the BODIPY chromophore.

Activation of BODIPY fluorescence by the photoinduced dealkylation of a pyridinium quencher.

The photoinduced cleavage of a 2-nitrobenzyl group from a pyridinium quencher covalently attached to the meso position of a BODIPY fluorophore activates the emission of the latter. This photochemical transformation prevents the transfer of one electron from the BODIPY platform to its heterocyclic appendage upon excitation and, as a result, permits the radiative deactivation of the excited fluorophore. This versatile mechanism for fluorescence switching can translate into the realization of an entire family of photoactivatable fluorophores based on the outstanding photophysical properties of BODIPY chromophores.