Synthesis and antitumor activity of benzophenone compound.

Seven benzophenone compounds were synthesized in one or two steps, then their antitumor activity was evaluated. The total yields ranged from 9% to 44%. Compounds 3c-5c exhibited obvious antitumor activity. Among them, compounds 3c and 4c exhibited excellent and broad-spectrum antitumor activity. Compound 3c exhibited much stronger inhibitory activities against fourteen cancer cells than cisplatin. In particular, compound 3c exhibited stronger cytotoxicity against hepatocarcinoma SMMC-7721 cells than Taxol, with a half maximal inhibitory concentration (IC50) of approximately 0.111 µM. These results demonstrated that compounds 3c, 4c and 5c were very promising antitumor leads for further structural modification.

Efficient synthesis, and antitumor and antioxidant activities of polyhydroxybenzophenone.

Five polyhydroxybenzophenones were synthesized, then their antitumor and antioxidant activities were evaluated. Compounds 1-3 and 5 exhibited obvious antitumor activity. Among them, compounds 1 and 2 exhibited stronger cytotoxicity against hepatocarcinoma SMMC-7721 cells than cisplatin, with half maximal inhibitory concentrations (IC50) of approximately 3.86 and 5.32 µM, respectively. Compounds 1, 2, and 3 exhibited stronger antioxidant activity than trolox, with IC50 values of 11.15, 10.15, and 8.91 µM, respectively, and the antioxidant mechanism and strength of all compounds were further verified using computational chemistry. These results demonstrated that compounds 1-3 and 5 were very promising leads for further structural modification.

Syntheses of xanthone derivatives and their bioactivity investigation.

Sixteen substituted 1-hydroxy-3-methylxanthones were synthesized in one step. The yields ranged from 33 to 76%. Then, the antitumor, antioxidant, anti-tyrosinase, anti-pancreatic lipase, and antifungal activities of compounds 1-16 were evaluated. Compounds 10-12 and 14 inhibited tyrosinase and pancreatic lipase activity to a certain extent, respectively. Compound 16 exhibited obvious cytotoxicity against fifteen cancer cells, moderate antioxidant activity, and moderate inhibitory activity against Candida albicans. In particular, compound 16 exhibited strong inhibitory activity against A-549 and A549/Taxol cells. These results demonstrated that compounds 10-12, 14, and 16 are promising leads for further structural modification.[Formula: see text].

Synthesis and antitumor, antityrosinase, and antioxidant activities of xanthone.

Ten substituted 1,3-dihydroxyxanthones were synthesized in one step. The yields ranged from 40 to 76%. Compounds 8-10 were first reported. Next, the compounds' in vitro anti-proliferative activities against nine human cancer cell lines, antityrosinase, and antioxidant activities were evaluated. Compounds 1, 4, 6-7, and 9-10 exhibited enhanced cytotoxicity against certain cancer cells. Compounds 2, 8, 9, and 10 inhibited tyrosinase activity to a certain extent. In addition, compound 4 exhibited the best antioxidant activity, which was consistent with theoretical calculations. These results demonstrated that compounds 1-2, 4, and 6-10 were promising leads for further investigation.

Pharmacokinetics and metabolism of AMG 232, a novel orally bioavailable inhibitor of the MDM2-p53 interaction, in rats, dogs and monkeys: in vitro-in vivo correlation.

1. AMG 232 is a novel inhibitor of the p53-MDM2 protein-protein interaction currently in Phase I clinical trials for multiple tumor indications. The objectives of the investigations reported in this article were to characterize the pharmacokinetic and drug metabolism properties of AMG 232 in pre-clinical species in vivo and in vitro, and in humans in vitro, and to predict its pharmacokinetics in humans through integrating PKDM data. 2. AMG 232 exhibited low clearance (<0.25 × Qh) and moderate to high oral bioavailability in mice, rats and monkeys (>42%), but high clearance (0.74 × Qh) and low oral exposure in dogs (18%). 3. Biotransformation was the major route of elimination of AMG 232 in rats, with only 7% of intravenously administered (14)C-labeled AMG 232 recovered as parent molecule in bile. The major metabolite was an acyl glucuronide as measured by in vivo rat studies and in vitro hepatocyte incubations in multiple species. 4. The in vitro-in vivo correlation of AMG 232 clearance was within 2-fold in pre-clinical species using hepatocytes. AMG 232 was predicted to exhibit low clearance, high volume distribution and long half-life in humans. The predictions are consistent with the preliminary human pharmacokinetic parameters of AMG 232 in clinical trials.

Discovery and molecular basis of potent noncovalent inhibitors of fatty acid amide hydrolase (FAAH).

Fatty acid amide hydrolase (FAAH), an amidase-signature family member, is an integral membrane enzyme that degrades lipid amides including the endogenous cannabinoid anandamide and the sleep-inducing molecule oleamide. Both genetic knock out and pharmacological administration of FAAH inhibitors in rodent models result in analgesic, anxiolytic, and antiinflammatory phenotypes. Targeting FAAH activity, therefore, presents a promising new therapeutic strategy for the treatment of pain and other neurological-related or inflammatory disorders. Nearly all FAAH inhibitors known to date attain their binding potency through a reversible or irreversible covalent modification of the nucleophile Ser241 in the unusual Ser-Ser-Lys catalytic triad. Here, we report the discovery and mechanism of action of a series of ketobenzimidazoles as unique and potent noncovalent FAAH inhibitors. Compound 2, a representative of these ketobenzimidazoles, was designed from a series of ureas that were identified from high-throughput screening. While urea compound 1 is characterized as an irreversible covalent inhibitor, the cocrystal structure of FAAH complexed with compound 2 reveals that these ketobenzimidazoles, though containing a carbonyl moiety, do not covalently modify Ser241. These inhibitors achieve potent inhibition of FAAH activity primarily from shape complementarity to the active site and through numerous hydrophobic interactions. These noncovalent compounds exhibit excellent selectivity and good pharmacokinetic properties. The discovery of this distinctive class of inhibitors opens a new avenue for modulating FAAH activity through nonmechanism-based inhibition.

FLT3 and CDK4/6 inhibitors: signaling mechanisms and tumor burden in subcutaneous and orthotopic mouse models of acute myeloid leukemia.

FLT3(ITD) subtype acute myeloid leukemia (AML) has a poor prognosis with currently available therapies. A number of small molecule inhibitors of FLT3 and/or CDK4/6 are currently under development. A more complete and quantitative understanding of the mechanisms of action of FLT3 and CDK4/6 inhibitors may better inform the development of current and future compounds that act on one or both of the molecular targets, and thus may lead to improved treatments for AML. In this study, we investigated in both subcutaneous and orthotopic AML mouse models, the mechanisms of action of three FLT3 and/or CDK4/6 inhibitors: AMG925 (Amgen), sorafenib (Bayer and Onyx), and quizartinib (Ambit Biosciences). A composite model was developed to integrate the plasma pharmacokinetics of these three compounds on their respective molecular targets, the coupling between the target pathways, as well as the resulting effects on tumor burden reduction in the subcutaneous xenograft model. A sequential modeling approach was used, wherein model structures and estimated parameters from upstream processes (e.g. PK, cellular signaling) were fixed for modeling subsequent downstream processes (cellular signaling, tumor burden). Pooled data analysis was employed for the plasma PK and cellular signaling modeling, while population modeling was applied to the tumor burden modeling. The resulting model allows the decomposition of the relative contributions of FLT3(ITD) and CDK4/6 inhibition on downstream signaling and tumor burden. In addition, the action of AMG925 on cellular signaling and tumor burden was further studied in an orthotopic tumor mouse model more closely representing the physiologically relevant environment for AML.

Development of a new synchronous fluorescence spectrometry combined with Al3+ sensitized for simultaneous and rapid determination of trace flumequine, ciprofloxacin and doxycycline hydrochloride residues in wastewater.

Antibiotics are a new type of environmental pollutants. Due to its wide application in many fields, antibiotic residues are ubiquitous in the wastewater environments. Given their potential threat on water ecosystem functioning and public health, the detection of antibiotic residues in wastewater environments has become very necessary. Based on the complexation of Al3+ with flumequine (FLU), ciprofloxacin (CIP) and doxycycline hydrochloride (DOX), their molecular conjugated area were increased and fluorescence intensity were enhanced, combined with synchronous fluorescence spectrometry (SFS) had good selectivity and high sensitivity, a novel method of Al3+ sensitized synchronous fluorescence spectrometry for the determination of FLU, CIP and DOX residues in wastewater was established. When the wavelength difference (Δλ) was selected 115.0 nm, synchronous fluorescence spectra of the three antibiotics could be well separated and the interference of wastewater matrix were eliminated primely. The new SFS made good use of spectral separation instead of conventional chemical separation, and the actual wastewater sample could be directly determined after simple filtration. The experiment results showed that the concentrations of FLU, CIP and DOX in the range of 0.5000-800.0 ng·mL-1, 0.5000-640.0 ng·mL-1 and 10.00-3500 ng·mL-1 had a good linear relationship with fluorescence intensity. The detection limits of three antibiotics were 0.02054 ng·mL-1, 0.03956 ng·mL-1 and 0.8524 ng·mL-1, respectively. Recovery rates of three antibiotics in wastewater samples were 90.72%-98.23%, 88.68%-95.08% and 85.94%-96.70%. The new SFS established in this experiment had the advantages of simple, rapid, sensitive, accurate and good selectivity. Simultaneous and rapid detection of FLU, CIP and DOX residues in wastewater was successfully realized. It had good application prospects in real-time water quality monitoring.

Structure guided design of a series of sphingosine kinase (SphK) inhibitors.

Sphingosine-1-phosphate (S1P) signaling plays a vital role in mitogenesis, cell migration and angiogenesis. Sphingosine kinases (SphKs) catalyze a key step in sphingomyelin metabolism that leads to the production of S1P. There are two isoforms of SphK and observations made with SphK deficient mice show the two isoforms can compensate for each other's loss. Thus, inhibition of both isoforms is likely required to block SphK dependent angiogenesis. A structure based approach was used to design and synthesize a series of SphK inhibitors resulting in the identification of the first potent inhibitors of both isoforms of human SphK. Additionally, to our knowledge, this series of inhibitors contains the only sufficiently potent inhibitors of murine SphK1 with suitable physico-chemical properties to pharmacologically interrogate the role of SphK1 in rodent models and to reproduce the phenotype of SphK1 (-/-) mice.

The Impact of Fitness Influencers on a Social Media Platform on Exercise Intention during the COVID-19 Pandemic: The Role of Parasocial Relationships.

In the context of COVID-19 pandemic lockdowns, fitness influencers on social media are greatly involved in people's home fitness processes, but there is limited research examining the role of fitness influencers on social media in exercise intention. This study aimed to explore whether people's perceptions of the personal attributes and content quality of fitness influencers can promote a strong emotional connection between the two, thereby influencing people's exercise intentions. Based on the theory of the parasocial relationship, we investigated the influence of social attractiveness (SA), physical attractiveness (PA), task attractiveness (TA), and content quality (CQ) of fitness influencers on the parasocial relationships (PSRs) between viewers and fitness influencers on social media and whether PSRs positively contribute to viewers' exercise intentions (EI). The results revealed that SA, PA, TA, and CQ have positive influences on PSRs and CQ; PSRs directly contribute to EI; and PSRs have a mediating effect between EI and CQ. This study provides new insights into understanding the relationship between fitness influencers and people's online fitness behaviors.

Rapid detection of four polycyclic aromatic hydrocarbons in drinking water by constant-wavelength synchronous fluorescence spectrometry.

Based on the advantages of the good selectivity and high sensitivity of the synchronous fluorescence method, an efficient method using constant-wavelength synchronous fluorescence spectrometry (CWSFS) for simultaneous and rapid determination of four polycyclic aromatic hydrocarbons (PAHs) (acenaphthene, phenanthrene, benzo[a]anthracene and fluoranthene) in drinking water was established in this study. When the difference in wavelength (Δλ) at 100 nm was chosen for CWSFS scanning, the synchronous fluorescence spectra of the four PAHs could be well separated with only one single scan. Different from conventional fluorescence analysis, the established method can avoid the interference among the four PAHs each other and the interference of the drinking water sample matrix, so the four PAHs in drinking water could be well distinguished and determined. The concentrations of four PAHs in the range of 0.05-100 µg/L, 0.1-400 µg/L, 0.05-100 µg/L and 0.5-2000 µg/L showed a good linear relationship with fluorescence intensity. The limits of detection were 0.0058 µg/L, 0.021 µg/L, 0.0061 µg/L and 0.056 µg/L, respectively. The recoveries were in the range of 86.55-98.74%. Overall, the established CWSFS had the characteristics of simple, rapid, sensitive and accuracy, and had been applied to the determination of the four PAHs in various drinking water with satisfactory results.

Identification of potent, noncovalent fatty acid amide hydrolase (FAAH) inhibitors.

Starting from a series of ureas that were determined to be mechanism-based inhibitors of FAAH, several spirocyclic ureas and lactams were designed and synthesized. These efforts identified a series of novel, noncovalent FAAH inhibitors with in vitro potency comparable to known covalent FAAH inhibitors. The mechanism of action for these compounds was determined through a combination of SAR and co-crystallography with rat FAAH.

Discovery of amide replacements that improve activity and metabolic stability of a bis-amide smoothened antagonist hit.

A bis-amide antagonist of Smoothened, a seven-transmembrane receptor in the Hedgehog signaling pathway, was discovered via high throughput screening. In vitro and in vivo experiments demonstrated that the bis-amide was susceptible to N-acyl transferase mediated amide scission. Several bioisosteric replacements of the labile amide that maintained in vitro potency were identified and shown to be metabolically stable in vitro and in vivo.

Establishment and assessment of a nomogram model for predicting the risk of fulminant myocarditis: A STROBE compliant cross-sectional study.

ABSTRACT: We aimed to identify potential clinical predictors associated with the risk of fulminant myocarditis, and further to establish and assess a nomogram model based on significant attributes for clinical practicability.This is a retrospective, cross-sectional study, involving 28 patients with fulminant myocarditis and 35 age-, and sex-matched patients with non-fulminant myocarditis. Effect-size estimates are expressed as odds ratio (OR) and 95% confidence interval (CI).Fifteen factors were primarily identified to be associated with the significant risk of fulminant myocarditis after adjusting for confounders. Due to strong correlation, 6 factors were retained, including mean arterial pressure (OR, 95% CI, P: .82, .72-.94, .005), creatinine (2.15, 1.13-4.10, 0.020), blood urea nitrogen (1.45, 1.04-2.02, 0.028), aspartate aminotransferase (2.62, 1.16-5.91, 0.021), troponin I (1.43, 1.07-1.90, 0.015), and ventricular wall motion abnormality (25.81, 2.52-264.69, 0.006). The contribution of the 6 significant factors to predicting fulminant myocarditis risk was significant from multi-angle analyses, and regressing these factors in a nomogram model exhibited good predictive accuracy, as reflected by both C-index (>90%, P < .001).We have identified 6 clinical factors in significant association with fulminant myocarditis, and their prediction capability was more obvious in a nomogram model. Further investigations with larger sample sizes and longer follow-up intervals are warranted.

MicroRNA-181b Serves as a Circulating Biomarker and Regulates Inflammation in Heart Failure.

Heart failure (HF) is the typical terminal stage of cardiac diseases involving inflammatory states. The function of microRNAs (miRNAs) in the progress of HF remains poorly understood. In this study, real-time PCR results showed a decreased expression of miRNA-181b (miR-181b) in HF patients compared with healthy individuals. Besides, miR-181b expressions were negatively correlated with hypersensitive C-reactive protein (hsCRP) levels in the serum of HF patients. Receiver operator characteristic (ROC) curve analysis showed that miR-181b was a diagnostic predictor of HF, and the area under the curve was 0.970 (DCM-induced HF group) and 0.962 (ICM-induced HF group). Strikingly, in HF rats induced by isoproterenol (ISO), the expression of miR-181b of heart tissue was suppressed before tumor necrosis factor-alpha (TNF-α), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6) increase, as revealed by western blot and real-time PCR. Besides, the overexpression of miR-181b also decreased the expression of TNF-α, IL-1ß, and IL-6 in lipopolysaccharide- (LPS-) induced neonatal cardiomyocytes. In conclusion, our results revealed that miR-181b might be a potential biomarker for HF and provided a novel target for anti-inflammatory therapy.

Discovery of Potent and Selective Methylenephosphonic Acid CD73 Inhibitors.

Solid tumors are often associated with high levels of extracellular ATP. Ectonucleotidases catalyze the sequential hydrolysis of ATP to adenosine, which potently suppresses T-cell and NK-cell functions via the adenosine receptors (A2a and A2b). The ectonucleotidase CD73 catalyzes the conversion of AMP to adenosine. Thus, increased CD73 enzymatic activity in the tumor microenvironment is a potential mechanism for tumor immune evasion and has been associated with poor prognosis in the clinic. CD73 inhibition is anticipated to restore immune function by skirting this major mechanism of adenosine generation. We have developed a series of potent and selective methylenephosphonic acid CD73 inhibitors via a structure-based design. Key binding interactions of the known inhibitor adenosine-5'-(α,ß-methylene)diphosphate (AMPCP) with hCD73 provided the foundation for our early designs. The structure-activity relationship study guided by this structure-based design led to the discovery of 4a, which exhibits excellent potency against CD73, exquisite selectivity against related ectonucleotidases, and a favorable pharmacokinetic profile.

Investigation of collision-induced dissociations involving odd-electron ion formation under positive electrospray ionization conditions using accurate mass.

Collision induced dissociation (CID) has been extensively used for structure elucidation. CID in the electrospray ionization (ESI) and atmospheric pressure chemical ionization (APCI) modes has been found to generate mostly even-electron fragment ions while it has been occasionally reported to form odd-electron free radical ions. However, the structural requirements and the fragmentation mechanisms for free-radical CIDs have not been well characterized in the literature. For this purpose, we studied a series of aromatic and non-aromatic compounds such as sulfonamides, N-aryl amides, tert-butyl-substituted aromatic compounds, aryl alkyl ethers, and O-alkyl aryl oximes using the LTQ and LTQ Orbitrap linear ion trap mass spectrometers. The accurate measurement of the fragment ion masses established the unambiguous assignment of the fragment structures resulting from the test compounds. Our results showed that free radical fragmentation is structure dependent and is to a large extent correlated with the neighboring groups in the structures that stabilize the newly formed free radical ions.

Addressing PXR liabilities of phthalazine-based hedgehog/smoothened antagonists using novel pyridopyridazines.

Pyridopyridazine antagonists of the hedgehog signaling pathway are described. Designed to optimize our previously described phthalazine smoothened antagonists, a representative compound eliminates a PXR liability while retaining potency and in vitro metabolic stability. Moreover, the compound has improved efficacy in a hedgehog/smoothened signaling mouse pharmacodynamic model.

Design of 1-piperazinyl-4-arylphthalazines as potent Smoothened antagonists.

The Hedgehog (Hh) signaling pathway regulates cell proliferation and differentiation in developing tissues, and abnormal activation of the Hh pathway has been linked to several tumor subsets. As a transducer of Hh signaling, the GPCR-like protein Smoothened (Smo) is a promising target for disruption of unregulated Hh signaling. A series of 1-amino-4-arylphthalazines was developed as potent and orally bioavailable inhibitors of Smo. A representative compound from this class demonstrated significant tumor volume reduction in a mouse medulloblastoma model.

Discovery of AB680: A Potent and Selective Inhibitor of CD73.

Extracellular adenosine (ADO), present in high concentrations in the tumor microenvironment (TME), suppresses immune function via inhibition of T cell and NK cell activation. Intratumoral generation of ADO depends on the sequential catabolism of ATP by two ecto-nucleotidases, CD39 (ATP → AMP) and CD73 (AMP → ADO). Inhibition of CD73 eliminates a major pathway of ADO production in the TME and can reverse ADO-mediated immune suppression. Extensive interrogation of structure-activity relationships (SARs), structure-based drug design, and optimization of pharmacokinetic properties culminated in the discovery of AB680, a highly potent (Ki = 5 pM), reversible, and selective inhibitor of CD73. AB680 is further characterized by very low clearance and long half-lives across preclinical species, resulting in a PK profile suitable for long-acting parenteral administration. AB680 is currently being evaluated in phase 1 clinical trials. Initial data show AB680 is well tolerated and exhibits a pharmacokinetic profile suitable for biweekly (Q2W) iv-administration in human.