Reversible Reactions of Nitric Oxide with a Binuclear Iron(III) Nitrophorin Mimic.

Construction of functional synthetic systems that can reversibly bind and transport the most biologically important gaseous molecules, oxygen and nitric oxide (NO), remains a contemporary challenge. Myoglobin and nitrophorin perform these respective tasks employing a protein-embedded heme center where one axial iron site is occupied by a histidine residue and the other is available for small molecule ligation, structural features that are extremely difficult to mimic in protein-free environments. Indeed, the hitherto reported designs rely on sophisticated multistep syntheses for limiting access to one of the two axial coordination sites in small molecules. We have shown previously that binuclear Ga(III) and Al(III) corroles have available axial sites, and now report a redox-active binuclear Fe(III) corrole, (1-Fe)2 , in which each (corrolato)Fe(III) center is 5-coordinate, with one axial site occupied by an imidazole from the other corrole. The binuclear structure is further stabilized by attractive forces between the corrole π systems. Reaction of NO with (1-Fe)2 affords mononuclear iron nitrosyls, and of functional relevance, the reaction is reversible: nitric oxide is released upon purging the nitrosyls with inert gases, thereby restoring (1-Fe)2 in solutions or films.

Hallmarks of anticancer and antimicrobial activities of corroles.

Corroles provide a remarkable opportunity for the development of cancer theranostic agents among other porphyrinoids. While most transition metal corrole complexes are only therapeutic, post-transition metallocorroles also find their applications in bioimaging. Moreover, corroles exhibit excellent photo-physicochemical properties, which can be harnessed for antitumor and antimicrobial interventions. Nevertheless, these intriguing, yet distinct properties of corroles, have not attained sufficient momentum in cancer research. The current review provides a comprehensive summary of various cancer-relevant features of corroles ranging from their structural and photophysical properties, chelation, protein/corrole interactions, to DNA intercalation. Another aspect of the paper deals with the studies of corroles conducted in vitro and in vivo with an emphasis on medical imaging (optical and magnetic resonance), photo/sonodynamic therapies, and photodynamic inactivation. Special attention is also given to a most recent finding that shows the development of pH-responsive phosphorus corrole as a potent antitumor drug for organelle selective antitumor cytotoxicity in preclinical studies. Another biomedical application of corroles is also highlighted, signifying the application of water-soluble and completely lipophilic corroles in the photodynamic inactivation of microorganisms. We strongly believe that future studies will offer a greater possibility of utilizing advanced corroles for selective tumor targeting and antitumor cytotoxicity. In the line with future developments, an ideal pipeline is envisioned on grounds of cancer targeting nanoparticle systems upon decoration with tumor-specific ligands. Hence, we envision that a bright future lies ahead of corrole anticancer research and therapeutics.

Corrole Nanoparticles for Chemotherapy of Castration-Resistant Prostate Cancer and as Sonodynamic Agents for Pancreatic Cancer Treatment.

A nanoparticle-based system, composed of the gallium(III) complex of a minimally substituted corrole that is coated by transferrin as a targeting vehicle (3-Ga NPs), has been used for pre-clinical evaluation of its efficacy against human metastatic castration-resistant prostate cancer (mCRPC) tumor xenografts. All mice (N = 9) responded to a dose of 10 mg/kg, with a remarkable tumor growth inhibition of 400% following 2 weeks of treatment; Ames and hERG tests excluded potential concerns regarding mutagenicity and cardiotoxicity, respectively. Also demonstrated is the potential application of these 3-Ga NPs as sonodynamic agents for the preclinical treatment of pancreatic cancer. 10 mg/kg 3-Ga NPs combined with exposure to ultrasound waves (2 min of 1 MHz 0.1 w/cm2 twice a week) induced up to 77% tumor shrinkage. Consistently, tumor/tissue distribution and serum levels of 3-Ga NPs in mice revealed high tumor specificity, favorable pharmacokinetics, fast absorption, slower redistribution, and very slow drug clearance.

Doubly Stimulated Corrole for Organelle-Selective Antitumor Cytotoxicity.

Balancing between safety and efficacy of cancer chemotherapeutics is achievable by relying on internal and/or external stimuli for selective and on-demand antitumor cytotoxicity. We now introduce the difluorophosphorus(V) corrole PC-Im, a theranostic agent with a pH-sensitive N-methylimidazole moiety. Structure/activity relationships, via comparison with the permanently charged PC-ImM+ and the lipophilic PC, uncovered the exceptional features of PC-Im: nanoparticular and monomeric at neutral and low pH, respectively, 10-fold increased light-induced singlet oxygen production at acidic pH, internalization into malignant cells within minutes, and selective accumulation within lysosomes. Submillimolar PC-Im concentrations are tolerable in the dark, while illumination induces nanomolar cytotoxic effects due to a multiplicity of cellular deleterious events: endoplasmic reticulum fragmentation, lysosome fusion and exocytosis, calcium leakage, mitochondrial fission, and swelling. PC-Im emerges as an antitumor agent, whose potency is triggered by endogenous and exogenous stimuli, assuring its cytotoxicity will occur selectively upon lysosomal accumulation and solely upon light activation.

Two decades of association mapping: Insights on disease resistance in major crops.

Climate change across the globe has an impact on the occurrence, prevalence, and severity of plant diseases. About 30% of yield losses in major crops are due to plant diseases; emerging diseases are likely to worsen the sustainable production in the coming years. Plant diseases have led to increased hunger and mass migration of human populations in the past, thus a serious threat to global food security. Equipping the modern varieties/hybrids with enhanced genetic resistance is the most economic, sustainable and environmentally friendly solution. Plant geneticists have done tremendous work in identifying stable resistance in primary genepools and many times other than primary genepools to breed resistant varieties in different major crops. Over the last two decades, the availability of crop and pathogen genomes due to advances in next generation sequencing technologies improved our understanding of trait genetics using different approaches. Genome-wide association studies have been effectively used to identify candidate genes and map loci associated with different diseases in crop plants. In this review, we highlight successful examples for the discovery of resistance genes to many important diseases. In addition, major developments in association studies, statistical models and bioinformatic tools that improve the power, resolution and the efficiency of identifying marker-trait associations. Overall this review provides comprehensive insights into the two decades of advances in GWAS studies and discusses the challenges and opportunities this research area provides for breeding resistant varieties.

Dimeric Corrole Analogs of Chlorophyll Special Pairs.

Chlorophyll special pairs in photosynthetic reaction centers function as both exciton acceptors and primary electron donors. Although the macrocyclic natural pigments contain Mg(II), the central metal in most synthetic analogs is Zn(II). Here we report that insertion of either Al(III) or Ga(III) into an imidazole-substituted corrole affords an exceptionally robust photoactive dimer. Notably, attractive electronic interactions between dimer subunits are relatively strong, as documented by signature changes in NMR and electronic absorption spectra, as well as by cyclic voltammetry, where two well-separated reversible redox couples were observed. EPR spectra of one-electron oxidized dimers closely mimic those of native special pairs, and strong through-space interactions between corrole subunits inferred from spectroscopic and electrochemical data are further supported by crystal structure analyses (3 Å interplanar distances, 5 Å lateral shifts, and 6 Å metal to metal distances).

Seasonal influence of tuberculosis diagnosis in Rwanda.

BACKGROUND: Tuberculosis (TB) remains a major global health concern. Previous research reveals that TB may have a seasonal peak during the spring and summer seasons in temperate climates; however, few studies have been conducted in tropical climates. This study evaluates the influence of seasonality on laboratory-confirmed TB diagnosis in Rwanda, a tropical country with two rainy and two dry seasons. METHODS: A retrospective chart review was performed at the University Teaching Hospital-Kigali (CHUK). From January 2016 to December 2017, 2717 CHUK patients with TB laboratory data were included. Data abstracted included patient demographics, season, HIV status, and TB laboratory results (microscopy, GeneXpert, culture). Univariate and multivariable logistic regression (adjusted for age, gender, and HIV status) analyses were performed to assess the association between season and laboratory-confirmed TB diagnoses. RESULTS: Patients presenting during rainy season periods had a lower odds of laboratory-confirmed TB diagnosis compared to the dry season (aOR=0.78, 95% CI 0.63-0.97, p=0.026) when controlling for age group, gender, and HIV status. Males, adults, and people living with HIV were more likely to have laboratory-confirmed TB diagnosis. On average, more people were tested for TB during the rainy season per month compared to the dry season (120.3 vs. 103.3), although this difference was not statistically significant. CONCLUSION: In Rwanda, laboratory-confirmed TB case detection shows a seasonal variation with patients having higher odds of TB diagnosis occurring in the dry season. Further research is required to further elucidate this relationship and to delineate the mechanism of season influence on TB diagnosis.

Trifluoromethyl Hydrolysis En Route to Corroles with Increased Druglikeness.

Heme-like metal-chelating macrocycles, including expanded and contracted porphyrins, are of everlasting interest as drug candidates for numerous diseases. Still, all reported corrole derivatives (and most other heme analogues) do not fulfill the most basic standards expected for oral drug administration: a combination of low molecular weight and reasonable water solubility. We now disclose a very straightforward synthetic method that relies on surprisingly facile trifluoromethyl hydrolysis for gaining access to a new class of corroles that do satisfy all druglikeness criteria. The relevance is briefly exemplified for the iron corroles by demonstrating the ability to affect their association with plasma proteins and their performance for catalase-like decomposition of hydrogen peroxide.

Investigation of the Mechanism Behind Conductive Fluorescent and Multistimuli-responsive Li+ -enriched Metallogel Formation.

A fluorescent metallogel (2.6 % w/v) has been obtained from two non-fluorescent components viz. phenyl-succinic acid derived pro-ligand H2 PSL and LiOH (2 equiv.) in DMF. Li+ ion not only plays a crucial role in gelation through aggregation, but also contributed towards enhancement of fluorescence by imposing restriction over excited state intramolecular proton transfer (ESIPT) followed by origin of chelation enhanced fluorescence (CHEF) phenomenon. Further, the participation of CHEF followed by aggregation-caused quenching (ACQ) and aggregation-induced emission (AIE) in the gelation process have been well established by fluorescence experiments. Transmission electron microscopy (TEM) analysis disclosed the sequential creation of nanonuclei followed by nanoballs and their alignment towards the generation of fibers of about 3, 31 and 40 nm diameter, respectively. The presence of a long-range fibrous morphology inside the metallogel was further attested by scanning electron microscopy (SEM). Rheological studies on the metallogel showed its true gel-phase material nature. Nyquist impedance study shows a resistance value of 7.4 kΩ for the metallogel which upon applying ultrasound increased to 8.5 kΩ, while an elevated temperature of 70 °C caused reduction in the resistance value to 4.8 kΩ. The mechanism behind metallogel formation has been well established by using FTIR, UV-vis, SEM, TEM, PXRD, 1 H NMR, fluorescence and ESI-MS.

Genomic marker assisted identification of genetic loci and genes associated with variation of grain zinc concentration in rice.

A study was conducted to examine the genetic divergence and to determine the genetic loci and genes associated with natural variation of grain zinc (Zn) concentration among 28 landraces, improved varieties and advanced breeding lines of rice using candidate gene specific primers. Field evaluation of the experimental material was conducted in randomized block design with three replications and Zn content in unpolished grains of the entries was determined by addition of nitric acid and perchloric acid (1:3) following the procedure of diacid digestion method. Statistical analysis revealed the exploitable extent of variability with respect to grain Zn concentration among the entries. Eighteen entries were selected from the two extremes of grain Zn distribution range and subjected to molecular profiling using a panel of 14 candidate genes specific 12 reported and 14 designed primer pairs. Only eight (OsZIP1-1, OsZIP3a, OsZIP4a, OsZIP5-3, OsZIP7-2, OsZIP8b, OsNRAMP7 and OsNAAT1) reported and eight (OsZIP3K, OsZIP4K, OsZIP5K, OsZIP7K, OsNRAMP7K, OsNAAT1K, OsNACK and OsYSL14K) designed primers generated polymorphic amplified products showing sequence length variation due to targeted amplification of candidate genes specific genomic regions. Ample genetic differentiation and divergence were revealed among the entries, which were accommodated into similarity coefficient-based six clusters, remarkably consistent with grain Zn concentration of the entries. Hierarchical classification pattern of entries was almost completely corroborated by principal co-ordinate analysis based spatial distribution pattern of their genetic profiles. Molecular analysis based on candidate genes specific primers appeared to be an efficient approach for the elucidation of genetic differentiation and divergence in relation to variation of grain Zn concentration among entries. Hence, these markers can be effectively and efficiently utilized for grain Zn concentration related discrimination of rice genotypes and selection of parental genotypes for grain Zn biofortification. Microsatellites were detected within the candidate genes and amplicons, thereby providing a basis to deduce that the repeat sequence length variation in candidate genes may be a role player in the differential grain Zn accumulation in rice varieties. Single marker analysis established the association of OsNACK, OsZIP1-1, OsNRAMP7 and OsNRAMP7K with grain Zn concentration. Thus, these four markers can be effectively used in marker-assisted selection programme for grain Zn biofortification in rice.

Validation of a wearable biosensor device for vital sign monitoring in septic emergency department patients in Rwanda.

OBJECTIVE: Critical care capabilities needed for the management of septic patients, such as continuous vital sign monitoring, are largely unavailable in most emergency departments (EDs) in low- and middle-income country (LMIC) settings. This study aimed to assess the feasibility and accuracy of using a wireless wearable biosensor device for continuous vital sign monitoring in ED patients with suspected sepsis in an LMIC setting. METHODS: This was a prospective observational study of pediatric (≥2 mon) and adult patients with suspected sepsis at the Kigali University Teaching Hospital ED. Heart rate, respiratory rate and temperature measurements were continuously recorded using a wearable biosensor device for the duration of the patients' ED course and compared to intermittent manually collected vital signs. RESULTS: A total of 42 patients had sufficient data for analysis. Mean duration of monitoring was 32.8 h per patient. Biosensor measurements were strongly correlated with manual measurements for heart rate (r = 0.87, p < 0.001) and respiratory rate (r = 0.75, p < 0.001), although were less strong for temperature (r = 0.61, p < 0.001). Mean (SD) differences between biosensor and manual measurements were 1.2 (11.4) beats/min, 2.5 (5.5) breaths/min and 1.4 (1.0)°C. Technical or practical feasibility issues occurred in 12 patients (28.6%) although were minor and included biosensor detachment, connectivity problems, removal for a radiologic study or exam, and patient/parent desire to remove the device. CONCLUSIONS: Wearable biosensor devices can be feasibly implemented and provide accurate continuous heart rate and respiratory rate monitoring in acutely ill pediatric and adult ED patients with sepsis in an LMIC setting.

Evaluation of polyherbal ayurvedic formulation 'Peedantak Vati' for anti-inflammatory and analgesic properties.

ETHNOPHARMACOLOGICAL RELEVANCE: Peedantak Vati (PV) is a polyherbal ayurvedic formulation, which is regularly prescribed by the ayurvedic practitioner for the inflammatory disorders and joints pain in India. It is composed of 23 different herbs and minerals, described in ayurvedic text for their anti-inflammatory and analgesic properties. AIM OF THE STUDY: To investigate anti-inflammatory and anti-nociceptive potential of 'Peedantak Vati' using in vitro and in vivo methods. MATERIALS AND METHODS: In-vitro anti-inflammatory activity of PV was studied by estimating nitric oxide (NO) and LPS-induced pro-inflammatory cytokines IL-6 and TNF-α, using murine macrophage RAW264.7 and human monocyte THP-1 cell lines. PV's anti-inflammatory potential was studied in vivo using carrageenan-induced rat paw edema model. Similarly, anti-nociceptive property of PV was evaluated using hot plate, tail flick, formalin and writhing tests on CD-1 mice. Phytochemical profiling of hydro-alcoholic extract of PV was done using HPLC and HPTLC techniques to identify different marker compounds. These identified marker compounds were confirmed using LC-MS/MS analysis. RESULTS: In vitro results strongly suggest that, PV significantly (p < 0.001) inhibited NO release and LPS-stimulated pro-inflammatory cytokines IL-6 and TNF-α, in murine RAW264.7 and human THP-1 cells. Further, PV demonstrated significant (p < 0.05) anti-inflammatory activity at different time points after carrageenan injection with maximum effect at 2 h (40.4 ±â€¯5.2% at 400 mg/kg). Similarly, PV significantly (p < 0.05) decreased nociceptive pain, studied using hot plate, tail flick, formalin and writhing tests. Moreover, HPLC and HPTLC methods were developed for the standardization of PV. Five marker phytocompounds viz. rutin, caffeic acid, colchicine, withaferin A and curcumin were identified and quantified by HPLC and HPTLC methods. The presence of these phytoconstituents was confirmed by LC-MS/MS analysis. CONCLUSION: The findings of the study strongly suggest that, the polyherbal ayurvedic formulation 'Peedantak Vati' possesses remarkable anti-inflammatory and analgesic property, providing potent alternative for currently available allopathic medicines such as non steroidal anti-inflammatory drugs (NSAIDs).

Identification of biomarker candidates for fertility in spermatozoa of crossbred bulls through comparative proteomics.

Associations between expression of some proteins in spermatozoa and fertility have been sought in recent years to identify the male fertility markers. Since the incidence of sub-fertility is high in crossbred bulls, the present investigation was carried out on high- and low-fertile crossbred bulls to identify fertility markers in spermatozoa through proteomics approach. Sperm proteome of high-fertile bulls were compared with low-fertile bulls using 2D-DIGE and MALDI-TOF-MS techniques and the results were validated with immuno-blotting. The proteins MDH2, ENO1, RIBC1, CAPN7, ATP5D, LacA like protein-2 like, NCAPD3, DECR1, GCNT2, GDI2, TOP and USP12 were over expressed in high-fertile spermatozoa, whereas DST like isoform 1, TMEM43 and BSP1 were over expressed in low-fertile spermatozoa (P < 0.05). The differential expression ranged from 1.57 (GDI2) to 5.1 (BSP1) fold between the two groups. Based on the GO annotation, majority of them were involved in cellular and metabolic processes, with catalytic and binding activities, and localized in cell and organelles. Among these proteins, ENO1 and BSP1 were selected based on the degree of differential expression and reliability in identification, for further validation. Immuno-blotting studies indicated that ENO1expression was positively correlated (P < 0.05) while the expression of BSP1 was negatively (P < 0.01) correlated with bull fertility. The proportion of capacitated spermatozoa in frozen thawed spermatozoa of low-fertile bulls was higher (P < 0.05) as compared to high-fertile bulls. Collectively, the study identified some potential molecules in spermatozoa of bulls, which may act as a panel of biomarkers for fertility.

Novel analogs of N-acylhydroxyethylaminomethyl-4H-chromen-4-one scaffold as IL-5 inhibitors.

A number of N-acyl substituted hydroxyethylaminomethyl-4H-chromen-4-ones 6a-u were prepared and evaluated for their IL-5 inhibitory activity. Among them, the compound 6r (95.0% inhibition at 30µM, IC50=10.0µM, ClogP=4.1549) showed most potent inhibitory activity. The structure activity relationship revealed that the bulkier or hydrophobic substituents at urea, carbamate or amide group resulted in good inhibitory activity against IL-5. Moreover, electron donating group at phenyl ring (6g and 6s) is much more active than electron withdrawing group (6f). Finally, replacement of cyclohexylmethoxy group at 5th position of ring A with bulky aliphatic substituents resulted in the loss of activity.

The Current State of Head and Neck Injuries in Extreme Sports.

BACKGROUND: Since their conception during the mid-1970s, international participation in extreme sports has grown rapidly. The recent death of extreme snowmobiler Caleb Moore at the 2013 Winter X Games has demonstrated the serious risks associated with these sports. PURPOSE: To examine the incidence and prevalence of head and neck injuries (HNIs) in extreme sports. STUDY DESIGN: Descriptive epidemiological study. METHODS: The National Electronic Injury Surveillance System (NEISS) was used to acquire data from 7 sports (2000-2011) that were included in the Winter and Summer X Games. Data from the NEISS database were collected for each individual sport per year and type of HNI. Cumulative data for overall incidence and injuries over the entire 11-year period were calculated. National estimates were determined using NEISS-weighted calculations. Incidence rates were calculated for extreme sports using data from Outdoor Foundation Participation Reports. RESULTS: Over 4 million injuries were reported between 2000 and 2011, of which 11.3% were HNIs. Of all HNIs, 83% were head injuries and 17% neck injuries. The 4 sports with the highest total incidence of HNI were skateboarding (129,600), snowboarding (97,527), skiing (83,313), and motocross (78,236). Severe HNI (cervical or skull fracture) accounted for 2.5% of extreme sports HNIs. Of these, skateboarding had the highest percentage of severe HNIs. CONCLUSION: The number of serious injuries suffered in extreme sports has increased as participation in the sports continues to grow. A greater awareness of the dangers associated with these sports offers an opportunity for sports medicine and orthopaedic physicians to advocate for safer equipment, improved on-site medical care, and further research regarding extreme sports injuries.

Economic and social impact of upper extremity fragility fractures in elderly patients.

BACKGROUND: Fragility fractures of the proximal humerus and distal radius can have a significant impact on the elderly population, both economically and physically. Limited data are available to demonstrate the functional and economic impact of upper extremity fragility fractures. AIMS: To investigate the economic and social impact that proximal humerus fragility fractures may have on an older population. METHODS: A retrospective chart review for patients ≥50 years old treated as an inpatient at a local hospital between 2006 and 2012 for a proximal humerus or a distal radius fracture was done. Patients were divided into two groups to show age impact; Group 1 = 50-79 years old and Group 2 = 80 years and older. Eighty-six charts were reviewed, 38 for Group 1 and 48 for Group 2. Demographic, admission, inpatient, and discharge data were compared between groups. RESULTS: A third of patients in each group had a previous fragility fracture. Inpatient length of stay was comparable between groups. Surgical treatment was used at a higher rate in the younger cohort (p = 0.06). Approximate average hospital charges for an inpatient surgical treatment were about twice those of the non-surgically treated patients. DISCUSSION: Our results illustrate the significant burden of upper extremity fractures in terms of loss of independence, inpatient hospitalizations and prolonged nursing home or rehabilitation needs, which account for considerable health care costs. CONCLUSION: Fractures of the humerus, forearm and wrist account for one-third of the total incidence of fractures and can be a significant burden to individuals and the community.

Synthesis and SAR studies of bis-chromenone derivatives for anti-proliferative activity against human cancer cells.

A novel family of 3-((4-oxo-4H-chromen-3-yl)methyl)-4H-chromen-4-one (bis-chromone) derivatives were designed, synthesized and studied for their anti-cancer activity using the XTT assay for the growth inhibition against various human cancer cells. Among them, 3-((5-(cyclohexylmethoxy)-4-oxo-4H-chromen-3-yl)methyl)-7-methoxy-4H-chromen-4-one and 3-((5-(cyclohexylmethoxy)-4-oxo-4H-chromen-3-yl)methyl)-7-hydroxy-4H-chromen-4-one showed micromolar level of in vitro anti-proliferative activity against human cancer cell lines. The SAR studies indicated bis-chromone as a basic scaffold to design anticancer agents. The 5-cyclohexylmethoxy on the first chromenone ring and electron donating group such as CH3, OCH3 or hydrogen bonding group (OH) on the other chromenone ring of bis-chromone increased the activity. However, saturation of one of chromenone to chromanone in bis-chromones decreased the activity.

Identification of putative fertility markers in seminal plasma of crossbred bulls through differential proteomics.

Sub-fertility is a major problem in crossbred bulls leading to disintegration of breeding systems and huge economic loss. Identification of some potential biomarkers to determine the latent fertility of bulls accurately has long been the interest of researchers. In this study, we analyzed the proteome of seminal plasma (SP) from bulls with varying fertility to identify the fertility-associated proteins. The proteomic profile of high- and low-fertile bulls was compared by two-dimensional difference gel electrophoresis and differentially expressed proteins were identified through matrix-assisted laser desorption/ionization-time of flight/mass spectrometry. Out of the 18 differentially expressed proteins (P < 0.05), 9 were overexpressed in SP of high-fertile bulls and 9 were overexpressed in SP of low-fertile bulls. The differential expressions ranged from 1.5- to 5.5-fold between the two groups, where protection of telomeres-1 protein (POT1) was highly overexpressed (2.9-fold) in high-fertile group and prostaglandin E2 receptor EP3 (PTGER3) was highly abundant (5.5-fold) in low-fertile group. The protein interaction network was elucidated using STRING software tool, and the functional bioinformatics analysis was done using Blast2Go software. Most of the differentially expressed proteins were found to be involved in cellular processes and biological regulation with binding and catalytic function. It is inferred that the expression of certain proteins in the SP varied with bull fertility, and concurrent appraisal of their expression along with other fertility assays may help in determining bull fertility.

Anti-proliferative effect of chalcone derivatives through inactivation of NF-κB in human cancer cells.

To investigate the anti-proliferative effect of NF-κB inhibitor, a series of analogs of (E)-1-(2-hydroxy-6-(isopentyloxy)phenyl)-3-(4-hydroxyphenyl)prop-2-en-1-one (5a) were prepared and evaluated for their NF-κB inhibition and anti-proliferative activity against various human cancer cell lines. Compounds (E)-1-(2-(3,3-dimethylbutoxy)-6-hydroxyphenyl)-3-(4-hydroxyphenyl)prop-2-en-1-one (5e) and (E)-4-(3-(2-(3,3-dimethylbutoxy)-6-hydroxyphenyl)-3-oxoprop-1-enyl)benzenesulfonamide (5p) showed good NF-κB inhibition as well as potent anti-proliferative activity. SAR studies showed that all the compounds with potent or moderate NF-κB inhibition displayed good anti-proliferative activity. All the analogs (5b-r) maintained a good correlation between their NF-κB inhibition and anti-proliferative activity though the extent is not directly proportional to each other.

Design and synthesis of novel chromenone derivatives as interleukin-5 inhibitors.

A novel series of chromenone analogs were synthesized and evaluated for their inhibitory activity against interleukin-5. Among them 5-(cyclohexylmethoxy)-3-[3-hydroxy-3-(4-hydroxyphenyl)propyl]-4H-chromen-4-one (9b, 94% inhibition at 30 µM, IC(50) = 4.0 µM) and 5-(cyclohexylmethoxy)-3-[3-hydroxy-3-(4-methoxyphenyl)propyl]-4H-chromen-4-one (9c, 94% inhibition at 30 µM, IC(50) = 6.5 µM) showed the most potent activity. According to the SAR studies introduction of propanone unit in between chromenone and ring B as in 5-(cyclohexylmethoxy)-3-[3-(4-phenyl)-3-oxopropyl]-4H-chromen-4-ones (8) moderately increased the activity. However, the reduction of these propanones 8 to propanols 9 remarkably enhanced the activity. A small substituent at position 4 of ring B in 9, especially with hydrogen bonding capability, provides favorable contribution. Disappearance of IL-5 inhibitory activity upon saturation of chroman-4-one of 9 to chroman-4-ones 10 proves the critical importance of planar chromen-4-one unit of this scaffold in the IL-5 inhibition.