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.

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).

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.

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.

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.

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.

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.

Structure-activity relationship of naphthaldehydethiosemicarbazones in melanogenesis inhibition.

2-(Naphthalen-1-ylmethylene)hydrazinecarbothioamide (14, IC(50)=1.1µM) was discovered as a highly potent inhibitor of melanogenesis. To define the role of hydrogens (at N1 and N3) and sulfur in 14, a series of analogs 15a-p were synthesized and evaluated for anti-melanogenic activity using melanoma B16 cells under the stimulus of α-MSH. It was observed that replacement of either of these hydrogens at N1 or N3 by substituents increases the activity significantly. Conversely, concomitant substitutions decrease the inhibitory potency. In addition, the presence of sulfur in thiosemicarbazone is essential for the activity.

Study on anti-proliferative effect of benzoxathiole derivatives through inactivation of NF-κB in human cancer cells.

To investigate the anti-proliferative effect of a newly discovered NF-kB inhibitor, 6,6-dimethyl-2-(phenylimino)-6,7-dihydrobenzo[d][1,3]oxathiol-4(5H)-one (1a), a series of its analogs (1b-n) were prepared and evaluated for their NF-κB inhibition and anti-proliferative activity against various human cancer cell lines. Slight variation of hydrophobicity by replacement of dimethyl group of 1a at 6-position with bulky isopropyl group and introduction of para-fluoro substitution on 2-phenyl group showed good NF-κB inhibitory activity and anti-proliferative activity. However, excessive increase in hydrophobicity with 2,4,6-trichloro substituents on phenyl group resulted in the loss of both the activities. From the SAR results, 2-phenylimino-6,7-dihydrobenzo[d][1,3]oxathiol-4(5H)-one was identified as the lead scaffold for investigating new anticancer agent through inactivation of NF-κB.

Novel interleukin-5 inhibitors based on hydroxyethylaminomethyl-4H-chromen-4-one scaffold.

Hydroxyethylaminomethyl-4H-chromenones were previously discovered as fairly strong IL-5 inhibitor. For determination of detail structure activity relationship, N-substituted hydroxyethylaminomethylchromenones 4a-n were prepared and evaluated for their IL-5 inhibitory activity. Shifting the hydrophobic group to nitrogen from 1-position of hydroxyethylamino moiety of hydroxyethylaminomethyl-4H-chromenones enhances the activity. The increment in bulkiness or hydrophobicity of alkyl side chain at amino group increases the activity. The same level of activity of 5-(cyclohexylmethoxy)-3-(N-benzyl-2-hydroxyethylaminomethyl)-4H-chromenone analogs regardless of hydrophobic or hydrophilic substituents at 4th position of phenyl ring might infer the existence of tunnel structure in the putative receptor for accepting these side chains.

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.

Ketonethiosemicarbazones: structure-activity relationships for their melanogenesis inhibition.

A series of 2-(1-phenylalkylidene)hydrazinecarbothioamides 2, 2-(1-phenylalkyl)hydrazinecarbothioamides 3, 2-(3,4-dihydronaphthalen-1(2H)-ylidene)hydrazinecarbothioamide (4), and 2-(1-(thiophen-2-yl)ethylidene)hydrazinecarbothioamide (5) were synthesized for their melanogenesis inhibition in melanoma B16 cells. The SAR of these ketonethiosemicarbazones revealed that the benzylidene hydrogen in aldehydethiosemicarbazones 1 can be replaced by hydrophobic moiety and substitutions with alkyl group for the terminal amino hydrogen of ketonethiosemicarbazones improved the activity appreciably. In addition, the double bond in thiosemicarbazones is an important factor for the increment of hydrophobicity. Thus hydrophobic ketonethiosemicarbazones are excellent inhibitors of melanogenesis like aldehydethiosemicarbazones.

Structural requirements of (E)-6-benzylidene-4a-methyl-4,4a,5,6,7,8-hexahydronaphthalen-2(3H)-one derivatives as novel melanogenesis inhibitors.

Chalcone type compound 1a ((E)-6'-benzylidene-4a'-methyl-4',4a',7',8'-tetrahydro-3'H-spiro[[1,3]dithiolane-2,2'-naphthalen]-5'(6'H)-one) was discovered as an potent inhibitor in melanogenesis. To define its structure-activity relationship, a series of analogs 1b-n, dithiolane truncated 2a-b and ring A removed 3a-e were prepared and evaluated. The electron donating substitution on the phenyl ring (ring C) rather than an electron withdrawing group and dithiolane motif of 1 are needed for the activity enhancement. The scaffold containing both rings A and B associated with α,ß-unsaturated system connected to phenyl of 1 was essential for antimelanogenesis.

Structure-activity relationship study of arylsulfonylimidazolidinones as anticancer agents.

In an effort to find novel N-arylsulfonylimidazolidinones as highly potent anticancer agent, the structure-activity relationship of ethyl 2-methyl-4-(2-oxo-4-phenylimidazolidin-1-ylsulfonyl)phenylcarbamate was explored through synthesis and evaluation of in vitro cytotoxicity of its analogs against HCT116, A549 and NCL-H460 cancer cell lines. Among the synthesized derivatives, the carbamate analogs (4a-f and 4k-p) exhibited superior cytotoxicity to doxorubicin for all cancer cell lines. The SAR studies of these derivatives confirm that the intact 4-phenyl-l-benzenesulfonylimidazolidinone has a pivotal role as a basic pharmacophore and hydrophobic substitutions only at 2-position of 1-aminobenzenesulfonyl moiety are beneficial for the enhancement of the activity.

Structural requirement of phenylthiourea analogs for their inhibitory activity of melanogenesis and tyrosinase.

Effect of a series of 1-phenylthioureas 1a-k and 1,3-disubstituted thioureas 2a-k were evaluated against melanin formation in melanoma B16 cell line and mushroom tyrosinase. Inhibitory activity of tyrosinase of 1-phenylthioureas 1a-k is parallel to their melanogenic inhibition. Thus, the melanogenic inhibition in melanoma B16 cells of 1-phenylthioureas could be the result of inhibition of tyrosinase. However, 1,3-diaryl or 1-phenyl-3-alkylthioureas, 2a-k, appears as melanogenic inhibitor without inhibition of tyrosinase. The molecular docking study of 1e and 2b to binding pocket of tyrosinase provided convincing explanation regarding the necessity of direct connection of planar phenyl to thiourea unit without N'-substitution of phenylthioureas 1 as tyrosinase inhibitor and 2 as non-tyrosinase inhibitor.

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.