Synthesis,SAR and Unanticipated Pharmacological Profiles of Analogues of the mGluR5 Ago‐potentiator ADX‐47273

An iterative analogue library synthesis strategy rapidly developed comprehensive SAR for the mGluR5 ago‐potentiator ADX‐47273. This effort identified key substituents in the 3‐position of oxadiazole that engendered either mGluR5 ago‐potentiation or pure mGluR5 positive allosteric modulation. The mGluR5 positive allosteric modulators identified possessed the largest fold shifts (up to 27.9‐fold) of the glutamate CRC reported to date as well as providing improved physiochemical properties.

     

Skin surface microflora of the saddle-back tamarin monkey,Saguinus fuscicollis

The resident skin surface microflora of 12 male and three femaleSaguinus fuscicollis was studied. The suprapubic-circumgenital gland surface and the perirectal area were most heavily colonized (10⁶–10⁸ colony forming units/cm²), but high numbers of organisms were also present on the abdomen, the sternal gland surface, and palms and plantar surfaces. Bacteria were also recovered from hair clippings as well as from shaven skin surface, although at much lower densities (10²–10⁴ colony forming units/cm²). Coagulase negative staphylococci, gram-negative bacteria,Streptococcus species and coryneform bacteria were most dominant.Staphylococcus aureus and species ofBacillus were also present. Fungi, yeast, and dermatophytes were infrequently recovered or completely absent. The microbial flora of these tamarins appears to be closely associated with the secretions of the circumgenital scent gland and would therefore be ideally situated to participate in the generation or modification of chemical signals.     

Solubility and agronomic effectiveness of partially acidulated phosphate rocks as influenced by their iron and aluminium oxide content

Partially acidulated phosphate rock (PAPR) has been shown to be an effective source of P for plants grown on acid soils. Less information in available, however, regarding the effect of the phosphate rock (PR) source on the solubility and agronomic effectiveness of PAPR.The effect of Fe₂O₃ + Al₂O₃ content in PR on the quality of PAPR produced was investigated in this study. Nine sources of PR from Africa, Latin America, and the United States, representing a range of Fe₂O₃ + Al₂O₃ from 0.7% to 12.4%, were used. In a single-step process, the finely ground PRs were partially acidulated with H₂SO₄ at the 30% or 50% acidulation level and granulated (–3.35 + 1.18 mm or –6 + 14 mesh). It was found that the water-soluble P content in PAPR decreased with increasing Fe₂O₃ + Al₂O content in the PR used. Apparently, the presence of Fe₂O₃ + Al₂O₃ resulted in a reversion of some of the water-soluble P to citrate-soluble P and sometimes even to citrate-insoluble P.A short-term (6 weeks) greenhouse study was conducted to evaluate crop response to PAPRs and single superphosphate (SSP); maize, the test crop, was grown on an acid soil (pH 4.5)—Hartsells silt loam (Typic Hapludults). The agronomic effectiveness of PAPRs with respect to SSP (in terms of dry-matter yield of maize) decreased with increasing Fe₂O₃ + Al₂O₃ content in PRs. Phosphorus uptake by maize from PAPRs was found to correlate well with water solubility but not with citrate solubility. The results obtained in this study show that the detrimental effect of Fe₂O₃ + Al₂O₃ content on the solubility and P availability of PAPR should be considered when selecting a PR for PAPR production.     

Synthesis of S-dithiocarbonates with polymer-supported xanthates

Summary Polymer-supported ammonium salts of methyl and ethyl xanthates react with alkyl halides to yield S-dithiocarbonates.     

Variations in Allelochemical Composition of Leachates of Different Organs and Maturity Stages of <Emphasis Type="Italic">Pinus halepensis</Emphasis>

We investigated changes in the occurrence of allelochemicals from leachates of different Pinus halepensis organs taking into account the stages of pine stand age (i.e., young  < 15-years-old, middle age ± 30-years, and old  > 60-years-old). GC-MS analysis of aqueous extracts revealed approx. 59 components from needles and roots. The major constituents were divided into different phytochemical groups—phenolics (50%), fatty acids (44%), and terpenoids. Further analyses were carried out to characterize the distribution of allelochemicals in different organs and P. halepensis successional stages. Roots and needles had two distinct chemical profiles, while needle leachates were composed mainly of oxygenated terpenoids (e.g., α-eudesmol, α-cadinol, and α-terpineol). Roots mainly contained fatty acids. Needles from young pine stands had the highest content of monoterpenes, suggesting their role as potential allelochemicals that could help young pine stands to establish. Pooling the different functional chemical groups showed that needles and, to a lesser extent, old roots, had higher chemical diversity than the roots of young and medium-aged pines. The highest diversity in phenolic constituents and fatty acids was in young needles (D_chem = 2.38). Finally, caffeic acid, a compound that has allelopathic properties was found in aqueous extracts at high concentrations in both young needles and old roots. The role of this compound in mediation of biological interactions in P. halepensis ecosystem functioning is discussed.     

Efficient Telomerization of Butadiene with Starch in Water: The Role of the Surfactant

The synthesis of hydrophobic starch was performed via palladium-catalyzed telomerization of butadiene with native starch. This reaction is efficiently performed in water in the presence of neutral or cationic surfactant with high HLB. After optimization of the reaction conditions, TOF up to 446 was achieved.     

Synthesis, cytotoxicity, and COMPARE analysis of ferrocene and [3]ferrocenophane tetrasubstituted olefin derivatives against human cancer cells

Herein we report the antiproliferative effects of a series of 28 compounds against the MDA-MB-231 breast cancer cell line, including the synthesis of seven new [3]ferrocenophanyl and four new ferrocenyl compounds. For each p-R-phenyl substitution pattern investigated, the [3]ferrocenophanyl derivatives were more cytotoxic than the corresponding ferrocenyl derivative, with the highest activity found for compounds with protic substituents. Theoretical calculations of the HOMO-LUMO gap for the molecules in the Fe3(+) oxidation state suggest a higher reactivity for the [3]ferrocenophanyl derivatives. A lead compound from each series, a [3]ferrocenophanyl and a ferrocenyl compound, possessing two phenol groups, were screened against the NCI/DTP 60-cell-line panel. The mean activity over all cell lines was better than cisplatin for both compounds, and both compounds showed subpanel selectivity for leukemia, CNS cancer, and renal cancer. Low systemic toxicity and lack of interaction with DNA (when in the reduced form), suggest that the compounds may act as prodrugs.     

Characteristics of Retinitis Pigmentosa Associated with ADGRV1 and Comparison with USH2A in Patients from a Multicentric Usher Syndrome Study Treatrush

In contrast to USH2A, variants in ADGRV1 are a minor cause of Usher syndrome type 2, and the associated phenotype is less known. The purpose of the study was to characterize the retinal phenotype of 18 ADGRV1 patients (9 male, 9 female; median age 52 years) and compare it with that of 204 USH2A patients (111 male, 93 female; median age 43 years) in terms of nyctalopia onset, best corrected visual acuity (BCVA), fundus autofluorescence (FAF), and optical coherence tomography (OCT) features. There was no statistical difference in the median age at onset (30 and 18 years; Mann–Whitney U test, p = 0.13); the mean age when 50% of the patients reached legal blindness (≥1.0 log MAR) based on visual acuity (64 years for both groups; log-rank, p = 0.3); the risk of developing advanced retinal degeneration (patch or atrophy) with age (multiple logistic regression, p = 0.8); or the frequency of cystoid macular edema (31% vs. 26%, Fisher’s exact test, p = 0.4). ADGRV1 and USH2A retinopathy were indistinguishable in all major functional and structural characteristics, suggesting that the loss of function of the corresponding proteins produces similar effects in the retina. The results are important for counseling ADGRV1 patients, who represent the minor patient subgroup.     

Platelet-Derived PCSK9 Is Associated with LDL Metabolism and Modulates Atherothrombotic Mechanisms in Coronary Artery Disease

Platelets play a significant role in atherothrombosis. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is critically involved in the regulation of LDL metabolism and interacts with platelet function. The effect of PCSK9 in platelet function is poorly understood. The authors of this article sought to characterize platelets as a major source of PCSK9 and PCSK9’s role in atherothrombosis. In a large cohort of patients with coronary artery disease (CAD), platelet count, platelet reactivity, and platelet-derived PCSK9 release were analyzed. The role of platelet PCSK9 on platelet and monocyte function was investigated in vitro. Platelet count and hyper-reactivity correlated with plasma LDL in CAD. The circulating platelets express on their surface and release substantial amounts of PCSK9. Release of PCSK9 augmented platelet-dependent thrombosis, monocyte migration, and differentiation into macrophages/foam cells. Platelets and PCSK9 accumulated in tissue derived from atherosclerotic carotid arteries in areas of macrophages. PCSK9 inhibition reduced platelet activation and platelet-dependent thrombo-inflammation. The authors identified platelets as a source of PCSK9 in CAD, which may have an impact on LDL metabolism. Furthermore, platelet-derived PCSK9 contributes to atherothrombosis, and inhibition of PCSK9 attenuates thrombo-inflammation, which may contribute to the reported beneficial clinical effects.