Preliminary Evaluation of a 3H Imidazoquinoline Library as Dual TLR7/TLR8 Antagonists

Toll-like receptors (TLR) -7 and -8 are thought to play an important role in immune activation processes underlying the pathophysiology of HIV and several clinically important autoimmune diseases. Based on our earlier findings of TLR7-antagonistic activity in a 3H imidazoquinoline, we sought to examine a pilot library of 3H imidazoquinolines for dual TLR7/8 antagonists, since they remain a poorly explored chemotype. Two-dimensional NOE experiments were employed to unequivocally characterize the compounds. A quinolinium compound 12, bearing p-methoxybenzyl substituents on N3 and N5 positions was identified as a lead. Compound 12 was found to inhibit both TLR7 and TLR8 at low micromolar concentrations. Our preliminary results suggest that alkylation with electron-rich substituents on the quinoline N5, or conversely, elimination of the fixed charge of the resultant quaternary amine on the quinolinium may yield more active compounds

Elastic shape matching of parameterized surfaces using square root normal fields.

In this paper we define a new methodology for shape analysis of parameterized surfaces, where the main issues are: (1) choice of metric for shape comparisons and (2) invariance to reparameterization. We begin by defining a general elastic metric on the space of parameterized surfaces. The main advantages of this metric are twofold. First, it provides a natural interpretation of elastic shape deformations that are being quantified. Second, this metric is invariant under the action of the reparameterization group. We also introduce a novel representation of surfaces termed square root normal fields or SRNFs. This representation is convenient for shape analysis because, under this representation, a reduced version of the general elastic metric becomes the simple \ensuremathL2\ensuremathL2 metric. Thus, this transformation greatly simplifies the implementation of our framework. We validate our approach using multiple shape analysis examples for quadrilateral and spherical surfaces. We also compare the current results with those of Kurtek et al. [1]. We show that the proposed method results in more natural shape matchings, and furthermore, has some theoretical advantages over previous methods

Diethyl 4-[5-(4-chloro­phen­yl)-1H-pyrazol-4-yl]-2,6-dimethyl-1,4-dihydro­pyridine-3,5-dicarboxyl­ate

In the title compound, C22H24ClN3O4, intra­molecular C—H⋯O and C—H⋯N hydrogen bonds form S(9) and S(7) ring motifs, respectively. The 1,4-dihydro­pyridine ring adopts a flattened boat conformation. The benzene ring makes a dihedral angle of 33.36 (6)° with the pyrazole ring. In the crystal, pairs of N—H⋯N hydrogen bonds link the mol­ecules into inversion dimers. The dimers are stacked in column along the a axis through N—H⋯O and C—H⋯N hydrogen bonds. The crystal packing also features C—H⋯π inter­actions involving the pyrazole ring

Potent Adjuvanticity of a Pure TLR7-Agonistic Imidazoquinoline Dendrimer

Engagement of toll-like receptors (TLRs) serve to link innate immune responses with adaptive immunity and can be exploited as powerful vaccine adjuvants for eliciting both primary and anamnestic immune responses. TLR7 agonists are highly immunostimulatory without inducing dominant proinflammatory cytokine responses. We synthesized a dendrimeric molecule bearing six units of a potent TLR7/TLR8 dual-agonistic imidazoquinoline to explore if multimerization of TLR7/8 would result in altered activity profiles. A complete loss of TLR8-stimulatory activity with selective retention of the TLR7-agonistic activity was observed in the dendrimer. This was reflected by a complete absence of TLR8-driven proinflammatory cytokine and interferon (IFN)-γ induction in human PBMCs, with preservation of TLR7-driven IFN-α induction. The dendrimer was found to be superior to the imidazoquinoline monomer in inducing high titers of high-affinity antibodies to bovine α-lactalbumin. Additionally, epitope mapping experiments showed that the dendrimer induced immunoreactivity to more contiguous peptide epitopes along the amino acid sequence of the model antigen.This work was supported by National Institutes of Health/National Institute of Allergy and Infectious Diseases contract HHSN272200900033C

Toll-Like Receptor (TLR)-7 and -8 Modulatory Activities of Dimeric Imidazoquinolines

Toll-like receptors (TLRs) are pattern recognition receptors that recognize specific molecular patterns present in molecules that are broadly shared by pathogens, but are structurally distinct from host molecules. The TLR7-agonistic imidazoquinolines are of interest as vaccine adjuvants given their ability to induce pronounced Th1-skewed humoral responses. Minor modifications on the imidazoquinoline scaffold result in TLR7-antagonistic compounds which may be of value in addressing innate immune activation-driven immune exhaustion observed in HIV. We describe the syntheses and evaluation of TLR7 and TLR8 modulatory activities of dimeric constructs of imidazoquinoline linked at the C2, C4, C8, and N1-aryl positions. Dimers linked at the C4, C8 and N1-aryl positions were agonistic at TLR7; only the N1-aryl dimer with a 12-carbon linker was dual TLR7/8 agonistic. Dimers linked at C2 position showed antagonistic activities at TLR7 and TLR8; the C2 dimer with a propylene spacer was maximally antagonistic at both TLR7 and TLR8

Grain refinement in additively manufactured ferritic stainless steel by in situ inoculation using pre-alloyed powder

For ferritic stainless steels, TiN has effectively been used as an inoculant to produce equiaxed grain structures in casting and welding. However, it is not established whether TiN would be an effective inoculant in additive manufacturing. In this study, the effectiveness of TiN as an inoculant in a ferritic stainless steel processed by laser powder-bed fusion is studied. An alloy without Ti is fabricated and compared to an alloy designed to form a high amount of TiN early during solidification. The work shows that the presence of TiN provides general grain refinement and that TiN-covered oxide particles are effective in enabling columnar-to-equiaxed transition in certain regions of the meltpool. The applied approach of pre-alloying powders with inoculant-forming elements offers a straightforward route to achieving fine, equiaxed grain structures in additively manufactured metallic materials. It also shows how oxygen present during the process can be utilized to nucleate effective inoculating phases

Diethyl 4-[2-(4-meth­oxy­phen­yl)-1H-pyrazol-3-yl]-2,6-dimethyl-1,4-dihydro­pyridine-3,5-dicarboxyl­ate

In the title compound, C23H27N3O5, the pyrazole ring is inclined at dihedral angles of 38.16 (6) and 80.80 (6)°, respectively, to the least-squares planes of the benzene and dihydro­pyridine rings. In the crystal, adjacent mol­ecules are linked via a pair of N—H⋯N hydrogen bonds, forming an inversion dimer. The dimers are stacked in a column along the a axis through N—H⋯O hydrogen bonds. Intra- and inter­molecular C—H⋯N and C—H⋯O hydrogen bonds are also observed

Structure-Activity Relationships in Nucleotide Oligomerization Domain-1 (Nod1)-Agonistic γ-Glutamyl-diaminopimelic Acid Derivatives

N-acyl-γ-glutamyl-diaminopimelic acid is a prototype ligand for Nod1. We report a detailed SAR of C12-γ-D-Glu-DAP. Analogues with glutaric or γ-aminobutyric acid replacing the glutamic acid show greatly attenuated Nod1-agonistic activity. Substitution of the meso-diaminopimelic (DAP) acid component with monoaminopimelic acid, L- or D-lysine, or cadaverine also results in reduced activity. The free amine on DAP is crucial. However, the N-acyl group on the D-glutamyl residue can be substituted with N-alkyl groups with full preservation of activity. The free carboxylates on the DAP and Glu components can also be esterified, resulting in more lipophilic, but active analogues. Transcriptomal profiling showed a dominant upregulation of IL-19, IL-20, IL-22, and IL-24, which may explain the pronounced Th2-polarizing activity of these compounds, and also implicate cell signaling mediated by TREM-1. These results may explain the hitherto unknown mechanism of synergy between Nod1- and TLR-agonists, and are likely to be useful in designing vaccine adjuvants