Carborane‐Containing Matrix Metalloprotease (MMP) Ligands as Candidates for Boron Neutron‐Capture Therapy (BNCT)

Based on the previously reported potent and selective sulfone hydroxamate inhibitors SC‐76276, SC‐78080 (SD‐2590), and SC‐77964, potent MMP inhibitors have been designed and synthesized to append a boron‐rich carborane cluster by employing click chemistry to target tumor cells that are known to upregulate gelatinases. Docking against MMP‐2 suggests binding involving the hydroxamate zinc‐binding group, key H‐bonds by the sulfone moiety with the peptide backbone residues Leu82 and Leu83, and a hydrophobic interaction with the deep P1’ pocket. The more potent of the two triazole regioisomers exhibits an IC50 of 3.7 nM versus MMP‐2 and IC50 of 46 nM versus MMP‐9

Toll-like receptor signaling adapter proteins govern spread of neuropathic pain and recovery following nerve injury in male mice.

BackgroundSpinal Toll-like receptors (TLRs) and signaling intermediaries have been implicated in persistent pain states. We examined the roles of two major TLR signaling pathways and selected TLRs in a mononeuropathic allodynia.MethodsL5 spinal nerve ligation (SNL) was performed in wild type (WT, C57BL/6) male and female mice and in male Tlr2-/-Tlr3-/-, Tlr4-/-, Tlr5-/-, Myd88-/-, Triflps2, Myd88/Triflps2, Tnf-/-, and Ifnar1-/- mice. We also examined L5 ligation in Tlr4-/- female mice. We examined tactile allodynia using von Frey hairs. Iba-1 (microglia) and GFAP (astrocytes) were assessed in spinal cords by immunostaining. Tactile thresholds were analyzed by 1- and 2-way ANOVA and the Bonferroni post hoc test was used.ResultsIn WT male and female mice, SNL lesions resulted in a persistent and robust ipsilateral, tactile allodynia. In males with TLR2, 3, 4, or 5 deficiencies, tactile allodynia was significantly, but incompletely, reversed (approximately 50%) as compared to WT. This effect was not seen in female Tlr4-/- mice. Increases in ipsilateral lumbar Iba-1 and GFAP were seen in mutant and WT mice. Mice deficient in MyD88, or MyD88 and TRIF, showed an approximately 50% reduction in withdrawal thresholds and reduced ipsilateral Iba-1. In contrast, TRIF and interferon receptor null mice developed a profound ipsilateral and contralateral tactile allodynia. In lumbar sections of the spinal cords, we observed a greater increase in Iba-1 immunoreactivity in the TRIF-signaling deficient mice as compared to WT, but no significant increase in GFAP. Removing MyD88 abrogated the contralateral allodynia in the TRIF signaling-deficient mice. Conversely, IFNβ, released downstream to TRIF signaling, administered intrathecally, temporarily reversed the tactile allodynia.ConclusionsThese observations suggest a critical role for the MyD88 pathway in initiating neuropathic pain, but a distinct role for the TRIF pathway and interferon in regulating neuropathic pain phenotypes in male mice

New Boron Delivery Agents

This proceeding article compiles current research on the development of boron delivery drugs for boron neutron capture therapy that was presented and discussed at the National Cancer Institute (NCI) Workshop on Neutron Capture Therapy that took place on April 20-22, 2022. The most used boron sources are icosahedral boron clusters attached to peptides, proteins (such as albumin), porphyrin derivatives, dendrimers, polymers, and nanoparticles, or encapsulated into liposomes. These boron clusters and/or carriers can be labeled with contrast agents allowing for the use of imaging techniques, such as PET, SPECT, and fluorescence, that enable quantification of tumor-localized boron and their use as theranostic agents.C.V. thanks the Spanish Ministerio de Economiay Competitividad (PID2019-106832RB-100) and the Generalitat de Catalunya (2017SGR1720). H.N. received a Grant-in-Aid for Scientific Research (B) (No. 21H02066) from MEXT, Japan. M.G.H.V. thanks the National Institutes of Health grant number T34 GM136452. R.P. thanks the National Institutes of Health, grant number R21 CA259911 and the Department of Neurosurgery, Cedars Sinai MedicalCenter, Los Angeles.With funding from the Spanish government through the ‘Severo Ochoa Centre of Excellence’ accreditation (CEX2019-000917-S).Peer reviewe

Carbon nitrides: synthesis and characterization of a new class of functional materials

Carbon nitride compounds with high N[thin space (1/6-em)]:[thin space (1/6-em)]C ratios and graphitic to polymeric structures are being investigated as potential next-generation materials for incorporation in devices for energy conversion and storage as well as for optoelectronic and catalysis applications. The materials are built from C- and N-containing heterocycles with heptazine or triazine rings linked via sp2-bonded N atoms (N(C)3 units) or –NH– groups. The electronic, chemical and optical functionalities are determined by the nature of the local to extended structures as well as the chemical composition of the materials. Because of their typically amorphous to nanocrystalline nature and variable composition, significant challenges remain to fully assess and calibrate the structure–functionality relationships among carbon nitride materials. It is also important to devise a useful and consistent approach to naming the different classes of carbon nitride compounds that accurately describes their chemical and structural characteristics related to their functional performance. Here we evaluate the current state of understanding to highlight key issues in these areas and point out new directions in their development as advanced technological materials.Our work on carbon nitride materials has been supported by the EPSRC (EP/L017091/1) and the EU Graphene Flagship grant agreement No. 696656 - GrapheneCore1. Additional support to advance the science and technology of these materials was also received from the UCL Enterprise Fund and the Materials Innovation Impact Acceleration funding enabled by the UK EPSRC

THE STRUCTURES OF 7-VERTEX AND 12-VERTEX STANNACARBABORANES AND THEIR RELATIONSHIP TO CYCLOPENTADIENYL TIN CATIONS

COWLEY AH, GALOW P, HOSMANE NS, Jutzi P, NORMAN NC. THE STRUCTURES OF 7-VERTEX AND 12-VERTEX STANNACARBABORANES AND THEIR RELATIONSHIP TO CYCLOPENTADIENYL TIN CATIONS. JOURNAL OF THE CHEMICAL SOCIETY-CHEMICAL COMMUNICATIONS. 1984;(23):1564-1565