Phosphate-Rich Biomimetic Peptides Shed Light on High-Affinity Hyperphosphorylated Uranyl Binding Sites in Phosphoproteins

Some phosphoproteins such as osteopontin (OPN) have been identified as high-affinity uranyl targets. However, the binding sites required for interaction with uranyl and therefore involved in its toxicity have not been identified in the whole protein. The biomimetic approach proposed here aimed to decipher the nature of these sites and should help to understand the role of the multiple phosphorylations in UO₂²⁺ binding. Two hyperphosphorylated cyclic peptides, pS₁₆₈ and pS₁₃₆₈ containing up to four phosphoserine (pSer) residues over the ten amino acids present in the sequences, were synthesized with all reactions performed in the solid phase, including post-phosphorylation. These β-sheet-structured peptides present four coordinating residues from four amino acid side chains pointing to the metal ion, either three pSer and one glutamate in pS₁₆₈ or four pSer in pS₁₃₆₈ . Significantly, increasing the number of pSer residues up to four in the cyclodecapeptide scaffolds produced molecules with an affinity constant for UO₂²⁺ that is as large as that reported for osteopontin at physiological pH. The phosphate-rich pS₁₃₆₈ can thus be considered a relevant model of UO₂²⁺ coordination in this intrinsically disordered protein, which wraps around the metal ion to gather four phosphate groups in the UO₂²⁺ coordination sphere. These model hyperphosphorylated peptides are highly selective for UO₂²⁺ with respect to endogenous Ca²⁺, which makes them good starting structures for selective UO₂²⁺ complexation.     

Effects of Sodium Butyrate on Cell Death Induced by Photodynamic Therapy in U373-MG and D54-MG Astrocytoma Cell Lines

The damage induced by end products of photodynamic therapy (PDT) in astrocytoma tumors leads to cytotoxicity and cell death. Chromatin modifiers such as sodium butyrate (NaB) induce several genes involved in apoptosis, among others. The PDT improvement was evaluated by the measurement of its effectiveness in the treatment of U373-MG and D54-MG astrocytoma cell lines exposed to NaB. Cells exposed to 80 μg mL⁻¹ of δ-aminolevulinic acid (ALA) as precursor of endogenous photosensitizer (PS), protoporphyrin IX (PpIX), induced 16.67% and 28.9% of mortality in U373-MG and D54-MG, respectively. The mortality increased to 70.62% and 96.7%, respectively, when U373-MG and D54-MG cells were exposed for 24 h to 8 m m NaB prior to ALA-induction. In this condition, re-expression of some genes related to apoptosis in U373-MG, and differentiation in D54-MG were induced. PpIX accumulation was higher than ALA-induction and the acetylation of histone H4 induced by NaB was verified by immunocytochemistry in both cells. It can be concluded that modified chromatin and genes induced by NaB increment the cellular death induced by PDT in astrocytoma cells using PpIX as endogenous PS.     

An exact algorithm for the bi-objective timing problem

The timing problem in the bi-objective just-in-time single-machine job-shop scheduling problem (JiT-JSP) is the task to schedule N jobs whose order is fixed, with each job incurring a linear earliness penalty for finishing ahead of its due date and a linear tardiness penalty for finishing after its due date. The goal is to minimize the earliness and tardiness simultaneously. We propose an exact greedy algorithm that finds the entire Pareto front in \(O(N^2)\) time. This algorithm is asymptotically optimal.     

α,α-Difluorophosphonohydroxamic Acid Derivatives among the Best Antibacterial Fosmidomycin Analogues

Three α,α-difluorophosphonate derivatives of fosmidomycin were synthesized from diethyl 1,1-difluorobut-3-enylphosphonate and were evaluated on Escherichia coli. Two of them are among the best 1-deoxy-d-xylulose 5-phosphate reductoisomerase inhibitors, with IC₅₀ in the nM range, much better than fosmidomycin, the reference compound. They also showed an enhanced antimicrobial activity against E. coli on Petri dishes in comparison with the corresponding phosphates and the non-fluorinated phosphonate.     

Über die Beeinflussung der Löslichkeit von Elektrolyten durch Nichtelektrolyte

Zusammenfassung Die Wirkung von Zusätzen von Alkohol, Aceton, Isopropylalkohol, Harnstoff und Glykokoll auf die Löslichkeit von binären Elektrolyten, hauptsächlich bestehend aus Komplexionen von der Wertigkeit 1 bis 3, wurde untersucht. Die einfache elektrostatische Theorie reicht, auch bei mehrwertigen Ionen, zur quantitativen Beschreibung der Effekte nicht aus. Nichtelektrostatische Kräfte sind in vielen Fällen nicht vernachlässigbar und in manchen ausschlaggebend.Herrn Prof. Dr.E. Abel zum 80. Geburtstag gewidmet.     

Stereospecific Polymerization of Isoprene with Nd(BH4)3(THF)3/MgBu2 as Catalyst

Summary: The neodymium trisborohydride Nd(BH₄)₃(THF)₃ (THF = tetrahydrofuran) has been used as a catalyst precursor for isoprene polymerization for the first time. Associated to an excess of Al(Et)₃, the resulting catalyst is moderately active, giving a mixture of cis‐ and trans‐ polymer. Addition of a stoichiometric amount of MgBu₂ to Nd(BH₄)₃(THF)₃ affords a stereospecific catalyst providing trans‐1,4‐polyisoprene, more than 96% regular. That dual component Nd/Mg system also shows a better efficiency and good control of the molecular weights. A molecular structure is tentatively attributed to a bimetallic active species, based on ¹H NMR experiments.

Possible Nd/Al and Nd/Mg active initiating species.     

Synthesis and Anti-Trypanosoma cruzi Biological Evaluation of Novel 2-Nitropyrrole Derivatives

Human American trypanosomiasis, called Chagas disease, caused by T. cruzi protozoan infection, represents a major public health problem, with about 7000 annual deaths in Latin America. As part of the search for new and safe anti-Trypanosoma cruzi derivatives involving nitroheterocycles, we report herein the synthesis of ten 1-substituted 2-nitropyrrole compounds and their biological evaluation. After an optimization phase, a convergent synthesis methodology was used to obtain these new final compounds in two steps from the 2-nitropyrrole starting product. All the designed derivatives follow Lipinski’s rule of five. The cytotoxicity evaluation on CHO cells showed no significant cytotoxicity, except for compound 3 (CC₅₀ = 24.3 µM). Compound 18 appeared to show activity against T. cruzi intracellular amastigotes form (EC₅₀ = 3.6 ± 1.8 µM) and good selectivity over the vero host cells. Unfortunately, this compound 18 showed an insufficient maximum effect compared to the reference drug (nifurtimox). Whether longer duration treatments may eliminate all parasites remains to be explored.