Investigation into the Use of Encorafenib to Develop Potential PROTACs Directed against BRAFV600E Protein

BRAF is a serine/threonine kinase frequently mutated in human cancers. BRAF^V600E mutated protein is targeted through the use of kinase inhibitors which are approved for the treatment of melanoma; however, their long-term efficacy is hampered by resistance mechanisms. The PROTAC-induced degradation of BRAF^V600E has been proposed as an alternative strategy to avoid the onset of resistance. In this study, we designed a series of compounds where the BRAF kinase inhibitor encorafenib was conjugated to pomalidomide through different linkers. The synthesized compounds maintained their ability to inhibit the kinase activity of mutated BRAF with IC₅₀ values in the 40–88 nM range. Selected compounds inhibited BRAF^V600E signaling and cellular proliferation of A375 and Colo205 tumor cell lines. Compounds 10 and 11, the most active of the series, were not able to induce degradation of mutated BRAF. Docking and molecular dynamic studies, conducted in comparison with the efficient BRAF degrader P5B, suggest that a different orientation of the linker bearing the pomalidomide substructure, together with a decreased mobility of the solvent-exposed part of the conjugates, could explain this behavior.     

Adunanza del 25 Dicembre 1904 [418a]

Rendiconti del Circolo Matematico di Palermo Series 1 -     

Adunanze dal 12 giugno all’II dicember 1904

Rendiconti del Circolo Matematico di Palermo Series 1 -     

Polyhydroxybutyrate (PHB) Synthesis by <Emphasis Type="Italic">Spirulina</Emphasis> sp. LEB 18 Using Biopolymer Extraction Waste

The reuse of waste as well as the production of biodegradable compounds has for years been the object of studies and of global interest as a way to reduce the environmental impact generated by unsustainable exploratory processes. The conversion of linear processes into cyclical processes has environmental and economic advantages, reducing waste deposition and reducing costs. The objective of this work was to use biopolymer extraction waste in the cultivation of Spirulina sp. LEB 18, for the cyclic process of polyhydroxybutyrate (PHB) synthesis. Concentrations of 10, 15, 20, 25, and 30% (v/v) of biopolymer extraction waste were tested. For comparison, two assays were used without addition of waste, Zarrouk (SZ) and modified Zarrouk (ZM), with reduction of nitrogen. The assays were carried out in triplicate and evaluated for the production of microalgal biomass and PHB. The tests with addition of waste presented a biomass production statistically equal to ZM (0.79 g L^?1) (p?<?0.1). The production of PHB in the assay containing 25% of waste was higher when compared to the other cultivations, obtaining 10.6% (w/w) of biopolymer. From the results obtained, it is affirmed that the use of PHB extraction waste in the microalgal cultivation, aiming at the synthesis of biopolymers, can occur in a cyclic process, reducing process costs and the deposition of waste, thus favoring the preservation of the environment.     

GaN/LiNbO3 (0 0 0 1) interface formation calculated from first-principles

The stable adsorption sites for both Ga and N ions on the ideal and on the reconstructed LiNbO₃ (0 0 0 1) surface are determined by means of first-principle total energy calculations. A single N layer is found to be more strongly bound to the substrate than a single Ga layer. The adsorption of a GaN monolayer on the polar substrate within different orientations is then modeled. On the basis of our results, we propose a microscopic model for the GaN/LiNbO₃ interface. The GaN and LiNbO₃ (0 0 0 1) planes are parallel, but rotated by 30° each other, with in-plane epitaxial relationship [1 0 0]_GaN‖ [1 1  0]_LiNbO3. In this way the (0 0 0 1) plane lattice mismatch between GaN and LiNbO₃ is minimal and equal to 6.9% of the GaN lattice constant. The adsorbed GaN and the underlying LiNbO₃ substrate have parallel c-axes.     

Chemical waves

In our paper we try to describe the basic concepts of chemical waves and spatial pattern formation in a simple way. We pay particular attention to self-organisation phenomena in extended excitable systems. These result in the appearance of travelling waves, spiral waves, target patterns, Turing structures or more complicated structures called scroll waves, which are three-dimensional systems. We describe the most famous oscillating reaction, the Belousov-Zhabotinsky (BZ) reaction, in greater detail. This is because it is of great interest in both physical chemistry and in studies on the evolution and sustenance of self-organising biological systems.     

On the chromatic polynomial of a graph

Let P(G,λ) be the chromatic polynomial of a graph G with n vertices, independence number α and clique number ω. We show that for every λ≥n, ()^α≤≤ () ^{n −ω}. We characterize the graphs that yield the lower bound or the upper bound.?These results give new bounds on the mean colour number μ(G) of G: n− (n−ω)() ^{n −ω}≤μ(G)≤n−α() ^α. Received: December 12, 2000 / Accepted: October 18, 2001?Published online February 14, 2002     

Structural and thermodynamic studies of the interaction of distamycin A with the parallel quadruplex structure [d(TGGGGT)]4

The complex between distamycin A and the parallel DNA quadruplex [d(TGGGGT)]4 has been studied by 1H NMR spectroscopy and isothermal titration calorimetry (ITC). To unambiguously assert that distamycin A interacts with the grooves of the quadruplex [d(TGGGGT)]4, we have analyzed the NMR titration profile of a modified quadruplex, namely [d(TGGMeGGT)]4, and we have applied the recently developed differential frequency-saturation transfer difference (DF-STD) method, for assessing the ligand-DNA binding mode. The three-dimensional structure of the 4:1 distamycin A/[d(TGGGGT)]4 complex has been determined by an in-depth NMR study followed by dynamics and mechanics calculations. All results unequivocally indicate that distamycin molecules interact with [d(TGGGGT)]4 in a 4:1 binding mode, with two antiparallel distamycin dimers that bind simultaneously two opposite grooves of the quadruplex. The affinity between distamycin A and [d(TGGGGT)]4 enhances ( approximately 10-fold) when the ratio of distamycin A to the quadruplex is increased. In this paper we report the first three-dimensional structure of a groove-binder molecule complexed to a DNA quadruplex structure.     

Structural determination of ruthenium-porphyrin complexes relevant to catalytic epoxidation of olefins

A reproducible synthesis of a competent epoxidation catalyst, [Ru(VI)(TPP)(O)2)] (TPP = tetraphenylporphyrin dianion), starting from [Ru(II)(TPP)(CO)L] (L = none or CH3OH), is described. The molecular structure of the complex was determined by using ab initio X-ray powder diffraction (XRPD) methods, and its solution behavior was in detail investigated by NMR techniques such as PGSE (pulsed field gradient spin-echo) measurements. [Ru(IV)(TPP)(OH)]2O, a reported byproduct in the synthesis of [Ru(VI)(TPP)(O)2], was synthesized in a pure form by oxidation of [Ru(II)(TPP)(CO)L] or by a coproportionation reaction of [Ru(VI)(TPP)(O)2] and [Ru(II)(TPP)(CO)L], and its molecular structure was then determined by XRPD analysis. [Ru(VI)(TPP)(O)2] can be reduced by dimethyl sulfoxide or by carbon monoxide to yield [Ru(II)(TPP)(S-DMSO)2] or [Ru(II)(TPP)(CO)(H2O)], respectively. These two species were characterized by conventional single-crystal X-ray diffraction analysis.