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Five new series of pyrrolo-fused heterocycles were designed through a scaffold hybridization strategy as analogs of the well-known microtubule inhibitor phenstatin. Compounds were synthesized using the 1,3-dipolar cycloaddition of cycloimmonium N-ylides to ethyl propiolate as a key step. Selected compounds were then evaluated for anticancer activity and ability to inhibit tubulin polymerization in vitro. Notably, pyrrolo[1,2-a]quinoline 10a was active on most tested cell lines, performing better than control phenstatin in several cases, most notably on renal cancer cell line A498 (GI50 27 nM), while inhibiting tubulin polymerization in vitro. In addition, this compound was predicted to have a promising ADMET profile. The molecular details of the interaction between compound 10a and tubulin were investigated through in silico docking experiments, followed by molecular dynamics simulations and configurational entropy calculations. Of note, we found that some of the initially predicted interactions from docking experiments were not stable during molecular dynamics simulations, but that configurational entropy loss was similar in all three cases. Our results suggest that for compound 10a, docking experiments alone are not sufficient for the adequate description of interaction details in terms of target binding, which makes subsequent scaffold optimization more difficult and ultimately hinders drug design. Taken together, these results could help shape novel potent antiproliferative compounds with pyrrolo-fused heterocyclic cores, especially from an in silico methodological perspective. [ABSTRACT FROM AUTHOR]

Gastroesophageal reflux disease (GERD) is one of the most commonly encountered disorders in clinical practice nowadays, with an increasing burden on healthcare systems worldwide. GERD-related respiratory symptoms such as unexplained chronic cough, bronchial asthma or chronic obstructive pulmonary disease (COPD) with frequent exacerbations often pose diagnostic and therapeutic challenges and may require a multidisciplinary approach. Moreover, a potential role of GERD as a risk factor has been proposed for chronic rejection in patients who underwent lung transplantation. Pepsin has gained considerable attention from the scientific community in the last few years as a possible surrogate biomarker for GERD. The aim of this narrative review was to provide an overview of the potential utility of pepsin detection as a marker of micro-aspiration in various biological fluids retrieved from patients with suspected GERD-induced respiratory manifestations and in lung transplant patients with allograft dysfunction. Data on the subject remains highly contradictory, and while certain studies support its applicability in investigating atypical GERD manifestations, at the moment, it would be realistic to accept a modest utility at best. A major lack of consensus persists regarding topics such as the optimal timeframe for fluid collection and cut-off values. Further research is warranted in order to address these issues. [ABSTRACT FROM AUTHOR]

The understanding of self-assembly conditions has become the main purpose of experimental and theoretical research studies on micelles. Association of the micelles in clusters is a challenging topic, given the enhanced complexity of cluster systems. This work reports molecular dynamics studies on micellar structures of azo-polysiloxanes modified with quaternary ammonium groups like triethylammonium or dimethyldodecilammonium chloride. Previously, our experimental results have shown a very particular type of aggregation of long hydrocarbon chain amine-based micelles, which was not yet mentioned in the literature. If tertiary amines are low size, such as triethylammonium, the aggregation process of micelles in clusters is no longer present. Molecular dynamics simulations revealed the formation of an amphiphilic layer mainly composed of hydrocarbon chains of the ammonium groups, together with chlorobenzyl and azobenzene moieties. This ordering manner opposes to the idea of a continuous electrical layer of low molecular weight molecules on the surface of the micelle, or to those of a compositionally uniform coating formed by copolymers (diblock, triblock or graft). The herein paper also reports force field parameters, such as quantum mechanical derived atomic partial charges for the studied compounds, bringing improvements to the force fields developed so far. Unlabelled Image • Molecular dynamics studies developed on micellar structures of azo-polysiloxanes randomly modified with quaternary ammonium groups are reported. • Molecular dynamics simulations revealed the formation of an amphiphilic layer at the micellar surface. • New partial charge parameters for azo-polysiloxanes were derived by fitting the molecular electrostatic potential using the RESP method. [ABSTRACT FROM AUTHOR]