Design, synthesis and biological evaluation of new pyrimidine derivatives as anticancer agents

BACKGROUND: Anticancer drug resistance is a challenging phenomenon of growing concern which arises from alteration in drug targets. Despite the fast speed of new chemotherapeutic agent design, the increasing prevalence of this phenomenon requires further research and treatment development. Recently, we reported a new aminopyrimidine compound-namely RDS 344-as a potential innovative anticancer agent.METHODS: Herein, we report the design, synthesis, and anti-proliferative activity of new aminopyrimidine derivatives structurally related to RDS 3442 obtained by carrying out substitutions at position 6 of the pyrimidine core and/or on the 2-aniline ring of our hit. The ability to inhibit cell proliferation was evaluated on different types of tumors, glioblastoma, triple-negative breast cancer, oral squamous cell carcinomas and colon cancer plus on human dermal fibroblasts chosen as control of normal cells.RESULTS: The most interesting compound was the N-benzyl counterpart of RDS 3442, namely 2a, that induced a significant decrease in cell viability in all the tested tumor cell lines, with EC50s ranging from 4 and 8 muM, 4-13 times more active of hit.CONCLUSIONS: These data suggest a potential role for this class of molecules as promising tool for new approaches in treating cancers of different histotype

Analytical characterization of an inulin-type fructooligosaccharide from root-tubers of Asphodelus ramosus L

Plant-based systems continue to play a pivotal role in healthcare, and their use has been extensively documented. Asphodelus L. is a genus comprising various herbaceous species, known by the trivial name Asphodelus. These plants have been known since antiquity for both food and therapeutic uses, especially for treating several diseases associated with inflammatory and infectious skin disorders. Phytochemical studies revealed the presence of different constituents, mainly anthraquinones, triterpenoids, phenolic acids, and flavonoids. Although extensive literature has been published on these constituents, a paucity of information has been reported regarding the carbohydrate composition, such as fructans and fructan-like derivatives. The extraction of watersoluble neutral polysaccharides is commonly performed using water extraction, at times assisted by microwaves and ultrasounds. Herein, we reported the investigation of the alkaline extraction of roottubers of Asphodelus ramosus L., analyzing the water-soluble polysaccharides obtained by precipitation from the alkaline extract and its subsequent purification by chromatography. A polysaccharide was isolated by alkaline extraction; the HPTLC study to determine its composition showed fructose as the main monosaccharide. FT-IR analysis showed the presence of an inulin-type structure, and NMR analyses allowed us to conclude that A. ramosus roots contain polysaccharide with an inulin-type fructooligosaccharide with a degree of polymerization of 7-8

Investigation of Commiphora myrrha (Nees) Engl. oil and its main components for antiviral activity

The resinous exudate produced by Commiphora myrrha (Nees) Engl. is commonly known as true myrrh and has been used since antiquity for several medicinal applications. Hundreds of metabolites have been identified in the volatile component of myrrh so far, mainly sesquiterpenes. Although several efforts have been devoted to identifying these sesquiterpenes, the phytochemical analyses have been performed by gas-chromatography/mass spectrometry (GC–MS) where the high temperature employed can promote degradation of the components. In this work, we report the extraction of C. myrrha by supercritical CO2, an extraction method known for the mild extraction conditions that allow avoiding undesired chemical reactions during the process. In addition, the analyses of myrrh oil and of its metabolites were performed by HPLC and GC–MS. Moreover, we evaluated the antiviral activity against influenza A virus of the myrrh extracts, that was possible to appreciate after the addition of vitamin E acetate (α-tocopheryl acetate) to the extract. Further, the single main bioactive components of the oil of C. myrrha commercially available were tested. Interestingly, we found that both furanodienone and curzerene affect viral replication by acting on different steps of the virus life cycle

Diketo acid inhibitors of nsp13 of SARS-CoV-2 block viral replication

For RNA viruses, RNA helicases have long been recognized to play critical roles during virus replication cycles, facilitating proper folding and replication of viral RNAs, therefore representing an ideal target for drug discovery. SARS-CoV-2 helicase, the non-structural protein 13 (nsp13) is a highly conserved protein among all known coronaviruses, and, at the moment, is one of the most explored viral targets to identify new possible antiviral agents. In the present study, we present six diketo acids (DKAs) as nsp13 inhibitors able to block both SARS-CoV-2 nsp13 enzymatic functions. Among them four compounds were able to inhibit viral replication in the low micromolar range, being active also on other human coronaviruses such as HCoV229E and MERS CoV. The experimental investigation of the binding mode revealed ATP-non-competitive kinetics of inhibition, not affected by substrate-displacement effect, suggesting an allosteric binding mode that was further supported by molecular modelling calculations predicting the binding into an allosteric conserved site located in the RecA2 domain

Variational Inference in Dynamical Systems

Dynamical systems are a powerful formalism to analyse the world around us. Many datasets are sequential in nature, and can be described by a discrete time evolution law. We are interested in approaching the analysis of such datasets from a probabilistic perspective. We would like to maintain justified beliefs about quantities which, though useful in explaining the behaviour of a system, may not be observable, as well as about the system's evolution itself, especially in regimes we have not yet observed in our data. The framework of statistical inference gives us the tools to do so, yet, for many systems of interest, performing inference exactly is not computationally or analytically tractable. The contribution of this thesis, then, is twofold: first, we uncover two sources of bias in existing variational inference methods applied to dynamical systems in general, and state space models whose transition function is drawn from a Gaussian process (GPSSM) in particular. We show bias can derive from assuming posteriors in non-linear systems to be jointly Gaussian, and from assuming that we can sever the dependence between latent states and transition function in state space model posteriors. Second, we propose methods to address these issues, undoing the resulting biases. We do this without compromising on computational efficiency or on the ability to scale to larger datasets and higher dimensions, compared to the methods we rectify. One method, the Markov Autoregressive Flow (Markov AF) addresses the Gaussian assumption, by providing a more flexible class of posteriors, based on normalizing flows, which can be easily evaluated, sampled, and optimised. The other method, Variationally Coupled Dynamics and Trajectories (VCDT), tackles the factorisation assumption, leveraging sparse Gaussian processes and their variational representation to reintroduce dependence between latent states and the transition function at no extra computational cost. Since the objective of inference is to maintain calibrated beliefs, if we employed approximations which are significantly biased in non-linear, noisy systems, or when there is little data available, we would have failed in our objective, as those are precisely the regimes in which uncertainty quantification is all the more important. Hence we think it is essential, if we wish to act optimally on such beliefs, to uncover, and, if possible, to correct, all sources of systematic bias in our inference methods.Qualcomm Innovation Fun

Self-constrained inversion of microgravity data along a segment of the Irpinia fault

A microgravity survey was completed to precisely locate and better characterize the near-surface geometry of a recent fault with small throw in a mountainous area in the Southern Apennines (Italy). The site is on a segment of the Irpinia fault,which is the source of theM6.9 1980 earthquake. This fault cuts a few meter of Mesozoic carbonate bedrock and its younger,mostly Holocene continental deposits cover. The amplitude of the complete Bouguer anomaly along two profiles across the fault is about 50 μGal. The data were analyzed and interpreted according to a self-constrained strategy, where some rapid estimation of source parameters was later used as constraint for the inversion. The fault has been clearly identified and localized in its horizontal position and depth. Interesting features in the overburden have been identified and their interpretation has allowed us to estimate the fault slip rate, which is consistent with independent geological estimates

Recent advances in recovery of lycopene from tomato waste. A potent antioxidant with endless benefits

Growing attention to environmental protection leads food industries to adopt a model of “circular economy” applying safe and sustainable technologies to recover, recycle and valorize by-products. Therefore, by-products become raw material for other industries. Tomato processing industry produces significant amounts of by-products, consisting of skins and seeds. Tomato skin is very rich in lycopene, and from its seeds, high nutritional oil can be extracted. Alternative use of the two fractions not only could cut disposal costs but also allow one to extract bioactive compounds and an oil with a high nutritional value. This review focused on the recent advance in extraction of lycopene, whose beneficial effects on health are widely recognized