Ion Channels and Transporters as Therapeutic Agents: From Biomolecules to Supramolecular Medicinal Chemistry

Ion channels and transporters typically consist of biomolecules that play key roles in a large variety of physiological and pathological processes. Traditional therapies include many ionchannel blockers, and some activators, although the exact biochemical pathways and mechanisms that regulate ion homeostasis are yet to be fully elucidated. An emerging area of research with great innovative potential in biomedicine pertains the design and development of synthetic ion channels and transporters, which may provide unexplored therapeutic opportunities. However, most studies in this challenging and multidisciplinary area are still at a fundamental level. In this review, we discuss the progress that has been made over the last five years on ion channels and transporters, touching upon biomolecules and synthetic supramolecules that are relevant to biological use. We conclude with the identification of therapeutic opportunities for future exploratio

Fluorescent and colorimetric sensors for anions: Highlights from 2020 to 2022

The development of colorimetric and fluorescent sensors continues apace. In this review, we highlight de-velopments made in this area from 2020 to 2022. The review is structured by the different non-covalent in-teractions used to bind anions in addition to covering photoswitchable systems, excimers and molecular logic gates, and arrays for anion sensing

Metal-based gels: Synthesis, properties, and applications

This review covers various aspects of recent developments on the design, the synthesis, the characterization of gels that: (i) are formed in the presence of metal ions (metallogels); (ii) are based on coordination complexes as gelators. Particular attention is devoted to systems that show recognition and sensing properties towards different analytes

Extensive carrier testing and CF birth prevalence: evidence for a negative correlation

Aim of the study was to evaluate if extensive CF carrier testing may be connected with the progressive decrease of CF birth incidence recorded in North Eastern Italy. From 1993 to 2007 an average 52,000 newborns per year underwent Neonatal Screening (NS), and 198 newborns with CF were detected (1/3937). A time related contraction in birth prevalence was confirmed, with an average annual percent decrease of 0.15 per 10,000 neonates (Poisson regression analysis p 0.003). In the NS area two sections were identified: the Western Region (WR), where CF carrier testing is not offered to couples from the general population, and the Eastern Region (ER), where CF carrier testing is widely offered to couples from the general population. In ER from 1995 to 2007 such testing practice has been steadily expanding, with a total of 87,721 CF carrier tests performed, 3460 carriers identified, and 238 carrier couples detected (data collection in progress). The prevalence of CF decreased by time (p<0.001) but the rate of decrease was more enhanced in ER as suggested by the existence of a statistically significant (p = 0.014) interaction term between time and region in the Poisson regression model. The overall negative trend in North Eastern Italy is due to a contraction of CF births in its Eastern part. In ER a negative correlation was found between CF incidence and the number of carrier tests (p 0.012). Prenatal diagnosis data collection is in progress. These data support the hypothesis that carrier screening may modify the incidence of CF

Potentiometric Sensing of Nonsteroidal Painkillers by Acyclic Squaramide Ionophores

We report here a small library of a new type of acyclic squaramide receptors (L1-L5) as selective ionophores for the detection of ketoprofen and naproxen anions (KF- and NS-, respectively) in aqueous media. 1H NMR binding studies show a high affinity of these squaramide receptors toward KF- and NS-, suggesting the formation of H-bonds between the two guests and the receptors through indole and −NH groups. Compounds L1-L5 have been tested as ionophores for the detection of KF- and NS- inside solvent PVC-based polymeric membranes. The optimal membrane compositions were established through the careful variation of the ligand/tridodecylmethylammonium chloride (TDMACl) anion-exchanger ratio. All of the tested acyclic squaramide receptors L1-L5 have high affinity toward KF- and NS- and anti-Hofmeister selectivity, with L4 and L5 showing the highest sensitivity and selectivity to NS-. The utility of the developed sensors for a high precision detection of KF- in pharmaceutical compositions with low relative errors of analysis (RSD, 0.99-1.4%) and recoveries, R%, in the range 95.1-111.8% has been demonstrated. Additionally, the chemometric approach has been involved to effectively discriminate between the structurally very similar KF- and NS-, and the possibility of detecting these analytes at concentrations as low as 0.07 μM with R2 of 0.947 and at 0.15 μM with R2 of 0.919 for NS- and KF-, respectively, was shown

Metformin as an adjuvant drug against pediatric sarcomas: hypoxia limits therapeutic effects of the drug.

Metformin, a well-known insulin-sensitizer commonly used for type 2 diabetes therapy, has recently emerged as potentially very attractive drug also in oncology. It is cheap, it is relatively safe and many reports have indicated effects in cancer prevention and therapy. These desirable features are particularly interesting for pediatric sarcomas, a group of rare tumors that have been shown to be dependent on IGF and insulin system for pathogenesis and progression. Metformin exerts anti-mitogenic activity in several cancer histotypes through several molecular mechanisms. In this paper, we analyzed its effects against osteosarcoma, Ewing sarcoma and rhabdomyosarcoma, the three most common pediatric sarcomas. Despite in vitro metformin gave remarkable antiproliferative and chemosensitizing effects both in sensitive and chemoresistant cells, its efficacy was not confirmed against Ewing sarcoma xenografts neither as single agent nor in combination with vincristine. This discrepancy between in vitro and in vivo effects may be due to hypoxia, a common feature of solid tumors. We provide evidences that in hypoxia conditions metformin was not able to activate AMPK and inhibit mTOR signaling, which likely prevents the inhibitory effects of metformin on tumor growth. Thus, although metformin may be considered a useful complement of conventional chemotherapy in normoxia, its therapeutic value in highly hypoxic tumors may be more limited. The impact of hypoxia should be considered when novel therapies are planned for pediatric sarcomas

Supramolecular self-associating amphiphiles: determination of molecular self-association properties and calculation of critical micelle concentration using a high-throughput, optical density based methodology

Supramolecular self-associating amphiphiles are a class of amphiphilic salt, the anionic component of which is 'frustrated' in nature, meaning multiple hydrogen bonding modes can be accessed simultaneously. Here we derive critical micelle concentration values for four supramolecular self-associating amphiphiles using the standard pendant drop approach and present a new high-throughput, optical density measurement based methodology, to enable the estimation of critical micelle concentrations over multiple temperatures. In addition, we characterise the low-level hydrogen bonded self-association events in the solid state, through single crystal X-ray diffraction, and in polar organic DMSO-d(6) solutions using a combination of H-1 NMR techniques. Moving into aqueous ethanol solutions (EtOH/H2O or EtOH/D2O (1 : 19 v/v)), we also show these amphiphilic compounds to form higher-order self-associated species through a combination of H-1 NMR, dynamic light scattering and zeta potential studies

Memory functions and Correlations in Additive Binary Markov Chains

A theory of additive Markov chains with long-range memory, proposed earlier in Phys. Rev. E 68, 06117 (2003), is developed and used to describe statistical properties of long-range correlated systems. The convenient characteristics of such systems, a memory function, and its relation to the correlation properties of the systems are examined. Various methods for finding the memory function via the correlation function are proposed. The inverse problem (calculation of the correlation function by means of the prescribed memory function) is also solved. This is demonstrated for the analytically solvable model of the system with a step-wise memory function.Comment: 11 pages, 5 figure

Coordination Chemistry and Sensing Properties Towards Anions and Metal Ions of a Simple Fluorescent Urea

The coordination and sensing properties towards anions and transition metal ions of the simple novel fluorescent urea 1-(2-aminophenyl)-3-(naphthalen-1)-yl)urea (L) were investigated in solution, and in the solid state. An electron donating amine group in the molecular skeleton of L decreased the acidity of the urea NHs that are usually deprotonated by basic anions and allowed for a good degree of affinity towards fluoride in DMSO-d6-0.5 %H2O. Moreover, the amine moiety acted as a further binding group for metal ions. Indeed, L was able to bind Zn2+ both in solution and in the solid state, and to respond to the presence of this metal ion in MeCN with an enhancement of the fluorescence emission. Although solution studies evidenced the formation of a 1 : 1 complex of L with Zn2+, complexes with a 2 : 1 ligand-to-metal stoichiometry were isolated in the solid state. DFT calculations helped to clarify the stability reasons behind these results