A Mini-Review on Thalidomide: Chemistry, Mechanisms of Action, Therapeutic Potential and Anti-Angiogenic Properties in Multiple Myeloma

Thalidomide is a drug with interesting therapeutic properties but also with severe side effects which require a careful and monitored use. Potential immunomodulatory, anti-inflammatory, anti-angiogenic and sedative properties make thalidomide a good candidate for the treatment of several diseases such as multiple myeloma. Through an increase in the degradation of TNF alpha-mRNA, thalidomide reduces the production of TNF alpha by monocytes and macrophages stimulated by lipopolysaccharide or by T lymphocytes induced by mitogenic stimuli. The decreased level of TNF alpha alters the mechanisms of intracellular transduction by preventing the activation of NF-kB and by decreasing the synthesis of proteins, in particular IL-6, involved in cell proliferation, inflammation, angiogenesis and protection from apoptosis. Furthermore, thalidomide affects VEGF levels by down-regulating its expression. Nowadays, new safer and less toxic drugs, analogs of thalidomide, are emerging as beneficial for a more targeted treatment of multiple myeloma and several other diseases such as Crohn's disease, rheumatoid arthritis, sarcoidosis, erythema nodosum leprosum, graft-versus-host disease

Synthesis, anticancer and antioxidant properties of new indole and pyranoindole derivatives

The indole scaffold has been recognized, over the years, as a model for the synthesis of compounds with anticancer activity by dint of its substantiated ability to act via multiple mechanisms, which also involves the inhibition of enzymes engaged in DNA replication. In this regard, a new series of indole and pyranoindole derivatives have been prepared, some of which showed good antitumor activity and proved their inhibitory effects on the tubulin target. The anticancer activity of the newly synthesized compounds has been evaluated on breast cancer cell lines, as MCF-7 and MDA-MB231, cervical cancer cells line HeLa and Ishikawa endometrial cancer cell line. Among the compounds under study, 7 exhibited a good antitumor activity on HeLa cell line (IC50 = 3.6 ± 0.5), leading to cell death by apoptosis due to the inhibition of tubulin polymerization, which demonstrated that the compound can explicate its function in a similar way to Vinblastine, a well-known inhibitor of tubulin polymerization. The data were also confirmed by in silico assays. No cytotoxicity against normal cells has been detected. Furthermore, in order to investigate the antioxidant properties, DPPH and ABTS tests were performed, together with fluorescence assays on 3T3-L1 cells. All our findings taken together led us to consider compound 7 a favourable candidate for the battle against cancer

Molecular Insights into the Local Anesthetic Receptor within Voltage-Gated Sodium Channels Using Hydroxylated Analogs of Mexiletine

We previously showed that the β-adrenoceptor modulators, clenbuterol and propranolol, directly blocked voltage-gated sodium channels, whereas salbutamol and nadolol did not (Desaphy et al., 2003), suggesting the presence of two hydroxyl groups on the aromatic moiety of the drugs as a molecular requisite for impeding sodium channel block. To verify such an hypothesis, we synthesized five new mexiletine analogs by adding one or two hydroxyl groups to the aryloxy moiety of the sodium channel blocker and tested these compounds on hNav1.4 channels expressed in HEK293 cells. Concentration–response relationships were constructed using 25-ms-long depolarizing pulses at −30 mV applied from an holding potential of −120 mV at 0.1 Hz (tonic block) and 10 Hz (use-dependent block) stimulation frequencies. The half-maximum inhibitory concentrations (IC50) were linearly correlated to drug lipophilicity: the less lipophilic the drug, minor was the block. The same compounds were also tested on F1586C and Y1593C hNav1.4 channel mutants, to gain further information on the molecular interactions of mexiletine with its receptor within the sodium channel pore. In particular, replacement of Phe1586 and Tyr1593 by non-aromatic cysteine residues may help in the understanding of the role of π–π or π–cation interactions in mexiletine binding. Alteration of tonic block suggests that the aryloxy moiety of mexiletine may interact either directly or indirectly with Phe1586 in the closed sodium channel to produce low-affinity binding block, and that this interaction depends on the electrostatic potential of the drug aromatic tail. Alteration of use-dependent block suggests that addition of hydroxyl groups to the aryloxy moiety may modify high-affinity binding of the drug amine terminal to Phe1586 through cooperativity between the two pharmacophores, this effect being mainly related to drug lipophilicity. Mutation of Tyr1593 further impaired such cooperativity. In conclusion, these results confirm our former hypothesis by showing that the presence of hydroxyl groups to the aryloxy moiety of mexiletine greatly reduced sodium channel block, and provide molecular insights into the intimate interaction of local anesthetics with their receptor

Microwave-Assisted Synthesis of (±)-Mandelic Acid-5 , ��tical Resolution, and A�solute Con�guration Deter�ination

An efficient microwave-assisted synthesis of (±)-mandelic acid-5 was developed. e racemic mixture was resolved by diastereomeric salt formation using 1-phenylethylamine enantiomers as resolving agents. At each step, the resolution process was checked by determining mandelic acid-5 enantiomer ee values directly on fractional crystallized diastereomeric salts by chiral capillary electrophoresis analysis. Highly enriched (−)-and (+)-mandelic acid-5 (95% and 90% ee, resp.) were obtained and their absolute con�gurations-and , respectively-were determined by correlation of the (−)-mandelic acid-5 circular dichroism spectrum to the (R)-mandelic acid one

Inhibition of voltage-gated sodium channels by sumatriptan bioisosteres

Voltage-gated sodium channels are known to play a pivotal role in perception and transmission of pain sensations. Gain-of-function mutations in the genes encoding the peripheral neuronal sodium channels, hNav1.7-1.9, cause human painful diseases. Thus while treatment of chronic pain remains an unmet clinical need, sodium channel blockers are considered as promising druggable targets. In a previous study, we evaluated the analgesic activity of sumatriptan, an agonist of serotonin 5HT1B/D receptors, and some new chiral bioisosteres, using the hot plate test in the mouse. Interestingly, we observed that the analgesic effectiveness was not necessarily correlated to serotonin agonism. In this study, we evaluated whether sumatriptan and its congeners may inhibit heterologously expressed hNav1.7 sodium channels using the patch-clamp method. We show that sumatriptan blocks hNav1.7 channels only at very high, supratherapeutic concentrations. In contrast, its three analogs, namely 20b, (R)-31b, and (S)-22b, exert a dose and use-dependent sodium channel block. At 0.1 and 10 Hz stimulation frequencies, the most potent compound, (S)-22b, was 4.4 and 1.7 fold more potent than the well-known sodium channel blocker mexiletine. The compound induces a negative shift of voltage dependence of fast inactivation, suggesting higher affinity to the inactivated channel. Accordingly, we show that (S)-22b likely binds the conserved local anesthetic receptor within voltage-gated sodium channels. Combining these results with the previous ones, we hypothesize that use-dependent sodium channel blockade contributes to the analgesic activity of (R)-31b and (S)-22b. These later compounds represent promising lead compounds for the development of efficient analgesics, the mechanism of action of which may include a dual action on sodium channels and 5HT1D receptors

Novel insights in health-promoting properties of sweet cherries

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Preservation of Abandoned Historic Centres — The Case of Poggioreale antica (Sicily)

Among the fourteen towns most damaged by the earthquake that struck western Sicily in 1968, Poggioreale was subjected to total relocation a few kilometres away, and to the transfer of its whole population. More than half a century later, the damaged settlement is still largely recognisable and has been experiencing a new season of interest for some years now, both from the local community and various kinds of outsiders who imagine economic spin-offs of an uncertain nature in its enhancement. The research we present questions the chance of survival for the settlement, forgotten for decades, in the context of interventions aimed at its reuse. Alternative strategies are discussed: on the one hand, that of bringing the ancient centre back to life, even in part, with a limited inclusion of collective functions and without claiming to inhabit it again; on the other hand, and in the authors’ opinion, more likely, that of reusing the ruins as an archaeological area preserving their memory in a different form. In either case, the kinds of operations to be carried out on the body of the ancient buildings for their physical preservation play a key role. These issues are addressed as a whole through the canonical procedure of correlating the phases of knowledge, interpretation, and definition of minimal and compatible intervention criteria

Determination of Commercial Animal and Vegetable Milks’ Lipid Profile and Its Correlation with Cell Viability and Antioxidant Activity on Human Intestinal Caco-2 Cells

none9openantonella aresta; Stefania De Santis; Alessia Carocci; Alexia Barbarossa; Andrea Ragusa; Nicoletta De Vietro; Maria Lisa Clodoveo; Filomena Corbo; Carlo ZAMBONINAresta, Antonella; De Santis, Stefania; Carocci, Alessia; Barbarossa, Alexia; Ragusa, Andrea; De Vietro, Nicoletta; Lisa Clodoveo, Maria; Corbo, Filomena; Zambonin, Carl