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The hypothesis that categorical information, distinguishing among word classes, such as nouns, verbs, etc., is an organizational principle of lexical knowledge in the brain, is supported by the observation of aphasic subjects who are selectively impaired in the processing of nouns and verbs. The study of lesion location in these patients has suggested that the left temporal lobe plays a crucial role in processing nouns, while the left frontal lobe is necessary for verbs. To delineate the brain areas involved in the processing of different word classes, we used PET to measure regional cerebral activity during tasks requiring reading of concrete and abstract nouns and verbs for lexical decision. These tasks activated an extensive network of brain areas, mostly in the left frontal and temporal cortex, which represents the neural correlate of single word processing. Some left hemispheric areas, including the dorsolateral frontal and lateral temporal cortex, were activated only by verbs, while there were no brain areas more active in response to nouns. Furthermore, the comparison of abstract and concrete words indicated that abstract word processing was associated with selective activations (right temporal pole and amygdala, bilateral inferior frontal cortex), while no brain areas were more active in response to concrete words. There were no significant interaction effects between word class and concreteness. Taken together, these findings are compatible with the view that lexical-semantic processing of words is mediated by an extensive, predominantly left hemispheric network of brain structures. Additional brain activations appear to be related to specific semantic content, or, in the case of verbs, may be associated with the automatic access of syntactic information.

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Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes is a series of editorials which is published on a biannual basis by the Editorial Board of the Medicinal Chemistry section of the journal Molecules. In these editorials, we highlight in brief reports (of about one hundred words) a number of recently published articles that describe crucial findings, such as the discovery of novel drug targets and mechanisms of action or novel classes of drugs, which may inspire future medicinal chemistry endeavors devoted to addressing prime unmet medical needs.

The insurgence of drug resistance in treating Multiple Myeloma (MM) still represents a major hamper in finding effective treatments, although over the past decades new classes of drugs, such as proteasome inhibitors and immunomodulatory drugs, have been discovered. Recently, our research team, within a Nature-Aided Drug Discovery project, isolated from Hibiscus Sabdariffa L. calyces the secondary metabolite called Hib-ester which possesses antiproliferative properties against human multiple myeloma RPMI 8226 cells, reduces migration and cell invasion and inhibits proteasome without neurotoxic effects. In the present study, we explored the chemical spaces of the hit compound Hib-ester. We explored the structure-activity relationships (SAR), and we optimized the scaffold through sequentially modifying Hib-ester subunits. Compound screening was performed based on cytotoxicity against the RPMI 8226 cells to assess the potential efficacy toward human MM. The ability of the most effective molecules to inhibit the proteasome was evaluated and the binding mode of the most promising compounds in the proteasome chymotrypsin binding pocket was deciphered through molecular modeling simulations. Compounds 13 and 14 are more potent than Hib-ester, demonstrating that our strategy was suitable for the identification of a novel chemotype for developing possible drug candidates and hopefully widening the drug armamentarium against MM.

The study reports an investigation on the role of argument structure complexity in the production of nouns and verbs in three Italian agrammatic patients. The patients, all showing a clear noun/verb dissociation in the assessment tests, were requested to produce either nouns or verbs in a picture naming task. Four sets of words were selected to be produced in the naming task: non-argumental nouns (e.g., medaglia-medal), argumental nouns (e.g., pianto-crying), one-place argument verbs (e.g., dormire-to sleep), and two-place argument verbs (e.g., sparare-to shoot). The performance of the three patients was almost identical. All made reliably fewer errors in the production of non-argumental nouns than in the production of verbs, thus replicating with the new materials the initially observed dissociation. Moreover, they made fewer errors with one-place than with two-place argument verbs, and with non-argumental than with argumental nouns. Finally, in contrast with the previously observed noun/verb dissociation, when their ability to produce argumental nouns and verbs was compared, no reliable difference was found. The results indicate that argument complexity may affect the ability of agrammatic patients to produce words. It is argued that since argument complexity is necessarily associated with verbs and only rarely with nouns, unless special attention is paid, argument complexity effects are easily confounded with grammatical class effects, possibly leading to erroneous interpretations of patients’ performance.

Despite the fact that significant advances in treatment of common cancers have been achieved over the years, orphan tumors still represent an important unmet medical need. Due to their complex multifactorial origin and limited number of cases, such pathologies often have very limited treatment options and poor prognosis. In the search for new anticancer agents, our group recently identified RC-106, a Sigma receptor modulator endowed with proteasome inhibition activity. This compound showed antiproliferative activity toward different cancer cell lines, among them glioblastoma (GB) and multiple myeloma (MM), two currently unmet medical conditions. In this work, we directed our efforts toward the exploration of chemical space around RC-106 to identify new active compounds potentially useful in cancer treatment. Thanks to a combinatorial approach, we prepared 41 derivatives of the compound and evaluated their cytotoxic potential against MM and GB. Three novel potential anticancer agents have been identified.

Effective therapies for multiple sclerosis (MS) are still missing. This neurological disease affects more than 2.5 million people worldwide. To date, biological immunomodulatory drugs are effective and safe during short-term treatment, but they are suitable only for parenteral administration and they are expensive. Accordingly, academic and industrial environments are still focusing their efforts toward the development of new MS drugs. Considering that neurodegeneration is a contributory factor in the onset of MS, herein we will focus on the crucial role played by sigma 1 receptors (S1Rs) in MS. A pilot study was performed, evaluating the effect of the S1R agonist (R)-RC33 on rat dorsal root ganglia experimental model. The encouraging results support the potential of S1R agonists for MS treatment.

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes is a series of Editorials which is published on a biannual basis by the Editorial Board of the Medicinal Chemistry section of the journal Molecules. In these Editorials, we highlight in brief reports (of about one hundred words) a number of recently published articles that describe crucial findings, such as the discovery of novel drug targets and mechanisms of action or novel classes of drugs, which may inspire future medicinal chemistry endeavors devoted to addressing prime unmet medical needs.

Multiple myeloma (MM) belongs to hematological cancers and its incidence is increasing worldwide. Despite recent advances in its therapy, MM still causes many deaths every year. In fact, current therapies sometimes fail and are associated with severe adverse effects, including neurotoxicity. As a part of our ongoing efforts to discover new potential therapies against MM, we prepared Hibiscus sabdariffa extracts obtained by a microwave-assisted solvent extraction and investigate their activity by in vitro assays on the RPMI-8226 cell line. The bioguided fractionation of the crude ethanolic extract allowed the identification of HsFC as the most effective extract. We assessed cell viability (MTT and Tripan blue test), cell migration (Boyden chamber assay), and neurotoxicity (DRG neurotoxicity assay). The promising results prompted us to further fractionate HsFC and we obtained two molecules effective against RPMI-8226 cells without neurotoxic effects at their active concentrations. Moreover, both compounds are able to significantly reduce cell migration.

Introduction: Pancreatic cancer (PC) is one of the most lethal tumor worldwide, with no prognosis improvement over the past 20-years. The silent progressive nature of this neoplasia hampers the early diagnosis, and the surgical resection of the tumor, thus chemotherapy remains the only available therapeutic option. Sigma receptors (SRs) are a class of receptors proposed as new cancer therapeutic targets due to their over-expression in tumor cells and their involvement in cancer biology. The main localization of these receptors strongly suggests their potential role in ER unfolded protein response (ER-UPR), a condition frequently occurring in several pathological settings, including cancer. Our group has recently identified RC-106, a novel pan-SR modulator with good in vitro antiproliferative activities toward a panel of different cancer cell lines. In the present study, we investigated the in vitro properties and pharmacological profile of RC-106 in PC cell lines with the aim to identify a potential lead candidate for the treatment of this tumor. Methods: Pancreatic cancer cell lines Panc-1, Capan-1, and Capan-2 have been used in all experiments. S1R and TMEM97/S2R expression in PC cell lines was quantified by Real-Time qRT-PCR and Western Blot experiments. MTS assay was used to assess the antiproliferative effect of RC-106. The apoptotic properties of RC-106 was evaluated by TUNEL and caspase activation assays. GRP78/BiP, ATF4, and CHOP was quantified to evaluate ER-UPR. Proteasome activity was investigated by a specific fluorescent-based assay. Scratch wound healing assay was used to asses RC-106 effect on cell migration. In addition, we delineated the in vivo pharmacokinetic profile and pancreas distribution of RC-106 in male CD-1 mice. Results: Panc-1, Capan-1, and Capan-2 express both SRs. RC-106 exerts an antiproliferative and pro-apoptotic effect in all examined cell lines. Cells exposure to RC-106 induces the increase of the expression of ER-UPR related proteins, and the inhibition of proteasome activity. Moreover, RC-106 is able to decrease PC cell lines motility. The in vivo results show that RC-106 is more concentrated in pancreas than plasma. Conclusion: Overall, our data evidenced that the pan-SR modulator RC-106 is an optimal candidate for in vivo studies in animal models of PC.

In this manuscript we report on the design, synthesis and evaluation of dual Sigma 1 Receptor (S1R) modulators/Acetylcholinesterase (AChE) inhibitors endowed with antioxidant and neurotrophic properties, potentially able to counteract neurodegeneration. The compounds based on arylalkylaminoketone scaffold integrate the pharmacophoric elements of RRC-33, a S1R modulator developed by us, donepezil, a well-known AChE inhibitor, and curcumin, a natural antioxidant compound with neuroprotective properties. A small library of compounds was synthesized and preliminary in vitro screening performed. Some compounds showed good S1R binding affinity, selectivity towards S2R and N-Methyl- d -Aspartate (NMDA) receptor, AChE relevant inhibiting activity and are potentially able to bypass the BBB, as predicted by the in silico study. For the hits 10 and 20, the antioxidant profile was assessed in SH-SY5Y human neuroblastoma cell lines by evaluating their protective effect against H2O2 cytotoxicity and reactive oxygen species (ROS) production. Tested compounds resulted effective in decreasing ROS production, thus ameliorating the cellular survival. Moreover, compounds 10 and 20 showed to be effective in promoting the neurite elongation of Dorsal Root Ganglia (DRG), thus demonstrating a promising neurotrophic activity. Of note, the tested compounds did not show any cytotoxic effect at the concentration assayed. Relying on these encouraging results, both compounds will undergo a structure optimization program for the development of therapeutic candidates for neurodegenerative diseases treatment.

Our recent research efforts identified racemic RC-33 as a potent and metabolically stable σ1 receptor agonist. Herein we describe the isolation of pure RC-33 enantiomers by chiral chromatography, assignment of their absolute configuration, and in vitro biological studies in order to address the role of chirality in the biological activity of these compounds and their metabolic processing. The binding of enantiopure RC-33 to the σ1 receptor was also investigated in silico by molecular dynamics simulations. Both RC-33 enantiomers showed similar affinities for the σ1 receptor and appeared to be almost equally effective as σ1 receptor agonists. However, the R-configured enantiomer showed higher in vitro hepatic metabolic stability in the presence of NADPH than the S enantiomer. Overall, the results presented herein led us to select (R)-RC-33 as the optimal candidate for further in vivo studies in an animal model of amyotrophic lateral sclerosis.

Embryonic lethal abnormal vision (ELAV) proteins are RNA-binding proteins that bind specific adenine and uridine-rich elements mainly located in the 3'-untranslated region of target mRNAs, preventing their otherwise rapid degradation and thus increasing gene expression. Starting from our previous discovery and applying an integrated in vitro/in silico approach, herein we report a deeper understanding of the mRNA-stabilizing activity of four peptides derived from the ELAV proteins structure. The stabilizing effect on the VEGF transcript (mRNAVEGF ) exerted by each peptide, tested individually, was initially evaluated, and no effects were evidenced. Hence, the biological effects of all peptides couples were investigated. Interestingly, in accordance with preliminary molecular dynamics results, only one of all possible peptide couples resulted highly effective in stabilizing mRNAVEGF . These two peptides were thus identified as valuable starting point for designing small molecules with ELAV-mimicking properties.

(R/S)-Naringenin is a flavanone, well-known for its beneficial health-related properties, such as anti-inflammatory activity. The preparative enantioselective chromatographic resolution of commercial (R/S)-Naringenin was performed on Chiralpak® AD-H column (500 x 50 mm I.D., dp = 20 μm) using methanol as eluent. The developed method is in accordance with the principles of green chemistry, since the environmental impact was lowered through the recycle of eluent. In this way, g-amounts of each enantiomer were recovered with high purity (chemical purity > 99%, enantiomeric excess > 94%). The racemic and enantiomeric Naringenin were subjected to an exhaustive in vitro investigation of anti-inflammatory activity, aimed at evaluating the relevance of chirality. The assay on cultured human peripheral blood mononuclear cells activated by Phytohemagglutinin A revealed that (R)-Naringenin is the most effective in inhibiting the T-cell proliferation, showed to be still active at lowest concentration. Moreover, (R)-Naringenin significantly reduced pro-inflammatory cytokines levels such as TNF-α and, with less potency, IL-6. These results evidenced the anti-inflammatory potential of Naringenin and the highest capacity of (R)-Naringenin to inhibit both in vitro PBMC proliferation and cytokines secretion at non toxic doses. Thus, (R)-Naringenin is a promising candidate for in vivo investigation.

Two cross-modal priming experiments tested whether lexical access is constrained by syllabic structure in Italian. Results extend the available Italian data on the processing of stressed syllables showing that syllabic information restricts the set of candidates to those structurally consistent with the intended word (Experiment 1). Lexical access, however, takes place as soon as possible and it is not delayed till the incoming input corresponds to the first syllable of the word. And, the initial activated set includes candidates whose syllabic structure does not match the intended word (Experiment 2). The present data challenge the early hypothesis that in Romance languages syllables are the units for lexical access during spoken word recognition. The implications of the results for our understanding of the role of syllabic information in language processing are discussed.

We describe here the synthesis and the binding interaction with sigma(1) and sigma(2) receptors of a series of new benzo[d]oxazol-2(3H)-one derivatives variously substituted on the N-benzyl moiety. The results of binding studies confirm the notion that the benzoxazolone moiety confers preference towards sigma(1) sites and establish that the ability to bind to sigma(1), but not to sigma(2) receptors, is strongly affected by the kind and the position of the substituents introduced in the N-benzyl ring. In fact, compounds with substitutions in para-position with atoms of Cl, H or F or with a CH(3) group exhibit a higher affinity for sigma(1) receptors than the corresponding ortho-substituted compounds. The highest affinity and selectivity, with K(i) values of 0.1 and 427 nM for sigma(1) and sigma(2) receptors, respectively, and a corresponding K(i)sigma(2)/K(i)sigma(1) selectivity ratio of 4270 were found for the Cl-substituted compound. These results indicate that benzo[d]oxazol-2(3H)-one derivatives are among the most selective and sigma(1) receptor-preferring ligands currently available.

Aim: Nowadays, there is a great interest in the therapeutic potential of sigma1 receptor ligands for treating different CNS pathologies. Our previous investigations led to identify (R)-RC-33 as a potent and selective S1R agonist. Results: Herein, we report the gram-scale synthesis, pharmacokinetic profile and CNS distribution of (R)-RC-33 in the mouse to determine the most suitable dosage schedule for in vivo administration. For comparative purposes, the same experiments were also performed with PRE-084, the most widely used S1R agonist commonly in pharmacological experiments. Discussion: (R)-RC-33 shows a similar pharmacokinetic profile and a better CNS distribution when compared with PRE-084. Conclusion: (R)-RC-33 may be a promising candidate for in vivo studies in animal models of neurodegenerative diseases.