Valutare a scuola, formare competenze

uesto volume si articola in tre parti. Nella prima vengono esaminati e discussi i termini caratteristici del dibattito (valutazione autentica, significativa, dinamica) alla luce delle ricerche sui processi di apprendimento; nella seconda parte vengono presentati gli strumenti e le modalità operative della valutazione e i dispositivi di verifica (prove di verifica dell’apprendimento, della comprensione, fogli di osservazione); nell’ultima sezione vengono riformulati il significato e le modalità di costruzione del portfolio, anche in base alle recenti disposizioni del Ministero della Pubblica Istruzion

Accessing simply-substituted 4-hydroxytetrahydroisoquinolines via Pomeranz-Fritsch-Bobbitt reaction with non-activated and moderately-activated systems

Background 1,2,3,4-Tetrahydroisoquinolines (THIQs) are common motifs in alkaloids and in medicinal chemistry. Synthetic access to THIQs via the Pomeranz-Fritsch-Bobbit (PFB) methodology using mineral acids for deactivated, electron poor aromatic systems, is scarcely represented in the literature. Here, the factors controlling the regiochemical outcome of cyclization are evaluated. Results A double reductive alkylation was telescoped into a one-pot reaction delivering good to excellent yields of desired aminoacetals for cyclization. Cyclization of activated systems proceeded smoothly under standard PFB conditions, but for non-activated systems use of HClO4 alone was effective. When cyclization was possible in both para- and ortho-positions to the substituent, 7-substituted derivatives formed with significant amounts of 5-substituted by-product. The formation of the 4-hydroxy THIQs vs. the 4-methoxy THIQ products could be controlled through modification of the reaction concentration. In addition, while a highly-activated system exclusively cyclized to the indole, this seems generally highly disfavored. When competition between 6- and 7-ring formation was investigated in non-activated systems, 5,7,8,13-tetrahydro-6,13-methanodibenzo[c,f]azonine was exclusively obtained. Furthermore, selective ring closure in the para-position could be achieved under standard PFB conditions, while a double ring closure could be obtained utilizing HClO4. Conclusions Reactivity differences in aminoacetal precursors can be employed to control cyclization using PFB methodology. It is now possible to select confidently the right conditions for synthesis of N-aryl-4-hydroxy-1,2,3,4-tetrahydroisoquinolines.</p

Accessing simply-substituted 4-hydroxytetrahydroisoquinolines via Pomeranz-Fritsch-Bobbitt reaction with non-activated and moderately-activated systems

Background 1,2,3,4-Tetrahydroisoquinolines (THIQs) are common motifs in alkaloids and in medicinal chemistry. Synthetic access to THIQs via the Pomeranz-Fritsch-Bobbit (PFB) methodology using mineral acids for deactivated, electron poor aromatic systems, is scarcely represented in the literature. Here, the factors controlling the regiochemical outcome of cyclization are evaluated. Results A double reductive alkylation was telescoped into a one-pot reaction delivering good to excellent yields of desired aminoacetals for cyclization. Cyclization of activated systems proceeded smoothly under standard PFB conditions, but for non-activated systems use of HClO4 alone was effective. When cyclization was possible in both para- and ortho-positions to the substituent, 7-substituted derivatives formed with significant amounts of 5-substituted by-product. The formation of the 4-hydroxy THIQs vs. the 4-methoxy THIQ products could be controlled through modification of the reaction concentration. In addition, while a highly-activated system exclusively cyclized to the indole, this seems generally highly disfavored. When competition between 6- and 7-ring formation was investigated in non-activated systems, 5,7,8,13-tetrahydro-6,13-methanodibenzo[c,f]azonine was exclusively obtained. Furthermore, selective ring closure in the para-position could be achieved under standard PFB conditions, while a double ring closure could be obtained utilizing HClO4. Conclusions Reactivity differences in aminoacetal precursors can be employed to control cyclization using PFB methodology. It is now possible to select confidently the right conditions for synthesis of N-aryl-4-hydroxy-1,2,3,4-tetrahydroisoquinolines.</p

N-Phenyl-1,2,3,4-tetrahydroisoquinoline: an alternative scaffold for design of 17-hydroxysteroid dehydrogenase 1 inhibitors

17β-Hydroxysteroid dehydrogenases catalyse interconversion at the C17 position between oxidized and reduced forms of steroidal nuclear receptor ligands. The type 1 enzyme, expressed in malignant cells, catalyses reduction of the less active estrone to estradiol and inhibitors have therapeutic potential in estrogen-dependent diseases such as breast and ovarian cancers and in endometriosis. Synthetic decoration of the nonsteroidal N-phenyl-1,2,3,4-tetrahydroisoquinoline (THIQ) template was pursued using Pomeranz-Fritsch-Bobbitt, Pictet-Spengler and Bischler-Napieralski approaches to explore the viability of this scaffold as a steroid mimic. Derivatives were evaluated biologically in vitro as type 1 enzyme inhibitors in a bacterial cell homogenate as source of recombinant protein. Structure-activity relationships are discussed. THIQs possessing a 6-hydroxyl group, lipophilic substitutions at the 1- or 4- positions in combination with N-4′-chlorophenyl substitution were most favourable for activity. Of these, one compound had an IC50 of ca. 350 nM as a racemate, testifying to the applicability of this novel approach

N‐Phenyl‐1,2,3,4‐tetrahydroisoquinoline:an alternative scaffold for design of 17β‐hydroxysteroid dehydrogenase 1 inhibitors

17β‐Hydroxysteroid dehydrogenases act at the pre‐receptor level, catalysing interconversion at the C17 position between oxidized and reduced forms of steroidal nuclear receptor ligands. The type 1 enzyme, expressed in malignant cells, catalyses reduction of the less active estrone to estradiol and inhibitors have therapeutic potential in estrogen‐dependent diseases such as breast and ovarian cancers and in endometriosis. Synthetic decoration of the nonsteroidal N ‐phenyl‐1,2,3,4‐tetrahydroisoquinoline (THIQ) template in all three ring systems was pursued using Pomeranz‐Fritsch‐Bobbitt, Pictet‐Spengler and Bischler‐Napieralski approaches to explore the viability of this scaffold as a steroid mimic. Derivatives were evaluated biologically in vitro as type 1 enzyme inhibitors in a bacterial cell homogenate as source of recombinant protein. Structure‐activity relationships are discussed. THIQs possessing a 6‐hydroxyl group, lipophilic substitutions at the 1‐ or 4‐ positions in combination with N ‐4′‐chlorophenyl substitution were most favourable for activity. Of these, racemic 41c had an IC 50 of ca. 350 nM, testifying to the applicability of this novel approach

Characterization of CM-398, a Novel Selective Sigma-2 Receptor Ligand, as a Potential Therapeutic for Neuropathic Pain

Sigma receptors modulate nociception, offering a potential therapeutic target to treat pain, but relatively little is known regarding the role of sigma-2 receptors (S2R) in nociception. The purpose of this study was to investigate the in vivo analgesic and anti-allodynic activity and liabilities of a novel S2R selective ligand, 1-[4-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)butyl]-3-methyl-1,3-dihydro-1,3-benzimidazol-2-one (CM-398). The inhibition of thermal, induced chemical, or inflammatory pain as well as the allodynia resulting from chronic nerve constriction injury (CCI) model of neuropathic pain were assessed in male mice. CM-398 dose-dependently (10&ndash;45 mg/kg i.p.) reduced mechanical allodynia in the CCI neuropathic pain model, equivalent at the higher dose to the effect of the control analgesic gabapentin (50 mg/kg i.p.). Likewise, pretreatment (i.p.) with CM-398 dose-dependently produced antinociception in the acetic acid writhing test (ED50 (and 95% C.I.) = 14.7 (10.6&ndash;20) mg/kg, i.p.) and the formalin assay (ED50 (and 95% C.I.) = 0.86 (0.44&ndash;1.81) mg/kg, i.p.) but was without effect in the 55 &deg;C warm-water tail-withdrawal assay. A high dose of CM-398 (45 mg/kg, i.p.) exhibited modest locomotor impairment in a rotarod assay and conditioned place aversion, potentially complicating the interpretation of nociceptive testing. However, in an operant pain model resistant to these confounds, mice experiencing CCI and treated with CM-398 demonstrated robust conditioned place preference. Overall, these results demonstrate the S2R selective antagonist CM-398 produces antinociception and anti-allodynia with fewer liabilities than established therapeutics, adding to emerging data suggesting possible mediation of nociception by S2R, and the development of S2R ligands as potential treatments for chronic pain

Synthesis of sulfonamide-containing N-hydroxyindole-2-carboxylates as inhibitors of human lactate dehydrogenase-isoform 5

N-Hydroxyindole-2-carboxylates possessing sulfonamide-substituents at either position 5 or 6 were designed and synthesized. The inhibitory activities of these compounds against isoforms 1 and 5 of human lactate dehydrogenase were analysed, and Ki values of the most efficient inhibitors were determined by standard enzyme kinetic studies. Some of these compounds displayed state-of-the-art inhibitory potencies against isoform 5 (Ki values as low as 5.6 μM) and behaved as competitive inhibitors versus both the substrate and the cofactor