Synthesis of pyrazole-4-carbohydrazide derivatives of pharmaceutical interest

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Psychological assessment in pathological gamblers treated with escitalopram

Pathological Gambling (PG) is classified as a "Disorder of Impulse Control", but due to similarities with drug addiction is frequently described as a drug-free addiction (Potenza et al., 2012). PG is conceptualized as a behavioural addiction because of its neurobiologic, neurophysiologic and psychological features. Current therapeutical approaches seem unsatisfactory as they do not achieve definitive positive outcomes. Considering the well known psycopathological comorbidities, PG represents both a social (impact on relatives money/life) and a sanitary cost, in terms of pharmacological and psychological support. The compulsive behaviour detectable in PG, is a disease with neurophysiopathological basis now fairly well-defined which affects particularly vulnerable people. PG is linked to important changes in brain systems such as the prefrontal cortex, the nucleus accumbens, the endogenous opioid system and the extended amygdale. Recent fMRI studies associate PG with blunted mesolimbic activation to non-specific rewards, whereas increased prefrontal cortex, anterior cingulate and ventral striatum activation is observed during gambling-related cue-exposure paradigms. Several neuropsychological studies show higher impulsivity in PG (Odlaug BL. et al., 2013) that, together with specific psychopathological symptoms, such as anxiety and depressed mood, characterize different PG subtypes (Blaszczynski A, Nower L. 2002). Impulsivity transcends multiple psychiatric disorders and is thought to be central to impulse control disorders such as PG. Furthermore, many PGs suffers from depression and decreased mood

Synthesis and biological evaluation of new indazole derivatives

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NUOVI DERIVATI 2-ACETAMMIDOBENZAMMIDICI: ATTIVITÀ ANTIPROLIFERATIVA E POSSIBILE MECCANISMO DI AZIONE

Le cinnammido benzammidi rappresentano una classe di sostanze biologicamente attive di grande interesse farmaceutico. Nonostante siano state descritte per svariate attività biologiche, nessun dato è stato riportato sulla loro attivita antitumorale. Inizialmente una serie di 2-cinammidobenzammidi variamente sostituite sono state sintetizzate e valutate per la loro attività antiproliferativa. Partendo dal derivato risultato più attivo, il 2-cinnammido-5-iodobenzammide, che ha mostrato una percentuale di inibizione della crescita sulle K562 del 74% a 10μM, sono stati sintetizzati una serie di derivati al fine di approfondirne la SAR.I composti così ottenuti sono risultati attivi nei confronti di numerose linee cellulari tumorali a concentrazioni micromolari e submicromololari inducendo un blocco del ciclo cellulare delle K562 in fase G2M. Inoltre i derivati sintetizzati sono in grado di indurre apoptosi nelle cellule HEP G2

Comparative studies of the Pschorr reaction in the pyrazole series. Access to the new dibenzo(e,g)pyrazolo(1,5-a)(1,3)diazocine system of pharmaceutical interest

The diazonium tetrafluoroborate 11 obtained from 2-amino-N-methyl-N-(1-phenyl-3-methylpyrazol-5-yl)benzamide was transformed in dry acetonitrile via an ionic or radical pathway. Diferences were observed with respect to ionic or radical transformations in aqueous media of the analogous diazonium hydrogen sulfate 1 derived from the same amine. In acetonitrile solution, the ionic pathway was characterized by an increased yield of 1,4-dimethyl-3-phenyl-pyrazolo[3,4-c]isoquinolin-5-one 4 and by the formation of its isomer, the new derivative 7,9-dimethyldibenzo[e,g]pyrazolo[1,5-a][1,3]diazocin-10(9H)-one 12. When the reaction folowed a radical pathway, the pyrazolo[3,4-c]isoquinoline derivative 4 and N-methyl-2-(1-phenyl-3-methylpyrazol-5-yl)benzamide 17, the later due to a 1,4-pyrazolyl transfer proces, were isolated in low yields. Decomposition of the solid diazonium tetrafluoroborate at its melting point gave compounds 4, 12 and the N-(1-phenyl-3-methylpyrazol-5-yl)-2-fluorobenzamide 17. The crystal structure of compound 12 was also determined

Synthesized benzamido derivatives exert antiproliferative effects by DNA damage and ROS generation.

In this study we explored the effect and the biological action of synthesized benzamido derivatives bearing the (1S,2S)-2-phenyl-cyclopropane-1-carboxamido, 1,1'-biphen-2-carboxamido and 1,1'-biphen-4-carboxamido moieties on K562, a human leukemia cell line. Among the synthesized compounds a particular antiproliferative action was observed with the benzamido derivative bearing the 2-1,1'-biphenyl moiety with the substitution at the 5 position of the benzamido moiety with iodine. This compound showed cytotoxic effects in K562 leukemic cells at nanomolar concentrations and was, therefore, chosen as compound to explore its mode of action. Our analyses provided evidence that this benzamido derivative induced a reduction in cell number and volume with the appearance of a shrunken cytoplasm at 24h, followed by a widespread cell fragmentation at 48h. As demonstrated by flow cytometry analyses, the effect was dose- and time-dependent, causing a G2/M cell cycle arrest in the first phase of treatment (24h), followed by an apoptotic death at 48h (IC50 0.5 μM ). The elucidation of the underlying mechanism also disclosed that DNA arrest in G2/M phase of cell cycle was consequent to DNA lesions, since an increase in phospho-ATM and yH2AX, two known markers of DNA repair response system, was observed. Prolonging the time of treatment, the effects, which were observed only in leukaemic cells but not in normal bronchial epithelial cells, were accompanied by ROS production, JNK phosphorylation and induction of a caspase-dependent apoptosis

Isoxazolo[3,4-d]pyridazin-7(6H)-one derivatives endowed with anti-proliferative Activity.

Isoxazolo[3,4-d]pyridazin-7(6H)-one derivatives endowed with antiproliferative Activity B. Maggio1, G. Cancemi1, D. Raffa1, M. V. Raimondi1, F. Plescia1, A. D’Anneo2,M. Lauricella3, G. Barone4, R. Bonsignore4, G. Daidone1 1. Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, Medicinal Chemistry and Pharmaceutical Technologies Section, University of Palermo, ViaArchirafi 32, 90123, Palermo, Italy 2. Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, Laboratory of Biochemistry, University of Palermo. 3.Department of Experimental Biomedicine and Clinical Neurosciences, Laboratory of Biochemistry, University of Palermo. 4. Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo. [email protected] A screening carried out by NCI (Bethesda, USA) on compounds available in our laboratory,in order to ascertain their antiproliferative activity against a panel of 60 human tumor cell lines, allowed to discovery the 3,4-diphenylisoxazolo[3,4-d]pyridazin-7(6H)-one 1a [1] as an hit compound, often showing GI50values at sub-micromolar level. We synthesized some analogs of 1a, i.e.1b-gand other derivatives in which the NHgroup is variably alkylated, with the aim to obtain more active compounds as well as to perform structure-activity relationship(SAR) studies. We obtained a quite active antiproliferative compound, the 3,4-di-p-tolylisoxazolo[3,4-d]pyridazin-7(6H)- one 1d, and verified the importance for the antiproliferative activity of the aril, and not alkyl, groups linked to the isoxazolo-pyridazinone moiety. Studies performed on the cell cycle progression and on some cellular target (ATM, procaspase-2 proteins and H2AX histone) demonstrated that 1d produces an increase of the cell population in pre-G0/G1 and induces cellular death by apoptosis, damaging the DNA by double strand breaks. UV-vis titration and viscosity measurement showed that the compound is able to give an interaction with the B-DNA. 1. Renzi G., Dal Piaz V. (2004)Gazz. Chim. It.95: 1478–149

Sintesi di un isostero del 3,5-dimetil-6-fenil-8-(trifluorometil)-5,6-diidropirazolo[3,4-f][1,2,3,5]tetrazepin-4(3H)-one (CF3-TZP) con potenziale attività biologica

In un precedente lavoro abbiamo mostrato i risultati relativi alla sintesi ed all’attività biologica del CF3-TZP 1[1] (Figura 1). Le attività antiproliferativa e apoptotica del composto 1 sono state testate su differenti linee cellulari, HL60 sensibili, HL60-R (MDR), K562 e K562-R (resistenti al Gleevec®), mostrando un profilo di attività biologica similare sulle cellule sensibili e resistenti nel range di 21-40 µM per l’IC50 e 36-62 µM per l’AC50. L’analisi citofluorimetrica sulle K562 sensibili ha indicato che il composto 1 determina un arresto dose-dipendente del ciclo cellulare in fase G0-G1 nelle prime 24 h di trattamento, mentre nelle successive 24 h si è notato una riduzione del picco G0-G1 ed un incremento del picco apoptotico subG0-G1. Gli incoraggianti risultati biologici ci hanno spinto a continuare gli studi su questa tipologia di molecole sintetizzando l’isostero 2 (Figura 1) attraverso una lunga via di sintesi (15 steps). Attualmente, sono in corso i saggi biologici per valutare le attività antiproliferativa e apoptotica. Bibliografia 1 Maggio, B.; et al, Eur. J. Med. Chem., 2008, 43, 120

Progettazione e sintesi di nuovi derivati 4-chinazolinonici potenziali inibitori della diidrofolato reduttasi

I chinazolinoni sono composti eterociclici azotati che, insieme alle chinazoline, rappresentano degli importanti farmacofori in possesso di un ampio spettro di proprietà biologiche tra cui quella antitumorale. Recentemente sono stati riportati in letteratura dei derivati 4-chinazolinonici in grado di inibire in vitro l’enzima diidrofolato reduttasi (DHFR) con IC50 comprese tra 0.4 e 1.0 µM [1]. Allo scopo di progettare la sintesi di nuovi potenziali inibitori della DHFR, è stato condotto uno studio di modellistica molecolare considerando tale enzima come biotarget. Tale studio ha portato alla selezione di 42 nuovi derivati 4-chinazolinonici (Figura 1). Attualmente, sono stati sintetizzati 20 dei 42 nuovi derivati 4-chinazolinonici, che sono stati saggiati preliminarmente sulla linea cellulare K562. Il derivato più attivo ha mostrato una IC50 di 18 µM. Sono in corso saggi enzimatici per valutare in vitro l’inibizione dell’enzima DHFR. Bibliografia 1 Al-Omary F.A.M.; et al, Bioorganic & Medicinal Chemistry, 2010, 18, 2849