Search

We previously demonstrated that natural product-inspired 3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-ones derivatives delivered potent and selective PIM kinases inhibitors however with non-optimal ADME/PK properties and modest oral bioavailability. Herein, we describe a structure-based scaffold decoration and a stereoselective approach to this chemical class. The synthesis, structure-activity relationship studies, chiral analysis, and pharmacokinetic data of compounds from this inhibitor class are presented herein. Compound 20c demonstrated excellent potency on PIM1 and PIM2 with exquisite kinases selectivity and PK properties that efficiently and dose-dependently promoted c-Myc degradation and appear to be promising lead compounds for further development.

Introduction: The implementation of interdisciplinary care strategies for the follow-up of patients with asthma has proven to be very effective in improving the long-term evolution of these children. Objectives: Describe the clinical, functional and therapeutic characteristics of patients with a diagnosis of uncontrolled severe asthma (UCSA), identify the differences in the characteristics in the management between patients with difficult-to-treat severe asthma (SDCA) and treatment-resistant severe asthma (STRA Materials: Analytical study of serial cases, patients were evaluated for 6 months, patients with UCSA diagnosis were admitted to the Pneumonology Service of the Pediatric Hospital of Córdoba, with ages between 5 and 15 years old. Results: 23 patients entered the study. 47.82% were defined as SDCA and 52.17% STRA. During the first 6 months of the program; hospitalizations were only 4% (p: 0.001). Besides, the number of visits to the emergency room decreased to 39.13% (p: 0.003). Regarding the Inhalation technique, 73.9% (n: 17) presented improvement (p: 0.0001). Only 13% (n = 3) of the patients continued with ACT

The two-component system DegS/U of Bacillus subtilis controls more than one hundred genes involved in several different cellular behaviours. Since the consensus sequence recognized by the response regulator DegU has not been clearly defined yet, mutations in either component have been crucial in the identification of the cellular targets of this regulatory system. Over the years, the degU32Hy mutant allele, that was supposed to mimic the activated regulator, has been commonly used to define the impact of this TCS on its regulated genes in domestic strains.SwrA encodes a small protein essential for swarming motility and for poly-γ-glutamate biosynthesis and is only present in wild strains. Previous work indicated that SwrA is partnering with DegU~P in exerting its role on both phenotypes.In this work, inserting a degS200Hy mutation in swrA+ and swrA- isogenic strains we demonstrate that SwrA modulates the action of DegU~P on two new phenotypes, subtilisin expression and competence for DNA uptake, with a remarkable effect on transformation. These effects cannot not be appreciated with the DegU32Hy mutant as it does not mirror the wild-type DegU protein in its ability to interact with SwrA.

La Odontología es una de las cinco profesiones más expuestas a contraer COVID-19, debido a la exposición -durante las actividades clínicas-al contacto con sangre, saliva, aerosoles, manipulación de sustancias potencialmente nocivas. El conocimiento de los riesgos propios de su entorno tiene como objetivo último evitar que los odontólogos y las personas vinculadas a la práctica profesional provoquen -por desconocimiento, inobservancia o falta de apropiación de los saberes-contagios y/o impactos desfavorables para ellos y el ambiente. Al minimizar el riesgo y la posibilidad de infecciones cruzadas se evitarán mayores contagios, en el contexto actual, sin desatender las emergencias odontológicas. publishedVersion Fil: Allende Posse, María. Universidad Nacional de Córdoba. Facultad de Odontología. Equipo de Investigación en Higiene y Bioseguridad y Centro de Bioseguridad; Argentina. Fil: Arévalo, Paola. Universidad Nacional de Córdoba. Facultad de Odontología. Equipo de Investigación en Higiene y Bioseguridad y Centro de Bioseguridad; Argentina. Fil: Bojanich, Alejandra. Universidad Nacional de Córdoba. Facultad de Odontología. Equipo de Investigación en Higiene y Bioseguridad y Centro de Bioseguridad; Argentina. Fil: Bono, A. Colegio Odontológico de la Provincia de Córdoba; Argentina. Fil: Busleiman, Federico. Universidad Nacional de Córdoba. Facultad de Odontología. Equipo de Investigación en Higiene y Bioseguridad y Centro de Bioseguridad; Argentina. Fil: Castillo, Beatriz. Universidad Nacional de Córdoba. Facultad de Odontología. Equipo de Investigación en Higiene y Bioseguridad y Centro de Bioseguridad; Argentina. Fil: Castillo, Graciela. Universidad Nacional de Córdoba. Facultad de Odontología. Equipo de Investigación en Higiene y Bioseguridad y Centro de Bioseguridad; Argentina. Fil: Castillo, María Cristina. Universidad Nacional de Córdoba. Facultad de Odontología. Equipo de Investigación en Higiene y Bioseguridad y Centro de Bioseguridad; Argentina. Fil: Ermoli, J. Colegio Odontológico de la Provincia de Córdoba; Argentina. Fil: Flores, N. Universidad Nacional de Córdoba. Facultad de Odontología. Equipo de Investigación en Higiene y Bioseguridad y Centro de Bioseguridad; Argentina. Fil: Gigena, Pablo. Universidad Nacional de Córdoba. Facultad de Odontología. Equipo de Investigación en Higiene y Bioseguridad y Centro de Bioseguridad; Argentina. Fil: Girardi, Mónica. Universidad Nacional de Córdoba. Facultad de Odontología. Equipo de Investigación en Higiene y Bioseguridad y Centro de Bioseguridad; Argentina. Fil: Gutvay, Ada. Universidad Nacional de Córdoba. Facultad de Odontología. Equipo de Investigación en Higiene y Bioseguridad y Centro de Bioseguridad; Argentina. Fil: Herrera, Analía. Universidad Nacional de Córdoba. Facultad de Odontología. Equipo de Investigación en Higiene y Bioseguridad y Centro de Bioseguridad; Argentina. Fil: Huespe Rico, Verónica. Universidad Nacional de Córdoba. Facultad de Odontología. Equipo de Investigación en Higiene y Bioseguridad y Centro de Bioseguridad; Argentina. Fil: Irazuzta, María Laura. Universidad Nacional de Córdoba. Facultad de Odontología. Equipo de Investigación en Higiene y Bioseguridad y Centro de Bioseguridad; Argentina. Fil: Martínez, Dora. Universidad Nacional de Córdoba. Facultad de Odontología. Equipo de Investigación en Higiene y Bioseguridad y Centro de Bioseguridad; Argentina. Fil: Moriconi, E. Provincia de Córdoba. Ministerio de Ciencia y Tecnología; Argentina. Fil: Pereyra, María Eugenia. Universidad Nacional de Córdoba. Facultad de Odontología. Equipo de Investigación en Higiene y Bioseguridad y Centro de Bioseguridad; Argentina. Fil: Priotto, Elba. Universidad Nacional de Córdoba. Facultad de Odontología. Equipo de Investigación en Higiene y Bioseguridad y Centro de Bioseguridad; Argentina. Fil: Raya Tonetti, G. Provincia de Córdoba. Ministerio de Ciencia y Tecnología; Argentina. Fil: Rezzónico, M. S. Universidad Nacional de Córdoba. Facultad de Odontología. Equipo de Investigación en Higiene y Bioseguridad y Centro de Bioseguridad; Argentina. Fil: Scatena, Gabriela. Universidad Nacional de Córdoba. Facultad de Odontología. Equipo de Investigación en Higiene y Bioseguridad y Centro de Bioseguridad; Argentina. Fil: Vera, Mónica. Universidad Nacional de Córdoba. Facultad de Odontología. Equipo de Investigación en Higiene y Bioseguridad y Centro de Bioseguridad; Argentina. Fil: Zorrilla, Inés. Universidad Nacional de Córdoba. Facultad de Odontología. Equipo de Investigación en Higiene y Bioseguridad y Centro de Bioseguridad; Argentina.

The two-component system DegSU of Bacillus subtilis controls more than one hundred genes involved in several different cellular behaviours. Over the last four decades, the degU32Hy allele, supposedly encoding a constitutively active mutant of the response regulator DegU, was exploited to define the impact of this system on cell physiology. Those studies concluded that phosphorylated DegU (DegU∼P) induced degradative enzyme expression while repressing flagellar motility and competence. Recent experiments, however, demonstrated that flagella expression is enhanced by DegU∼P if SwrA, a protein only encoded by wild strains, is present. Yet, to promote motility, SwrA must interact with DegU∼P produced by a wild-type degU allele, as it cannot correctly cooperate with the mutant DegU32Hy protein. In this work, the impact of DegSU was reanalysed in the presence or absence of SwrA employing a DegS kinase mutant, degS200Hy, to force the activation of the TCS. Our results demonstrate that the role of SwrA in B. subtilis physiology is wider than expected and affects several other DegSU targets. SwrA reduces subtilisin, cellulases and xylanases production while, besides motility, it also positively modulates competence for DNA uptake, remarkably relieving the inhibition caused by DegU∼P alone and restoring transformability in degS200Hy strains.

Background: Recently attention has been addressed to the role of 5-HT in cognition and several experimental studies revealed that manipulations of the central 5-HT system can produce quite specific changes in cognitive functioning. These results may suggest new treatment strategies to improve cognition in psychiatric conditions characterized by neuropsychological impairments, such as schizophrenia. It is possible to investigate the involvement of 5-HT in cognition by examining the impact of genetic variation in key regulators of serotoninergic neurotransmission. Among these, the serotonin transporter (5-HTT) presents a functional polymorphism in the transcriptional control region of the gene (5-HTTLPR) affecting transcriptional efficiency. In the present study, we aimed to analyze the effect of 5-HTTLPR polymorphism on specific cognitive functions, known to be affected by 5-HT manipulation and altered in schizophrenia. Methods: 223 schizophrenia patients were tested with Wisconsin Card Sorting Test (WCST), for the evaluation of cognitive flexibility, Continuous Performance Test (CPT), for the evaluation of attention, and genotyped for the 5-HTTLPR. Results: We found a significant association between HTT polymorphism and executive functions and inversely with sustained attention. The presence of the high-activity long (L) allele in homozygosis was a predictor of better executive performances and poorer performances of attention. Conclusions: Our findings suggest that factors affecting serotonin availability may play a specific role in cognitive processes, probably through complex modulation of the different performance components. (C) 2009 Elsevier Inc. All rights reserved. Background: Recently attention has been addressed to the role of 5-HT in cognition and several experimental studies revealed that manipulations of the central 5-HT system can produce quite specific changes in cognitive functioning. These results may suggest new treatment strategies to improve cognition in psychiatric conditions characterized by neuropsychological impairments, such as schizophrenia. It is possible to investigate the involvement of 5-HT in cognition by examining the impact of genetic variation in key regulators of serotoninergic neurotransmission. Among these, the serotonin transporter (5-HTT) presents a functional polymorphism in the transcriptional control region of the gene (5-HTTLPR) affecting transcriptional efficiency. In the present study, we aimed to analyze the effect of 5-HTTLPR polymorphism on specific cognitive functions, known to be affected by 5-HT manipulation and altered in schizophrenia. Methods: 223 schizophrenia patients were tested with Wisconsin Card Sorting Test (WCST), for the evaluation of cognitive flexibility, Continuous Performance Test (CPT), for the evaluation of attention, and genotyped for the 5-HTTLPR. Results: We found a significant association between HTT polymorphism and executive functions and inversely with sustained attention. The presence of the high-activity long (L) allele in homozygosis was a predictor of better executive performances and poorer performances of attention. Conclusions: Our findings suggest that factors affecting serotonin availability may play a specific role in cognitive processes, probably through complex modulation of the different performance components. (C) 2009 Elsevier Inc. All rights reserved.

Treatment of guanosine with arylmethyl halides in N,N-dimethylacetamide results in a series of 3,7-bis(arylmethyl) guanines and 7,9-bis(arylmethyl)guaninium halides. The same reaction on 7-arylmethyl guanines yields 3,7- and 7,9- differently disubstituted guanines. When 7-arylmethyl guanines are reacted with (hetero)arylmethyl halides in the presence of sodium hydride in N,N-dimethylformamide, 3,7- and 1,7-disubstituted guanines are obtained. All of these compounds, but one, are new and the preparation of 3,7-bis(substituted) guanines from guanosine as well as of 3,7- and 1,7-di(hetero)arylmethyl guanines from 7-substituted guanine is unprecedented.

RET, a receptor tyrosine kinase (RTK) expressed mainly in neural crest-derived tissues, plays a role in cell growth and differentiation and its physiological activation depends upon binding to the GDNF family. Genetic aberrations leading to constitutive RET activation are well-established as oncogenic events. Activating point mutations of RET, for example, are present in ca. 70% of medullary thyroid carcinoma patients including all hereditary cases, while RET gene rearrangements resulting in production of activated RET fusion proteins occur in approximately 10% of sporadic papillary thyroid carcinomas. More recently, recurring RET gene rearrangements have also been found in 1-2 % of lung adenocarcinomas and subsets of other solid tumors including colorectal and salivary gland carcinomas. Thus RET kinase represents an actionable therapeutic target in multiple clinical settings with high medical need. Consequently several small-molecule inhibitors targeting this kinase have been explored in clinical settings. A common feature of most advanced agents is their lack of selectivity and in particular their potent cross-reactivity against VEGFR2, an RTK whose inhibition is associated with serious, dose-limiting cardiovascular toxicity. Indeed, the high homology between the two kinases renders identification of ATP competitive compounds that selectively inhibit RET over VEGFR2 a highly challenging task. Here we describe the preclinical activity of NMS-E668, a potent and selective ATP-competitive RET inhibitor characterized by favorable activity, selectivity and ADME profiles. Biochemically, NMS-E668 has an excellent selectivity profile against a panel of >50 kinases, notably including >10-fold selectivity over VEGFR2. Selectivity of NMS-E668 for RET vs. VEGFR2 was confirmed in NIH-3T3 cells engineered to express activated forms of these kinases. NMS-E668 potently (IC50 circa 50 nM) and selectively inhibited proliferation of RET-dependent tumor cells, including TT medullary carcinoma cells harboring a RET C634W activating point mutation and LC2/ad lung carcinoma cells bearing the oncogenic fusion protein CCDC6-RET. NMS-E668 also potently inhibited IL3-independent growth of Ba/F3 cells expressing KIF5B-RET, the RET rearrangement that is most commonly found in lung adenocarcinomas. Cellular mechanism studies confirmed that NMS-E668 inhibits RET autophosphorylation and downstream signaling at doses consistent with antiproliferative activity. Tested in vivo against KIF5B-RET-driven Ba/F3 tumors, NMS-E668 displayed >90% tumor growth inhibition accompanied by target modulation following oral administration at 10 and 20 mg/kg, with prolonged tumor regressions observed at the higher dose. Thus NMS-E668, a potent and VEGFR2-sparing RET inhibitor is an innovative and highly promising candidate for further development. Citation Format: Elena Ardini, Patrizia Banfi, Nilla Avanzi, Marina Ciomei, Paolo Polucci, Alessandra Cirla, Antonella Ermoli, Ilaria Motto, Elena Casale, Giulia Canevari, Cinzia Cristiani, Sonia Troiani, Federico Riccardi Sirtori, Nadia Amboldi, Dario Ballinari, Francesco Caprera, Eduard Felder, Arturo Galvani, Daniele Donati, Antonella Isacchi, Maria Menichincheri. NMS-E668, a potent and selective RET kinase inhibitor characterized by specificity towards VEGFR2 and high antitumor efficacy against RET-driven models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2082. doi:10.1158/1538-7445.AM2017-2082

"Theory of mind" (ToM) is the ability to judge the mental states of the self and others. It is currently considered as a part of the broader concept of social cognition, known to influence the social behaviour of patients affected by schizophrenia. Recently it has been hypothesized that the impairment of ToM is a trait that can be detected both in patients with schizophrenia and in non-psychotic relatives of patients, but it still not clear what the contribution of the familial patterns of cognitive impairment is. The aim of this study is to assess parental impairments of ToM performance considering the effects of the neurocognitive abilities known to be impaired in their first-degree relatives and to influence ToM in schizophrenic patients. Patients, their parents and control trios were assessed with the Wisconsin Card Sorting Test (WCST), the Symbol Coding Task and the ToM Picture Sequencing Task. The ANCOVA analysis on 47 trios including a schizophrenic offspring and 47 healthy trios showed a statistically significant Poorer performance of patients and their parents in comparison to control trios at Symbol Coding Task and ToM task. Moreover a regression analysis showed that the neuropsychological abilities tested were significant predictors of ToM performance only in patients. Results confirm a ToM impairment among parents of patients with schizophrenia that is not directly correlated to other aspects of neurocognitive functioning. (C) 2009 Elsevier B.V. All rights reserved. "Theory of mind" (ToM) is the ability to judge the mental states of the self and others. It is currently considered as a part of the broader concept of social cognition, known to influence the social behaviour of patients affected by schizophrenia. Recently it has been hypothesized that the impairment of ToM is a trait that can be detected both in patients with schizophrenia and in non-psychotic relatives of patients, but it still not clear what the contribution of the familial patterns of cognitive impairment is. The aim of this study is to assess parental impairments of ToM performance considering the effects of the neurocognitive abilities known to be impaired in their first-degree relatives and to influence ToM in schizophrenic patients. Patients, their parents and control trios were assessed with the Wisconsin Card Sorting Test (WCST), the Symbol Coding Task and the ToM Picture Sequencing Task. The ANCOVA analysis on 47 trios including a schizophrenic offspring and 47 healthy trios showed a statistically significant Poorer performance of patients and their parents in comparison to control trios at Symbol Coding Task and ToM task. Moreover a regression analysis showed that the neuropsychological abilities tested were significant predictors of ToM performance only in patients. Results confirm a ToM impairment among parents of patients with schizophrenia that is not directly correlated to other aspects of neurocognitive functioning. (C) 2009 Elsevier B.V. All rights reserved.

Cdc7 kinase has recently emerged as an attractive target for cancer therapy and low-molecular-weight inhibitors of Cdc7 kinase have been found to be effective in the inhibition of tumor growth in animal models. In this paper, we describe synthesis and structure-activity relationships of new 1H-pyrrolo[2,3-b]pyridine derivatives identified as inhibitors of Cdc7 kinase. Progress from (Z)-2-phenyl-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethylene)-3,5-dihydro-4H-imidazol-4-one (1) to [(Z)-2-(benzylamino)-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethylene)-1,3-thiazol-4(5H)-one] (42), a potent ATP mimetic inhibitor of Cdc7 kinase with IC(50) value of 7 nM, is also reported.

To provide normative values for the Italian population for the Brief Assessment of Cognition in Schizophrenia (BACS), a recent brief neuropsychological instrument for the assessment of cognition in patients with schizophrenia.Data were collected from 204 healthy adult Italian subjects, stratified by gender, education and age.Tests included in the BACS are the following: list learning, digit sequencing, verbal fluency, token motor task, symbol-coding and Tower of London. Normative values were established using the Equivalent Scores method in order to enable comparison with other neuropsychological tasks commonly used in the assessment of the Italian population. Performance on the BACS was influenced by the commonest demographic variables such as age and education.The availability of normative data for the Italian population will increase the usefulness of this test for both clinical and experimental purposes.

Schizophrenic patients are known to show a deficit in the source monitoring function, which refers to the set of processes involved in the attribution of an origin to memories and beliefs. A failure in source monitoring was found to be associated with Schneiderian delusions in the recent literature. This study aimed to explore in a sample of schizophrenic patients and controls two aspects of the source monitoring process-recognition and source attribution- and their possible correlation with psychopathology and basic neuropsycho logical performances. A group of 45 stabilized schizophrenic patients and 54 normal volunteers were studied with a Source Monitoring Task and a battery of neurocognitive functions known to be disturbed in schizophrenia. Recognition of self-generated items was significantly worse than control values in Schneiderian delusional patients only, while source attribution of recognized self-generated items was significantly biased towards the external sources in all delusional patients in comparison to controls. Among schizophrenic patients, source misattribution of self-generated items was significantly correlated to executive, planning performance. Both performances were correlated to verbal memory in controls. Results confirm an impairment of different subcomponents of source monitoring performance in schizophrenia, heterogeneously related to psychopathological features and neuropsycho logical performances known to be impaired in schizophrenia. (c) 2005 Elsevier Ireland Ltd. All rights reserved.

To compare speech recognition in noise for the Nucleus Freedom and CP810 sound processors using different directional settings among those available in the SmartSound portfolio.Single-subject, repeated measures study.Tertiary care referral center.Thirty-one monoaurally and binaurally implanted subjects (24 children and 7 adults) were enrolled. They were all experienced Nucleus Freedom sound processor users and achieved a 100% open set word recognition score in quiet listening conditions. Each patient was fitted with the Freedom and the CP810 processor. The program setting incorporated Adaptive Dynamic Range Optimization (ADRO) and adopted the directional algorithm BEAM (both devices) and ZOOM (only on CP810). Speech reception threshold (SRT) was assessed in a free-field layout, with disyllabic word list and interfering multilevel babble noise in the 3 different pre-processing configurations.On average, CP810 improved significantly patients' SRTs as compared to Freedom SP after 1 hour of use. Instead, no significant difference was observed in patients' SRT between the BEAM and the ZOOM algorithm fitted in the CP810 processor.The results suggest that hardware developments achieved in the design of CP810 allow an immediate and relevant directional advantage as compared to the previous-generation Freedom device.

Novel small molecule inhibitors of heat shock protein 90 (Hsp90) were discovered with the help of a fragment based drug discovery approach (FBDD) and subsequent optimization with a combination of structure guided design, parallel synthesis and application of medicinal chemistry principles. These efforts led to the identification of compound 18 (NMS-E973), which displayed significant efficacy in a human ovarian A2780 xenograft tumor model, with a mechanism of action confirmed in vivo by typical modulation of known Hsp90 client proteins, and with a favorable pharmacokinetic and safety profile.

Cdc7 serine/threonine kinase is a key regulator of DNA synthesis in eukaryotic organisms. Cdc7 inhibition through siRNA or prototype small molecules causes p53 independent apoptosis in tumor cells while reversibly arresting cell cycle progression in primary fibroblasts. This implies that Cdc7 kinase could be considered a potential target for anticancer therapy. We previously reported that pyrrolopyridinones (e.g., 1) are potent and selective inhibitors of Cdc7 kinase, with good cellular potency and in vitro ADME properties but with suboptimal pharmacokinetic profiles. Here we report on a new chemical class of 5-heteroaryl-3-carboxamido-2-substituted pyrroles (1A) that offers advantages of chemistry diversification and synthetic simplification. This work led to the identification of compound 18, with biochemical data and ADME profile similar to those of compound 1 but characterized by superior efficacy in an in vivo model. Derivative 18 represents a new lead compound worthy of further investigation toward the ultimate goal of identifying a clinical candidate.

A new synthesis of 3'-fluoro-3'-deoxyadenosine is described. Starting from adenosine via a suitably protected intermediate by triflate activation and nucleophilic displacement with sodium acetate, the xylo epimer is obtained in two cases with different silyl groups protecting the 2'-position. Treatment of the xylo derivatives with diethylaminosulphur trifluoride gives the corresponding 3'-fluoro derivatives with inversion of the configuration. The reaction sequence afford protected allowing selective deblocking of the 5' or 2'-position

Treatment of guanosine with arylmethyl halides in N,N-dimethylacetamide results in a series of 3,7-bis(arylmethyl) guanines and 7,9-bis(arylmethyl)guaninium halides. The same reaction on 7-arylmethyl guanines yields 3,7- and 7,9- differently disubstituted guanines. When 7-arylmethyl guanines are reacted with (hetero)arylmethyl halides in the presence of sodium hydride in N,N-dimethylformamide, 3,7- and 1,7-disubstituted guanines are obtained. All of these compounds, but one, are new and the preparation of 3,7-bis(substituted) guanines from guanosine as well as of 3,7- and 1,7-di(hetero)arylmethyl guanines from 7-substituted guanine is unprecedented.

The syntheses of 3H- and 14C-labelled cabergoline (FCE 21336), namely N-(3-dimethylaminopropyl)-N-(ethylamino-carbonyl)-6-(2-propenyl)ergoline-8 β -carboxamide 1 and its analogues are described. Tritiated cabergoline ([3H]cabergoline) 6, namely N-(3-dimethylaminopropyl)-N-(ethylaminocarbonyl)-6-(2- [2,3-3H]-propenyl)ergoline-8β-carboxamide, was obtained, by catalytic reduction with tritium gas, according to two different synthetic procedures: A- a three step route, starting from 6-(2-propargyl)-dihydro lysergic acid-methyl ester 3 gave [3H]cabergoline, 97% radiochemically pure, with a specific radioactivity of 11.19 GBq/mmol and in an overall radiochemical yield of 3.5%. B- a one step route, starting from 1-ethyl-3-(3-dimethyl-aminopropyl)-3-6′-(2-propargyl)ergoline-8′β- carbonyflurea 5′ yielded [3H]cabergoline with a radiochemical purity >97%, specific radioactivity 1.06 TBq/mmol and radiochemical yield of 23%. A modification of this last procedure also gave [3H]dihydro cabergoline ([3H]FCE 23411), namely N-(3-dimethylaminopropyl) -N-(ethylaminocarbonyl)-6-(2-[2,3-3H]propyl)ergoline-8β-carboxamide 7, 97% radiochemically pure and with a specific radioactivity up to 4.03 TBq/mmol. The synthesis of [14C]cabergoline was carried out, in a three step route, by addition of potassium[14C]cyanide to 6-(2-propenyl)-8β-chloroergoline 12 to give the expected N-(dimethylaminopropyl)-N-(ethylaminocarbonyl)-6-(2-propenyl)-ergoline-8β- [14C]carboxamide 15′, 97% radiochemically pure with a specific radioactivity of 2.09 GBq/mmol and an overall radiochemical yield of 16%.

A new synthesis of 3'-fluoro-3'-deoxyadenosine is described. Starting from adenosine via a suitably protected intermediate by triflate activation and nucleophilic displacement with sodium acetate, the xylo epimer is obtained in two cases with different silyl groups protecting the 2'-position. Treatment of the xylo derivatives with diethylaminosulphur trifluoride gives the corresponding 3'-fluoro derivatives with inversion of the configuration. The reaction sequence afford protected allowing selective deblocking of the 5' or 2'-position

The synthesis and the preliminary expansion of this new class of CDK2 inhibitors are presented. The synthesis was accomplished using a solution-phase protocol amenable to rapid parallel expansion and suitable to be scaled-up in view of possible lead development. Following a medicinal chemistry program aimed at improving cell permeability and selectivity, a series of compounds with nanomolar activity in the biochemical assay and able to efficiently inhibit tumor cell proliferation has been obtained.