Synthesis and reactivity of aryl iodo difluorides

Organofluorine substrates are molecules of increasing demand in both academic and industrial settings. Organofluorine compounds are very rare in nature and therefore several approaches to their synthesis have been developed. In the work performed during this research tenure, the approach towards the synthesis of organofluorine substrates is based on the use of hypervalent iodine reagents. The structure of the research program can be summarized into three main sections: Synthesis of aryl iodo difluorides; Reactivity of aryl iodo difluorides towards organoselenium substrates; Approach toward stereoselective fluorinations with the synthesis of chiral iodo difluorides. Aryl iodo difluorides reagents have been known for more than a century but they have not been extensively used mainly due to their difficulty of synthesis, which require harmful and hazardous reagents. We have developed an alternative method for their preparation involving three synthetic steps: perborate oxidation of an aryl iodide, followed by basic hydrolysis and subsequent treatment with hydrofluoric acid. A number of aryl iodo difluorides were synthesized using this procedure and each of them is characterized by high purity and high yield. The reactivity of (difluoroiodo)toluene (DFIT) as a fluorinating agent was tested on organoselenium substrates. a-Seleno esters, amide and nitriles undergo a-fluorination when treated with 2 equivalents of DFIT. Under these conditions, the monofluoro derivatives were obtained with yields ranging from 20% to 65%. Additionally, (difluoroiodo)toluene can be employed in oxidative fluorinations. The exploitation of its oxidative nature produced tetraethyl ammonium iodo difluoride, and preliminary results indicate that it can be used as fluorinating agent, as well. The third aspect of the research dealt with stereoselective fluorination reactions. The synthesis of an opportune chiral iodo difluoride can provide the further development of hypervalent iodine reagents as fluorinating reagents. Different substrates were used to reach this goal and the study conducted in this direction brought about the synthesis of a difluoride with the iodine atom in oxidation state V, which can be use as chiral fluorine transfer after a simple modification of its structure

Does a social/behavioural gradient in dental health exist among adults? A cross-sectional study

Objective To explore the potential presence of a social/behavioural gradient in dental health among Italian adults using a cross-sectional study. Methods Caries indices were recorded among 480 subjects (52.9% men, 47.1% women) who also completed a structured self-administered social and behavioural questionnaire. A social/behavioural gradient was generated as the sum of the worst circumstances recorded on the questionnaire (cariogenic diet, smoking, lowest occupational profile, brushing teeth < twice daily, lowest educational level, uneven dental examination attendance). Results Caries figures (DMFT) and the number of filled sound teeth (FS-T) were statistically significantly linked to the social/behavioural gradient (DMFT: χ(2)(9) = 20.17 p = 0.02, Z = 0.02 p = 0.99; FS-T: χ(2)(9) = 25.68 p < 0.01, Z = -4.31 p < 0.01). DMFT was statistically significantly associated with gender and with social and behavioural variables. FS-T was higher in women (p = 0.03) and was linked to smoking ( p < 0.01). Conclusions The proposed social/behavioural gradient demonstrated how subjects reporting the worst circumstances on the questionnaire exhibited the worst dental health. The use of the gradient demonstrates that health promotion and prevention cannot be compartmentalized

Oral health status and caries trend among 12-year old Palestine refugee students: results from the UNRWA’s oral health surveys 2011 and 2016

Background: In 2016 the United Nation Relief and Work Agency for Palestine refugees in the Near East (UNRWA) commissioned a survey on oral health among 12-year-old students at UNRWA schools in five fields of operation (Jordan, Lebanon, Syria, Gaza Strip and West Bank), following World Health Organization guidelines. The survey aimed to determine the prevalence of dental caries and periodontal diseases among Palestine students attending UNRWA schools and how this has changed over time. Methods: A two-stage stratified cluster sample design was used. For each Field of operation, the sample size was calculated based on 95% confidence level, 80% power and margin of error of 4%. Clinical examination was carried out by trained Field Oral Health services Officers (FOHSOs) from the 5 fields. Teeth presence and condition, gingival bleeding and calculus and the presence of dental sealants in occlusal surfaces of permanent molars were recorded. Behavior information of students/parents were collected using a questionnaire that was self-completed by the child/parent under supervision. Results were compared with those from a previous survey carried out in 2011 with the same methodology. Results: In the two surveys the distributions of students who had caries experience in their permanent teeth were similar (73.1% in 2011 vs 72.8% in 2016, p = 0.83). In 2016 a significant increase of missing teeth (p < 0.01) and sealants (p < 0.01) was observed. Both surveys have identified behavioral determinants for dental caries, particularly dietary habits such as soft drinks consumption. Gingival health also showed statistical differences among the fields. Conclusions: The prevalence of caries experience was very high in all fields and, with regard to main oral health indices, no trend of improvement was observed through 2011 and 2016. Surveys’ results advocates the need of a large-scale integrated preventive approach toward oral health and the emerging growth of Noncommunicable Diseases (NCDs), in line with the WHO recommendations

Phosphorodiamidates as a promising new phosphate prodrug motif for antiviral drug discovery: application to anti-HCV agents

We herein report phosphorodiamidates as a significant new phosphate prodrug motif. Sixty-seven phosphorodiamidates are reported of two 6-O-alkyl 2′-C-methyl guanosines, with significant variation in the diamidate structure. Both symmetrical and asymmetric phosphorodiamidates are reported, derived from various esterified amino acids, both d and l, and also from various simple amines. All of the compounds were evaluated versus hepatitis C virus in replicon assay, and nanomolar activity levels were observed. Many compounds were noncytotoxic at 100 μM, leading to high antiviral selectivities. The agents are stable in acidic, neutral, and moderately basic media and in selected biological media but show efficient processing by carboxypeptidases and efficiently yield the free nucleoside monophosphate in cells. On the basis of in vitro data, eight leads were selected for additional in vivo evaluation, with the intent of selecting one candidate for progression toward clinical studies. This phosphorodiamidate prodrug method may have broad application outside of HCV and antivirals as it offers many of the advantages of phosphoramidate ProTides but without the chirality issues present in most cases

Phosphorodiamidates as a Promising New Phosphate Prodrug Motif for Antiviral Drug Discovery: Application to Anti-HCV Agents

We herein report phosphorodiamidates as a significant new phosphate prodrug motif. Sixty-seven phosphorodiamidates are reported of two 6-<i>O</i>-alkyl 2′-<i>C</i>-methyl guanosines, with significant variation in the diamidate structure. Both symmetrical and asymmetric phosphorodiamidates are reported, derived from various esterified amino acids, both d and l, and also from various simple amines. All of the compounds were evaluated versus hepatitis C virus in replicon assay, and nanomolar activity levels were observed. Many compounds were noncytotoxic at 100 μM, leading to high antiviral selectivities. The agents are stable in acidic, neutral, and moderately basic media and in selected biological media but show efficient processing by carboxypeptidases and efficiently yield the free nucleoside monophosphate in cells. On the basis of in vitro data, eight leads were selected for additional in vivo evaluation, with the intent of selecting one candidate for progression toward clinical studies. This phosphorodiamidate prodrug method may have broad application outside of HCV and antivirals as it offers many of the advantages of phosphoramidate ProTides but without the chirality issues present in most cases

Phosphorodiamidates as a Promising New Phosphate Prodrug Motif for Antiviral Drug Discovery: Application to Anti-HCV Agents

We herein report phosphorodiamidates as a significant new phosphate prodrug motif. Sixty-seven phosphorodiamidates are reported of two 6-O-alkyl 2′-C-methyl guanosines, with significant variation in the diamidate structure. Both symmetrical and asymmetric phosphorodiamidates are reported, derived from various esterified amino acids, both d and l, and also from various simple amines. All of the compounds were evaluated versus hepatitis C virus in replicon assay, and nanomolar activity levels were observed. Many compounds were noncytotoxic at 100 μM, leading to high antiviral selectivities. The agents are stable in acidic, neutral, and moderately basic media and in selected biological media but show efficient processing by carboxypeptidases and efficiently yield the free nucleoside monophosphate in cells. On the basis of in vitro data, eight leads were selected for additional in vivo evaluation, with the intent of selecting one candidate for progression toward clinical studies. This phosphorodiamidate prodrug method may have broad application outside of HCV and antivirals as it offers many of the advantages of phosphoramidate ProTides but without the chirality issues present in most cases