Solvent and substituent effects on the kinetics of thermolysis of cis-fused 1,2,4-trioxanes

The kinetics of the thermal decomposition reaction of cis-6-phenyl-5,6-(2- phenylpropyliden)-3,3-pentamethylene-1,2,4-trioxacyclohexane (Ia) were investigated in benzene and methanol solutions in the temperature and concentration ranges of 353.3-413.2 K and (1.1 - 13.1)×10-3 M, respectively. First-order rate constant values were obtained for up to at least ca. 20% conversions of that cyclic peroxide. The activation parameter values for the initial unimolecular homolysis of that molecule, results supported by the effect of the addition of di-tert-butyl-p-cresol as a free radical scavenger, indicate a stepwise reaction mechanism which is in keeping with the reaction products analysis. The corresponding activation parameters for the reaction of Ia in methanol (ΔH# = 20.2 ± 0.6 kcal mol-1; ΔS# = 0.1 ± 1.6 cal mol-1K-1; ΔG# = 20.2 ± 0.6 kcal mol-1 and in benzene (ΔH# = 15.4 ± 0.2 kcal mol-1; ΔS# = -13.2 ± 0.5 cal mol-1K-1; ΔG# = 20.5 ± 0.2 kcal mol-1 solutions are compared with values obtained for cis-6-phenyl-5,6-(2-phenylpropyliden)-3,3- tetramethylene-1,2,4-trioxacyclohexane (Ib) thermolysis in the same solvents. The thermolysis kinetics of Ia are less sensitive to solvent changes compared to the behaviour already reported for the analogous reactions of Ib. Because both molecules in solution are flexible structures due to their configurations, the relatively small solvent effect found on the former trioxane reaction is attributed to the extent of the chain of methylene groups attached on C-3 of the corresponding molecular rings. Furthermore, the pertinent substituent effect on the peroxidic bond strength of those molecules in solution was evaluated.Facultad de Ciencias Exacta

Photo-oxygenation of Indene and 1,2-Dihydronaphthalene: Formation of 1,2-Dioxetanes and 1,2,4-Trioxanes

The methylene blue (MB)-sensitized photo-oxygenation of indene (1) in CH3OH gave trans-2-hydroperoxy-1-methoxyindane (9), homophthalaldehyde (4), and its cyclic acetal 8. The same reaction conducted in acetaldehyde gave only 4. Repetition of the photo-oxygenation of 1 in slightly acidic aq. acetone (1:9) gave essentially trans-2-hydroperoxy-1-hydroxyindane (14) together with some cis-5,6-dihydro-3,3-dimethyl-1,2,4-trioxinol[1,2-e]indene. The MB-sensitized photo-oxygenation of 1,2-dihydronaphthalene (16) in CH3OH gave l,4-dihydro-1-hydroperoxynaphthalene (17) and trans-l,2,3,4-tetrahydro-2-hydroperoxy-1-methoxynaphthalene (19). In acetaldehyde, 16 furnished only 17. In aq. acetone (1:9) 16 gave 17 and trans-2-hydroperoxy-1-hydroxy-1,2,3,4-tetrahydronaphthalene (23). Product compositions were rationalized in terms of the 2-peroxides of the 1-cation of 1 and 16, namely 11 and 20. Treatment of 23 with aldehydes and ketones on catalysis with Amberlyst-15 or trimethylsilyl trifluoromethanesulfonate afforded the trans-fused 1,2,4-trioxanes 25. The 1,2-dioxetanes of 1 and 16 condensed with acetaldehyde on catalysis with CF3COOH to give the cis-fused 1,2,4-trioxanes 12 and 22

Solvent and substituent effects on the kinetics of thermolysis of cis-fused 1,2,4-trioxanes

The kinetics of the thermal decomposition reaction of cis-6-phenyl-5,6-(2- phenylpropyliden)-3,3-pentamethylene-1,2,4-trioxacyclohexane (Ia) were investigated in benzene and methanol solutions in the temperature and concentration ranges of 353.3-413.2 K and (1.1 - 13.1)×10-3 M, respectively. First-order rate constant values were obtained for up to at least ca. 20% conversions of that cyclic peroxide. The activation parameter values for the initial unimolecular homolysis of that molecule, results supported by the effect of the addition of di-tert-butyl-p-cresol as a free radical scavenger, indicate a stepwise reaction mechanism which is in keeping with the reaction products analysis. The corresponding activation parameters for the reaction of Ia in methanol (ΔH# = 20.2 ± 0.6 kcal mol-1; ΔS# = 0.1 ± 1.6 cal mol-1K-1; ΔG# = 20.2 ± 0.6 kcal mol-1 and in benzene (ΔH# = 15.4 ± 0.2 kcal mol-1; ΔS# = -13.2 ± 0.5 cal mol-1K-1; ΔG# = 20.5 ± 0.2 kcal mol-1 solutions are compared with values obtained for cis-6-phenyl-5,6-(2-phenylpropyliden)-3,3- tetramethylene-1,2,4-trioxacyclohexane (Ib) thermolysis in the same solvents. The thermolysis kinetics of Ia are less sensitive to solvent changes compared to the behaviour already reported for the analogous reactions of Ib. Because both molecules in solution are flexible structures due to their configurations, the relatively small solvent effect found on the former trioxane reaction is attributed to the extent of the chain of methylene groups attached on C-3 of the corresponding molecular rings. Furthermore, the pertinent substituent effect on the peroxidic bond strength of those molecules in solution was evaluated.Facultad de Ciencias Exacta

A kinetic and mechanistic study on the thermal decomposition reactions of cis- and trans- fused 1,2,4-trioxanes

The kinetics of the thermal decomposition reactions of artemisinine (1), a cis-fused 1,2,4-trioxane, and trans-3,3dimethyl-1,2,4-trioxane (6) in solutions of benzene, toluene, and methanol in sealed tubes were compared at temperatures between 100.1° and 171.4 °C. Pseudo first-order rate constant values were determined for conversions of both cyclic peroxides up to ca. 60%. The activation parameters and the composition of the reaction products were indicative of homolytic cleavage of their O-O bonds as the rate-determining steps followed by stepwise fragmentation. The free energies of activation (ΔG#) for 1 and 6 reactions in the aromatic solvents were calculated at the middle of each temperature range, giving values of 30.7 and 35.1 kcal/mol, respectively, which are evaluated considering their different molecular configurations. Furthermore, the rates of the thermal decomposition reactions of those trioxanes were sensitive to solvent effects.Laboratorio de Estudio de Compuestos OrgánicosCentro de Investigación y Desarrollo en Ciencias Aplicada

A kinetic and mechanistic study on the thermal decomposition reactions of cis- and trans- fused 1,2,4-trioxanes

The kinetics of the thermal decomposition reactions of artemisinine (1), a cis-fused 1,2,4-trioxane, and trans-3,3dimethyl-1,2,4-trioxane (6) in solutions of benzene, toluene, and methanol in sealed tubes were compared at temperatures between 100.1° and 171.4 °C. Pseudo first-order rate constant values were determined for conversions of both cyclic peroxides up to ca. 60%. The activation parameters and the composition of the reaction products were indicative of homolytic cleavage of their O-O bonds as the rate-determining steps followed by stepwise fragmentation. The free energies of activation (ΔG#) for 1 and 6 reactions in the aromatic solvents were calculated at the middle of each temperature range, giving values of 30.7 and 35.1 kcal/mol, respectively, which are evaluated considering their different molecular configurations. Furthermore, the rates of the thermal decomposition reactions of those trioxanes were sensitive to solvent effects.Laboratorio de Estudio de Compuestos OrgánicosCentro de Investigación y Desarrollo en Ciencias Aplicada

Unusually stable abnormal karyotype in a highly aggressive melanoma negative for telomerase activity

Malignant melanomas are characterized by increased karyotypic complexity, extended aneuploidy and heteroploidy. We report a melanoma metastasis to the peritoneal cavity with an exceptionally stable, abnormal pseudodiploid karyotype as verified by G-Banding, subtelomeric, centromeric and quantitative Fluorescence in Situ Hybridization (FISH). Interestingly this tumor had no detectable telomerase activity as indicated by the Telomere Repeat Amplification Protocol. Telomeric Flow-FISH and quantitative telomeric FISH on mitotic preparations showed that malignant cells had relatively short telomeres. Microsatellite instability was ruled out by the allelic pattern of two major mononucleotide repeats. Our data suggest that a combination of melanoma specific genomic imbalances were sufficient and enough for this fatal tumor progression, that was not accompanied by genomic instability, telomerase activity, or the engagement of the alternative recombinatorial telomere lengthening pathway

Rheumatology clinicians’ experiences of brief training and implementation of skills to support patient self-management

BACKGROUND: Self-management of arthritis requires informed, activated patients to manage its physical and psychosocial consequences. Patient activation and self-management can be enhanced through the use of cognitive-behavioural approaches, which have a strong evidence base and provide insight into the variation in outcome of patients with ostensibly the same degree of disease activity. However, training for rheumatology health professionals in theory and skills underpinning the facilitation of self-management is not widely available. To develop such training, this study explored rheumatology clinicians’ experiences of a variety of brief skills training courses to understand which aspects were helpful or unhelpful, and to identify the barriers and facilitators of applying the skills in clinical practice. METHODS: 16 clinicians who had previously attended communication and self-management skills training participated in semi-structured interviews: 3 physicians, 3 physiotherapists, 4 nurses, 6 occupational therapists. Transcripts were analysed (ED) using a hybrid inductive and deductive thematic approach, with a subset independently analysed (SH, RG-H, RJ). RESULTS: 3 overarching themes captured views about training undertaken and subsequent use of approaches to facilitate self-management. In ‘putting theory into practice’, clinicians felt that generic training was not as relevant as rheumatology-specific training. They wanted a balance between theory and skills practice, and identified the importance of access to ongoing support. In ‘challenging professional identity’, models of care and working cultures influenced learning and implementation. Training often challenged a tendency to problem-solve on behalf of patients and broadened clinicians’ remit from a primary focus on physical symptoms to the mind and body interaction. In ‘enhanced practice’, clinicians viewed consultations as enhanced after training. Focus had shifted from clinicians’ agendas to those of patients, and clinicians reported eliciting patients’ priorities and the use of theoretically-driven strategies such as goal-setting. CONCLUSIONS: To varying extents, clinicians were able to learn and implement new approaches to support patient self-management after brief training. They believed that cognitive behavioural and communication skills to facilitate self-management enhanced their practice. To optimise self-management support in routine care brief, skills-based, rheumatology-specific training needs to be developed, alongside ongoing clinical supervision. Further research should examine patients’ perspectives of care based on these approaches

New applications of peroxides and their equivalents for synthesizing oxygen heterocycles

The action of aqueous hydrochloric, hydrobromic and trifluoroacetic and formic acids with amberlyst-15 as catalyst on the 1,4-endoperoxide of 1,4-dimethylnaphthalene afforded the monochloro and analogously substituted 1-methyl derivatives of the last compound. Acid catalysis of the endoperoxide in the presence of aldehydes and ketones gave the cis fused 3-derivatives of 6,10b-dimethyl-4a,10b-dihydronaphtho[2,1-e]-1,2,4-trioxin in high yields. The trioxanes obtained from formaldehyde were converted quantitatively on treatment with benzylamine in dichloromethane into their corresponding cis 1,2-diols. An equivalent of trimethylsilyl trifluoromethanesulfonate on 3,3,6, 1Ob-tetrarnethyl-4a,10b-dihydronaphtho[2, 1-e]-1,2,4-trioxin furnished 2-(2-oxopropyl)-3-methylbenzo[b]furan exclusively.</p

New developments in synthetic peroxidic drugs as artemisinin mimics

The present review describes the current status of synthetic cyclic peroxides, trioxanes and trioxolanes that show significant promise as antimalarial drugs because of their artemisinin-like activity. The literature from 1996 onwards is critically surveyed to provide an update on how an age-old, persistent, debilitating and frequently deadly disease could be treated by new, affordable and effective medicines possessing the peroxide pharmacophore. The review is not exhaustive and does not cover recent progress on the lead structure artemisinin and its derivatives. Nevertheless, some mechanistic aspects gleaned from artemisinin that have relevance to synthetic peroxides are discussed