From green innovations in oligopeptide to oligonucleotide sustainable synthesis: differences and synergies in TIDES chemistry

The growing market for therapeutic peptides and oligonucleotides (TIDES) draws attention towards their manufacture, aiming at efficient and sustainable productive processes in view of the predicted massive application of these molecules in several therapeutic areas in the near future. A comparative assessment of the principal innovations in the synthesis of these molecules is described herein, with a major focus on solid-phase synthesis (SPS), describing particularly the less-explored field of solid-phase oligonucleotide synthesis (SPOS). A head-to-head analysis of SPS techniques applied to peptides and oligonucleotides was performed, highlighting the strengths and weaknesses of these iterative synthetic approaches. The green innovations introduced in solid-phase peptide synthesis (SPPS), namely reduction or replacement with greener alternatives of solvents and reagents, and implementations in purification techniques, were reviewed and projected to potential targets and sustainable practices in modern SPOS, including their application in P(v) chemistry for the synthesis of stereopure oligonucleotides. By a comparative analysis, the key elements for the development of overall green procedures for oligonucleotide manufacturing were emphasized. In addition, due to the intrinsically more sustainable profile of liquid-phase synthetic techniques (LPS), recent advancements in the field reported for both TIDES were analyzed to prove the industrial interest in the manufacturing of these classes of molecules, underlining the importance of investment and modernization in the development of stronger and greener synthetic pathways

Side chain effect in the modulation of αvβ3/α5β1 integrin activity via clickable isoxazoline-RGDmimetics: development of molecular delivery systems

View references (57) Construction of small molecule ligand (SML) based delivery systems has been performed starting from a polyfunctionalized isoxazoline scaffold, whose \u3b1v\u3b23 and \u3b15\u3b21 integrins\u2019 potency has been already established. The synthesis of this novel class of ligands was obtained by conjugation of linkers to the heterocyclic core via Huisgen-click reaction, with the aim to use them as \u201cshuttles\u201d for selective delivery of diagnostic agents to cancer cells, exploring the effects of the side chains in the interaction with the target. Compounds 17b and 24 showed excellent potency towards \u3b15\u3b21 integrin acting as selective antagonist and agonist respectively. Further investigations confirmed their effects on target receptor through the analysis of fibronectin-induced ERK1/2 phosphorylation. In addition, confocal microscopy analysis allowed us to follow the fate of EGFP conjugated \u3b15\u3b21 integrin and 17b FITC-conjugated (compound 31) inside the cells. Moreover, the stability in water solution at different values of pH and in bovine serum confirmed the possible exploitation of these peptidomimetic molecules for pharmaceutical application

Steps towards sustainable solid phase peptide synthesis: use and recovery ofN-octyl pyrrolidone

The investigation of new green biogenic pyrrolidinones as alternative solvents toN,N-dimethylformamide (DMF) for solid phase peptide synthesis (SPPS) led to the identification ofN-octyl pyrrolidone (NOP) as the best candidate. NOP showed good performances in terms of swelling, coupling efficiency and low isomerization generating peptides with very high purity. A mixture of NOP with 20% dimethyl carbonate (DMC) allowed a decrease in solvent viscosity, making the mixture suitable for the automated solid-phase protocol. Aib-enkephalin and linear octreotide were successfully used to test the methodologies. It is worth noting that NOP, DMC and the piperidine used in the deprotection step could be easily recovered by direct distillation from the process waste mixture. The process mass intensity (PMI), being reduced by 63-66%, achieved an outstanding value representing a clear step forward in achieving green SPPS

Sustainability in peptide chemistry: current synthesis and purification technologies and future challenges.

Developing greener synthesis processes is an inescapable necessity to transform the industrial landscape, mainly in the pharmaceutical sector, into a long-term, sustainable reality. In this context, the renaissance of peptides as medical treatments, and the enforcement of more stringent sustainability requirements by regulatory agencies, pushed chemists toward the introduction of sustainable processes to prepare highly pure, active pharmaceutical ingredients (APIs). Innovative upstream (synthesis) and downstream (purification) methodologies have been developed during the last 5 years with the introduction and optimization of several technologies in solid-phase peptide synthesis (SPPS), liquid-phase peptide synthesis (LPPS), chemoenzymatic peptide synthesis (CEPS), and chromatographic procedures. These innovations are also moving toward the introduction of continuous processes that represent one of the most important targets for iterative processes. This overview discusses the most recent efforts in making peptide chemistry greener. The extensive studies that were carried out on green solvents, reaction conditions, auxiliary reagents and purification technologies in the peptide segment can be useful to other fields of organic synthesi

Assessing ADHD symptoms in children and adults:Evaluating the role of objective measures

Background: Diagnostic guidelines recommend using a variety of methods to assess and diagnose ADHD. Applying subjective measures always incorporates risks such as informant biases or large differences between ratings obtained from diverse sources. Furthermore, it has been demonstrated that ratings and tests seem to assess somewhat different constructs. The use of objective measures might thus yield valuable information for diagnosing ADHD. This study aims at evaluating the role of objective measures when trying to distinguish between individuals with ADHD and controls. Our sample consisted of children (n = 60) and adults (n = 76) diagnosed with ADHD and matched controls who completed self- and observer ratings as well as objective tasks. Diagnosis was primarily based on clinical interviews. A popular pattern recognition approach, support vector machines, was used to predict the diagnosis. Results: We observed relatively high accuracy of 79% (adults) and 78% (children) applying solely objective measures. Predicting an ADHD diagnosis using both subjective and objective measures exceeded the accuracy of objective measures for both adults (89.5%) and children (86.7%), with the subjective variables proving to be the most relevant. Conclusions: We argue that objective measures are more robust against rater bias and errors inherent in subjective measures and may be more replicable. Considering the high accuracy of objective measures only, we found in our study, we think that they should be incorporated in diagnostic procedures for assessing ADHD

Reliabilität und Validität des Wender-Reimherr-Interviews (WRI). Ein Instrument zur Diagnostik der ADHS im Erwachsenenalter [freier Beitrag]

Grundlage der Diagnostik der ADHS (Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung) im Erwachsenenalter ist in der Regel die DSM-IV- oder ICD-10-Klassifikation. Für die Psychopathologie der Erwachsenen sind diese Systeme nur bedingt geeignet. Die Utah-Kriterien, die mit dem Wender-Reimher-Interview (WRI) erfasst werden können, beziehen sich explizit auf das Erwachsenenalter. Ziel der vorliegenden Studie war, die psychometrischen Charakteristiken sowie die Verteilung und Kombination der sieben Bereiche des WRI zu untersuchen und zudem einen Vergleich mit anderen Selbst- und Fremdbeurteilungsverfahren der ADHS-Diagnostik zu ziehen. Die Skalenhomogenität des WRI lag mit einem Cronbachs α von .88 hoch. Die Interrater-Reliabilität lag auf Itemebene zwischen .45 und .95. Hohe Korrelationen mit anderen Instrumenten bestätigten die konvergente Validität des Interviews. Das WRI erwies sich als ein reliables und valides Instrument, das über das dreidimensionale Modell der ADHS Unaufmerksamkeit, Hyperaktivität und Impulsivität hinausgeht und dabei die Symptomatik der erwachsenen ADHS-Patienten besser berücksichtigt

Speeding up sustainable solution-phase peptide synthesis using T3P® as a green coupling reagent: methods and challenges

In peptide synthesis, the issues related to poor sustainability, long reaction times and high process mass intensity (PMI) are necessary to promote actions aimed at redefining procedural aspects pro jected towards more sustainable synthetic processes. Herein, we report a fast, widely applicable and green solution-phase peptide synthesis (GSolPPS) via a continuous protocol using propylpho sphonic anhydride T3P® as the coupling reagent and N-benzyloxycarbonyl-protecting group (Z), which is easily removed by hydrogenation. Because N,N-dimethylformamide (DMF) replacement was a priority, the iterative process was per formed in EtOAc, pushing further on overall sustainability. The efficiency of the synthetic protocol in terms of conversion, racemi zation and reaction times allowed extending the scope of the work to the synthesis of the standard peptide Leu-enkephalin as a proof of concept. Among the various explored procedures, the one-pot protocol (Acont plus), avoiding work-ups, intermediate purification and any dispersion effect, allowed the achievement of PMI = 30 for each deprotection/coupling sequence necessary to introduce a single amino acid in the iterative process, without considering the possibility of solvent and base recovery. This value is the lowest reported for an oligopeptide synthesis protocol to dat