C2-Symmetric Val-Val Dipeptide Isosteres via Diethylaluminium Azide Ring Opening of Epoxyalcohols

Diethylaluminium azide has been used as a highly regio- and stereo-selective reagent for the ring opening of valine-derived, sterically hindered epoxyalcohols. This reagent has enabled extending a previously described synthesis of diaminodiol dipeptide isosteres (P1-Ψ[CH(OH)-CH(OH)]-P1\u27) also to isosteres with branched residues in position P1\u27. The new methodology is compatible with Boe and Cbz proteetion of the starting aminoacid and has been applied to the synthesis of a C2-symmetric diaminodiol Val-Val dipeptide isostere 11, starting from the methyl ester of L-valine, in 25% over-all yield over seven (for Boe proteetion) or six (for Cbz proteetion) passages. A C2-symmetric di-MEM proteeted diaminodiol 17 and a mono-Boc proteeted, desymmetrized derivative 10 have also been obtained by the same approach. Compounds 10, 11 and 17 can be used as core units of C2-symmetric and non-symmetric peptido-mimetic inhibitors of aspartic proteases and as intermediates for the synthesis of cyclic urea inhibitors of HIV-protease

Pregled tehnologija remedijacije perzistentnih otrovnih tvari

This paper gives a review of established and emerging technologies for the treatment of wastes and soils contaminated by Persistent Toxic Substances which include the Persistent Organic Pollutants. The technologies are classified as biological, physico-chemical, and thermal treatments, describing main unit operations and comparing technical, social and environmental limitations, including some potential risks and environmental impacts. Estimated overall costs, cleanup times, reliability, and maintenance levels are also presented in order to assess advantages and limitations of each technology.Ovaj članak donosi pregled postojećih i novonastajućih tehnologija obrade otpada i tla onečišćenog perzistentnim otrovnim tvarima uključujući i perzistentna organska onečišćivala (engl. persistent organic pollutants). Autor dijeli tehnologije obrade na biološke, fizikalno-kemijske i termalne te opisuje rad osnovnih uređaja i uspoređuje tehnička, društvena i ekološka ograničenja, uključujući moguće rizike i učinke na okoliš. Članak također razmatra ukupne procijenjene troškove, vrijeme potrebno za čišćenje te razine odgovornosti i održavanja dajući na uvid prednosti i ograničenja svake tehnologije zasebno

C2-Symmetric Val-Val Dipeptide Isosteres via Diethylaluminium Azide Ring Opening of Epoxyalcohols

Diethylaluminium azide has been used as a highly regio- and stereo-selective reagent for the ring opening of valine-derived, sterically hindered epoxyalcohols. This reagent has enabled extending a previously described synthesis of diaminodiol dipeptide isosteres (P1-Ψ[CH(OH)-CH(OH)]-P1\u27) also to isosteres with branched residues in position P1\u27. The new methodology is compatible with Boe and Cbz proteetion of the starting aminoacid and has been applied to the synthesis of a C2-symmetric diaminodiol Val-Val dipeptide isostere 11, starting from the methyl ester of L-valine, in 25% over-all yield over seven (for Boe proteetion) or six (for Cbz proteetion) passages. A C2-symmetric di-MEM proteeted diaminodiol 17 and a mono-Boc proteeted, desymmetrized derivative 10 have also been obtained by the same approach. Compounds 10, 11 and 17 can be used as core units of C2-symmetric and non-symmetric peptido-mimetic inhibitors of aspartic proteases and as intermediates for the synthesis of cyclic urea inhibitors of HIV-protease

Ethical considerations regarding animal experimentation

Animal experimentation is widely used around the world for the identification of the root causes of various diseases in humans and animals and for exploring treatment options. Among the several animal species, rats, mice and purpose-bred birds comprise almost 90% of the animals that are used for research purpose. However, growing awareness of the sentience of animals and their experience of pain and suffering has led to strong opposition to animal research among many scientists and the general public. In addition, the usefulness of extrapolating animal data to humans has been questioned. This has led to Ethical Committees’ adoption of the ‘four Rs’ principles (Reduction, Refinement, Replacement and Responsibility) as a guide when making decisions regarding animal experimentation. Some of the essential considerations for humane animal experimentation are presented in this review along with the requirement for investigator training. Due to the ethical issues surrounding the use of animals in experimentation, their use is declining in those research areas where alternative in vitro or in silico methods are available. However, so far it has not been possible to dispense with experimental animals completely and further research is needed to provide a road map to robust alternatives before their use can be fully discontinued

Methodology for clinical research

A clinical research requires a systematic approach with diligent planning, execution and sampling in order to obtain reliable and validated results, as well as an understanding of each research methodology is essential for researchers. Indeed, selecting an inappropriate study type, an error that cannot be corrected after the beginning of a study, results in flawed methodology. The results of clinical research studies enhance the repertoire of knowledge regarding a disease pathogenicity, an existing or newly discovered medication, surgical or diagnostic procedure or medical device. Medical research can be divided into primary and secondary research, where primary research involves conducting studies and collecting raw data, which is then analysed and evaluated in secondary research. The successful deployment of clinical research methodology depends upon several factors. These include the type of study, the objectives, the population, study design, methodology/techniques and the sampling and statistical procedures used. Among the different types of clinical studies, we can recognize descriptive or analytical studies, which can be further categorized in observational and experimental. Finally, also pre-clinical studies are of outmost importance, representing the steppingstone of clinical trials. It is therefore important to understand the types of method for clinical research. Thus, this review focused on various aspects of the methodology and describes the crucial steps of the conceptual and executive stages

Inhibitors of HIV-Protease from Computational Design. A History of Theory and Synthesis Still to be Fully Appreciated

Despite the fact that HIV-Protease is an over 20 years old target, computational approaches to rational design of its inhibitors still have a great potential to stimulate the synthesis of new compounds and the discovery of new, potent derivatives, ever capable to overcome the problem of drug resistance. This review deals with successful examples of inhibitors identified by computational approaches, rather than by knowledge-based design. Such methodologies include the development of energy and scoring functions, docking protocols, statistical models, virtual combinatorial chemistry. Computations addressing drug resistance, and the development of related models as the substrate envelope hypothesis are also reviewed. In some cases, the identified structures required the development of synthetic approaches in order to obtain the desired target molecules; several examples are reported

The Effects of Combinatorial Chemistry and Technologies on Drug Discovery and Biotechnology – a Mini Review

The review will focus on the aspects of combinatorial chemistry and technologies that are more relevant in the modern pharmaceutical process. An historical, critical introduction is followed by three chapters, dealing with the use of combinatorial chemistry/high throughput synthesis in medicinal chemistry; the rational design of combinatorial libraries using computer-assisted combinatorial drug design; and the use of combinatorial technologies in biotechnology. The impact of “combinatorial thinking” in drug discovery in general, and in the examples reported in details, is critically discussed. Finally, an expert opinion on current and future trends in combinatorial chemistry and combinatorial technologies is provided

Design of Thymidine Analogues Targeting Thymidilate Kinase of Mycobacterium tuberculosis

We design here new nanomolar antituberculotics, inhibitors of Mycobacterium tuberculosis thymidine monophosphate kinase (TMPKmt), by means of structure-based molecular design. 3D models of TMPKmt-inhibitor complexes have been prepared from the crystal structure of TMPKmt cocrystallized with the natural substrate deoxythymidine monophosphate (dTMP) (1GSI) for a training set of 15 thymidine analogues (TMDs) with known activity to prepare a QSAR model of interaction establishing a correlation between the free energy of complexation and the biological activity. Subsequent validation of the predictability of the model has been performed with a 3D QSAR pharmacophore generation. The structural information derived from the model served to design new subnanomolar thymidine analogues. From molecular modeling investigations, the agreement between free energy of complexation (ΔΔGcom) and Ki values explains 94% of the TMPKmt inhibition (pKi=-0.2924ΔΔGcom+3.234;R2=0.94) by variation of the computed ΔΔGcom and 92% for the pharmacophore (PH4) model (pKi=1.0206×pKipred-0.0832,  R2=0.92). The analysis of contributions from active site residues suggested substitution at the 5-position of pyrimidine ring and various groups at the 5′-position of the ribose. The best inhibitor reached a predicted Ki of 0.155 nM. The computational approach through the combined use of molecular modeling and PH4 pharmacophore is helpful in targeted drug design, providing valuable information for the synthesis and prediction of activity of novel antituberculotic agents