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Functional Molecular Systems by Template-Guided-Click Assembly

Final Report Summary - CLICK-FUN (Functional molecular systems by template-guided-click assembly)

The objective of the project was testing an innovative concept to shape functional molecules by template-guided click chemistry assembly 'target around'. This approach entails the pre-organisation of complementary low-molecular template, azide and alkyne pair from libraries of azido- and alkyne-functionalised interactive fragments. In the frame of work following achievements have been completed:

- synthesis of large library of azido-modified aminoacids, di- and tripeptides. These includes a new compounds not yet described in the literature - interesting, chiral clickable intermediates with potential application in stereoselective catalysis and recognition systems. In the course of these syntheses several routes have been tested including azidotransfer and nucleofilic substitution reactions and stereochemical integrity of the products has been confirmed. These compounds have been further utilised in screening experiments and now are also investigated in current research.

- development of quick, cheap and general method for staining of azides on TLC plates. This is first and general method allowed easy monitoring and purity assessment of azido-compounds especially useful for the compounds lacking in UV-adsorbing chromophore e.g. most of natural aminoacids and peptides of therefore. Scope of this protocol has successfully been tested on large library of azides (synthesised in the frame of this project) and the developed method is especially attractive for checking the progress of reaction and the differentiation of amines and azides - interconvertable pair of compounds.

- circular dichroism studies of taxol. Although taxol has been largely used in modern chemocancer therapy, its systematic circular dichroism characteristics have only been partially investigated. In the frame of project taxol has been selected as a templating molecule - its chiroptical properties (CD) has been systematically investigated (manuscript in preparation).

- association studies of b-cyclodextrin and azido-modified b-cyclodextrins with taxol, cinchona alkaloids and acetylene bearing guest by circular dichroism and UV adsorption. Inclusion complexes of taxol and b-cyclodextrines have been developed as carriers for taxol dosage in therapy. Inclusion complexes of azido-modified cyclodextrines and taxol has been prepared and investigated by CD to check the possibility of partial docking of taxol and other guest for further assembling by click chemistry. Presence of taxol-b-cyclodextrin complex has also been detected by MALDI-TOF experiment.

- discovery of 'click-trap' - non-catalytic Huisgen cycloaddition at room temperature of azidomodified b-cyclodextrines and several acetylene-bearing guests has been detected. Such non-catalytic reactivity has been only rarely observed only after entrapment of azides and acetylenes into binding pockets of enzymes or cucurbituril cavity so the results obtained here with modified b-cyclodextrines expanded the knowledge about the molecular requirements leading to the chemical reactivity. At this point there is not clear why 1:1, 1:2 and even 1:3 (host:guest) complexes were formed as well as what is the role of inclusion (studies on this phenomena are in progress). Unfortunately this reactivity gives in each case (combination azide-acetylene) a positive reaction so incubation of these pairs with template has not been resulted in discrimination of particular combination of clicking partners. To overcome this problem, several new, interesting polyfunctional hybrids based on azido-modified cyclodextrines have been synthetised as candidates for taxol and other biologically important molecules. These are currently under investigation.