Forschungs- & Entwicklungsinformationsdienst der Gemeinschaft - CORDIS

Final Activity Report Summary - SOPHOLIDES (Solid phase phospholipid and dendrimer synthesis)

Lipids are central to the regulation and control of cellular function and to disease, and lipidomics is beginning to make significant contributions to our understanding of cellular and pathophysiological processes. Alkyllysophospholipid analogues have recently received much attention because of their antineoplastic, immunomodulatory and antiparasitic properties.

One of the objectives of the SOPHOLIDES project was the development of a cost effective, reliable and efficient methodology based on solid phase chemistry (SPOS) for the synthesis of phospholipid analogues for specific biological applications, including antiprotozoal therapeutics and anticancer compounds. Two solid supports were investigated, more specifically Wang resin and Tentagel, which possessed better swelling properties in polar solvents. The methodology that was developed employed diphenyl phosphite, an inexpensive and easy to handle liquid, as the phosphorylation reagent. This reagent had not been utilised previously in solid phase synthesis. The diester H-phosphonate solid supported key intermediate was utilised to generate phosphotriesters, phosphonolipids or phosphoramidates.

A second research objective was the preparation of dendrimeric materials and dendrimer modified resins designed to provide increased loading capacity for solid supports. We initially performed the synthesis of the first generation dendron using solution phase chemistry. Two cores were investigated, i.e. a benzylic and a phenolic core, and the point of attachment to the solid support was the benzylic or phenolic hydroxyl, respectively. These modified resins were successfully evaluated for phospholipid solid phase synthesis, using the new methodology that we developed. Polyethylene glycol ether spacers were introduced to the first generation dendrons to reduce the steric hindrance between the generations of dendrimers and improve the swelling of the eventual dendrimeric resin.

In addition, via utilising tris(hydroxymethyl) aminomethane (TRIS) and employing click chemistry two dendrons bearing 18 and 36 silyl protected hydroxyl functions, a dendron with 18 free hydroxyl groups and one dendrimer containing 54-protected hydroxyls were synthesized. These compounds were planned to be investigated as drug delivery systems. Furthemore, five 1,2,3-triazole-containing glycodendrons were synthesised utilising alkynyl-substituted TRIS and azido galactose or azido lactose. These compounds were tested by co-crystallisation with the sclerotium rolfsii lectin as potential anticancer agents.

To complement these activities, microwave irradiation and ultrasound were employed in several synthetic steps with beneficial results, mainly in reactions involving click chemistry and Suzuki-Miyaura coupling reactions. The phospholipid analogues were evaluated for their antileishmanial activity against leishmania infantum amastigotes in collaboration with the University of Crete and were found to be active and not cytotoxic or heamolytic. Thus, based on the biological data we employed comparative molecular similarity indices (CoMSIA) methodologies in order to obtain three-dimensional structure-activity relationships for the anltilesihmanial activity and cytotoxicity against THP-1 macrophages of phospholipid derivatives. Our results revealed a complementarity of structural features required for antiparasitic activity with those disfavouring toxicity.

An essential component to the successful implementation of the SOPHOLIDES project was the valuable and productive interaction with the three partner laboratories which assisted the Institute of Organic and Pharmaceutical Chemistry (IOPC) in its objectives in the context of SOPHOLIDES and beyond, benefiting from a number of ongoing projects within IOPC and contributing to the initiation of new research directions, such as SPOS, glycodendrimers and MAOS.

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