Objetivo
The goal of this proposal is to develop new synthetic analogues of natural isoflavonoids, containing pharmacophoric polyoxygen-substituted aryl and heteroaryl fragments as effective inhibitors of mitosis.
Classical Fries rearrangement and Houben-Hoesch reactions will be used for the synthesis of the initial polyoxygenated 4-hydroxycoumarin derivatives. Application of catalytic cross-coupling and reductive coupling arylation procedures shall permit to carry out the functionalization of the 4-hydroxycoumarin derivatives into 3- and 4-positions, leading to a wide range of new isoflavonoid compounds, containing polymethoxy- and/or polyhydroxy-substituted phenyl and azole groups, as well as polymethoxy- and polyhydroxy substituted benzopyrane, isoquinoline or indole fragments. The proposed synthetic strategies, involving utilization of organic and heteroatomic reagents (I, Bi, B, Pb), containing two electrophilic centers with different reactivity can give access to the desired products via 2 - 5 one pot sequences. Moreover, adaptation of these methods to the use of the environmentally friendly water medium will be an important goal.
Based upon the structure - biological activity analysis, carried out on tubuline polymerisation inhibitors and on antitopoisomerase agents, the high antitumour activities of the selected target structures could be predicted.
In spite of the complexity of the proposed task, the expertise of the five contributing teams in the synthesis and biological evaluation of natural and pharmacologically active compounds will allow us to fulfil the present project. Ecologically clean cascade synthetic strategies proposed in our project for the preparation of natural products, are attractive for industrial organic synthesis. Moreover discovery of novel agents acting on specific phases of the mitotic cycle will allow clearer definition of the relationships between discrete mechanical phases of spindle function, regulation of cell-cycle progression and programmed cell death.
Tema(s)
Convocatoria de propuestas
Data not availableRégimen de financiación
Data not availableCoordinador
13397 Marseille
Francia