WP5: Synthesis of heterocycle-derived structural analogues of sorgolact


The aim of the project related to workpackage 5 is to assess the germination stimulant abilities of a number of synthetic strigolactone analogues, in order to better understand the role of the structural features of the molecules involved. A first generation of analogues of natural strigolactones in which the A-ring of the molecule is an heterocycle will be synthesised and their biological activity will be checked. The initial approach will be focused on the A ring of the tricyclic framework of the target molecule. The scheduling of work package 5 will be planned as follows:

Synthesis of four structural analogues of 5-deoxystrigol in which the A ring of the molecule will be respectively a carbacycle, an O-, N- and S- derivative. To our knowledge, up to date, no heterocycles analogues have ever been synthesized. With respect to N-heterocycles we will consider the possibility of quaternarization of the N atom: as a consequence, the corresponding ammonium salts are expected to be more soluble in the biological medium and, we hope, more active.

Biological tests on fungal germination (Isagro).

Use of bioinformatics proprietary package in order to perform a screening of possible candidate molecules to be designed and synthesized by partner 6 (Isagro).

On the basis of the bioassays results of this first class of analogues and the indications arising from the bioinformatics package (Geol, WP4), our attention will be focused on the more active molecules. The aim is to obtain compounds that are suitable to be produced in an industrial plant (WP6), are environmentally stable and have low general and ecological toxicity. A new generation of derivatives will then be synthesized, allowing our synthetic sequence the introduction of a number of substituents on ring A. Moreover, we plan to achieve a complete enantioselective synthesis of the most promising structural analogue, so that the biological activity of both enantiomers will be compared.

In addition, knowledge of which part of the molecule can be elaborate without significantly impairing the germination activity would be useful in the design of labelled analogues suitable for determining the site and mode of action. The choice of suitable functional substituents on ring A, will allow the introduction of fluorescent probes and molecular imaging investigations. In view of biotechnological applications, our attentions will be directed on the enol ether functionality that links the tricyclic framework ABC of the target molecule to ring D. It has been reported (Zwanenburg et al. J. Agric. Food Chem. 1992) that the first interaction with the receptor, involves a nucleophilic attack at the enol ether bridge with consequent release of the D-ring as a leaving group. The fact that the germination stimulant activity of strigolactones is critically dependent by the presence of the labile enol ether D-ring structural unit has meant that it has not so far been possible to synthesise active analogues with a soil halflife sufficient to provide activity in a single treatment at low concentration. From an organic chemistry point of view, our efforts will be directed to change the enol ether bridge with a less sensitive functionality (i.e. an imine), so that the structural features could be considered compatible both with bioactivity and with treatment in soil.

As far as the target molecules have been synthesized in a stable form, greenhouse experiments in the presence of the host plant would be undertaken by the industrial partner. The collaboration is expected to result in the possible applications of these molecules to increase the root colonization as well as in the field of biocontrol against pests.