SYNTHESIS AND BIOLOGICAL EVALUATION OF NEW C-24 ANALOGUES OF THE DAF-12 RECEPTOR WITH POTENTIAL USE IN CONTROLLING THE NEMATODE LIFE CYCLE

CRISTIAN R. RODRIGUEZ; GUIDO OPEZZO; GERARDO BURTON; VANESSA SANTILLÁN; ADRIANA VELEIRO; MARIA C DEL FUEYO; OLGA CASTRO

Viena

Congreso; EFMC-ASMC'17 EFMC International Symposium on Advances in Synthetic and Medicinal Chemistry; 2017

The European Federation for Medicinal Chemistry (EFMC)

The DAF-12 receptor regulates the development timing, stage specification and longevity in the nematodeCaenorhabditis elegans.[1] Recently we evaluated the in vivo activity of a series of analogues of natural ligandsof DAF-12 and our results revealed that the C-24 alcohol, 24-hydroxy-4-cholen-3-one (1) was an antagonist ofDAF-12 receptor.[2] Since C. elegans and parasitic nematodes share the DA system as an endocrine corecomponent for dauer and infective larvae formation, the studies related to CeDAF-12 activity provide a generalstrategy for controlling nematode parasitism in animals and plants. We now report the synthesis and the in vivoactivity of three analogues of the antagonist (1), two fluorinated compounds, 2 and 3 in which the C-24 hydroxylwas replaced by a difluoromethyl group, and compound 4 with a cyclic side chain. The key step employed toobtained compounds 2 and 3 was based on a difluoromethylation reaction starting from compound 5,[2] using adifluoromethylene phosphabetaine (Scheme 1).[3] In the case of compound 2, the difluroromethylation reactiontook place in the presence of TMSCl leading to the formation of 6, followed by a Barton-McCombiedeoxygenation to remove the 24-hydroxyl. Compound 4 was obtained by a 2-carbons homologation usingpregnenolone as starting material (Scheme 2), the key steps for this transformation were a Grignard reactionfollowed by reduction of the hemiketal 8 with NaCNBH3-HCl(pH3). The DAF-12 antagonist activity ofcompounds 2, 3 and 4 was tested in vivo. Wild-type nematodes were allowed to develop in presence ofincreasing concentrations of compounds 1, 2, 3 or 4 or in absence of added compounds as a control and thepercentage of nematodes in each developmental stage was determined at different periods of time. We observeda dose dependent delay in the development of the nematodes grown in presence of 1, 2 and 3 with respect tocontrol. The delay observed in presence of compound 2 was even greater than that previously reported forcompound 1.