Synthesis and First Biological Evaluation of an Iron-Containing HETE Analogue

As previous studies in the field of bioorganometallic chemistry have unveiled, metal-containing analogues of natural products frequently exhibit surprising biological activities. In this context, a synthetic approach to analogues of the eicosanoids 5-HETE and 8-HETE possessing a 1,3-butadiene-Fe(CO)(3) substructure was elaborated. The chosen structures are characterized by a central (2E, 4Z)-hexa-2,4-dien-1-ol-Fe(CO)(3) moiety (as the potential metal pharmacophore) and carry a lipophilic omega-6-substituent as well as a hydrophilic alpha-side chain (carboxylic acid). Using the cationic complex tricarbonyl[eta(5)-1-(methoxycarbonyl)pentadienyl] iron hexa-fluorophosphate (rac-4) as a starting material, the synthesis of a simplified Fe(CO)(3)-complexed HETE analogue (rac-3) was achieved by exploiting the addition of an alkynyl Cu species to rac-4. The carbon skeleton was completed through diastereo(Psi-exo)selective addition of a titanium-zinc organyl [prepared from ethyl 4-iodobutyrate, activated Zn powder, and Ti(OiPr)(3)Cl] as a butyrate D-4 synthon to an aldehyde function by using 2-Me-THF as the solvent of choice. The (sensitive) target compound rac-3 was shown to induce apoptosis at moderate concentrations in cancer cells (BJAB and Nalm-6).