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

Abstract

AbstractAs 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 ω‐6‐substituent as well as a hydrophilic α‐side chain (carboxylic acid). Using the cationic complex tricarbonyl[η5‐1‐(methoxycarbonyl)pentadienyl]iron hexafluorophosphate (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(Ψ‐exo)selective addition of a titanium–zinc organyl [prepared from ethyl 4‐iodobutyrate, activated Zn powder, and Ti(OiPr)3Cl] as a butyrate D4 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).