First iron(II) organometallic compound acting as ABCB1 inhibitor

Abstract

Five new iron (II) complexes bearing imidazole-based (Imi-R) ligands with the general formula [Fe(η⁵-C₅H₅)(CO)(PPh₃)(Imi-R)][CF₃SO₃] were synthesized and fully characterized by several spectroscopic and analytical techniques. All compounds crystallize in centrosymmetric space groups in a typical "piano stool" distribution. Given the growing importance of finding alternatives to overcome different forms of multidrug resistance, all compounds were tested against cancer cell lines with different ABCB1 efflux pump expression, namely, the doxorubicin-sensitive (Colo205) and doxorubicin-resistant (Colo320) human colon adenocarcinoma cell lines. Compound 3 bearing 1-benzylimidazole was the most active in both cell lines with IC₅₀ values of 1.26 ± 0.11 and 2.21 ± 0.26 μM, respectively, being also slightly selective against the cancer cells (vs. MRC5 normal human embryonic fibroblast cell lines). This compound, together with compound 2 bearing 1H-1,3-benzodiazole, were found to display very potent ABCB1 inhibitory effect. Compound 3 also showed the ability to induce cell apoptosis. Iron cellular accumulation studies by ICP-MS and ICP-OES methods revealed that the compounds' cytotoxicity is not related to the extent of iron accumulation. Yet, it is worth mentioning that, from the compounds tested, 3 was the only one where iron accumulation was greater in the resistant cell line than in the sensitive one, validating the possible role of ABCB1 inhibition in its mechanism of action.

Keywords: ABCB1 inhibitor; Cancer multidrug resistance; Colon adenocarcinoma; Iron-cyclopentadienyl.