Making organoruthenium complexes of 8-hydroxyquinolines more hydrophilic: impact of a novel l-phenylalanine-derived arene ligand on the biological activity

Abstract

Ru(arene) compounds have many desirable features making them promising candidates for further development in anticancer drug research. While a lot of emphasis has been placed on the modification of the ancillary ligands, there are not many examples of arene ligands bearing functional groups. Herein, we report the preparation of [Ru(arene)(8-oxyquinolinato)Cl] complexes with the arene being a protected form of the amino acid l-phenylalanine and 8-oxyquinolinato ligand substituted with halogens. With this approach we aimed to alter the pharmacological properties of the complexes and address issues with the aqueous solubility of the analogous p-cymene complexes. The complexes were shown to be stable in DMSO and water and reacted readily with l-histidine and 9-ethylguanine as protein and DNA models, respectively. Assaying the antiproliferative activity in cancer cells gave IC values in the low μM range. While the lipophilicity of the p-cymene analogues correlated well with their in vitro cytotoxicity, the potency of the complexes with the l-phenylalanine-derived arene was independent of lipophilicity.

Quinoline‐Conjugated Ruthenacarboranes: Toward Hybrid Drugs with a Dual Mode of Action

“…Activation of the carboxylic group of 3 with di‐ tert ‐butyl dicarbonate (Boc 2 O), in CH 2 Cl 2 /pyridine, followed by reaction with sodium quinolin‐8‐olate (or [(7‐chloroquinolin‐4‐yl)oxy]butanol‐1‐ate), yielded ruthenacarborane esters 4 and 5 , in 18 % and 21 % yield, respectively. 8‐hydroxyquinoline (8‐HQ) was chosen due to the plethora of studies which combine a ruthenium(II)‐arene fragment with 8‐HQ, and [(7‐chloroquinolin‐4‐yl)oxy]butanol because of its structural similarity to CQ, but still suitable for the synthesis of an ester bond. The low yields of isolated final products can be attributed, at least partially, to the instability of the carborane‐bound ester bonds on chromatography columns (see also ester 6 (19 %)), as we have frequently observed in our group, for both ester and amide bonds (see for example ref.…”

“…Combinations of a ruthenium(II)‐arene fragment with chloroquine (CQ) or 8‐hydroxyquinoline (8‐HQ) derivatives have been reported by many in the literature (Gobec et al., Mitrović et al., Kubanik et al., Glans et al., Movassaghi et al., Martinez et al. ), showing modulation of the biological activity with respect to the two scaffolds alone, for potential applications as chemotherapeutic agents in different types of tumors (e. g. leukemia, colorectal, lung and cervical cancers),– and as antiparasitic agents –…”

An 8-hydroxyquinoline–proline hybrid with multidrug resistance reversal activity and the solution chemistry of its half-sandwich organometallic Ru and Rh complexes

“…Movassaghi et al introduced a more polar aromatic ligand (N-acetyl-L-phenylalanine ethyl ester) instead of p-cymene, and with this modification the solubility could be improved, while the cytotoxicity remained at the low-micromolar level. 22 The hydrophilic nature of the complexes can be increased via the improved water solubility of the coordinating HQ derivative by the introduction of polar functional groups. However, the use of 8-hydroxyquinoline-5-sulfonate with excellent water-solubility caused the loss of the anticancer activity reported in our previous study.…”

Impact of copper and iron binding properties on the anticancer activity of 8-hydroxyquinoline derived Mannich bases

“…13 CQ can also act as an ionophore, inducing the transfer of metal ions across biological membranes, either in or out of cells. 10 The antitumor activity of 8-hydroxyquinolines may also be linked to the toxicity of their metal complexes, as shown for copper(II), 6,14 ternary ruthenium(II), 15 half-sandwich organoruthenium, [16][17][18][19] organorhodium, 16 platinum(II) 20 and gallium(III). 21,22 Mannich bases of 8-hydroxyquinolines were reported to possess high potency against human cancer cells, 23,24 and our meta-analysis of the cytotoxicity of various 8-hydroxyquinolines revealed the importance of the CH 2 -N subunit at position 7 for cytotoxicity.…”