Iron Dienylphosphate Tricarbonyl Complexes as Water-Soluble Enzyme-Triggered CO-Releasing Molecules (ET-CORMs)

Abstract

A series of racemic phosphoryloxy-substituted (η 4 -cyclohexadiene)Fe(CO) 3 complexes was synthesized by exploiting the O-phosphorylation of (dienol)Fe(CO) 3 intermediates generated in situ from the corresponding triisopropylsiloxyprotected complexes. The phosphorylated products were fully characterized by spectroscopic methods, including single-crystal Xray diffraction in four cases. Monodeprotection of two dimethyl phosphate derivatives with trimethylamine led to the tetramethylammonium salts of the (cyclohexadienyl methyl phosphate)Fe(CO) 3 complexes. These compounds are the first water-soluble enzyme-trigged CO-releasing molecules (ET-CORMs). The phosphatase-induced CO release was monitored by means of GC. The biological activity was assessed in different cellular assays. The compounds were shown to be only slightly toxic, and a moderate anti-inflammatory potential was determined in an assay based on the inhibition of inducible NO synthase (iNOS)-induced NO production.

Toward Carbon Monoxide–Based Therapeutics: Critical Drug Delivery and Developability Issues

“…To improve the water solubility of ET-CO-RMs, cyclohexadienyl methyl phosphate iron tricarbonyl complex-based compound 5 was synthesized. 82 Besides improved water solubility, it showed less toxicity than other esterase sensitive ET-CO-RMs, and also a moderate level of anti-inflammatory effect. The IC 20 of compound 5 in RAW 246.7 cells was determined to be 252 μM, and 100 μM of 5 resulted in 31% inhibition of NO production in RAW264.7 cells.…”

Carbon monoxide – physiology, detection and controlled release

“…139,140 This substance class has been well studied for many years. 152–154 However, the recently studied use as ET-CORMs is surprisingly convenient.…”

PhotoCORMs: CO release moves into the visible

“…Enzyme-triggered CORMs (ET-CORMs) make use of the presence of esterases in cells to bring about CO release at metal centres. [21][22][23][24] Triggering using small molecules is also possible, with the combination of a CORM with a second chemical agent [25][26][27] allowing temporal control of release. More exotic approaches have also been explored, for example release triggered by electromagnetic heating.…”