Ferrocene

The scope of the present review will focus primarily on the use of organoiron compounds in therapeutics. Fortunately or otherwise, organoiron chemistry is dominated by a single compound - ferrocene (1) or di(^5-cyclopentadienyl)-iron(II)- whose accidental discovery in 1951 was instrumental in opening up a new area of research in organometallic chemistry. Ferrocene comprises a ferrous ion (Fe2+) coordinated to two cyclopentadienyl rings. The exceptional stability of ferrocene is attributed to the distribution of 18^ electrons in the e2g and a1g non-bonding molecular orbitals.

Compared to other metallocenes, ferrocene (1) has been widely used in drug design, usually as a substitute for the phenyl or alkyl group. This is prompted by several factors. First, ferrocene is more lipophilic than benzene (^ferrocene 2.46 compared to ^benzene 1.96)8 and its inclusion into a molecule is expected to enhance the membrane permeability and possibly bioavailability of the final compound. Since inappropriate pharmacokinetic properties are the main reasons why compounds fail to transform into effective drugs,9 the potential utility of the ferrocene moiety in this regard is readily embraced by medicinal chemists. Secondly, novel compounds are obtained when the ferrocene ring is introduced into lead compounds. Ferrocene is an isostere of benzene. It is aromatic but is more electron donating than benzene (cpara of benzene: —0.01; cpara of ferrocene: —0.18).8 In terms of shape, ferrocene is probably as 'wide' as benzene but it is considerably 'thicker', being as 'thick' as it is 'wide'.

Moreover, ferrocene is widely regarded as a 'safe' metallocene. Acute and chronic toxicity tests of ferrocene and some derivatives attest to the relative safety of ferrocene in many mammalian species (dogs, rats, mice, mon-keys).10 12 However, the issue of whether iron is released from ferrocene-containing compounds during metabolism is not completely resolved and is a matter of concern. Free iron can potentially catalyze free-radical reactions, leading to lipid peroxidation of cellular membranes and the formation of reactive oxygen species via the Fenton reaction.13 Hanzlik and Soine noted that ferrocene is metabolized by various phase 1 and 2 reactions (hydroxyl-ation, glucuronidation, sulphation) without loss of the metal, implying that the ferrous ion in ferrocene is resistant to removal.14 Another study showed that more than 60% of 59Fe activity was detected in urine (as ferrocene metabolites or intact ferrocene) after oral administration to rats.15 In contrast, the ferrous ion appears to be readily released from substituted ferrocenes during metabolism. This is well illustrated in (3,5,5-trimethylhexanoyl) ferrocene (2, TMH ferrocene), which is used to deliver iron to biological systems.16

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