Ferrocene conjugated peptides

In contrast to the amino acid, peptide, and protein conjugates, where a number of different organometallic complexes were used for labeling, DNA derivatives are by and large limited to ferrocene. This is very likely due to the attractive electrochemical properties of ferrocene. Indeed, electrochemical DNA sensors are covered in more detail in Section 1.31.5.2. Two recent reviews cover the ferrocene conjugates with nucleobases, nucleosides and nucleotides,... 

Figure 10.3 The ferrocene-peptide conjugate family. Arrows point from the C to the N termini of the peptides. Copyright Wiley-VCH Verlag GmhH Co. KGaA. Reproduced with permission from Ref. 40.

Recently, the synthesis of l,l -bis(rert-butoxycarbonylamino)ferrocene 52 was reported, a convenient synthon of 1,1 -diaminoferrocene 30, which circumvents the problems encountered with the explosive diazide. The bis-Boc derivative is compatible with the peptide synthesis protocol, as is demonstrated by the preparation of its first amino acid conjugates. 1,1 -Bis(carbonylazido)ferrocene was synthesized from l,l -ferrocenedicarboxylic acid 7 by... 

In this chapter, we have reviewed ferrocene peptide conjugates with particular emphasis on derivatives that are amenable to polycondensation reactions and cyclization reactions. 

Figure 3 Cellular uptake and intracellular distribution of metallocene-peptide conjugates (see text) (a) cobaltocenium-NLS (16co), (b) ferrocene-NLS (16pe) and (c) ferrocene-TAT (ISpe)- Nuclear localization is seen for the two NLS conjugates, while the ferrocene-TAT conjugate accumulates almost exclusively in the cytoplasm and does not enter the nucleus.

Pepstatin is a potent naturally occurring inhibitor of aspartic proteases, including HIV-1 protease and pepsin [29-31]. It will be interesting to investigate the physiological applications of these ferrocene peptide conjugates (see also Section 5.3). 

Frejd and coworkers then used lactam 45 as a structural H-Phe-Phe-OH mimic in peptides (116). The resulting conjugate 48 was expected to function as a structural mimic of substance P (Scheme 5.25). However, CD spectroscopic studies indicated that the constraints imposed by the l,l -ferrocenophane prohibited the peptide to adopt the characteristic a-hehcal secondary structure found for native SP in a biomimetic SDS (Sodium n-Dodecyl Sulfate) micellar environment. In another interesting paper, Frejd and coworkers prepared a [Leu ]-Enkephalin mimetic in which the H-Tyr-Gly-Gly-Phe-subunit has been replaced by a Gly-Gly-looped l,l -ferrocenyl-bis-alanine residue (49, Scheme 5.25) [117]. The ferrocene Cp rings of this constrained compound constitute a substitute for the aromatic phenol (Tyr) and phenyl (Phe) rings. NMR-spectroscopic studies revealed this... 

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